Radiation dose to the global flying population.

PubMed

Alvarez, Luis E; Eastham, Sebastian D; Barrett, Steven R H

2016-03-01

Civil airliner passengers and crew are exposed to elevated levels of radiation relative to being at sea level. Previous studies have assessed the radiation dose received in particular cases or for cohort studies. Here we present the first estimate of the total radiation dose received by the worldwide civilian flying population. We simulated flights globally from 2000 to 2013 using schedule data, applying a radiation propagation code to estimate the dose associated with each flight. Passengers flying in Europe and North America exceed the International Commission on Radiological Protection annual dose limits at an annual average of 510 or 420 flight hours per year, respectively. However, this falls to 160 or 120 h on specific routes under maximum exposure conditions.

Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

PubMed

Triplett, Brandon M; Kuttab, Hani I; Kang, Guolian; Leung, Wing

2015-12-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

PubMed

Böttcher, M; Lentini, S; Arens, E R; Kaiser, A; van der Mey, D; Thuss, U; Kubitza, D; Wensing, G

2018-07-01

Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l -1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l -1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia. © 2018 The British Pharmacological Society.

Kodak EDR2 film for patient skin dose assessment in cardiac catheterization procedures.

PubMed

Morrell, R E; Rogers, A T

2006-07-01

Patient skin doses were measured using Kodak EDR2 film for 20 coronary angiography (CA) and 32 percutaneous transluminal coronary angioplasty (PTCA) procedures. For CA, all skin doses were well below 1 Gy. However, 23% of PTCA patients received skin doses of 1 Gy or more. Dose-area product (DAP) was also recorded and was found to be an inadequate indicator of maximum skin dose. Practical compliance with ICRP recommendations requires a robust method for skin dosimetry that is more accurate than DAP and is applicable over a wider dose range than EDR2 film.

Influence of intravenous opioid dose on postoperative ileus.

PubMed

Barletta, Jeffrey F; Asgeirsson, Theodor; Senagore, Anthony J

2011-07-01

Intravenous opioids represent a major component in the pathophysiology of postoperative ileus (POI). However, the most appropriate measure and threshold to quantify the association between opioid dose (eg, average daily, cumulative, maximum daily) and POI remains unknown. To evaluate the relationship between opioid dose, POI, and length of stay (LOS) and identify the opioid measure that was most strongly associated with POI. Consecutive patients admitted to a community teaching hospital who underwent elective colorectal surgery by any technique with an enhanced-recovery protocol postoperatively were retrospectively identified. Patients were excluded if they received epidural analgesia, developed a major intraabdominal complication or medical complication, or had a prolonged workup prior to surgery. Intravenous opioid doses were quantified and converted to hydromorphone equivalents. Classification and regression tree (CART) analysis was used to determine the dosing threshold for the opioid measure most associated with POI and define high versus low use of opioids. Risk factors for POI and prolonged LOS were determined through multivariate analysis. The incidence of POI in 279 patients was 8.6%. CART analysis identified a maximum daily intravenous hydromorphone dose of 2 mg or more as the opioid measure most associated with POI. Multivariate analysis revealed maximum daily hydromorphone dose of 2 mg or more (p = 0.034), open surgical technique (p = 0.045), and days of intravenous narcotic therapy (p = 0.003) as significant risk factors for POI. Variables associated with increased LOS were POI (p < 0.001), maximum daily hydromorphone dose of 2 mg or more (p < 0.001), and age (p = 0.005); laparoscopy (p < 0.001) was associated with a decreased LOS. Intravenous opioid therapy is significantly associated with POI and prolonged LOS, particularly when the maximum hydromorphone dose per day exceeds 2 mg. Clinicians should consider alternative, nonopioid-based pain management options when this occurs.

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

PubMed

Pernas, Sonia; Martin, Miguel; Kaufman, Peter A; Gil-Martin, Marta; Gomez Pardo, Patricia; Lopez-Tarruella, Sara; Manso, Luis; Ciruelos, Eva; Perez-Fidalgo, Jose Alejandro; Hernando, Cristina; Ademuyiwa, Foluso O; Weilbaecher, Katherine; Mayer, Ingrid; Pluard, Timothy J; Martinez Garcia, Maria; Vahdat, Linda; Perez-Garcia, Jose; Wach, Achim; Barker, Debra; Fung, Samson; Romagnoli, Barbara; Cortes, Javier

2018-04-26

The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m 2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m 2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. Polyphor. Copyright © 2018 Elsevier Ltd. All rights reserved.

Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial.

PubMed

Mulder, Gerit; Tallis, Arthur J; Marshall, V Tracy; Mozingo, David; Phillips, Laurie; Pierce, Glenn F; Chandler, Lois A; Sosnowski, Barbara K

2009-01-01

The results from a Phase 1/2 study of a replication-defective adenovirus encoding human platelet-derived growth factor (PDGF)-B formulated in a bovine collagen (Ad-5PDGF-B; 2.6% collagen; GAM501) gel for nonhealing neuropathic diabetic foot ulcers is reported. The primary objectives of the study were to evaluate the safety, maximum-tolerated dose, and preliminary biological activity of GAM501. Fifteen patients enrolled into the study with chronic, nonhealing ulcers received either a single administration of GAM501 at one of three dose levels, or up to four administrations of GAM501 at 1-week intervals. All patients received standard of care treatment including debridement and were required to wear an off-loading shoe. GAM501 was found to be safe and well tolerated with no evidence of systemic or local toxicity at all doses so no maximum-tolerated dose was reached. Serum antibody titers to platelet-derived growth factor-B homodimer and collagen were negative and adenoviral DNA was not detected in the blood. In the 12 patients that completed the study, ulcer closure was observed by Month 3 in 10 patients, seven of whom received a single application of GAM501. In conclusion, GAM501 did not appear to have any toxicity at doses that showed biological activity. GAM501 holds promise as a potentially effective treatment for nonhealing diabetic foot ulcers.

SU-E-J-33: Cardiac Movement in Deep Inspiration Breath-Hold for Left-Breast Cancer Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, M; Lee, S; Suh, T

Purpose: The present study was designed to investigate the displacement of heart using Deep Inspiration Breath Hold (DIBH) CT data compared to free-breathing (FB) CT data and radiation exposure to heart. Methods: Treatment planning was performed on the computed tomography (CT) datasets of 20 patients who had received lumpectomy treatments. Heart, lung and both breasts were outlined. The prescribed dose was 50 Gy divided into 28 fractions. The dose distributions in all the plans were required to fulfill the International Commission on Radiation Units and Measurement specifications that include 100% coverage of the CTV with ≥ 95% of the prescribedmore » dose and that the volume inside the CTV receiving > 107% of the prescribed dose should be minimized. Displacement of heart was measured by calculating the distance between center of heart and left breast. For the evaluation of radiation dose to heart, minimum, maximum and mean dose to heart were calculated. Results: The maximum and minimum left-right (LR) displacements of heart were 8.9 mm and 3 mm, respectively. The heart moved > 4 mm in the LR direction in 17 of the 20 patients. The distances between the heart and left breast ranged from 8.02–17.68 mm (mean, 12.23 mm) and 7.85–12.98 mm (mean, 8.97 mm) with DIBH CT and FB CT, respectively. The maximum doses to the heart were 3115 cGy and 4652 cGy for the DIBH and FB CT dataset, respectively. Conclusion: The present study has demonstrated that the DIBH technique could help to reduce the risk of radiation dose-induced cardiac toxicity by using movement of cardiac; away from radiation field. The DIBH technique could be used in an actual treatment room for a few minutes and could effectively reduce the cardiac dose when used with a sub-device or image acquisition standard to maintain consistent respiratory motion.« less

Individual dose adjustment of riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

PubMed

Hill, Nicholas S; Rahaghi, Franck F; Sood, Namita; Frey, Reiner; Ghofrani, Hossein-Ardeschir

2017-08-01

Riociguat is a soluble guanylate cyclase stimulator that has been approved for the treatment of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension following pulmonary endarterectomy. Riociguat is administered using an 8-week individual dose-adjustment scheme whereby a patient initially receives riociguat 1.0 mg three times daily (tid), and the dose is then increased every 2 weeks in the absence of hypotension, indicated by systolic blood pressure measurements and symptoms, up to a maximum dose of 2.5 mg tid. The established riociguat dose-adjustment scheme allows the dose of riociguat to be individually optimized in terms of tolerability and efficacy. The majority of patients in the phase III clinical trials and their long-term extension phases achieved the maximum riociguat dose, whereas some patients remained on lower doses. There is evidence that these patients may experience benefits at riociguat doses lower than 2.5 mg tid, with improvement in exercise capacity being observed after only 2-4 weeks of treatment in the phase III studies and in the exploratory 1.5 mg-maximum patient group of PATENT-1. This review aims to provide an overview of the rationale behind the riociguat dose-adjustment scheme and examine its application to both clinical trials and real-life clinical practice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Spinal Cord Tolerance to Reirradiation With Single-Fraction Radiosurgery: A Swine Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.edu; Foster, Ryan D.; Kogel, Albert J. van der

2012-07-01

Purpose: This study was performed to determine swine spinal cord tolerance to single-fraction, partial-volume irradiation 1 year after receiving uniform irradiation to 30 Gy in 10 fractions. Methods and Materials: A 10-cm length of spinal cord (C3-T1) was uniformly irradiated to 30 Gy in 10 consecutive fractions and reirradiated 1 year later with a single radiosurgery dose centered within the previously irradiated segment. Radiosurgery was delivered to a cylindrical volume approximately 5 cm in length and 2 cm in diameter, which was positioned laterally to the cervical spinal cord, resulting in a dose distribution with the 90%, 50%, and 10%more » isodose lines traversing the ipsilateral, central, and contralateral spinal cord, respectively. Twenty-three pigs were stratified into six dose groups with mean maximum spinal cord doses of 14.9 {+-} 0.1 Gy (n = 2), 17.1 {+-} 0.3 Gy (n = 3), 19.0 {+-} 0.1 Gy (n = 5), 21.2 {+-} 0.1 Gy (n = 5), 23.4 {+-} 0.2 Gy (n = 5), and 25.4 {+-} 0.4 Gy (n = 3). The mean percentage of spinal cord volumes receiving {>=}10 Gy for the same groups were 34% {+-} 1%, 40% {+-} 1%, 46% {+-} 3%, 52% {+-} 1%, 56 {+-} 3%, and 57% {+-} 1%. The study endpoint was motor neurologic deficit as determined by a change in gait during a 1- year follow-up period. Results: A steep dose-response curve was observed with a 50% incidence of paralysis (ED{sub 50}) for the maximum point dose of 19.7 Gy (95% confidence interval, 17.4-21.4). With two exceptions, histology was unremarkable in animals with normal neurologic status, while all animals with motor deficits showed some degree of demyelination and focal white matter necrosis on the irradiated side, with relative sparing of gray matter. Histologic comparison with a companion study of de novo irradiated animals revealed that retreatment responders had more extensive tissue damage, including infarction of gray matter, only at prescription doses >20 Gy. Conclusion: Pigs receiving spinal radiosurgery 1 year after receiving 30 Gy in 10 fractions were not at significantly higher risk of developing motor deficits than pigs that received radiosurgery alone.« less

Treatment Plan Technique and Quality for Single-Isocenter Stereotactic Ablative Radiotherapy of Multiple Lung Lesions with Volumetric-Modulated Arc Therapy or Intensity-Modulated Radiosurgery

PubMed Central

Quan, Kimmen; Xu, Karen M.; Lalonde, Ron; Horne, Zachary D.; Bernard, Mark E.; McCoy, Chuck; Clump, David A.; Burton, Steven A.; Heron, Dwight E.

2015-01-01

The aim of this study is to provide a practical approach to the planning technique and evaluation of plan quality for the multi-lesion, single-isocenter stereotactic ablative radiotherapy (SABR) of the lung. Eleven patients with two or more lung lesions underwent single-isocenter volumetric-modulated arc therapy (VMAT) radiosurgery or IMRS. All plans were normalized to the target maximum dose. For each plan, all targets were treated to the same dose. Plan conformity and dose gradient were maximized with dose-control tuning structures surrounding targets. For comparison, multi-isocenter plans were retrospectively created for four patients. Conformity index (CI), homogeneity index (HI), gradient index (GI), and gradient distance (GD) were calculated for each plan. V5, V10, and V20 of the lung and organs at risk (OARs) were collected. Treatment time and total monitor units (MUs) were also recorded. One patient had four lesions and the remainder had two lesions. Six patients received VMAT and five patients received intensity-modulated radiosurgery (IMRS). For those treated with VMAT, two patients received 3-arc VMAT and four received 2-arc VMAT. For those treated with IMRS, two patients were treated with 10 and 11 beams, respectively, and the rest received 12 beams. Prescription doses ranged from 30 to 54 Gy in three to five fractions. The median prescribed isodose line was 84% (range: 80–86%). The median maximum dose was 57.1 Gy (range: 35.7–65.1 Gy). The mean combined PTV was 49.57 cm3 (range: 14.90–87.38 cm3). For single-isocenter plans, the median CI was 1.15 (range: 0.97–1.53). The median HI was 1.19 (range: 1.16–1.28). The median GI was 4.60 (range: 4.16–7.37). The median maximum radiation dose (Dmax) to total lung was 55.6 Gy (range: 35.7–62.0 Gy). The median mean radiation dose to the lung (Dmean) was 4.2 Gy (range: 1.1–9.3 Gy). The median lung V5 was 18.7% (range: 3.8–41.3%). There was no significant difference in CI, HI, GI, GD, V5, V10, and V20 (lung, heart, trachea, esophagus, and spinal cord) between single-isocenter and multi-isocenter plans. This multi-lesion, single-isocenter lung SABR planning technique demonstrated excellent plan quality and clinical efficiency and is recommended for radiosurgical treatment of two or more lung targets for well-suited patients. PMID:26500888

An Open-Label Trial of Escitalopram in Pervasive Developmental Disorders.

ERIC Educational Resources Information Center

Owley, Thomas; Walton, Laura; Salt, Jeff; Guter, Stephen J., Jr.; Winnega, Marrea; Leventhal, Bennett L.; Cook, Edwin H., Jr.

2005-01-01

Objective: To assess the effect of escitalopram in the treatment of pervasive developmental disorders (PDDs). Method: This 10-week study had a forced titration, open-label design. Twenty-eight subjects (mean age 125.1 [+ or -] 33.5 months) with a PDD received escitalopram at a dose that increased weekly to a maximum dose of 20 mg as tolerated. The…

Advanced proton beam dosimetry part II: Monte Carlo vs. pencil beam-based planning for lung cancer.

PubMed

Maes, Dominic; Saini, Jatinder; Zeng, Jing; Rengan, Ramesh; Wong, Tony; Bowen, Stephen R

2018-04-01

Proton pencil beam (PB) dose calculation algorithms have limited accuracy within heterogeneous tissues of lung cancer patients, which may be addressed by modern commercial Monte Carlo (MC) algorithms. We investigated clinical pencil beam scanning (PBS) dose differences between PB and MC-based treatment planning for lung cancer patients. With IRB approval, a comparative dosimetric analysis between RayStation MC and PB dose engines was performed on ten patient plans. PBS gantry plans were generated using single-field optimization technique to maintain target coverage under range and setup uncertainties. Dose differences between PB-optimized (PBopt), MC-recalculated (MCrecalc), and MC-optimized (MCopt) plans were recorded for the following region-of-interest metrics: clinical target volume (CTV) V95, CTV homogeneity index (HI), total lung V20, total lung V RX (relative lung volume receiving prescribed dose or higher), and global maximum dose. The impact of PB-based and MC-based planning on robustness to systematic perturbation of range (±3% density) and setup (±3 mm isotropic) was assessed. Pairwise differences in dose parameters were evaluated through non-parametric Friedman and Wilcoxon sign-rank testing. In this ten-patient sample, CTV V95 decreased significantly from 99-100% for PBopt to 77-94% for MCrecalc and recovered to 99-100% for MCopt (P<10 -5 ). The median CTV HI (D95/D5) decreased from 0.98 for PBopt to 0.91 for MCrecalc and increased to 0.95 for MCopt (P<10 -3 ). CTV D95 robustness to range and setup errors improved under MCopt (ΔD95 =-1%) compared to MCrecalc (ΔD95 =-6%, P=0.006). No changes in lung dosimetry were observed for large volumes receiving low to intermediate doses (e.g., V20), while differences between PB-based and MC-based planning were noted for small volumes receiving high doses (e.g., V RX ). Global maximum patient dose increased from 106% for PBopt to 109% for MCrecalc and 112% for MCopt (P<10 -3 ). MC dosimetry revealed a reduction in target dose coverage under PB-based planning that was regained under MC-based planning along with improved plan robustness. MC-based optimization and dose calculation should be integrated into clinical planning workflows of lung cancer patients receiving actively scanned proton therapy.

Advanced proton beam dosimetry part II: Monte Carlo vs. pencil beam-based planning for lung cancer

PubMed Central

Maes, Dominic; Saini, Jatinder; Zeng, Jing; Rengan, Ramesh; Wong, Tony

2018-01-01

Background Proton pencil beam (PB) dose calculation algorithms have limited accuracy within heterogeneous tissues of lung cancer patients, which may be addressed by modern commercial Monte Carlo (MC) algorithms. We investigated clinical pencil beam scanning (PBS) dose differences between PB and MC-based treatment planning for lung cancer patients. Methods With IRB approval, a comparative dosimetric analysis between RayStation MC and PB dose engines was performed on ten patient plans. PBS gantry plans were generated using single-field optimization technique to maintain target coverage under range and setup uncertainties. Dose differences between PB-optimized (PBopt), MC-recalculated (MCrecalc), and MC-optimized (MCopt) plans were recorded for the following region-of-interest metrics: clinical target volume (CTV) V95, CTV homogeneity index (HI), total lung V20, total lung VRX (relative lung volume receiving prescribed dose or higher), and global maximum dose. The impact of PB-based and MC-based planning on robustness to systematic perturbation of range (±3% density) and setup (±3 mm isotropic) was assessed. Pairwise differences in dose parameters were evaluated through non-parametric Friedman and Wilcoxon sign-rank testing. Results In this ten-patient sample, CTV V95 decreased significantly from 99–100% for PBopt to 77–94% for MCrecalc and recovered to 99–100% for MCopt (P<10−5). The median CTV HI (D95/D5) decreased from 0.98 for PBopt to 0.91 for MCrecalc and increased to 0.95 for MCopt (P<10−3). CTV D95 robustness to range and setup errors improved under MCopt (ΔD95 =−1%) compared to MCrecalc (ΔD95 =−6%, P=0.006). No changes in lung dosimetry were observed for large volumes receiving low to intermediate doses (e.g., V20), while differences between PB-based and MC-based planning were noted for small volumes receiving high doses (e.g., VRX). Global maximum patient dose increased from 106% for PBopt to 109% for MCrecalc and 112% for MCopt (P<10−3). Conclusions MC dosimetry revealed a reduction in target dose coverage under PB-based planning that was regained under MC-based planning along with improved plan robustness. MC-based optimization and dose calculation should be integrated into clinical planning workflows of lung cancer patients receiving actively scanned proton therapy. PMID:29876310

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.

PubMed

Lee, Daniel W; Kochenderfer, James N; Stetler-Stevenson, Maryalice; Cui, Yongzhi K; Delbrook, Cindy; Feldman, Steven A; Fry, Terry J; Orentas, Rimas; Sabatino, Marianna; Shah, Nirali N; Steinberg, Seth M; Stroncek, Dave; Tschernia, Nick; Yuan, Constance; Zhang, Hua; Zhang, Ling; Rosenberg, Steven A; Wayne, Alan S; Mackall, Crystal L

2015-02-07

Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. National Institutes of Health Intramural funds and St Baldrick's Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Real-time eye lens dose monitoring during cerebral angiography procedures.

PubMed

Safari, M J; Wong, J H D; Kadir, K A A; Thorpe, N K; Cutajar, D L; Petasecca, M; Lerch, M L F; Rosenfeld, A B; Ng, K H

2016-01-01

To develop a real-time dose-monitoring system to measure the patient's eye lens dose during neuro-interventional procedures. Radiation dose received at left outer canthus (LOC) and left eyelid (LE) were measured using Metal-Oxide-Semiconductor Field-Effect Transistor dosimeters on 35 patients who underwent diagnostic or cerebral embolization procedures. The radiation dose received at the LOC region was significantly higher than the dose received by the LE. The maximum eye lens dose of 1492 mGy was measured at LOC region for an AVM case, followed by 907 mGy for an aneurysm case and 665 mGy for a diagnostic angiography procedure. Strong correlations (shown as R(2)) were observed between kerma-area-product and measured eye doses (LOC: 0.78, LE: 0.68). Lateral and frontal air-kerma showed strong correlations with measured dose at LOC (AKL: 0.93, AKF: 0.78) and a weak correlation with measured dose at LE. A moderate correlation was observed between fluoroscopic time and dose measured at LE and LOC regions. The MOSkin dose-monitoring system represents a new tool enabling real-time monitoring of eye lens dose during neuro-interventional procedures. This system can provide interventionalists with information needed to adjust the clinical procedure to control the patient's dose. Real-time patient dose monitoring helps interventionalists to monitor doses. Strong correlation was observed between kerma-area-product and measured eye doses. Radiation dose at left outer canthus was higher than at left eyelid.

Pharmacology of 13-cis-retinoic acid in humans.

PubMed

Kerr, I G; Lippman, M E; Jenkins, J; Myers, C E

1982-05-01

Vitamin A and its analogs (retinoids) have shown great promise for the chemoprevention of cancer as well as being a possible new class of chemotherapeutic agents. A Phase I and II trial of 13-cis-retinoic acid in advanced cancers was initiated, and the clinical pharmacology of the drug was studied. All patients received p.o. 13-cis-retinoic acid starting at 0.5 mg/kg/day, escalating over 4 weeks to a maximum dose of 8 mg/kg/day in divided doses. Although there was a linear correlation of plasma concentration with dose escalation, large inter-individual variations in peak plasma concentrations were noted. At the maximum drug dose, the mean peak plasma concentration was 4 X 10(-6) M. There was little drug accumulation on this schedule, as trough concentrations between p.o. doses often dropped below 1 X 10(-6) M. The drug was metabolized extensively to a metabolite, the concentrations of which exceeding parent 13-cis-retinoic acid concentrations with chronic dosing. Retinol concentrations were below the normal range.

Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

PubMed

Ito, Yoshinori; Suenaga, Mitsukuni; Hatake, Kiyohiko; Takahashi, Shunji; Yokoyama, Masahiro; Onozawa, Yusuke; Yamazaki, Kentaro; Hironaka, Shuichi; Hashigami, Kiyoshi; Hasegawa, Hirotaka; Takenaka, Nobuko; Boku, Narikazu

2012-04-01

Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.

PubMed

Pardo, Beatriz; Paz-Ares, Luis; Tabernero, Josep; Ciruelos, Eva; García, Margarita; Salazar, Ramón; López, Ana; Blanco, María; Nieto, Antonio; Jimeno, José; Izquierdo, Miguel Angel; Trigo, José Manuel

2008-02-15

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 microg/m(2), and dose escalation proceeded based on the worst toxicity found in the previous cohort. Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 microg/m(2). Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 microg/m(2), and the recommended dose for phase II studies was 650 microg/m(2). No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. The maximum tolerated dose was 800 microg/m(2). Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

Method for microbeam radiation therapy

DOEpatents

Slatkin, D.N.; Dilmanian, F.A.; Spanne, P.O.

1994-08-16

A method is disclosed of performing radiation therapy on a patient, involving exposing a target, usually a tumor, to a therapeutic dose of high energy electromagnetic radiation, preferably X-ray radiation. The dose is in the form of at least two non-overlapping microbeams of radiation, each microbeam having a width of less than about 1 millimeter. Target tissue exposed to the microbeams receives a radiation dose during the exposure that exceeds the maximum dose that such tissue can survive. Non-target tissue between the microbeams receives a dose of radiation below the threshold amount of radiation that can be survived by the tissue, and thereby permits the non-target tissue to regenerate. The microbeams may be directed at the target from one direction, or from more than one direction in which case the microbeams overlap within the target tissue enhancing the lethal effect of the irradiation while sparing the surrounding healthy tissue. No Drawings

Long-term outcome of accelerated partial breast irradiation using a multilumen balloon applicator in a patient with existing breast implants.

PubMed

Akhtari, Mani; Nitsch, Paige L; Bass, Barbara L; Teh, Bin S

2015-01-01

Accelerated partial breast irradiation is now an accepted component of breast-conserving therapy. However, data regarding long-term outcomes of patients treated with multilumen catheter systems who have existing breast implants are limited. We report the treatment and outcome of our patient who had existing bilateral silicone subpectoral implants at the time of presentation. Ultrasound-guided core needle biopsy of the right breast showed infiltrating mucinous carcinoma. Right breast lumpectomy revealed an 8 mm area of infiltrating ductal carcinoma with mucinous features and nuclear grade 1. A 4-5 cm Contura (Bard Biopsy Systems, Tempe, AZ) device was placed, and she was treated over the course of 5 days twice daily to a dose of 34 Gy using a high-dose-rate iridium-192 source. The planning target volume for evaluation was 73.9 cc. The percentage of the planning target volume for evaluation receiving 90%, 95%, and 100% of the prescribed dose was 99.9%, 99.3%, and 97.8%, respectively. The total implant volume was 234.5 cc and received a mean dose of 15.4 Gy and a maximum dose of 72.8 Gy. The percentage of implant volume receiving 50%, 75%, 100%, and 200% of the prescribed dose was 31.1%, 16.5%, 8.6%, 2.0%, and 0%, respectively. Maximum skin dose was 97% of the prescribed dose. With a followup of nearly 5 years, she continues to be cancer free with minimal late toxicities and good to excellent cosmetic outcome. Accelerated partial breast irradiation using a multilumen balloon applicator in patients with existing breast implants can safely be performed with excellent long-term cosmetic outcome. Further studies are needed to establish the absolute dosimetric tolerance of breast implants. Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study.

PubMed

Auger, R Robert; Goodman, Scott H; Silber, Michael H; Krahn, Lois E; Pankratz, V Shane; Slocumb, Nancy L

2005-06-01

To ascertain complications associated with high-dose stimulant therapy in patients with narcolepsy or idiopathic hypersomnia. Case-control, retrospective chart review. Sleep center in an academic hospital. 116 patients with narcolepsy or idiopathic hypersomnia were individually matched by sex, diagnosis, age of onset, and duration of follow-up from both onset and diagnosis. Members of the high-dose group (n = 58) had received at least 1 stimulant at a dosage > or = 120% of the maximum recommended by the American Academy of Sleep Medicine Standards of Practice Committee. The standard-dose control group (n = 58) had received stimulants at a dosage < or = 100% of the American Academy of Sleep Medicine guidelines. N/A. The prevalence of psychosis (odds ratio = 12.0 [1.6-92.0]), alcohol or polysubstance misuse (odds ratio = 4.3 [1.2-15.2]), and psychiatric hospitalization (odds ratio = 3.2 [1.1-10.0]) was significantly increased in the high-dose group. More high-dose patients also experienced tachyarrhythmias (odds ratio = 3.3 [0.92-12.1] and anorexia or weight loss (odds ratio = 11.0 [1.4-85.2]). The frequency of physician-diagnosed depression, drug-seeking and suicide-related behaviors, hypertension, and cardiovascular disease did not differ significantly between the groups. This study demonstrated a significantly higher occurrence of psychosis, substance misuse, and psychiatric hospitalizations in patients using high-dose stimulants compared to those using standard doses. Tachyarrhythmias and anorexia or weight loss were also more common in this group as compared with controls. Clinicians should be very cautious in prescribing dosages that exceed maximum guidelines.

A phase I/II study of carfilzomib 2-10-min infusion in patients with advanced solid tumors.

PubMed

Papadopoulos, Kyriakos P; Burris, Howard A; Gordon, Michael; Lee, Peter; Sausville, Edward A; Rosen, Peter J; Patnaik, Amita; Cutler, Richard E; Wang, Zhengping; Lee, Susan; Jones, Suzanne F; Infante, Jeffery R

2013-10-01

Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2-10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study. Adult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m(2) in week 1 of cycle 1 and 20, 27, or 36 mg/m(2) thereafter. The maximum tolerated dose or protocol-defined maximum planned dose (MPD) identified during dose escalation was administered to an expansion cohort and to patients with small cell lung, non-small cell lung, ovarian, and renal cancer in phase II tumor-specific cohorts. Fourteen patients received carfilzomib during dose escalation. The single dose-limiting toxicity at 20/36 mg/m(2) was grade 3 fatigue, establishing the MPD as the expansion and phase II dose. Sixty-five additional patients received carfilzomib at the MPD. Adverse events included fatigue, nausea, anorexia, and dyspnea. Carfilzomib PK was dose proportional with a half-life <1 h. All doses resulted in at least 80 % proteasome inhibition in blood. Partial responses occurred in two patients in phase I, with 21.5 % stable disease after four cycles in evaluable patients in the expansion and phase II cohorts. Carfilzomib 20/36 mg/m(2) was well tolerated when administered twice weekly by 2-10-min IV infusion. At this dose and infusion rate, carfilzomib inhibited the proteasome in blood but demonstrated limited antitumor activity in patients with advanced solid tumors.

Assessment of human exposure doses received by activation of medical linear accelerator components

NASA Astrophysics Data System (ADS)

Lee, D.-Y.; Kim, J.-H.; Park, E.-T.

2017-08-01

This study analyzes the radiation exposure dose that an operator can receive from radioactive components during maintenance or repair of a linear accelerator. This study further aims to evaluate radiological safety. Simulations are performed on 10 MV and 15 MV photon beams, which are the most frequently used high-energy beams in clinics. The simulation analyzes components in order of activity and the human exposure dose based on the amount of neutrons received. As a result, the neutron dose, radiation dose, and human exposure dose are ranked in order of target, primary collimator, flattening filter, multi-leaf collimator, and secondary collimator, where the minimum dose is 9.34E-07 mSv/h and the maximum is 1.71E-02 mSv/h. When applying the general dose limit (radiation worker 20 mSv/year, pubic 1 mSv/year) in accordance with the Nuclear Safety Act, all components of a linear accelerator are evaluated as below the threshold value. Therefore, the results suggest that there is no serious safety issue for operators in maintaining and repairing a linear accelerator. Nevertheless, if an operator recognizes an exposure from the components of a linear accelerator during operation and considers the operating time and shielding against external exposure, exposure of the operator is expected to be minimized.

Stereotactic Body Radiation Therapy Boost After Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Dose Escalation Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hepel, Jaroslaw T., E-mail: jhepel@lifespan.org; Department of Radiation Oncology, Tufts Medical Center, Tufts University, Boston, Massachusetts; Leonard, Kara Lynne

Purpose: Stereotactic body radiation therapy (SBRT) boost to primary and nodal disease after chemoradiation has potential to improve outcomes for advanced non-small cell lung cancer (NSCLC). A dose escalation study was initiated to evaluate the maximum tolerated dose (MTD). Methods and Materials: Eligible patients received chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (<120 cc and <60 cc, respectively). SBRT was delivered in 2 fractions after chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fraction increments, resulting in 4 dose cohorts. MTD was defined when ≥2 of 6 patients permore » cohort experienced any treatment-related grade 3 to 5 toxicity within 4 weeks of treatment or the maximum dose was reached. Late toxicity, disease control, and survival were also evaluated. Results: Twelve patients (3 per dose level) underwent treatment. All treatment plans met predetermined dose-volume constraints. The mean age was 64 years. Most patients had stage III disease (92%) and were medically inoperable (92%). The maximum dose level was reached with no grade 3 to 5 acute toxicities. At a median follow-up time of 16 months, 1-year local-regional control (LRC) was 78%. LRC was 50% at <24 Gy and 100% at ≥24 Gy (P=.02). Overall survival at 1 year was 67%. Late toxicity (grade 3-5) was seen in only 1 patient who experienced fatal bronchopulmonary hemorrhage (grade 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient's 4-cc PBV dose was substantially higher than that received by other patients in all 4 cohorts and was associated with the toxicity observed: 20.3 Gy (P<.05) and 73.5 Gy (P=.07) for SBRT boost and total treatment, respectively. Conclusions: SBRT boost to both primary and nodal disease after chemoradiation is feasible and well tolerated. Local control rates are encouraging, especially at doses ≥24 Gy in 2 fractions. Toxicity at the PBV is a concern but potentially can be avoided with strict dose-volume constraints.« less

Effect of the Maximum Dose on White Matter Fiber Bundles Using Longitudinal Diffusion Tensor Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Tong; Chapman, Christopher H.; Tsien, Christina

2016-11-01

Purpose: Previous efforts to decrease neurocognitive effects of radiation focused on sparing isolated cortical structures. We hypothesize that understanding temporal, spatial, and dosimetric patterns of radiation damage to whole-brain white matter (WM) after partial-brain irradiation might also be important. Therefore, we carried out a study to develop the methodology to assess radiation therapy (RT)–induced damage to whole-brain WM bundles. Methods and Materials: An atlas-based, automated WM tractography analysis was implemented to quantify longitudinal changes in indices of diffusion tensor imaging (DTI) of 22 major WM fibers in 33 patients with predominantly low-grade or benign brain tumors treated by RT. Sixmore » DTI scans per patient were performed from before RT to 18 months after RT. The DTI indices and planned doses (maximum and mean doses) were mapped onto profiles of each of 22 WM bundles. A multivariate linear regression was performed to determine the main dose effect as well as the influence of other clinical factors on longitudinal percentage changes in axial diffusivity (AD) and radial diffusivity (RD) from before RT. Results: Among 22 fiber bundles, AD or RD changes in 12 bundles were affected significantly by doses (P<.05), as the effect was progressive over time. In 9 elongated tracts, decreased AD or RD was significantly related to maximum doses received, consistent with a serial structure. In individual bundles, AD changes were up to 11.5% at the maximum dose locations 18 months after RT. The dose effect on WM was greater in older female patients than younger male patients. Conclusions: Our study demonstrates for the first time that the maximum dose to the elongated WM bundles causes post-RT damage in WM. Validation and correlative studies are necessary to determine the ability and impact of sparing these bundles on preserving neurocognitive function after RT.« less

A comparison of skin and chest wall dose delivered with multicatheter, Contura multilumen balloon, and MammoSite breast brachytherapy.

PubMed

Cuttino, Laurie W; Todor, Dorin; Rosu, Mihaela; Arthur, Douglas W

2011-01-01

Skin and chest wall doses have been correlated with toxicity in patients treated with breast brachytherapy . This investigation compared the ability to control skin and chest wall doses between patients treated with multicatheter (MC), Contura multilumen balloon (CMLB), and MammoSite (MS) brachytherapy. 43 patients treated with the MC technique, 45 patients treated with the CMLB, and 83 patients treated with the MS were reviewed. The maximum doses delivered to the skin and chest wall were calculated for all patients. The mean maximum skin doses for the MC, CMLB, and MS were 2.3 Gy (67% of prescription dose), 2.8 Gy (82% of prescription dose), and 3.2 Gy per fraction (94% of prescription dose), respectively. Although the skin distances were similar (p = 0.23) for the two balloon techniques, the mean skin dose with the CMLB was significantly lower than with the MS (p = 0.05). The mean maximum rib doses for the MC, CMLB, and MS were 2.3 Gy (67% of prescription dose), 2.8 Gy (82% of prescription dose), and 3.6 Gy per fraction (105% of prescription dose), respectively. Again, the mean rib dose with the CMLB was significantly lower than with the MS (p = 0.002). The MC and CMLB techniques are associated with significantly lower mean skin and rib doses than is the MS. Treatment with the MS was associated with significantly more patients receiving doses to the skin or rib in excess of 125% of the prescription. Treatment with the CMLB may prove to yield less normal tissue toxicity than treatment with the MS. Copyright © 2011 Elsevier Inc. All rights reserved.

A Comparison of Skin and Chest Wall Dose Delivered With Multicatheter, Contura Multilumen Balloon, and MammoSite Breast Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cuttino, Laurie W., E-mail: lcuttino@mcvh-vcu.ed; Todor, Dorin; Rosu, Mihaela

2011-01-01

Purpose: Skin and chest wall doses have been correlated with toxicity in patients treated with breast brachytherapy . This investigation compared the ability to control skin and chest wall doses between patients treated with multicatheter (MC), Contura multilumen balloon (CMLB), and MammoSite (MS) brachytherapy. Methods and Materials: 43 patients treated with the MC technique, 45 patients treated with the CMLB, and 83 patients treated with the MS were reviewed. The maximum doses delivered to the skin and chest wall were calculated for all patients. Results: The mean maximum skin doses for the MC, CMLB, and MS were 2.3 Gy (67%more » of prescription dose), 2.8 Gy (82% of prescription dose), and 3.2 Gy per fraction (94% of prescription dose), respectively. Although the skin distances were similar (p = 0.23) for the two balloon techniques, the mean skin dose with the CMLB was significantly lower than with the MS (p = 0.05). The mean maximum rib doses for the MC, CMLB, and MS were 2.3 Gy (67% of prescription dose), 2.8 Gy (82% of prescription dose), and 3.6 Gy per fraction (105% of prescription dose), respectively. Again, the mean rib dose with the CMLB was significantly lower than with the MS (p = 0.002). Conclusion: The MC and CMLB techniques are associated with significantly lower mean skin and rib doses than is the MS. Treatment with the MS was associated with significantly more patients receiving doses to the skin or rib in excess of 125% of the prescription. Treatment with the CMLB may prove to yield less normal tissue toxicity than treatment with the MS.« less

“Hallucinations” Following Acute Cannabis Dosing: A Case Report and Comparison to Other Hallucinogenic Drugs

PubMed Central

Barrett, Frederick S.; Schlienz, Nicolas J.; Lembeck, Natalie; Waqas, Muhammad; Vandrey, Ryan

2018-01-01

Abstract Introduction: Cannabis has been historically classified as a hallucinogen. However, subjective cannabis effects do not typically include hallucinogen-like effects. Empirical reports of hallucinogen-like effects produced by cannabis in controlled settings, particularly among healthy research volunteers, are rare and have mostly occurred after administration of purified Δ-9 tetrahydrocannabinol (THC) rather than whole plant cannabis. Methods: The case of a healthy 30-year-old male who experienced auditory and visual hallucinations in a controlled laboratory study after inhaling vaporized cannabis that contained 25 mg THC (case dose) is presented. Ratings on the Hallucinogen Rating Scale (HRS) following the case dose are compared with HRS ratings obtained from the participant after other doses of cannabis and with archival HRS data from laboratory studies involving acute doses of cannabis, psilocybin, dextromethorphan (DXM), and salvinorin A. Results: Scores on the Volition subscale of the HRS were greater for the case dose than for the maximum dose administered in any other comparison study. Scores on the Intensity and Perception subscales were greater for the case dose than for the maximum dose of cannabis, psilocybin, or salvinorin A. Scores on the Somaesthesia subscale were greater for the case dose than for the maximum dose of DXM, salvinorin A, or cannabis. Scores on the Affect and Cognition subscales for the case dose were significantly lower than for the maximum doses of psilocybin and DXM. Conclusion: Acute cannabis exposure in a healthy adult male resulted in self-reported hallucinations that rated high in magnitude on several subscales of the HRS. However, the hallucinatory experience in this case was qualitatively different than that typically experienced by participants receiving classic and atypical hallucinogens, suggesting that the hallucinatory effects of cannabis may have a unique pharmacological mechanism of action. This type of adverse event needs to be considered in the clinical use of cannabis. PMID:29682608

Fractionated Radioimmunotherapy With 90Y-Clivatuzumab Tetraxetan and Low-Dose Gemcitabine Is Active in Advanced Pancreatic Cancer

PubMed Central

Ocean, Allyson J.; Pennington, Kenneth L.; Guarino, Michael J.; Sheikh, Arif; Bekaii-Saab, Tanios; Serafini, Aldo N.; Lee, Daniel; Sung, Max W.; Gulec, Seza A.; Goldsmith, Stanley J.; Manzone, Timothy; Holt, Michael; O’Neil, Bert H.; Hall, Nathan; Montero, Alberto J.; Kauh, John; Gold, David V.; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2014-01-01

BACKGROUND It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2–4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. RESULTS Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses. CONCLUSIONS Fractionated radioimmunotherapy with 90Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma. PMID:22569804

Radiation Exposure to Relatives of Patients Treated with Iodine-131 for Thyroid Cancer at Siriraj Hospital.

PubMed

Tonnonchiang, Siriporn; Sritongkul, Nopamon; Chaudakshetrin, Pachee; Tuntawiroon, Malulee

2016-02-01

Thyroid cancer patients treated with 1-131 are potential source of radiation exposure to relatives who are knowingly and willingly exposed to ionizing radiation as a result of providing comfort to patients undergoing I-131 therapy. This study aims to determine radiation dose received by relatives who care for non self-supporting 1-131 patients at Siriraj Hospital. Twenty caregivers of 20 patients underwent I-131 therapy for thyroid cancer with a standard protocol were given specific instructions with regard to radiation safety and provided with electronic digital dosimeter to continuously measure radiation dose received on daily basis, three days in the hospital. On the day patient is released, thyroid uptake estimates were performed to assess internal radiation dose received by caregivers. The 3-day accumulative doses to caregivers to patients receiving 150 mCi (n = 11) and 200 mCi (n = 9) of I-131 ranged from 37 to 333 uSv and 176 to 1,920 pSv respectively depending on the level of supports required. Thyroid uptake estimates in all caregivers were undetectable. Dosimeter indicated a maximum whole-body dose of1.92 mSv was more than the public dose limit of] mSv but within the dose constraint of 5 mSv for caregivers. Radiation dose to caregivers of a non self-supporting hospitalized patient undergoing 1-131 therapy were well below the limits recommended by the ICRP. The patients can be comforted with confidence that dose to caregivers will be less than the limit. This study provides guidance for medical practitioners to obtain practical radiation safety concerns associated with hospitalized patients receiving I-131 therapy especially when patient needs assistance.

Volumetric-modulated arc therapy (VMAT) for whole brain radiotherapy: not only for hippocampal sparing, but also for reduction of dose to organs at risk.

PubMed

Sood, Sumit; Pokhrel, Damodar; McClinton, Christopher; Lominska, Christopher; Badkul, Rajeev; Jiang, Hongyu; Wang, Fen

2017-01-01

A prospective clinical trial, Radiation Therapy Oncology Group (RTOG) 0933, has demonstrated that whole brain radiotherapy (WBRT) using conformal radiation delivery technique with hippocampal avoidance is associated with less memory complications. Further sparing of other organs at risk (OARs) including the scalp, ear canals, cochleae, and parotid glands could be associated with reductions in additional toxicities for patients treated with WBRT. We investigated the feasibility of WBRT using volumetric-modulated arc therapy (VMAT) to spare the hippocampi and the aforementioned OARs. Ten patients previously treated with nonconformal WBRT (NC-WBRT) using opposed lateral beams were retrospectively re-planned using VMAT with hippocampal sparing according to the RTOG 0933 protocol. The OARs (scalp, auditory canals, cochleae, and parotid glands) were considered as dose-constrained structures. VMAT plans were generated for a prescription dose of 30 Gy in 10 fractions. Comparison of the dosimetric parameters achieved by VMAT and NC-WBRT plans was performed using paired t-tests using upper bound p-value of < 0.001. Average beam on time and monitor units (MUs) delivered to the patients on VMAT were compared with those obtained with NC-WBRT. All VMAT plans met RTOG 0933 dosimetric criteria including the dose to hippocampi of 100% of the volume (D 100% ) of 8.4 ± 0.3 Gy and maximum dose of 15.6 ± 0.4 Gy, respectively. A statistically significant dose reduction (p < 0.001) to all OARs was achieved. The mean and maximum scalp doses were reduced by an average of 9 Gy (32%) and 2 Gy (6%), respectively. The mean and maximum doses to the auditory canals were reduced from 29.5 ± 0.5 Gy and 31.0 ± 0.4 Gy with NC-WBRT, to 21.8 ± 1.6 Gy (26%) and 27.4 ± 1.4 Gy (12%) with VMAT. VMAT also reduced mean and maximum doses to the cochlea by an average of 4 Gy (13%) and 2 Gy (6%), respectively. The parotid glands mean and maximum doses with VMAT were 4.4 ± 1.9 Gy and 15.7 ± 5.0 Gy, compared to 12.8 ± 4.9 Gy and 30.6 ± 0.5 Gy with NC-WBRT, respectively. The average dose reduction of mean and maximum of parotid glands from VMAT were 65% and 50%, respectively. The average beam on time and MUs were 2.3minutes and 719 on VMAT, and 0.7 minutes and 350 on NC-WBRT. This study demonstrated the feasibility of WBRT using VMAT to not only spare the hippocampi, but also significantly reduce dose to OARs. These advantages of VMAT could potentially decrease the toxicities associated with NC-WBRT and improve patients' quality of life, especially for patients with favorable prognosis receiving WBRT or patients receiving prophylactic cranial irradiation (PCI). Published by Elsevier Inc.

SU-F-J-87: Impact Of The Dosimetric Consequences From Minimal Displacements Throughout The Treatment Time In APBI With SAVI Applicators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chandrasekara, S; Pella, S; Hyvarinen, M

2016-06-15

Purpose: To assess the variation in dose received by the organs at risk (OARs) due to inter-fractional motion by SAVI to determine the importance of providing proper immobilization Methods: An analysis of 15 patients treated with SAVI applicators were considered for this study. Treatment planning teams did not see significant changes in their CT scans through scout images and initial treatment plan was used for the entire treatment. These scans, taken before each treatment were imported in to the treatment planning system and were fused together with respective to the applicator, using landmark registration. Dosimetric evaluations were performed. Dose receivedmore » by skin, ribs and PTV(Planning target volume) respect to the initial treatment plan were measured. Results: Contours of the OARs were not similar with the initial image. Deduction in volumes of PTV and cavity, small deviations in displacements from the applicator to the OARs, difference in doses received by the OARs between treatments were noticed. The maximum, minimum, average doses varied between 10% to 20% 5% to 8% and 15% to 20% in ribs and skin. The 0.1cc doses to OARs showed an average change of 10% of the prescribed dose. PTV was receiving a different dose than the estimated dose Conclusion: The variation in volumes and isodoses related to the OARs, PTV receiving a lesser dose than the prescribed dose indicate that the estimated doses are different from the received dose. This study reveals the urgent need of improving the immobilization methods. Taking a CT scan before each treatment and replanning is helpful to minimize the risk of delivering undesired high doses to the OARs. Patient positioning, motion, respiration, observer differences and time lap between the planning and treating can arise more complications. VacLock, Positioning cushions, Image guided brachytherapy and adjustable registration should be used for further improvements.« less

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma1

PubMed Central

Quinn, Jennifer A.; Reardon, David A.; Friedman, Allan H.; Rich, Jeremy N.; Sampson, John H.; Vredenburgh, James; Gururangan, Sridharan; Provenzale, James M.; Walker, Amy; Schweitzer, Holly; Bigner, Darell D.; Tourt-Uhlig, Sandra; Herndon, James E.; Affronti, Mary Lou; Jackson, Susanne; Allen, Deborah; Ziegler, Karen; Bohlin, Cindy; Lentz, Christy; Friedman, Henry S.

2004-01-01

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs. PMID:15134629

Radiopharmaceutical therapy of patients with metastasized melanoma with the melanin-binding benzamide 131I-BA52.

PubMed

Mier, Walter; Kratochwil, Clemens; Hassel, Jessica C; Giesel, Frederik L; Beijer, Barbro; Babich, John W; Friebe, Matthias; Eisenhut, Michael; Enk, Alexander; Haberkorn, Uwe

2014-01-01

The performance of cytotoxic drugs is defined by their selectivity of uptake and action in tumor tissue. Recent clinical responses achieved by treating metastatic malignant melanoma with therapeutic modalities based on gene expression profiling showed that malignant melanoma is amenable to systemic treatment. However, these responses are not persistent, and complementary targeted treatment strategies are required for malignant melanoma. Here we provide our experience with different labeling procedures for the radioiodination of benzamides and report on initial dosimetry data and the first therapeutic application of (131)I-BA52, a novel melanin-binding benzamide in patients with metastatic malignant melanoma. Twenty-six adults with histologically documented metastasized malignant melanoma received a single dose of 235 ± 62 MBq of (123)I-BA52 for planar and SPECT/CT imaging. Nine patients were selected for radionuclide therapy and received a median of 4 GBq (minimum, 0.51 GBq; maximum, 6.60 GBq) of the β-emitting radiopharmaceutical (131)I-BA52. A trimethyltin precursor-based synthesis demonstrated high radiochemical yields in the large-scale production of radioiodinated benzamides required for clinical application. (123)I-BA52 showed specific uptake and long-term retention in tumor tissue with low transient uptake in the excretory organs. In tumor tissue, a maximum dose of 12.2 Gy per GBq of (131)I-BA52 was calculated. The highest estimated dose to a normal organ was found for the lung (mean, 3.1 Gy/GBq). No relevant acute or mid-term toxicity was observed with the doses administered until now. Even though dosimetric calculations reveal that the doses applied in this early phase of clinical application can be significantly increased, we observed antitumor effects with follow-up imaging, and single patients of the benzamide-positive cohort of patients (3/5 of the patients receiving a dose > 4.3 GBq) demonstrated a surprisingly long survival of more than 2 y. These data indicate that systemic radionuclide therapy using (131)I-BA52 as a novel approach for the therapy of malignant melanoma is of considerable potential. Future trials should be done to enhance the precision of dosimetry, validate the maximum tolerable dose, and evaluate the effectiveness of the treatment in a prospective manner.

Dosimetric feasibility of an “off-target isocenter” technique for cranial intensity-modulated radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calvo-Ortega, Juan Francisco, E-mail: jfcdrr@yahoo.es; Moragues, Sandra; Pozo, Miquel

2015-01-01

To evaluate the dosimetric effect of placing the isocenter away from the planning target volume (PTV) on intensity-modulated radiosurgery (IMRS) plans to treat brain lesions. A total of 15 patients who received cranial IMRS at our institution were randomly selected. Each patient was treated with an IMRS plan designed with the isocenter located at the target center (plan A). A second off-target isocenter plan (plan B) was generated for each case. In all the plans,100% of the prescription dose covered 99% of the target volume. The plans A and B were compared for the target dosage (conformity index [CI] andmore » homogeneity index) and organs-at-risk (OAR) dose sparing. Peripheral dose falloff was compared by using the metrics volume of normal brain receiving more than 12-Gy dose (V12) and CI at the level of the 50% of the prescription dose (CI 50%). The values found for each metric (plan B vs plan A) were (mean ± standard deviation [SD]) as follows—CI: 1.28 ± 0.15 vs 1.28 ± 0.15, p = 0.978; homogeneity index (HI): 1.29 ± 0.14 vs 1.34 ± 0.17, p = 0.079; maximum dose to the brainstem: 2.95 ± 2.11 vs 2.89 ± 1.88 Gy, p = 0.813; maximum dose to the optical pathway: 2.65 ± 4.18 vs 2.44 ± 4.03 Gy, p = 0.195; and maximum dose to the eye lens: 0.33 ± 0.73 vs 0.33 ± 0.53 Gy, p = 0.970. The values of the peripheral dose falloff were (plan B vs plan A) as follows—V12: 5.98 ± 4.95 vs 6.06 ± 4.92 cm{sup 3}, p = 0.622, and CI 50%: 6.08 ± 2.77 vs 6.28 ± 3.01, p = 0.119. The off-target isocenter solution resulted in dosimetrically comparable plans as the center-target isocenter technique, by avoiding the risk of gantry-couch collision during the cone beam computed tomography (CBCT) acquisition.« less

Dosimetric verification of IMRT treatment planning using Monte Carlo simulations for prostate cancer

NASA Astrophysics Data System (ADS)

Yang, J.; Li, J.; Chen, L.; Price, R.; McNeeley, S.; Qin, L.; Wang, L.; Xiong, W.; Ma, C.-M.

2005-03-01

The purpose of this work is to investigate the accuracy of dose calculation of a commercial treatment planning system (Corvus, Normos Corp., Sewickley, PA). In this study, 30 prostate intensity-modulated radiotherapy (IMRT) treatment plans from the commercial treatment planning system were recalculated using the Monte Carlo method. Dose-volume histograms and isodose distributions were compared. Other quantities such as minimum dose to the target (Dmin), the dose received by 98% of the target volume (D98), dose at the isocentre (Diso), mean target dose (Dmean) and the maximum critical structure dose (Dmax) were also evaluated based on our clinical criteria. For coplanar plans, the dose differences between Monte Carlo and the commercial treatment planning system with and without heterogeneity correction were not significant. The differences in the isocentre dose between the commercial treatment planning system and Monte Carlo simulations were less than 3% for all coplanar cases. The differences on D98 were less than 2% on average. The differences in the mean dose to the target between the commercial system and Monte Carlo results were within 3%. The differences in the maximum bladder dose were within 3% for most cases. The maximum dose differences for the rectum were less than 4% for all the cases. For non-coplanar plans, the difference in the minimum target dose between the treatment planning system and Monte Carlo calculations was up to 9% if the heterogeneity correction was not applied in Corvus. This was caused by the excessive attenuation of the non-coplanar beams by the femurs. When the heterogeneity correction was applied in Corvus, the differences were reduced significantly. These results suggest that heterogeneity correction should be used in dose calculation for prostate cancer with non-coplanar beam arrangements.

Repaglinide pharmacokinetics in healthy young adult and elderly subjects.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (> or = 65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (Cmax), time to Cmax, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.

SU-E-J-52: Dosimetric Benefit of Adaptive Re-Planning in Lung Cancer Stereotactic Body Radiotherapy (SBRT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jia, J; Tian, Z; Gu, X

Purpose: To investigate the dosimetric benefit of adaptive re-planning for lung stereotactic body radiotherapy(SBRT). Methods: Five lung cancer patients with SBRT treatment were retrospectively investigated. Our in-house supercomputing online re-planning environment (SCORE) was used to realize the re-planning process. First a deformable image registration was carried out to transfer contours from treatment planning CT to each treatment CBCT. Then an automatic re-planning using original plan DVH guided fluence-map optimization is performed to get a new plan for the up-to-date patient geometry. We compared the re-optimized plan to the original plan projected on the up-to-date patient geometry in critical dosimetric parameters,more » such as PTV coverage, spinal cord maximum and volumetric constraint dose, esophagus maximum and volumetric constraint dose. Results: The average volume of PTV covered by prescription dose for all patients was improved by 7.56% after the adaptive re-planning. The volume of the spinal cord receiving 14.5Gy and 23Gy (V14.5, V23) decreased by 1.48% and 0.68%, respectively. For the esophagus, the volume receiving 19.5Gy (V19.5) reduced by 1.37%. Meanwhile, the maximum dose dropped off by 2.87% for spinal cord and 4.80% for esophagus. Conclusion: Our experimental results demonstrate that adaptive re-planning for lung SBRT has the potential to minimize the dosimetric effect of inter-fraction deformation and thus improve target coverage while reducing the risk of toxicity to nearby normal tissues.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, Xiaodong, E-mail: lxdctopone@sina.com; Ni, Lingqin; Hu, Wei

The objective of this study was to evaluate the dose conformity and feasibility of whole-brain radiotherapy with a simultaneous integrated boost by forward intensity-modulated radiation therapy in patients with 1 to 3 brain metastases. Forward intensity-modulated radiation therapy plans were generated for 10 patients with 1 to 3 brain metastases on Pinnacle 6.2 Treatment Planning System. The prescribed dose was 30 Gy to the whole brain (planning target volume [PTV]{sub wbrt}) and 40 Gy to individual brain metastases (PTV{sub boost}) simultaneously, and both doses were given in 10 fractions. The maximum diameters of individual brain metastases ranged from 1.6 tomore » 6 cm, and the summated PTVs per patient ranged from 1.62 to 69.81 cm{sup 3}. Conformity and feasibility were evaluated regarding conformation number and treatment delivery time. One hundred percent volume of the PTV{sub boost} received at least 95% of the prescribed dose in all cases. The maximum doses were less than 110% of the prescribed dose to the PTV{sub boost}, and all of the hot spots were within the PTV{sub boost}. The volume of the PTV{sub wbrt} that received at least 95% of the prescribed dose ranged from 99.2% to 100%. The mean values of conformation number were 0.682. The mean treatment delivery time was 2.79 minutes. Ten beams were used on an average in these plans. Whole-brain radiotherapy with a simultaneous integrated boost by forward intensity-modulated radiation therapy in 1 to 3 brain metastases is feasible, and treatment delivery time is short.« less

Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer

PubMed Central

Shaw, Alice T.; Kim, Dong-Wan; Mehra, Ranee; Tan, Daniel S.W.; Felip, Enriqueta; Chow, Laura Q.M.; Camidge, D. Ross; Vansteenkiste, Johan; Sharma, Sunil; De Pas, Tommaso; Riely, Gregory J.; Solomon, Benjamin J.; Wolf, Juergen; Thomas, Michael; Schuler, Martin; Liu, Geoffrey; Santoro, Armando; Lau, Yvonne Y.; Goldwasser, Meredith; Boral, Anthony L.; Engelman, Jeffrey A.

2014-01-01

BACKGROUND Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.) PMID:24670165

Occupational radiation exposure in vascular interventional radiology: A complete evaluation of different body regions.

PubMed

Bacchim Neto, Fernando Antonio; Alves, Allan Felipe Fattori; Mascarenhas, Yvone Maria; Nicolucci, Patrícia; Pina, Diana Rodrigues de

2016-08-01

To perform a complete evaluation on radiation doses, received by primary and assistant medical staff, while performing different vascular interventional radiology procedures. We evaluated dose received in different body regions during three categories of vascular procedures: lower limb angiography (Angiography), lower limb percutaneous transluminal angioplasty (Angioplasty) and stent graft placement for abdominal aortic aneurysm treatment (A. A. A. Treatment). We positioned the dosimeters near the eye lens, thyroid, chest, abdomen, hands, and feet of the interventional physicians. Equivalent dose was compared with annual dose limits for workers in order to determine the maximum number of procedures per year that each physician could perform. We assessed 90 procedures. We found the highest equivalent doses in the A. A. A. Treatment, in which 90% of the evaluations indicated at least one region receiving more than 1mSv per procedure. Angioplasty was the only procedural modality that provided statistically different doses for different professionals, which is an important aspect on regards to radiological protection strategies. In comparison with the dose limits, the most critical region in all procedures was the eye lens. Since each body region of the interventionist is exposed to different radiation levels, dose distribution measurements are essential for radiological protection strategies. These results indicate that dosimeters placed in abdomen instead of chest may represent more accurately the whole body doses received by the medical staff. Additional dosimeters and a stationary shield for the eye lens are strongly recommended. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

High dose of antacid (Mylanta II) reduces bioavailability of ranitidine.

PubMed Central

Mihaly, G W; Marino, A T; Webster, L K; Jones, D B; Louis, W J; Smallwood, R A

1982-01-01

To investigate the effect of antacid on the bioavailability and disposition of ranitidine six healthy volunteers were studied on two occasions one week apart. In the first study the received ranitidine 150 mg with 60 ml water, and in the second study they received ranitidine 150 mg plus 30 ml of an aluminium/magnesium hydroxide mixture (Mylanta II) and 30 ml water. Giving antacid reduced both the maximum plasma ranitidine concentration and the area under the curve by one-third; elimination of the drug was not changed. Thus giving a high dose of antacid significantly diminished the bioavailability of ranitidine. PMID:6289961

Method for microbeam radiation therapy

DOEpatents

Slatkin, Daniel N.; Dilmanian, F. Avraham; Spanne, Per O.

1994-01-01

A method of performing radiation therapy on a patient, involving exposing a target, usually a tumor, to a therapeutic dose of high energy electromagnetic radiation, preferably X-ray radiation, in the form of at least two non-overlapping microbeams of radiation, each microbeam having a width of less than about 1 millimeter. Target tissue exposed to the microbeams receives a radiation dose during the exposure that exceeds the maximum dose that such tissue can survive. Non-target tissue between the microbeams receives a dose of radiation below the threshold amount of radiation that can be survived by the tissue, and thereby permits the non-target tissue to regenerate. The microbeams may be directed at the target from one direction, or from more than one direction in which case the microbeams overlap within the target tissue enhancing the lethal effect of the irradiation while sparing the surrounding healthy tissue.

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Landau, David B., E-mail: david.landau@kcl.ac.uk; Hughes, Laura; Baker, Angela

2016-08-01

Purpose: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumormore » doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.« less

Patient-controlled oral analgesia for postoperative pain management following total knee replacement.

PubMed

Kastanias, Patti; Gowans, Sue; Tumber, Paul S; Snaith, Kianda; Robinson, Sandra

2010-01-01

To investigate whether patient-controlled oral analgesia (PCOA) used by individuals receiving a total knee replacement could reduce pain, increase patient satisfaction, reduce opioid use and/or reduce opioid side effects when compared with traditional nurse (RN)-administered oral analgesia. Patients who underwent an elective total knee replacement at a quaternary care centre (Toronto Western Hospital, Toronto, Ontario) were randomly assigned to either PCOA or RN-administered short-acting oral opioids on postoperative day 2. Subjects in the RN group called the RN to receive their prescribed short-acting opioid. Subjects in the PCOA group kept a single dose of their prescribed oral opioid at their bedside and took this dose when they felt they needed it, to a maximum of one dose every 2 h. Study outcomes, collected on postoperative day 2, included pain (measured by the Brief Pain Inventory - Short Form), patient satisfaction (measured by the Pain Outcome Questionnaire Satisfaction subscale - component II), opioid use (oral morphine equivalents), opioid side effects (nausea, pruritus and/or constipation) and knee measures (maximum passive knee flexion and pain at maximum passive knee flexion, performed on the operative knee). Study outcomes were analyzed twice. First, for a subset of 73 subjects who remained in their randomly assigned group (PCOA group, n=36; RN group, n=37), randomized analyses were performed. Second, for the larger sample of 88 subjects who were categorized by their actual method of receiving oral opioids (PCOA group, n=41; RN group, n=47), as-treated analyses were performed. There were no differences in study outcomes between the PCOA and RN groups in either analysis. PCOA was not superior to RN administration on study outcomes. However, PCOA did not increase opioid use or pain. PCOA remains an important element in the patient-centred care facility.

Spacecraft shielding for a Mars mission

NASA Astrophysics Data System (ADS)

O'Brien, K.

Calculations of the effective radiation dose due to cosmic rays in the interplanetary medium between Earth and Mars show that, as in the atmosphere above the Pfotzer Maximum, the dose rate increases with increasing wall thickness. An unshielded space crew member would receive almost 70 rem (0.70 Sv) a year. The effect of a typically proposed composite space-craft hull of aluminum and polyethylene would increase the dose rate by a few percent. However, 100 g/cm2 of almost any light material would more than double the cosmic radiation exposure of the crew.

A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer.

PubMed

Center, Brian; Petty, William Jeffrey; Ayala, Diandra; Hinson, William H; Lovato, James; Capellari, James; Oaks, Timothy; Miller, Antonius A; Blackstock, Arthur William

2010-01-01

Concurrent radiation and chemotherapy is the standard of care for good performance status patients with stage III non-small cell lung cancer. Locoregional control remains a significant factor relating to poor outcome. Preclinical and early clinical data suggest that docetaxel and gefitinib have radiosensitizing activity. This study sought to define the maximum tolerated dose of weekly docetaxel that could be given with daily gefitinib and concurrent thoracic radiation therapy. Patients with histologically confirmed, inoperable stage III non-small cell lung cancer and good performance status (Eastern Cooperative Oncology Group 0-1) were eligible for this study. Patients received three-dimensional conformal thoracic radiation to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. Sixteen patients were enrolled on the study between December 2003 and April 2007 with the following characteristics: median age, 64 years (range 43-79 years); M/F: 9/7; and performance status 0/1, 1/15. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2, resulting in a maximum tolerated dose of 20 mg/m2/wk. Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The overall response rate was 46%, and the median survival for all patients was 21 months. Concurrent thoracic radiation with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2.

Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.

PubMed

Castelli, Joel; Simon, Antoine; Louvel, Guillaume; Henry, Olivier; Chajon, Enrique; Nassef, Mohamed; Haigron, Pascal; Cazoulat, Guillaume; Ospina, Juan David; Jegoux, Franck; Benezery, Karen; de Crevoisier, Renaud

2015-01-09

Large anatomical variations occur during the course of intensity-modulated radiation therapy (IMRT) for locally advanced head and neck cancer (LAHNC). The risks are therefore a parotid glands (PG) overdose and a xerostomia increase. The purposes of the study were to estimate: - the PG overdose and the xerostomia risk increase during a "standard" IMRT (IMRTstd); - the benefits of an adaptive IMRT (ART) with weekly replanning to spare the PGs and limit the risk of xerostomia. Fifteen patients received radical IMRT (70 Gy) for LAHNC. Weekly CTs were used to estimate the dose distributions delivered during the treatment, corresponding either to the initial planning (IMRTstd) or to weekly replanning (ART). PGs dose were recalculated at the fraction, from the weekly CTs. PG cumulated doses were then estimated using deformable image registration. The following PG doses were compared: pre-treatment planned dose, per-treatment IMRTstd and ART. The corresponding estimated risks of xerostomia were also compared. Correlations between anatomical markers and dose differences were searched. Compared to the initial planning, a PG overdose was observed during IMRTstd for 59% of the PGs, with an average increase of 3.7 Gy (10.0 Gy maximum) for the mean dose, and of 8.2% (23.9% maximum) for the risk of xerostomia. Compared to the initial planning, weekly replanning reduced the PG mean dose for all the patients (p<0.05). In the overirradiated PG group, weekly replanning reduced the mean dose by 5.1 Gy (12.2 Gy maximum) and the absolute risk of xerostomia by 11% (p<0.01) (30% maximum). The PG overdose and the dosimetric benefit of replanning increased with the tumor shrinkage and the neck thickness reduction (p<0.001). During the course of LAHNC IMRT, around 60% of the PGs are overdosed of 4 Gy. Weekly replanning decreased the PG mean dose by 5 Gy, and therefore by 11% the xerostomia risk.

Comparison of dose volume parameters evaluated using three forward planning – optimization techniques in cervical cancer brachytherapy involving two applicators

PubMed Central

Basu-Roy, Somapriya; Kar, Sanjay Kumar; Das, Sounik; Lahiri, Annesha

2017-01-01

Purpose This study is intended to compare dose-volume parameters evaluated using different forward planning- optimization techniques, involving two applicator systems in intracavitary brachytherapy for cervical cancer. It looks for the best applicator-optimization combination to fulfill recommended dose-volume objectives in different high-dose-rate (HDR) fractionation schedules. Material and methods We used tandem-ring and Fletcher-style tandem-ovoid applicator in same patients in two fractions of brachytherapy. Six plans were generated for each patient utilizing 3 forward optimization techniques for each applicator used: equal dwell weight/times (‘no optimization’), ‘manual dwell weight/times’, and ‘graphical’. Plans were normalized to left point A and dose of 8 Gy was prescribed. Dose volume and dose point parameters were compared. Results Without graphical optimization, maximum width and thickness of volume enclosed by 100% isodose line, dose to 90%, and 100% of clinical target volume (CTV); minimum, maximum, median, and average dose to both rectum and bladder are significantly higher with Fletcher applicator. Even if it is done, dose to both points B, minimum dose to CTV, and treatment time; dose to 2 cc (D2cc) rectum and rectal point etc.; D2cc, minimum, maximum, median, and average dose to sigmoid colon; D2cc of bladder remain significantly higher with this applicator. Dose to bladder point is similar (p > 0.05) between two applicators, after all optimization techniques. Conclusions Fletcher applicator generates higher dose to both CTV and organs at risk (2 cc volumes) after all optimization techniques. Dose restriction to rectum is possible using graphical optimization only during selected HDR fractionation schedules. Bladder always receives dose higher than recommended, and 2 cc sigmoid colon always gets permissible dose. Contrarily, graphical optimization with ring applicators fulfills all dose volume objectives in all HDR fractionations practiced. PMID:29204164

Erlotinib in African Americans with Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Study with Genetic and Pharmacokinetic Analysis

PubMed Central

Phelps, Mitch A.; Stinchcombe, Thomas E.; Blachly, James S.; Zhao, Weiqiang; Schaaf, Larry J.; Starrett, Sherri L.; Wei, Lai; Poi, Ming; Wang, Danxin; Papp, Audrey; Aimiuwu, Josephine; Gao, Yue; Li, Junan; Otterson, Gregory A.; Hicks, William J.; Socinski, Mark A.; Villalona-Calero, Miguel A.

2014-01-01

Prospective studies focusing on EGFR inhibitors in African Americans with NSCLC have not been previously performed. In this phase II randomized study, 55 African Americans with NSCLC received erlotinib 150mg/day or a body weight adjusted dose with subsequent escalations to the maximum allowable, 200mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower compared to previous reports, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics revealed only two EGFR mutations, EGFR amplification in 17/47 samples, 8 KRAS mutations and 5 EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Observed low incidence of toxicity and low erlotinib exposure suggest standardized and maximum allowable dosing may be suboptimal in African Americans. PMID:24781527

A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children’s Oncology Group Phase I Consortium Report

PubMed Central

Bender, Julia Glade; Blaney, Susan M.; Borinstein, Scott; Reid, Joel M.; Baruchel, Sylvain; Ahern, Charlotte; Ingle, Ashish M.; Yamashiro, Darrell J.; Chen, Alice; Weigel, Brenda; Adamson, Peter C.; Park, Julie R.

2012-01-01

Background Aflibercept is a novel decoy receptor that efficiently neutralizes circulating vascular endothelial growth factor (VEGF). A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of aflibercept. Methods Cohorts of 3–6 children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5 or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were performed with the initial dose. Results 21 eligible patients were enrolled; 18 were fully evaluable for toxicity. One of 6 patients receiving 2.0 mg/kg/dose developed dose-limiting intra-tumoral hemorrhage and 2 of 6 receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the 6 patients receiving 2.5 mg/kg/dose developed DLT, defining this as the MTD. The most common non-dose limiting toxicities were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free to bound aflibercept serum concentration was 2.10 on day 8, but only 0.44 by day 15. A rapid decrease in VEGF (p<0.05) and increase in PlGF (p<0.05) from baseline was observed in response to aflibercept by day 2. Conclusion The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower that the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of anti-tumor activity, but were dose-limiting. PMID:22791883

UVER and UV index at high altitude in Northwestern Argentina.

PubMed

Utrillas, M P; Marín, M J; Esteve, A R; Salazar, G; Suarez, H; Castillo, J; Martínez-Lozano, J A

2016-10-01

Measurements of ultraviolet erythemal radiation (UVER) made during two years at three sites located at altitudes over 1000ma.s.l. in Northwestern Argentina (Salta, San Carlos, and El Rosal) have been used to estimate and analyze the UV Index (UVI) and the cumulative doses at these locations. For the UVER irradiance, data of January (maximum values) and June (minimum values) have been analyzed as representative of the year for all locations. The UVI reaches extreme (>11) values in >20% of the analyzed days in Salta (1190ma.s.l.), while these are reached in San Carlos (1611ma.s.l.) and El Rosal (3355ma.s.l.) in >40% of the analyzed days. Finally, the cumulative doses over an average year have also been studied for each location. The doses received during austral summer and autumn are of the same order, and represent one third of the annual dose, while the doses received during austral winter and spring represent one sixth of the annual dose approximately. Copyright © 2016 Elsevier B.V. All rights reserved.

Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration.

PubMed

Karschner, Erin L; Darwin, W David; Goodwin, Robert S; Wright, Stephen; Huestis, Marilyn A

2011-01-01

Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia

PubMed Central

Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P.; Snyder, David S.; Khoury, Jean; Bhalla, Kapil N.; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C.; Rutkoski, Thomas J.; Smith, Bryan D.; Flynn, Daniel L.; Kantarjian, Hagop M.; Rosen, Oliver; Van Etten, Richard A.

2017-01-01

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5′-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138). PMID:27927766

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.

PubMed

Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P; Snyder, David S; Khoury, Jean; Bhalla, Kapil N; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C; Rutkoski, Thomas J; Smith, Bryan D; Flynn, Daniel L; Kantarjian, Hagop M; Rosen, Oliver; Van Etten, Richard A

2017-03-01

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib ( clinicaltrials.gov Identifier:00827138 ). Copyright© Ferrata Storti Foundation.

Phase I trial of capecitabine rapidly disintegrating tablets and concomitant radiation therapy in children with newly diagnosed brainstem gliomas and high-grade gliomas

PubMed Central

Kilburn, Lindsay B.; Kocak, Mehmet; Schaedeli Stark, Franziska; Meneses-Lorente, Georgina; Brownstein, Carrie; Hussain, Sazzad; Chintagumpala, Murali; Thompson, Patrick A.; Gururangan, Sri; Banerjee, Anuradha; Paulino, Arnold C.; Kun, Larry; Boyett, James M.; Blaney, Susan M.

2013-01-01

Background We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas. Methods Children 3–21 y with newly diagnosed intrinsic brainstem or high-grade gliomas were eligible for enrollment. The starting dose was 500 mg/m2, given twice daily, with subsequent cohorts enrolled at 650 mg/m2 and 850 mg/m2 using a 3 + 3 phase I design. Children received capecitabine at the assigned dose daily for 9 wks starting from the first day of radiation therapy (RT). Following a 2-wk break, patients received 3 courses of capecitabine 1250 mg/m2 twice daily for 14 days followed by a 7-day rest. Pharmacokinetic sampling was performed in consenting patients. Six additional patients with intrinsic brainstem gliomas were enrolled at the maximum tolerated dose to further characterize the pharmacokinetic and toxicity profiles. Results Twenty-four patients were enrolled. Twenty were fully assessable for toxicity. Dose-limiting toxicities were palmar plantar erythroderma (grades 2 and 3) and elevation of alanine aminotransferase (grades 2 and 3). Systemic exposure to capecitabine and metabolites was similar to or slightly lower than predicted based on adult data. Conclusions Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m2, administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030). PMID:23592571

Plasma Cannabinoid Pharmacokinetics following Controlled Oral Δ9-Tetrahydrocannabinol and Oromucosal Cannabis Extract Administration

PubMed Central

Karschner, Erin L.; Darwin, W. David; Goodwin, Robert S.; Wright, Stephen; Huestis, Marilyn A.

2013-01-01

BACKGROUND Sativex®, a cannabis extract oromucosal spray containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC’s effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. METHODS Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board–approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor-9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. RESULTS Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (Cmax) and areas under the curve from 0–10.5 h postdose (AUC0→10.5) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in Cmax, time to maximum concentration or in the AUC0→10.5 between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. CONCLUSION These data suggest that CBD modulation of THC’s effects is not due to a pharmacokinetic interaction at these therapeutic doses. PMID:21078841

Evaluations of secondary cancer risk in spine radiotherapy using 3DCRT, IMRT, and VMAT: A phantom study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rehman, Jalil ur, E-mail: jalil_khanphy@yahoo.com; Department of Radiation Physics, UT MD Anderson Cancer Center, Houston, TX; Tailor, Ramesh C.

2015-04-01

This study evaluated the secondary cancer risk from volumetric-modulated arc therapy (VMAT) for spine radiotherapy compared with intensity-modulated radiotherapy (IMRT) and 3-dimensional conformal radiotherapy (3DCRT). Computed tomography images of an Radiological Physics Center spine anthropomorphic phantom were exported to a treatment planning system (Pinnacle{sup 3}, version 9.4). Radiation treatment plans for spine were prepared using VMAT (dual-arc), 7-field IMRT (beam angles: 110°, 130°, 150°, 180°, 210°, 230°, and 250°), and 4-field 3DCRT technique. The mean and maximum doses, dose-volume histograms, and volumes receiving more than 2 and 4 Gy to organs at risk (OARs) were calculated and compared. The lifetimemore » risk for secondary cancers was estimated according to the National Cancer Registry Programme Report 116. VMAT delivered the lowest maximum dose to the esophagus (4.03 Gy), bone (8.11 Gy), heart (2.11 Gy), spinal cord (6.45 Gy), and whole lung (5.66 Gy) as compared with other techniques (IMRT and 3DCRT). The volumes of OAR (esophagus) receiving more than 4 Gy were 0% for VMAT, 27.06% for IMRT, and up to 32.35% for 3DCRT. The estimated risk for secondary cancer in the respective OAR is considerably lower in VMAT compared with other techniques. The results of maximum doses and volumes of OARs suggest that the risk of secondary cancer induction for the spine in VMAT is lower than IMRT and 3DCRT, whereas VMAT has the best target coverage compared with the other techniques.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayo, Charles, E-mail: charles.mayo@umassmemorial.or; Yorke, Ellen; Merchant, Thomas E.

Publications relating brainstem radiation toxicity to quantitative dose and dose-volume measures derived from three-dimensional treatment planning were reviewed. Despite the clinical importance of brainstem toxicity, most studies reporting brainstem effects after irradiation have fewer than 100 patients. There is limited evidence relating toxicity to small volumes receiving doses above 60-64 Gy using conventional fractionation and no definitive criteria regarding more subtle dose-volume effects or effects after hypofractionated treatment. On the basis of the available data, the entire brainstem may be treated to 54 Gy using conventional fractionation using photons with limited risk of severe or permanent neurological effects. Smaller volumesmore » of the brainstem (1-10 mL) may be irradiated to maximum doses of 59 Gy for dose fractions <=2 Gy; however, the risk appears to increase markedly at doses >64 Gy.« less

WE-E-BRE-09: Investigation of the Association Between Radiation-Induced Pain and Radiation Dose in Head and Neck Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gay, H; Dyk, P; Mullen, D

Purpose: Patients with head and neck cancer who undergo radiotherapy often experience several undesirable side-effects, including xerostomia, trismus, and pain in the head and neck area, but little is know about the dose-volume predictors of such pain. We investigated the association between radiation dose and both throat and esophagus pain during radiotherapy. Methods: We analyzed 124 head and neck patients who received radiotherapy at the Washington University School of Medicine in Saint Louis. For these patients, weekly PROs were recorded, including 16 pain and anatomical location questions. In addition, 17 observational symptoms were recorded. Patients were asked to describe theirmore » pain at each site according to a four-level scale: none (0), mild (1), moderate (2), and severe (3). We explored the association between throat pain and the mean dose received in oral cavity and between esophageal pain and the mean dose received in the esophagus. The severity of pain was determined by the difference between the baseline (week 1) pain score and the maximum pain score during treatment. The baseline pain score was defined as the first available pain score before receiving 10 Gy because radiotherapy pain originates later during treatment. Dose-volume metrics were extracted from treatment plans using CERR. To evaluate the correlation between pain and radiation dose, Spearman's correlation coefficient (Rs) was used. Results: The associations between throat pain and the mean dose to the oral cavity, and between esophagus pain and the mean dose to the esophagus, were both statistically significant, with Rs=0.320 (p=0.003) and Rs=0.424 (p<0.0001), respectively. Mean dose, for each structure, was a better predictor of pain than total integral dose. Conclusion: We demonstrated that pain during radiotherapy in head and neck patients highly correlates with the dose delivered. We will further investigate the association between other pain locations and relevant normal tissue dose characteristics.« less

Dosimetric comparison between VMAT with different dose calculation algorithms and protons for soft-tissue sarcoma radiotherapy.

PubMed

Fogliata, Antonella; Scorsetti, Marta; Navarria, Piera; Catalano, Maddalena; Clivio, Alessandro; Cozzi, Luca; Lobefalo, Francesca; Nicolini, Giorgia; Palumbo, Valentina; Pellegrini, Chiara; Reggiori, Giacomo; Roggio, Antonella; Vanetti, Eugenio; Alongi, Filippo; Pentimalli, Sara; Mancosu, Pietro

2013-04-01

To appraise the potential of volumetric modulated arc therapy (VMAT, RapidArc) and proton beams to simultaneously achieve target coverage and enhanced sparing of bone tissue in the treatment of soft-tissue sarcoma with adequate target coverage. Ten patients presenting with soft-tissue sarcoma of the leg were collected for the study. Dose was prescribed to 66.5 Gy in 25 fractions to the planning target volume (PTV) while significant maximum dose to the bone was constrained to 50 Gy. Plans were optimised according to the RapidArc technique with 6 MV photon beams or for intensity modulated protons. RapidArc photon plans were computed with: 1) AAA; 2) Acuros XB as dose to medium; and 3) Acuros XB as dose to water. All plans acceptably met the criteria of target coverage (V95% >90-95%) and bone sparing (D(1 cm3) <50 Gy). Significantly higher PTV dose homogeneity was found for proton plans. Near-to-maximum dose to bone was similar for RapidArc and protons, while volume receiving medium/low dose levels was minimised with protons. Similar results were obtained for the remaining normal tissue. Dose distributions calculated with the dose to water option resulted ~5% higher than corresponding ones computed as dose to medium. High plan quality was demonstrated for both VMAT and proton techniques when applied to soft-tissue sarcoma.

Lhermitte Sign After Chemo-IMRT of Head-and-Neck Cancer: Incidence, Doses, and Potential Mechanisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pak, Daniel; Vineberg, Karen; Feng, Felix

2012-08-01

Purpose: We have observed a higher rate of Lhermitte sign (LS) after chemo-intensity-modulated radiotherapy (IMRT) of head-and-neck cancer than the published rates after conventional radiotherapy. We hypothesized that the inhomogeneous spinal cord dose distributions produced by IMRT caused a 'bath-and-shower' effect, characterized by low doses in the vicinity of high doses, reducing spinal cord tolerance. Methods and Materials: Seventy-three patients with squamous cell carcinoma of the oropharynx participated in a prospective study of IMRT concurrent with weekly carboplatin and paclitaxel. Of these, 15 (21%) reported LS during at least 2 consecutive follow-up visits. Mean dose, maximum dose, and partial volumemore » and absolute volume (in milliliters) of spinal cord receiving specified doses ({>=}10 Gy, {>=}20 Gy, {>=}30 Gy, and {>=}40 Gy), as well as the pattern of dose distributions at the 'anatomic' spinal cord (from the base of the skull to the aortic arch) and 'plan-related' spinal cord (from the top through the bottom of the planning target volumes), were compared between LS patients and 34 non-LS patients. Results: LS patients had significantly higher spinal cord mean doses, V{sub 30}, V{sub 40}, and absolute volumes receiving 30 Gy or more and 40 Gy or more compared with the non-LS patients (p < 0.05). The strongest predictors of LS were higher V{sub 40} and higher cord volumes receiving 40 Gy or more (p {<=} 0.007). There was no evidence of larger spinal cord volumes receiving low doses in the vicinity of higher doses (bath-and-shower effect) in LS compared with non-LS patients. Conclusions: Greater mean dose, V{sub 30}, V{sub 40}, and cord volumes receiving 30 Gy or more and 40 Gy or more characterized LS compared with non-LS patients. Bath-and-shower effects could not be validated in this study as a potential contributor to LS. The higher-than-expected rates of LS may be because of the specific concurrent chemotherapy agents or more accurate identification of LS in the setting of a prospective study.« less

Dose commitments due to radioactive releases from nuclear power plant sites: Methodology and data base. Supplement 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.

1996-06-01

This manual describes a dose assessment system used to estimate the population or collective dose commitments received via both airborne and waterborne pathways by persons living within a 2- to 80-kilometer region of a commercial operating power reactor for a specific year of effluent releases. Computer programs, data files, and utility routines are included which can be used in conjunction with an IBM or compatible personal computer to produce the required dose commitments and their statistical distributions. In addition, maximum individual airborne and waterborne dose commitments are estimated and compared to 10 CFR Part 50, Appendix 1, design objectives. Thismore » supplement is the last report in the NUREG/CR-2850 series.« less

[An investigation of ionizing radiation dose in a manufacturing enterprise of ion-absorbing type rare earth ore].

PubMed

Zhang, W F; Tang, S H; Tan, Q; Liu, Y M

2016-08-20

Objective: To investigate radioactive source term dose monitoring and estimation results in a manufacturing enterprise of ion-absorbing type rare earth ore and the possible ionizing radiation dose received by its workers. Methods: Ionizing radiation monitoring data of the posts in the control area and supervised area of workplace were collected, and the annual average effective dose directly estimated or estimated using formulas was evaluated and analyzed. Results: In the control area and supervised area of the workplace for this rare earth ore, α surface contamination activity had a maximum value of 0.35 Bq/cm 2 and a minimum value of 0.01 Bq/cm 2 ; β radioactive surface contamination activity had a maximum value of 18.8 Bq/cm 2 and a minimum value of 0.22 Bq/cm 2 . In 14 monitoring points in the workplace, the maximum value of the annual average effective dose of occupational exposure was 1.641 mSv/a, which did not exceed the authorized limit for workers (5 mSv/a) , but exceeded the authorized limit for general personnel (0.25 mSv/a) . The radionuclide specific activity of ionic mixed rare earth oxides was determined to be 0.9. Conclusion: The annual average effective dose of occupational exposure in this enterprise does not exceed the authorized limit for workers, but it exceeds the authorized limit for general personnel. We should pay attention to the focus of the radiation process, especially for public works radiation.

Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.

PubMed

Czito, Brian G; Deming, Dustin A; Jameson, Gayle S; Mulcahy, Mary F; Vaghefi, Houman; Dudley, Matthew W; Holen, Kyle D; DeLuca, Angela; Mittapalli, Rajendar K; Munasinghe, Wijith; He, Lei; Zalcberg, John R; Ngan, Samuel Y; Komarnitsky, Philip; Michael, Michael

2017-06-01

Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m 2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20-400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5-10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy (<400 mg, n=16; 400 mg, n=15). During dose escalation, grade 2 dose-limiting toxic effects occurred in two patients; no grade 3-4 dose-limiting toxic effects were noted. Therefore, the maximum tolerated dose was not reached; the recommended phase 2 dose was selected as 400 mg twice daily. The most common treatment-emergent adverse events in all 32 patients were nausea (17 [53%]), diarrhoea (16 [50%]), and fatigue (16 [50%]). Grade 3 diarrhoea was noted in three (9%) of 32 patients; no grade 4 events were reported. Veliparib pharmacokinetics were dose proportional, with no effect on capecitabine pharmacokinetics. Tumour downstaging after surgery was noted in 22 (71%) of 31 patients; nine (29%) of 31 patients achieved a pathological complete response. Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. AbbVie Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Serum and tissue concentrations of gallium after oral administration of gallium nitrate and gallium maltolate to neonatal calves.

PubMed

Monk, Caroline S; Sweeney, Raymond W; Bernstein, Lawrence R; Fecteau, Marie-Eve

2016-02-01

To determine serum and tissue concentrations of gallium (Ga) after oral administration of gallium nitrate (GaN) and gallium maltolate (GaM) to neonatal calves. 8 healthy neonatal calves. Calves were assigned to 1 of 2 groups (4 calves/group). Gallium (50 mg/kg) was administered as GaN or GaM (equivalent to 13.15 mg of Ga/kg for GaN and 7.85 mg of Ga/kg for GaM) by oral gavage once daily for 5 days. Blood samples were collected 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after Ga administration on day 1; 4 and 24 hours after Ga administration on days 2, 3, and 4; and 4, 12, and 24 hours after Ga administration on day 5. On day 6, calves were euthanized and tissue samples were obtained. Serum and tissue Ga concentrations were measured by use of mass spectrometry. Data were adjusted for total Ga dose, and comparisons were made between the 2 groups. Calves receiving GaM had a significantly higher dose-adjusted area under the curve and dose-adjusted maximum serum Ga concentration than did calves receiving GaN. Despite receiving less Ga per dose, calves receiving GaM had tissue Ga concentrations similar to those for calves receiving GaN. In this study, calves receiving GaM had significantly higher Ga absorption than did calves receiving GaN. These findings suggested that GaM might be useful as a prophylactic agent against Mycobacterium avium subsp paratuberculosis infection in neonatal calves.

Evaluation of image-guided helical tomotherapy for the retreatment of spinal metastasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahan, Stephen L.; Ramsey, Chester R.; Scaperoth, Daniel D.

Introduction: Patients with vertebral metastasis that receive radiation therapy are typically treated to the spinal cord tolerance dose. As such, it is difficult to successfully deliver a second course of radiation therapy for patients with overlapping treatment volumes. In this study, an image-guided helical tomotherapy system was evaluated for the retreatment of previously irradiated vertebral metastasis. Methods and Materials: Helical tomotherapy dose gradients and maximum cord doses were measured in a cylindrical phantom for geometric test cases with separations between the planning target volume (PTV) and the spinal cord organ at risk (OAR) of 2 mm, 4 mm, 6 mm,more » 8 mm, and 10 mm. Megavoltage computed tomography (CT) images were examined for their ability to localize spinal anatomy for positioning purposes by repeat imaging of the cervical spine in an anthropomorphic phantom. In addition to the phantom studies, 8 patients with cord compressions that had received previous radiation therapy were retreated to a mean dose of 28 Gy using conventional fractionation. Results and Discussion: Megavoltage CT images were capable of positioning an anthropomorphic phantom to within {+-}1.2 mm (2{sigma}) superior-inferiorly and within {+-}0.6 mm (2{sigma}) anterior-posteriorly and laterally. Dose gradients of 10% per mm were measured in phantom while PTV uniformity indices of less than 11% were maintained. The calculated maximum cord dose was 25% of the prescribed dose for a 10-mm PTV-to-OAR separation and 71% of the prescribed dose for a PTV-to-OAR separation of 2 mm. Eight patients total have been treated without radiation-induced myelopathy or any other adverse effects from treatment. Conclusions: A technique has been evaluated for the retreatment of vertebral metastasis using image-guided helical tomotherapy. Phantom and patient studies indicated that a tomotherapy system is capable of delivering dose gradients of 10% per mm and positioning the patient within 1.2 mm without the use of special stereotactic immobilization.« less

Phase I Study of Concurrent High-Dose Three-Dimensional Conformal Radiotherapy With Chemotherapy Using Cisplatin and Vinorelbine for Unresectable Stage III Non-Small-Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sekine, Ikuo, E-mail: isekine@ncc.go.jp; Sumi, Minako; Ito, Yoshinori

Purpose: To determine the maximum tolerated dose in concurrent three-dimensional conformal radiotherapy (3D-CRT) with chemotherapy for unresectable Stage III non-small-cell lung cancer (NSCLC). Patients and Methods: Eligible patients with unresectable Stage III NSCLC, age {>=}20 years, performance status 0-1, percent of volume of normal lung receiving 20 GY or more (V{sub 20}) {<=}30% received three to four cycles of cisplatin (80 mg/m{sup 2} Day 1) and vinorelbine (20 mg/m{sup 2} Days 1 and 8) repeated every 4 weeks. The doses of 3D-CRT were 66 Gy, 72 Gy, and 78 Gy at dose levels 1 to 3, respectively. Results: Of themore » 17, 16, and 24 patients assessed for eligibility, 13 (76%), 12 (75%), and 6 (25%) were enrolled at dose levels 1 to 3, respectively. The main reasons for exclusion were V{sub 20} >30% (n = 10) and overdose to the esophagus (n = 8) and brachial plexus (n = 2). There were 26 men and 5 women, with a median age of 60 years (range, 41-75). The full planned dose of radiotherapy could be administered to all the patients. Grade 3-4 neutropenia and febrile neutropenia were noted in 24 (77%) and 5 (16%) of the 31 patients, respectively. Grade 4 infection, Grade 3 esophagitis, and Grade 3 pulmonary toxicity were noted in 1 patient, 2 patients, and 1 patient, respectively. The dose-limiting toxicity was noted in 17% of the patients at each dose level. The median survival and 3-year and 4-year survival rates were 41.9 months, 72.3%, and 49.2%, respectively. Conclusions: 72 Gy was the maximum dose that could be achieved in most patients, given the predetermined normal tissue constraints.« less

Population dose commitments due to radioactive releases from nuclear power plant sites in 1987

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1987. Fifty-year dose commitments for a one-year exposure from both liquid and atmospheric releases were calculated for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each of 70 reactor sites. This report tabulates the results of these calculations, showing the dose commitments for both water and airborne pathways for each age group and organ. Also included for reach of the sites is a histogram showing the fraction of the total population within 2 to 80 kmmore » around each site receiving various average dose commitments from the airborne pathways. The site average individual dose commitment from all pathways ranged from a low of 2 {times} 10{sup {minus}6} mrem to a high of 0.009 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites. However, licensee calculation of doses to the maximally exposed individual at some sites indicated values of up to approximately 100 times average individual doses (on the order of a few millirem per year). 2 refs., 2 figs., 7 tabs.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pantelis, Evaggelos, E-mail: vpantelis@phys.uoa.g; Medical Physics Laboratory, Medical School, University of Athens, Athens; Papadakis, Nikolaos

Purpose: To study the efficacy of the integration of functional magnetic resonance imaging (fMRI) and diffusion tensor imaging tractography data into stereotactic radiosurgery clinical practice. Methods and Materials: fMRI and tractography data sets were acquired and fused with corresponding anatomical MR and computed tomography images of patients with arteriovenous malformation (AVM), astrocytoma, brain metastasis, or hemangioma and referred for stereotactic radiosurgery. The acquired data sets were imported into a CyberKnife stereotactic radiosurgery system and used to delineate the target, organs at risk, and nearby functional structures and fiber tracts. Treatment plans with and without the incorporation of the functional structuresmore » and the fiber tracts into the optimization process were developed and compared. Results: The nearby functional structures and fiber tracts could receive doses of >50% of the maximum dose if they were excluded from the planning process. In the AVM case, the doses received by the Broadmann-17 structure and the optic tract were reduced to 700 cGy from 1,400 cGy and to 1,200 cGy from 2,000 cGy, respectively, upon inclusion into the optimization process. In the metastasis case, the motor cortex received 850 cGy instead of 1,400 cGy; and in the hemangioma case, the pyramidal tracts received 780 cGy instead of 990 cGy. In the astrocytoma case, the dose to the motor cortex bordering the lesion was reduced to 1,900 cGy from 2,100 cGy, and therefore, the biologically equivalent dose in three fractions was delivered instead. Conclusions: Functional structures and fiber tracts could receive high doses if they were not considered during treatment planning. With the aid of fMRI and tractography images, they can be delineated and spared.« less

SU-F-T-117: A Pilot Study of Organ Dose Reconstruction for Wilms Tumor Patients Treated with Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makkia, R; Pelletier, C; Jung, J

Purpose: To reconstruct major organ doses for the Wilms tumor pediatric patients treated with radiation therapy using pediatric computational phantoms, treatment planning system (TPS), and Monte Carlo (MC) dose calculation methods. Methods: A total of ten female and male pediatric patients (15–88 months old) were selected from the National Wilms Tumor Study cohort and ten pediatric computational phantoms corresponding to the patient’s height and weight were selected for the organ dose reconstruction. Treatment plans were reconstructed on the computational phantoms in a Pinnacle TPS (v9.10) referring to treatment records and exported into DICOM-RT files, which were then used to generatemore » the input files for XVMC MC code. The mean doses to major organs and the dose received by 50% of the heart were calculated and compared between TPS and MC calculations. The same calculations were conducted by replacing the computational human phantoms with a series of diagnostic patient CT images selected by matching the height and weight of the patients to validate the anatomical accuracy of the computational phantoms. Results: Dose to organs located within the treatment fields from the computational phantoms and the diagnostic patient CT images agreed within 2% for all cases for both TPS and MC calculations. The maximum difference of organ doses was 55.9 % (thyroid), but the absolute dose difference in this case was 0.33 Gy which was 0.96% of the prescription dose. The doses to ovaries and testes from MC in out-of-field provided more discrepancy (the maximum difference of 13.2% and 50.8%, respectively). The maximum difference of the 50% heart volume dose between the phantoms and the patient CT images was 40.0%. Conclusion: This study showed the pediatric computational phantoms are applicable to organ doses reconstruction for the radiotherapy patients whose three-dimensional radiological images are not available.« less

Phase I Trial of Anti-CS1 Monoclonal Antibody Elotuzumab in Combination With Bortezomib in the Treatment of Relapsed/Refractory Multiple Myeloma

PubMed Central

Jakubowiak, Andrzej J.; Benson, Don M.; Bensinger, William; Siegel, David S.D.; Zimmerman, Todd M.; Mohrbacher, Ann; Richardson, Paul G.; Afar, Daniel E.H.; Singhal, Anil K.; Anderson, Kenneth C.

2012-01-01

Purpose To evaluate the maximum-tolerated dose (MTD), safety, and efficacy of elotuzumab in combination with bortezomib in patients with relapsed or relapsed and refractory multiple myeloma (MM). Patients and Methods Elotuzumab (2.5, 5.0, 10, or 20 mg/kg intravenously [IV]) and bortezomib (1.3 mg/m2 IV) were administered on days 1 and 11 and days 1, 4, 8, and 11, respectively, in 21-day cycles by using a 3 + 3 dose-escalation design. Patients with stable disease or better after four cycles could continue treatment until disease progression or unexpected toxicity. Responses were assessed during each cycle by using European Group for Blood and Marrow Transplantation (EBMT) criteria. Results Twenty-eight patients with a median of two prior therapies were enrolled; three patients each received 2.5, 5.0, and 10 mg/kg of elotuzumab and 19 received 20 mg/kg (six during dose escalation and 13 during an expansion phase). No dose-limiting toxicities were observed during cycle 1 of the dose-escalation phase, and the MTD was not reached up to the maximum planned dose of 20 mg/kg. The most frequent grade 3 to 4 adverse events (AEs) were lymphopenia (25%) and fatigue (14%). Two elotuzumab-related serious AEs of chest pain and gastroenteritis occurred in one patient. An objective response (a partial response or better) was observed in 13 (48%) of 27 evaluable patients and in two (67%) of three patients refractory to bortezomib. Median time to progression was 9.46 months. Conclusion The combination of elotuzumab and bortezomib was generally well-tolerated and showed encouraging activity in patients with relapsed/refractory MM. PMID:22291084

Postoperative Intensity-Modulated Radiotherapy in Low-Risk Endometrial Cancers: Final Results of a Phase I Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Macchia, Gabriella, E-mail: gmacchia@rm.unicatt.i; Cilla, Savino M.P.; Ferrandina, Gabriella

2010-04-15

Purpose: To determine the maximum tolerated dose of short-course radiotherapy (intensity-modulated radiotherapy technique) to the upper two thirds of the vagina in endometrial cancers with low risk of local recurrence. Patients and Methods: A Phase I clinical trial was performed. Eligible patients had low-risk resected primary endometrial adenocarcinomas. Radiotherapy was delivered in 5 fractions over 1 week. The planning target volume was the clinical target volume plus 5 mm. The clinical target volume was defined as the upper two thirds of the vagina as evidenced at CT simulation by a vaginal radio-opaque device. The planning target volume was irradiated bymore » a seven-field intensity-modulated radiotherapy technique, planned by the Plato Sunrise inverse planning system. A first cohort of 6 patients received 25 Gy (5-Gy fractions), and a subsequent cohort received 30 Gy (6-Gy fractions). The Common Toxicity Criteria scale, version 3.0, was used to score toxicity. Results: Twelve patients with endometrial cancer were enrolled. Median age was 58 years (range, 49-74 years). Pathologic stage was IB (83.3%) and IC (16.7%). Median tumor size was 30 mm (range, 15-50 mm). All patients completed the prescribed radiotherapy. No patient experienced a dose-limiting toxicity at the first level, and the radiotherapy dose was escalated from 25 to 30 Gy. No patients at the second dose level experienced dose-limiting toxicity. The most common Grade 2 toxicity was gastrointestinal, which was tolerable and manageable. Conclusions: The maximum tolerated dose of short-course radiotherapy was 30 Gy at 6 Gy per fraction. On the basis of this result, we are conducting a Phase II study with radiotherapy delivered at 30 Gy.« less

Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis ▿ §

PubMed Central

Cornely, O. A.; Vehreschild, J. J.; Vehreschild, M. J. G. T.; Würthwein, G.; Arenz, D.; Schwartz, S.; Heussel, C. P.; Silling, G.; Mahne, M.; Franklin, J.; Harnischmacher, U.; Wilkens, A.; Farowski, F.; Karthaus, M.; Lehrnbecher, T.; Ullmann, A. J.; Hallek, M.; Groll, A. H.

2011-01-01

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥4 in 2 of 8 patients or ≥3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin. PMID:21911573

Dose verification to cochlea during gamma knife radiosurgery of acoustic schwannoma using MOSFET dosimeter.

PubMed

Sharma, Sunil D; Kumar, Rajesh; Akhilesh, Philomina; Pendse, Anil M; Deshpande, Sudesh; Misra, Basant K

2012-01-01

Dose verification to cochlea using metal oxide semiconductor field effect transistor (MOSFET) dosimeter using a specially designed multi slice head and neck phantom during the treatment of acoustic schwannoma by Gamma Knife radiosurgery unit. A multi slice polystyrene head phantom was designed and fabricated for measurement of dose to cochlea during the treatment of the acoustic schwannoma. The phantom has provision to position the MOSFET dosimeters at the desired location precisely. MOSFET dosimeters of 0.2 mm x 0.2 mm x 0.5 μm were used to measure the dose to the cochlea. CT scans of the phantom with MOSFETs in situ were taken along with Leksell frame. The treatment plans of five patients treated earlier for acoustic schwannoma were transferred to the phantom. Dose and coordinates of maximum dose point inside the cochlea were derived. The phantom along with the MOSFET dosimeters was irradiated to deliver the planned treatment and dose received by cochlea were measured. The treatment planning system (TPS) estimated and measured dose to the cochlea were in the range of 7.4 - 8.4 Gy and 7.1 - 8 Gy, respectively. The maximum variation between TPS calculated and measured dose to cochlea was 5%. The measured dose values were found in good agreement with the dose values calculated using the TPS. The MOSFET dosimeter can be a suitable choice for routine dose verification in the Gamma Knife radiosurgery.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, D; Sood, S; Badkul, R

Purpose: To evaluate XVMC computed rib doses for peripherally located non-small-cell-lung tumors treated with SBRT following RTOG-0915 guidelines. Methods: Twenty patients with solitary peripherally located non-small-cell-lung tumors were treated using XVMC-based SBRT to 50–54Gy in 5−3 fractions, respectively, for PTV(V100%)=95%. Based on 4D-CT, ITV was delineated on MaximumIP images and organs-at-risk(OARs) including ribs were contoured on MeanIP images. Mean PTV(ITV+5mm uniform margin) was 46.1±38.7cc (range, 11.1–163.0cc). XVMC SBRT treatment plans were generated with a combination of non-coplanar 3D-conformal arcs/beams, and were delivered by Novalis-TX consisting of HD-MLCs and a 6MV-SRS(1000MU/min) beam, following RTOG-0915 criteria. XVMC rib maximum dose and dosemore » to <1cc, <5cc, <10cc were evaluated as a function of PTV, prescription dose and 3D-distance from tumor isocenter to the most proximal rib contour. Plans were re-computed using heterogeneity-corrected pencil-beam (PB-hete) algorithm utilizing identical beam geometry/MLC positions and MUs and subsequently compared to XVMC. Results: XVMC average maximum rib dose was 50.9±6.4Gy (range, 35.1–59.3Gy). XVMC mean rib dose to <1cc was 41.6±5.6Gy (range, 27.9–47.9Gy), <5cc was 31.2±7.3Gy (range, 10.6–43.1Gy), and <10cc was 21.2±8.7Gy (range, 1.1–36Gy), respectively. For the given prescription, correlation between PTV and rib doses to <5cc (p=0.005) and <10cc (p=0.018) was observed. 3D-distance from the tumor isocenter to the proximal rib contour strongly correlated with maximum rib dose (p=0.0001). PB-hete algorithm overestimated maximum rib dose and dose to <1cc, <5cc, and <10cc of ribs by 5%, 3%, 3%, and 3%, respectively. Conclusion: PB-hete overestimates ribs dose relative to XVMC. Since all the clinical XVMC plans were generated without compromising the target coverage (per RTOG-0915), almost all patient’s ribs doses were higher than the protocol guidelines. As expected, larger tumor size and proximity to ribs received higher absolute dose to ribs. Prospective observation is needed to determine if XVMC delivered rib doses correlates with patient symptoms including chest wall pain and/or rib fractures.« less

An assessment of the doses received by members of the public in Japan following the nuclear accident at Fukushima Daiichi nuclear power plant.

PubMed

Bedwell, P; Mortimer, K; Wellings, J; Sherwood, J; Leadbetter, S J; Haywood, S M; Charnock, T; Jones, A R; Hort, M C

2015-12-01

The earthquake and tsunami on 11 March 2011, centred off the east coast of Japan, caused considerable destruction and substantial loss of life along large swathes of the Japanese coastline. The tsunami damaged the Fukushima Daiichi nuclear power plant (NPP), resulting in prolonged releases of radioactive material into the environment. This paper assesses the doses received by members of the public in Japan. The assessment is based on an estimated source term and atmospheric dispersion modelling rather than monitoring data. It is evident from this assessment that across the majority of Japan the estimates of dose are very low, for example they are estimated to be less than the annual average dose from natural background radiation in Japan. Even in the regions local to Fukushima Daiichi NPP (and not affected by any form of evacuation) the maximum lifetime effective dose is estimated to be well below the cumulative natural background dose over the same period. The impact of the urgent countermeasures on the estimates of dose was considered. And the relative contribution to dose from the range of exposure pathways and radionuclides were evaluated. Analysis of estimated doses focused on the geographic irregularity and the impact of the meteorological conditions. For example the dose to an infant's thyroid received over the first year was estimated to be greater in Hirono than in the non-evacuated region of Naraha, despite Hirono being further from the release location. A number of factors were identified and thought to contribute towards this outcome, including the local wind pattern which resulted in the recirculation of part of the release. The non-uniform nature of dose estimates strengthens the case for evaluations based on dispersion modelling.

Speechlessness in Gilles de la Tourette Syndrome: Cannabis-Based Medicines Improve Severe Vocal Blocking Tics in Two Patients

PubMed Central

Jakubovski, Ewgeni; Müller-Vahl, Kirsten

2017-01-01

We report the cases of two young German male patients with treatment-resistant Tourette syndrome (TS), who suffer from incapacitating stuttering-like speech disfluencies caused by vocal blocking tics and palilalia. Case 1: a 19-year old patient received medical cannabis at a dose of 1 × 0.1 g cannabis daily. Case 2: a 16-year old patient initially received dronabinol at a maximum dose of 22.4–33.6 mg daily. Both treatments provided significant symptom improvement of vocal blocking tics as well as of comorbid conditions and were well tolerated. Thus, cannabis-based medicine appears to be effective in treatment-resistant TS patients with vocal blocking tics. PMID:28796166

Speechlessness in Gilles de la Tourette Syndrome: Cannabis-Based Medicines Improve Severe Vocal Blocking Tics in Two Patients.

PubMed

Jakubovski, Ewgeni; Müller-Vahl, Kirsten

2017-08-10

We report the cases of two young German male patients with treatment-resistant Tourette syndrome (TS), who suffer from incapacitating stuttering-like speech disfluencies caused by vocal blocking tics and palilalia. Case 1: a 19-year old patient received medical cannabis at a dose of 1 × 0.1 g cannabis daily. Case 2: a 16-year old patient initially received dronabinol at a maximum dose of 22.4-33.6 mg daily. Both treatments provided significant symptom improvement of vocal blocking tics as well as of comorbid conditions and were well tolerated. Thus, cannabis-based medicine appears to be effective in treatment-resistant TS patients with vocal blocking tics.

SU-E-T-503: Intensity Modulated Proton Therapy (IMPT) Versus Intensity Modulated X-Ray Therapy (IMRT) for Patient with Hepatocellular Carcinoma: A Dosimetric Comparison

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, H; Zhao, L; Prabhu, K

2015-06-15

Purpose This study compares the dosimetric parameters in treatment of unresectable hepatocellular carcinoma between intensity modulated proton therapy (IMPT) and intensity modulated x-ray radiation therapy (IMRT). Methods and Materials: We studied four patients treated at our institution. All patients were simulated supine with 4D-CT using a GE light speed simulator with a maximum slice thickness of 3mm. The average CT and an internal target volume to account for respiration motion were used for planning. Both IMRT and IMPT plans were created using Elekta’s CMSXiO treatment planning system (TPS). The prescription dose was 58.05 CGE in 15 fractions. The IMRT plansmore » had five beams with combination of co-planar and non-co-planar. The IMPT plans had 2 to 3 beams. Dose comparison was performed based on the averaged results of the four patients. Results The mean dose and V95% to PTV were 58.24CGE, 98.57% for IMPT, versus 57.34CGE and 96.68% for IMRT, respectively. The V10, V20, V30 and mean dose of the normal liver for IMPT were 23.10%, 18.61%, 13.75% and 9.78 CGE; and 47.19%, 37.55%, 22.73% and 17.12CGE for IMRT. The spinal cord didn’t receive any dose in IMPT technique, but received a maximum of 18.77CGE for IMRT. The IMPT gave lower maximum dose to the stomach as compared to IMRT (19.26 vs 26.35CGE). V14 for left and right kidney was 0% and 2.32% for IMPT and 3.89% and 29.54% for IMRT. The mean dose, V35, V40 and V45 for small bowl were similar in both techniques, 0.74CGE, 6.27cc, 4.85cc and 3.53 cc for IMPT, 3.47CGE, 9.73cc, 7.61cc 5.35cc for IMRT. Conclusion Based on this study, IMPT plans gave less dose to the critical structures such as normal liver, kidney, stomach and spinal cord as compared to IMRT plans, potentially leading to less toxicity and providing better quality of life for patients.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lafata, K; Ren, L; Wu, Q

Purpose: To develop a data-mining methodology based on quantum clustering and machine learning to predict expected dosimetric endpoints for lung SBRT applications based on patient-specific anatomic features. Methods: Ninety-three patients who received lung SBRT at our clinic from 2011–2013 were retrospectively identified. Planning information was acquired for each patient, from which various features were extracted using in-house semi-automatic software. Anatomic features included tumor-to-OAR distances, tumor location, total-lung-volume, GTV and ITV. Dosimetric endpoints were adopted from RTOG-0195 recommendations, and consisted of various OAR-specific partial-volume doses and maximum point-doses. First, PCA analysis and unsupervised quantum-clustering was used to explore the feature-space tomore » identify potentially strong classifiers. Secondly, a multi-class logistic regression algorithm was developed and trained to predict dose-volume endpoints based on patient-specific anatomic features. Classes were defined by discretizing the dose-volume data, and the feature-space was zero-mean normalized. Fitting parameters were determined by minimizing a regularized cost function, and optimization was performed via gradient descent. As a pilot study, the model was tested on two esophageal dosimetric planning endpoints (maximum point-dose, dose-to-5cc), and its generalizability was evaluated with leave-one-out cross-validation. Results: Quantum-Clustering demonstrated a strong separation of feature-space at 15Gy across the first-and-second Principle Components of the data when the dosimetric endpoints were retrospectively identified. Maximum point dose prediction to the esophagus demonstrated a cross-validation accuracy of 87%, and the maximum dose to 5cc demonstrated a respective value of 79%. The largest optimized weighting factor was placed on GTV-to-esophagus distance (a factor of 10 greater than the second largest weighting factor), indicating an intuitively strong correlation between this feature and both endpoints. Conclusion: This pilot study shows that it is feasible to predict dose-volume endpoints based on patient-specific anatomic features. The developed methodology can potentially help to identify patients at risk for higher OAR doses, thus improving the efficiency of treatment planning. R01-184173.« less

Radiation exposure of German aircraft crews under the impact of solar cycle 23 and airline business factors.

PubMed

Frasch, Gerhard; Kammerer, Lothar; Karofsky, Ralf; Schlosser, Andrea; Stegemann, Ralf

2014-12-01

The exposure of German aircraft crews to cosmic radiation varies both with solar activity and operational factors of airline business. Data come from the German central dose registry and cover monthly exposures of up to 37,000 German aircraft crewmembers that were under official monitoring. During the years 2004 to 2009 of solar cycle 23 (i.e., in the decreasing phase of solar activity), the annual doses of German aircraft crews increased by an average of 20%. Decreasing solar activity allows more galactic radiation to reach the atmosphere, increasing high-altitude doses. The rise results mainly from the less effective protection from the solar wind but also from airline business factors. Both cockpit and cabin personnel differ in age-dependent professional and social status. This status determines substantially the annual effective dose: younger cabin personnel and the elder pilots generally receive higher annual doses than their counterparts. They also receive larger increases in their annual dose when the solar activity decreases. The doses under this combined influence of solar activity and airline business factors result in a maximum of exposure for German aircrews for this solar cycle. With the increasing solar activity of the current solar cycle 24, the doses are expected to decrease again.

Investigation into scatter radiation dose levels received by a restrainer in small animal radiography.

PubMed

Barber, J; McNulty, J P

2012-10-01

To measure the intensity and distribution of scatter radiation received by a restrainer in veterinary radiography including the intensity of scatter radiation passing through lead protective devices at pre-defined positions. Anthropomorphic phantoms and a Labrador dog cadaver were used to simulate a restrainer and patient. Scatter dose measurements were recorded at the position of the restraining hands, thyroid, breast and gonads with and without appropriate lead protection. This was repeated for the eight most common projections as identified in an initial retrospective survey. Manual restraint of an animal for a radiographic procedure will result in a scatter radiation dose to the restrainer. The level of radiation dose varies between body regions and between projections. The use of appropriate lead protection resulted in statistically significant dose reductions to all body regions with maximum scatter dose reductions between 93 and 100%. While the doses recorded were small (μGy) in terms of associated risk, they are nonetheless cumulative which can result in a more significant dose. Therefore manual restraint should be avoided and forms of immobilisation should be used such as mechanical means, sedation or general anaesthesia. However, if completely necessary both principles of distance and adequate lead protection should be employed. © 2012 British Small Animal Veterinary Association.

Bioavailability in healthy adults of efavirenz capsule contents mixed with a small amount of food.

PubMed

Kaul, Sanjeev; Ji, Ping; Lu, Michael; Nguyen, Kim L; Shangguan, Tong; Grasela, Dennis

2010-02-01

The effect of mixing the contents of efavirenz capsules (sprinkles) with a small amount of food on the bioavailability and pharmacokinetics of efavirenz in healthy adults was evaluated. In a randomized, three-period, crossover study, 24 healthy adult subjects were divided equally into two groups. Group I received treatments A, B, and C, and those in group II received treatments A, D, and E. Treatment A was three efavirenz 200-mg intact capsules under fasting conditions. Treatments B, C, D, and E were three efavirenz 200-mg capsule contents mixed with two teaspoons of applesauce, grape jelly, yogurt, or infant formula, respectively. A single dose was given on days 1, 21, and 41. The steady-state mean maximum observed concentration, time of maximum observed concentration, area under the concentration-time curve (AUC) half-life, taste, and safety were assessed. The AUC after administration of a single 600-mg dose of efavirenz sprinkles mixed with two teaspoons of any of the food vehicles to healthy adults was bioequivalent to a 600-mg efavirenz dose given as intact capsules under fasting conditions. Subjects rated efavirenz mixed with grape jelly as the most palatable. Adverse events and laboratory abnormalities were similar for all treatments. The AUC of efavirenz 600 mg administered as capsule sprinkles with two teaspoons of applesauce, grape jelly, yogurt, or infant formula was bioequivalent to a single dose of efavirenz 600 mg given as intact capsules under fasting conditions in healthy adults.

A phase III, open-label, single-arm study of tenecteplase for restoration of function in dysfunctional central venous catheters.

PubMed

Tebbi, Cameron; Costanzi, John; Shulman, Robert; Dreisbach, Luke; Jacobs, Brian R; Blaney, Martha; Ashby, Mark; Gillespie, Barbara S; Begelman, Susan M

2011-08-01

To evaluate, in a phase III, single-arm study, the safety and efficacy of the thrombolytic agent tenecteplase in restoring function to dysfunctional central venous catheters (CVCs). Pediatric and adult patients with dysfunctional CVCs were eligible to receive as much as 2 mL (2 mg) of intraluminal tenecteplase, which was left to dwell in the CVC lumen for a maximum of 120 minutes. If CVC function was not restored at 120 minutes, a second dose was instilled for an additional 120 minutes. Tenecteplase was administered to 246 patients. Mean patient age was 44 years (range, 0-92 y); 72 patients (29%) were younger than 17 years of age. Chemotherapy was the most common reason for catheter insertion. Restoration of CVC function was achieved in 177 patients (72%) within 120 minutes after the first dose. After instillation of a maximum of two doses of tenecteplase, CVC function was restored in 200 patients (81%), with similar frequencies in pediatric (83%) and adult (80%) patients. Adverse events (AEs) were reported in 31 patients (13%); fever (2%), neutropenia (1%), and nausea (0.8%) were most common. One serious AE, an allergic hypersensitivity reaction, was judged to be related to tenecteplase and/or a chemotherapeutic agent that the patient was receiving concurrently. Consecutive administration of one or two doses of tenecteplase into CVCs showed efficacy in the restoration of catheter function in patients with dysfunctional CVCs. Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Chin-Cheng; Lee, Chen-Chiao, E-mail: joelee168@hotmail.co; Mah, Dennis

Because of the dose limit for critical structures such as brainstem and spinal cord, administering a dose of 60 Gy to patients with recurrent head and neck cancer is challenging for those who received a previous dose of 60-70 Gy. Specifically, previously irradiated head and neck patients may have received doses close to the tolerance limit to their brainstem and spinal cord. In this study, a reproducible intensity-modulated radiation therapy (IMRT) treatment design is presented to spare the doses to brainstem and spinal cord, with no compromise of prescribed dose delivery. Between July and November 2008, 7 patients with previouslymore » irradiated, recurrent head and neck cancers were treated with IMRT. The jaws of each field were set fixed with the goal of shielding the brainstem and spinal cord at the sacrifice of partial coverage of the planning target volume (PTV) from any particular beam orientation. Beam geometry was arranged to have sufficient coverage of the PTV and ensure that the constraints of spinal cord <10 Gy and brainstem <15 Gy were met. The mean maximum dose to the brainstem was 12.1 Gy (range 6.1-17.3 Gy), and the corresponding mean maximum dose to spinal cord was 10.4 Gy (range 8.2-14.1 Gy). For most cases, 97% of the PTV volume was fully covered by the 95% isodose volume. We found empirically that if the angle of cervical spine curvature (Cobb's angle) was less than {approx}30{sup o}, patients could be treated by 18 fields. Six patients met these criteria and were treated in 25 minutes per fraction. One patient exceeded a 30{sup o} Cobb's angle and was treated by 31 fields in 45 minutes per fraction. We have demonstrated a new technique for retreatment of head and neck cancers. The angle of cervical spine curvature plays an important role in the efficiency and effectiveness of our approach.« less

Hypothyroidism as a Consequence of Intensity-Modulated Radiotherapy With Concurrent Taxane-Based Chemotherapy for Locally Advanced Head-and-Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diaz, Roberto; Jaboin, Jerry J.; Morales-Paliza, Manuel

Purpose: To conduct a retrospective review of 168 consecutively treated locally advanced head-and-neck cancer (LAHNC) patients treated with intensity-modulated radiotherapy (IMRT)/chemotherapy, to determine the rate and risk factors for developing hypothyroidism. Methods and Materials: Intensity-modulated radiotherapy was delivered in 33 daily fractions to 69.3 Gy to gross disease and 56.1 Gy to clinically normal cervical nodes. Dose-volume histograms (DVHs) of IMRT plans were used to determine radiation dose to thyroid and were compared with DVHs using conventional three-dimensional radiotherapy (3D-RT) in 10 of these same patients randomly selected for replanning and with DVHs of 16 patients in whom the thyroidmore » was intentionally avoided during IMRT. Weekly paclitaxel (30 mg/m{sup 2}) and carboplatin area under the curve-1 were given concurrently with IMRT. Results: Sixty-one of 128 evaluable patients (47.7%) developed hypothyroidism after a median of 1.08 years after IMRT (range, 2.4 months to 3.9 years). Age and volume of irradiated thyroid were associated with hypothyroidism development after IMRT. Compared with 3D-RT, IMRT with no thyroid dose constraints resulted in significantly higher minimum, maximum, and median dose (p < 0.0001) and percentage thyroid volume receiving 10, 20, and 60 Gy (p < 0.05). Compared with 3D-RT, IMRT with thyroid dose constraints resulted in lower median dose and percentage thyroid volume receiving 30, 40, and 50 Gy (p < 0.005) but higher minimum and maximum dose (p < 0.005). Conclusions: If not protected, IMRT for LAHNC can result in higher radiation to the thyroid than with conventional 3D-RT. Techniques to reduce dose and volume of radiation to thyroid tissue with IMRT are achievable and recommended.« less

Patient-controlled oral analgesia for postoperative pain management following total knee replacement

PubMed Central

Kastanias, Patti; Gowans, Sue; Tumber, Paul S; Snaith, Kianda; Robinson, Sandra

2010-01-01

PURPOSE: To investigate whether patient-controlled oral analgesia (PCOA) used by individuals receiving a total knee replacement could reduce pain, increase patient satisfaction, reduce opioid use and/or reduce opioid side effects when compared with traditional nurse (RN)-administered oral analgesia. METHODS: Patients who underwent an elective total knee replacement at a quaternary care centre (Toronto Western Hospital, Toronto, Ontario) were randomly assigned to either PCOA or RN-administered short-acting oral opioids on postoperative day 2. Subjects in the RN group called the RN to receive their prescribed short-acting opioid. Subjects in the PCOA group kept a single dose of their prescribed oral opioid at their bedside and took this dose when they felt they needed it, to a maximum of one dose every 2 h. Study outcomes, collected on postoperative day 2, included pain (measured by the Brief Pain Inventory – Short Form), patient satisfaction (measured by the Pain Outcome Questionnaire Satisfaction sub-scale – component II), opioid use (oral morphine equivalents), opioid side effects (nausea, pruritis and/or constipation) and knee measures (maximum passive knee flexion and pain at maximum passive knee flexion, performed on the operative knee). RESULTS: Study outcomes were analyzed twice. First, for a subset of 73 subjects who remained in their randomly assigned group (PCOA group, n=36; RN group, n=37), randomized analyses were performed. Second, for the larger sample of 88 subjects who were categorized by their actual method of receiving oral opioids (PCOA group, n=41; RN group, n=47), as-treated analyses were performed. There were no differences in study outcomes between the PCOA and RN groups in either analysis. CONCLUSION: PCOA was not superior to RN administration on study outcomes. However, PCOA did not increase opioid use or pain. PCOA remains an important element in the patient-centred care facility. PMID:20195553

A comprehensive dose reconstruction methodology for former rocketdyne/atomics international radiation workers.

PubMed

Boice, John D; Leggett, Richard W; Ellis, Elizabeth Dupree; Wallace, Phillip W; Mumma, Michael; Cohen, Sarah S; Brill, A Bertrand; Chadda, Bandana; Boecker, Bruce B; Yoder, R Craig; Eckerman, Keith F

2006-05-01

Incomplete radiation exposure histories, inadequate treatment of internally deposited radionuclides, and failure to account for neutron exposures can be important uncertainties in epidemiologic studies of radiation workers. Organ-specific doses from lifetime occupational exposures and radionuclide intakes were estimated for an epidemiologic study of 5,801 Rocketdyne/Atomics International (AI) radiation workers engaged in nuclear technologies between 1948 and 1999. The entire workforce of 46,970 Rocketdyne/AI employees was identified from 35,042 Kardex work histories cards, 26,136 electronic personnel listings, and 14,189 radiation folders containing individual exposure histories. To obtain prior and subsequent occupational exposure information, the roster of all workers was matched against nationwide dosimetry files from the Department of Energy, the Nuclear Regulatory Commission, the Landauer dosimetry company, the U.S. Army, and the U.S. Air Force. Dosimetry files of other worker studies were also accessed. Computation of organ doses from radionuclide intakes was complicated by the diversity of bioassay data collected over a 40-y period (urine and fecal samples, lung counts, whole-body counts, nasal smears, and wound and incident reports) and the variety of radionuclides with documented intake including isotopes of uranium, plutonium, americium, calcium, cesium, cerium, zirconium, thorium, polonium, promethium, iodine, zinc, strontium, and hydrogen (tritium). Over 30,000 individual bioassay measurements, recorded on 11 different bioassay forms, were abstracted. The bioassay data were evaluated using ICRP biokinetic models recommended in current or upcoming ICRP documents (modified for one inhaled material to reflect site-specific information) to estimate annual doses for 16 organs or tissues taking into account time of exposure, type of radionuclide, and excretion patterns. Detailed internal exposure scenarios were developed and annual internal doses were derived on a case-by-case basis for workers with committed equivalent doses indicated by screening criteria to be greater than 10 mSv to the organ with the highest internal dose. Overall, 5,801 workers were monitored for radiation at Rocketdyne/AI: 5,743 for external exposure and 2,232 for internal intakes of radionuclides; 41,169 workers were not monitored for radiation. The mean cumulative external dose based on Rocketdyne/AI records alone was 10.0 mSv, and the dose distribution was highly skewed with most workers experiencing low cumulative doses and only a few with high doses (maximum 500 mSv). Only 45 workers received greater than 200 mSv while employed at Rocketdyne/AI. However, nearly 32% (or 1,833) of the Rocketdyne/AI workers had been monitored for radiation at other nuclear facilities and incorporation of these doses increased the mean dose to 13.5 mSv (maximum 1,005 mSv) and the number of workers with >200 mSv to 69. For a small number of workers (n=292), lung doses from internal radionuclide intakes were relatively high (mean 106 mSv; maximum 3,560 mSv) and increased the overall population mean dose to 19.0 mSv and the number of workers with lung dose>200 mSv to 109. Nearly 10% of the radiation workers (584) were monitored for neutron exposures (mean 1.2 mSv) at Rocketdyne/AI, and another 2% were monitored for neutron exposures elsewhere. Interestingly, 1,477 workers not monitored for radiation at Rocketdyne/AI (3.6%) were found to have worn dosimeters at other nuclear facilities (mean external dose of 2.6 mSv, maximum 188 mSv). Without considering all sources of occupational exposure, an incorrect characterization of worker exposure would have occurred with the potential to bias epidemiologic results. For these pioneering workers in the nuclear industry, 26.5% of their total occupational dose (collective dose) was received at other facilities both prior to and after employment at Rocketdyne/AI. In addition, a small number of workers monitored for internal radionuclides contributed disproportionately to the number of workers with high lung doses. Although nearly 12% of radiation workers had been monitored for neutron exposures during their career, the cumulative dose levels were small in comparison with other external and internal exposure. Risk estimates based on nuclear worker data must be interpreted cautiously if internally deposited radionuclides and occupational doses received elsewhere are not considered.

Electrocardiographic effects of hawthorn (Crataegus oxyacantha) in healthy volunteers: A randomized controlled trial.

PubMed

Trexler, Stephanie E; Nguyen, Elaine; Gromek, Samantha M; Balunas, Marcy J; Baker, William L

2018-04-19

The objective of this study was to evaluate the electrocardiographic effects of hawthorn in healthy adult volunteers. It was double-blind cross-over trial randomized 20 healthy adult volunteers to receive either a single oral 160-mg dose of hawthorn or matching placebo. Triplicate 12-lead electrocardiograms were taken before treatment and at 1-, 2-, 4-, and 6-hr post-dose. Following at least a 7-day washout period, participants were crossed over to the opposing treatment arm and had the measurements repeated. The primary endpoint was the change in corrected (Fridericia) QT intervals (QT c I) at 4 and 6 hr. Maximum post-dose QT c I and changes in PR and QRS intervals were measured. No significant differences in 4- or 6-hr QT c I were seen between hawthorn and placebo. Maximum post-dose QT c I in the hawthorn and placebo groups were similar (346 ± 35 vs 346 ± 40 ms; p = .979). No significant adverse events were seen. In conclusion, a single dose of oral hawthorn had no effect on electrocardiographic parameters in healthy volunteers. Copyright © 2018 John Wiley & Sons, Ltd.

Using SAFRAN Software to Assess Radiological Hazards from Dismantling of Tammuz-2 Reactor Core at Al-tuwaitha Nuclear Site

NASA Astrophysics Data System (ADS)

Abed Gatea, Mezher; Ahmed, Anwar A.; jundee kadhum, Saad; Ali, Hasan Mohammed; Hussein Muheisn, Abbas

2018-05-01

The Safety Assessment Framework (SAFRAN) software has implemented here for radiological safety analysis; to verify that the dose acceptance criteria and safety goals are met with a high degree of confidence for dismantling of Tammuz-2 reactor core at Al-tuwaitha nuclear site. The activities characterizing, dismantling and packaging were practiced to manage the generated radioactive waste. Dose to the worker was considered an endpoint-scenario while dose to the public has neglected due to that Tammuz-2 facility is located in a restricted zone and 30m berm surrounded Al-tuwaitha site. Safety assessment for dismantling worker endpoint-scenario based on maximum external dose at component position level in the reactor pool and internal dose via airborne activity while, for characterizing and packaging worker endpoints scenarios have been done via external dose only because no evidence for airborne radioactivity hazards outside the reactor pool. The in-situ measurements approved that reactor core components are radiologically activated by Co-60 radioisotope. SAFRAN results showed that the maximum received dose for workers are (1.85, 0.64 and 1.3mSv/y) for activities dismantling, characterizing and packaging of reactor core components respectively. Hence, the radiological hazards remain below the low level hazard and within the acceptable annual dose for workers in radiation field

Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase 1 NCI Organ Dysfunction Working Group Study NCI-6432

PubMed Central

LoRusso, Patricia M; Venkatakrishnan, Karthik; Ramanathan, Ramesh K; Sarantopoulos, John; Mulkerin, Daniel; Shibata, Stephen I; Hamilton, Anne; Dowlati, Afshin; Mani, Sridhar; Rudek, Michelle A; Takimoto, Chris H; Neuwirth, Rachel; Esseltine, Dixie-Lee; Ivy, Percy

2013-01-01

Purpose The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Methods Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m2, respectively, up to a 1.3 mg/m2 maximum. Serial blood samples were collected for 24 hours post-dose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC0-tlast) or Cmax compared with patients with normal function. Mean dose-normalized AUC0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2. PMID:22394984

Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials.

PubMed

Bastiaens, Guido J H; Tiono, Alfred B; Okebe, Joseph; Pett, Helmi E; Coulibaly, Sam A; Gonçalves, Bronner P; Affara, Muna; Ouédraogo, Alphonse; Bougouma, Edith C; Sanou, Guillaume S; Nébié, Issa; Bradley, John; Lanke, Kjerstin H W; Niemi, Mikko; Sirima, Sodiomon B; d'Alessandro, Umberto; Bousema, Teun; Drakeley, Chris

2018-01-01

Primaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria. In Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0.25 (n = 20) or 0.40 mg/kg (n = 20) dosage; G6PD-normal males received AL plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. In The Gambia, G6PDd adult males and boys received DP alone (n = 10) or with 0.25 mg/kg PQ (n = 20); G6PD-normal males received DP plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. The primary study endpoint was change in hemoglobin concentration during the 28-day follow-up. Cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer status, gametocyte carriage, haptoglobin, lactate dehydrogenase levels and reticulocyte counts were also determined. In Burkina Faso, the mean maximum absolute change in hemoglobin was -2.13 g/dL (95% confidence interval [CI], -2.78, -1.49) in G6PDd individuals randomized to 0.25 PQ mg/kg and -2.29 g/dL (95% CI, -2.79, -1.79) in those receiving 0.40 PQ mg/kg. In The Gambia, the mean maximum absolute change in hemoglobin concentration was -1.83 g/dL (95% CI, -2.19, -1.47) in G6PDd individuals receiving 0.25 PQ mg/kg. After adjustment for baseline concentrations, hemoglobin reductions in G6PDd individuals in Burkina Faso were more pronounced compared to those in G6PD-normal individuals receiving the same PQ doses (P = 0.062 and P = 0.022, respectively). Hemoglobin levels normalized during follow-up. Abnormal haptoglobin and lactate dehydrogenase levels provided additional evidence of mild transient hemolysis post-PQ. Single low-dose PQ in combination with AL and DP was associated with mild and transient reductions in hemoglobin. None of the study participants developed moderate or severe anemia; there were no severe adverse events. This indicates that single low-dose PQ is safe in G6PDd African males when used with artemisinin-based combination therapy. Clinicaltrials.gov NCT02174900 Clinicaltrials.gov NCT02654730.

Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials

PubMed Central

Pett, Helmi E.; Coulibaly, Sam A.; Gonçalves, Bronner P.; Affara, Muna; Ouédraogo, Alphonse; Bougouma, Edith C.; Sanou, Guillaume S.; Nébié, Issa; Bradley, John; Lanke, Kjerstin H. W.; Niemi, Mikko; Sirima, Sodiomon B.; d’Alessandro, Umberto; Bousema, Teun; Drakeley, Chris

2018-01-01

Background Primaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria. Methods and findings In Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0.25 (n = 20) or 0.40 mg/kg (n = 20) dosage; G6PD-normal males received AL plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. In The Gambia, G6PDd adult males and boys received DP alone (n = 10) or with 0.25 mg/kg PQ (n = 20); G6PD-normal males received DP plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. The primary study endpoint was change in hemoglobin concentration during the 28-day follow-up. Cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer status, gametocyte carriage, haptoglobin, lactate dehydrogenase levels and reticulocyte counts were also determined. In Burkina Faso, the mean maximum absolute change in hemoglobin was -2.13 g/dL (95% confidence interval [CI], -2.78, -1.49) in G6PDd individuals randomized to 0.25 PQ mg/kg and -2.29 g/dL (95% CI, -2.79, -1.79) in those receiving 0.40 PQ mg/kg. In The Gambia, the mean maximum absolute change in hemoglobin concentration was -1.83 g/dL (95% CI, -2.19, -1.47) in G6PDd individuals receiving 0.25 PQ mg/kg. After adjustment for baseline concentrations, hemoglobin reductions in G6PDd individuals in Burkina Faso were more pronounced compared to those in G6PD-normal individuals receiving the same PQ doses (P = 0.062 and P = 0.022, respectively). Hemoglobin levels normalized during follow-up. Abnormal haptoglobin and lactate dehydrogenase levels provided additional evidence of mild transient hemolysis post-PQ. Conclusions Single low-dose PQ in combination with AL and DP was associated with mild and transient reductions in hemoglobin. None of the study participants developed moderate or severe anemia; there were no severe adverse events. This indicates that single low-dose PQ is safe in G6PDd African males when used with artemisinin-based combination therapy. Trial registration Clinicaltrials.gov NCT02174900 Clinicaltrials.gov NCT02654730 PMID:29324864

Non-corticosteroid risk factors of symptomatic avascular necrosis of bone in systemic lupus erythematosus: A retrospective case-control study.

PubMed

Faezi, Seyedeh Tahereh; Hoseinian, Azam Sadat; Paragomi, Pedram; Akbarian, Mahmood; Esfahanian, Fatemeh; Gharibdoost, Farhad; Akhlaghi, Maassoumeh; Nadji, Abdolhadi; Jamshidi, Ahmad Reza; Shahram, Farhad; Nejadhosseinian, Mohammad; Davatchi, Fereydoun

2015-07-01

Avascular necrosis of bone (AVN) is an important complication of systemic lupus erythematosus (SLE). Corticosteroid therapy has been underlined as a main risk factor for osteonecrosis. However, AVN development in patients who have never received corticosteroid and the absence of AVN in the majority of the patients, who received corticosteroid, propose a role for non-corticosteroid risk factors in AVN development. This case-control study included two subsets: oral corticosteroid (66 AVN and 248 non-AVN patients) and pulse-therapy subset (39 AVN and 312 non-AVN patients) who have attended our Lupus clinic from 1979 to 2009. Patients received similar cumulative dose corticosteroid, equal maximum dose and 1-year maximum dose of corticosteroid. The demographic data (including sex, age of disease onset, age at the diagnosis of AVN), organs involvement, SLE Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics/American College of Rheumatology-Damage index (SLICC/ACR-DI), number of disease flare ups were compared between two subsets. The mean age of SLE onset was younger (P value = 0.04) in the AVN patients. In oral corticosteroid subset, malar rash (P value < 0.001) and oral ulcer (P value = 0.003) were seen more frequently in non-AVN patients, whereas psychosis (P value = 0.03) was significantly more prevalent AVN subset in oral corticosteroid subset. In corticosteroid pulse subset, no significant difference in clinical features was noted. In oral corticosteroid subset, younger age of disease onset and psychosis were significantly associated with AVN, whereas malar rash and oral ulcer showed negative association AVN.

Whole-remnant and maximum-voxel SPECT/CT dosimetry in {sup 131}I-NaI treatments of differentiated thyroid cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mínguez, Pablo, E-mail: pablo.minguezgabina@osakid

Purpose: To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC). Methods: Eighteen DTC patients were administered 1.11 GBq of {sup 131}I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3–7 days after administration. The activity, the remnant mass, and the maximum-voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimatedmore » using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry. Results: The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2–176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2–145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 ± 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in the S-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients. Conclusions: Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.« less

Phase I study of topical epigallocatechin-3-gallate (EGCG) in patients with breast cancer receiving adjuvant radiotherapy.

PubMed

Zhao, Hanxi; Zhu, Wanqi; Jia, Li; Sun, Xiaorong; Chen, Guanxuan; Zhao, Xianguang; Li, Xiaolin; Meng, Xiangjiao; Kong, Lingling; Xing, Ligang; Yu, Jinming

2016-01-01

The purpose of this study was to investigate the safety, tolerability and preliminary effectiveness of topical epigallocatechin-3-gallate (EGCG) for radiation dermatitis in patients with breast cancer receiving adjuvant radiotherapy. Patients with breast cancer who received radiotherapy to the chest wall after mastectomy were enrolled. EGCG solution was sprayed to the radiation field from the initiation of Grade 1 radiation dermatitis until 2 weeks after completion of radiotherapy. EGCG concentration escalated from 40 to 660 μmol l(-1) in 7 levels with 3-6 patients in each level. EGCG toxicity was graded using the NCI (National Cancer Institute Common Terminology Criteria for Adverse Events) v. 3.0. Any adverse event >Grade 1 attributed to EGCG was considered dose-limiting toxicity. The maximum tolerated dose was defined as the dose level that induced dose-limiting toxicity in more than one-third of patients at a given cohort. Radiation dermatitis was recorded weekly by the Radiation Therapy Oncology Group scoring and patient-reported symptoms. From March 2012 to August 2013, 24 patients were enrolled. Acute skin redness was observed in 1 patient and considered to be associated with the EGCG treatment at 140 μmol l(-1) level. Three more patients were enrolled at this level and did not experience toxicity to EGCG. The dose escalation stopped at 660 μmol l(-1). No other reported acute toxicity was associated with EGCG. Grade 2 radiation dermatitis was observed in eight patients during or after radiotherapy, but all decreased to Grade 1 after EGCG treatments. Patient-reported symptom scores were significantly decreased at 2 weeks after the end of radiotherapy in pain, burning, itching and tenderness, p < 0.05. The topical administration of EGCG was well tolerated and the maximum tolerated dose was not found. EGCG may be effective in treating radiation dermatitis with preliminary investigation. EGCG solution seemed to be feasible for treating radiation dermatitis in patients with breast cancer after mastectomy. It should be tested as a way to reduce radiation-induced normal tissue toxicity and complications in future years.

Dose to the Developing Dentition During Therapeutic Irradiation: Organ at Risk Determination and Clinical Implications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thompson, Reid F., E-mail: Reid.Thompson@uphs.upenn.edu; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania; Schneider, Ralf A., E-mail: ralf.schneider@psi.ch

Purpose: Irradiation of pediatric facial structures can cause severe impairment of permanent teeth later in life. We therefore focused on primary and permanent teeth as organs at risk, investigating the ability to identify individual teeth in children and infants and to correlate dose distributions with subsequent dental toxicity. Methods and Materials: We retrospectively reviewed 14 pediatric patients who received a maximum dose >20 Gy(relative biological effectiveness, RBE) to 1 or more primary or permanent teeth between 2003 and 2009. The patients (aged 1-16 years) received spot-scanning proton therapy with 46 to 66 Gy(RBE) in 23 to 33 daily fractions formore » a variety of tumors, including rhabdomyosarcoma (n=10), sarcoma (n=2), teratoma (n=1), and carcinoma (n=1). Individual teeth were contoured on axial slices from planning computed tomography (CT) scans. Dose-volume histogram data were retrospectively obtained from total calculated delivered treatments. Dental follow-up information was obtained from external care providers. Results: All primary teeth and permanent incisors, canines, premolars, and first and second molars were identifiable on CT scans in all patients as early as 1 year of age. Dose-volume histogram analysis showed wide dose variability, with a median 37 Gy(RBE) per tooth dose range across all individuals, and a median 50 Gy(RBE) intraindividual dose range across all teeth. Dental follow-up revealed absence of significant toxicity in 7 of 10 patients but severe localized toxicity in teeth receiving >20 Gy(RBE) among 3 patients who were all treated at <4 years of age. Conclusions: CT-based assessment of dose distribution to individual teeth is feasible, although delayed calcification may complicate tooth identification in the youngest patients. Patterns of dental dose exposure vary markedly within and among patients, corresponding to rapid dose falloff with protons. Severe localized dental toxicity was observed in a few patients receiving the largest doses of radiation at the youngest ages; however, multiple factors including concurrent chemotherapy confounded the dose-effect relationship. Further studies with larger cohorts and appropriate controls will be required.« less

An analysis of interplanetary space radiation exposure for various solar cycles

NASA Technical Reports Server (NTRS)

Badhwar, G. D.; Cucinotta, F. A.; O'Neill, P. M.; Wilson, J. W. (Principal Investigator)

1994-01-01

The radiation dose received by crew members in interplanetary space is influenced by the stage of the solar cycle. Using the recently developed models of the galactic cosmic radiation (GCR) environment and the energy-dependent radiation transport code, we have calculated the dose at 0 and 5 cm water depth; using a computerized anatomical man (CAM) model, we have calculated the skin, eye and blood-forming organ (BFO) doses as a function of aluminum shielding for various solar minima and maxima between 1954 and 1989. These results show that the equivalent dose is within about 15% of the mean for the various solar minima (maxima). The maximum variation between solar minimum and maximum equivalent dose is about a factor of three. We have extended these calculations for the 1976-1977 solar minimum to five practical shielding geometries: Apollo Command Module, the least and most heavily shielded locations in the U.S. space shuttle mid-deck, center of the proposed Space Station Freedom cluster and sleeping compartment of the Skylab. These calculations, using the quality factor of ICRP 60, show that the average CAM BFO equivalent dose is 0.46 Sv/year. Based on an approach that takes fragmentation into account, we estimate a calculation uncertainty of 15% if the uncertainty in the quality factor is neglected.

Etirinotecan pegol administration is associated with lower incidences of neutropenia compared to irinotecan administration.

PubMed

Sy, S Kenneth; Sweeney, Theresa D; Ji, Chunmei; Hoch, Ute; Eldon, Michael A

2017-01-01

The relationship between incidences of neutropenia and 10-hydroxy-7-ethyl camptothecin (SN38) exposure was explored using SN38 pharmacokinetic and neutrophil count data from toxicology studies of etirinotecan pegol (EP) and irinotecan in beagle dogs. Dogs received four weekly intravenous infusions of either vehicle control (n = 22), EP (6, 15, 20, 25, 40/25 mg/kg; n = 3-9 dogs/dose group/sex; n = 48), or irinotecan (20 or 25 mg/kg n = 3-4 dogs/dose group/sex; n = 14). Blood samples were collected up to 50 days post-dose for characterization of SN38 pharmacokinetics. Two separate models were created describing SN38 concentration time profiles after either irinotecan or EP administrations to project the AUC 0-168h after Day 1 and Day 22 doses. The relationship between incidence of neutropenia and SN38 exposure was explored using logistic regression. The incidence of neutropenia in dogs receiving weekly doses of irinotecan or EP was strongly correlated with maximum plasma SN38 concentration (C max ), but not SN38 area under the concentration-time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 C max of 13.5 and 26.3 ng/mL for 20 and 25 mg/kg, respectively). No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg (mean SN38 C max of 3.4 and 4.9 ng/mL for 20 and 25 mg/kg, respectively), despite 2.5-3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses. EP administration avoids both high SN38 C max values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses.

Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

PubMed

El-Kersh, Karim; Ruf, Kathryn M; Smith, J Shaun

There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

Population dose commitments due to radioactive releases from nuclear-power-plant sites in 1978

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peloquin, R.A.; Schwab, J.D.; Baker, D.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1978. Fifty-year dose commitments from a one-year exposure were calculated from both liquid and atmospheric releases for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each site. This report tabulates the results of these calculations, showing the dose commitments for both liquid and airborne pathways for each age group and organ. Also included for each site is a histogram showing the fraction of the total population within 2 to 80 km around each site receiving variousmore » average dose commitments from the airborne pathways. The total dose commitment from both liquid and airborne pathways ranged from a high of 200 person-rem to a low of 0.0004 person-rem with an arithmetic mean of 14 person-rem. The total population dose for allsites was estimated at 660 person-rem for the 93 million people considered at risk. The average individual dose commitment from all pathways on a site basis ranged from a low of 3 x 10/sup -6/ mrem to a high of 0.08 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites.« less

Population dose commitments due to radioactive releases from Nuclear-Power-Plant Sites in 1979

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.; Peloquin, R.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1979. Fifty-year dose commitments from a one-year exposure were calculated from both liquid and atmospheric releases for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each site. This report tabulates the results of these calculations, showing the dose commitments for both liquid and airborne pathways for each age group and organ. Also included for each site is a histogram showing the fraction of the total population within 2 to 80 km around each site receiving variousmore » average dose commitments from the airborne pathways. The total dose commitment from both liquid and airborne pathways ranged from a high of 1300 person-rem to a low of 0.0002 person-rem with an arithmetic mean of 38 person-rem. The total population dose for all sites was estimated at 1800 person-rem for the 94 million people considered at risk. The average individual dose commitment from all pathways on a site basis ranged from a low of 2 x 10/sup -6/ mrem to a high of 0.7 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites.« less

Population Dose Commitments Due to Radioactive Releases from Nuclear Power Plant Sites in 1977

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D. A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1977. Fifty-year dose commitments from a one-year exposure were calculated from both liquid and atmospheric releases for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each site. This report tabulates the results of these calculations, showing the dose commitments for both liquid and airborne pathways for each age group and organ, Also included for each site is a histogram showing the fraction of the total population within 2 to 80 km around each site receiving variousmore » average dose commitments from the airborne pathways. The total dose commitment from both liquid and airborne pathways ranged from a high of 220 person-rem to a low of 0.003 person-rem with an arithmetic mean of 16 person-rem. The total population dose for all sites was estimated at 700 person-rem for the 92 million people considered at risk. The average individual dose commitment from all pathways on a site basis ranged from a low of 2 x 10{sup -5} mrem to a high of 0.1 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites.« less

A pharmacokinetic/pharmacodynamic investigation: assessment of edivoxetine and atomoxetine on systemic and central 3,4-dihydroxyphenylglycol, a biochemical marker for norepinephrine transporter inhibition.

PubMed

Kielbasa, William; Pan, Alan; Pereira, Alvaro

2015-03-01

Inhibition of norepinephrine (NE) reuptake into noradrenergic nerves is a common therapeutic target in the central nervous system (CNS). In noradrenergic nerves, NE is oxidized by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). In this study, 40 healthy male subjects received the NE transporter (NET) inhibitor edivoxetine (EDX) or atomoxetine (ATX), or placebo. The pharmacokinetic and pharmacodynamic profile of these drugs in plasma and cerebrospinal fluid (CSF) was assessed. In Part A, subjects received EDX once daily (QD) for 14 or 15 days at targeted doses of 6mg or 9mg. In Part B, subjects received 80mg ATX QD for 14 or 15 days. Each subject received a lumbar puncture before receiving drug and after 14 or 15 days of dosing. Plasma and urine were collected at baseline and after 14 days of dosing. Edivoxetine plasma and CSF concentrations increased dose dependently. The time to maximum plasma concentration of EDX was 2h, and the half-life was 9h. At the highest EDX dose of 9mg, DHPG concentrations were reduced from baseline by 51% at 8h postdose in CSF, and steady-state plasma and urine DHPG concentrations decreased by 38% and 26%, respectively. For 80mg ATX, the decrease of plasma, CSF, or urine DHPG was similar to EDX. Herein we provide clinical evidence that EDX and ATX decrease DHPG concentrations in the periphery and CNS, presumably via NET inhibition. EDX and ATX concentrations measured in the CSF confirmed the availability of those drugs in the CNS. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Phase I Trial of Bortezomib and Concurrent External Beam Radiation in Patients With Advanced Solid Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pugh, Thomas J.; Chen Changhu; Rabinovitch, Rachel

Purpose: To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy. Methods and Materials: An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m{sup 2}, 1.3 mg/m{sup 2}, and 1.6 mg/m{sup 2}/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, definedmore » as any grade 4 hematologic toxicity, any grade {>=}3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for {>=}2 weeks. Results: A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m{sup 2}. One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients). Conclusions: The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m{sup 2} is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m{sup 2}.« less

Spinal Cord Tolerance to Single-Fraction Partial-Volume Irradiation: A Swine Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.ed; Foster, Ryan D.; Kogel, Albert J. van der

2011-01-01

Purpose: To determine the spinal cord tolerance to single-fraction, partial-volume irradiation in swine. Methods and Materials: A 5-cm-long cervical segment was irradiated in 38-47-week-old Yucatan minipigs using a dedicated, image-guided radiosurgery linear accelerator. The radiation was delivered to a cylindrical volume approximately 5 cm in length and 2 cm in diameter that was positioned lateral to the cervical spinal cord, resulting in a dose distribution with the 90%, 50%, and 10% isodose lines traversing the ipsilateral, central, and contralateral spinal cord, respectively. The dose was prescribed to the 90% isodose line. A total of 26 pigs were stratified into eightmore » dose groups of 12-47 Gy. The mean maximum spinal cord dose was 16.9 {+-} 0.1, 18.9 {+-} 0.1, 21.0 {+-} 0.1, 23.0 {+-} 0.2, and 25.3 {+-} 0.3 Gy in the 16-, 18-, 20-, 22-, and 24-Gy dose groups, respectively. The mean percentage of spinal cord volumes receiving {>=}10 Gy for the same groups were 43% {+-} 3%, 48% {+-} 4%, 51% {+-} 2%, 57% {+-} 2%, and 59% {+-} 4%. The study endpoint was motor neurologic deficit determined by a change in gait during a 1-year follow-up period. Results: A steep dose-response curve was observed with a median effective dose for the maximum dose point of 20.0 Gy (95% confidence interval, 18.3-21.7). Excellent agreement was observed between the occurrence of neurologic change and the presence of histologic change. All the minipigs with motor deficits showed some degree of demyelination and focal white matter necrosis on the irradiated side, with relative sparing of the gray matter. The histologic findings were unremarkable in the minipigs with normal neurologic status. Conclusions: Our results have indicated that for a dose distribution with a steep lateral gradient, the pigs had a lower median effective dose for paralysis than has been observed in rats and more closely resembles that for rats, mice, and guinea pigs receiving uniform spinal cord irradiation.« less

Isotretinoin kinetics after 80 to 320 mg oral doses.

PubMed

Colburn, W A; Gibson, D M

1985-04-01

Twelve healthy male subjects received 80, 160, 240, and 320 mg doses of oral isotretinoin as multiples of 40 mg capsules separated by 2-week washout periods in a randomized, crossover design. Blood samples were drawn at specific times over a 72-hour period after dosing. Blood concentrations of isotretinoin as well as its major metabolite, 4-oxo-isotretinoin, were determined by a specific HPLC method. In addition to the normal laboratory battery of tests, serum triglyceride levels were determined before the first dose and again 72 hours after each of the four doses. Mean (+/- SD) maximum concentrations after 80 to 320 mg doses were 366 +/- 159, 820 +/- 474, 1056 +/- 547, and 981 +/- 381 ng/ml, whereas the respective AUC0-infinity values were 3690 +/- 1280, 7030 +/- 4140, 9780 +/- 6080, and 9040 +/- 2900 ng X hr/ml. The observed apparent elimination t1/2 remained approximately the same (14.7 hours) for each dose. The maximum concentration and AUC values for isotretinoin appear to be dose proportional from 80 to 240 mg but plateau at the 320 mg dose level. Therefore, because isotretinoin blood concentrations may not increase with higher doses in the fasting state, single, oral doses in excess of 240 mg should be used with caution. The data also suggest that elevated triglyceride levels are not a simple function of isotretinoin blood concentrations across the entire study population and dose range studied, but that in subjects with triglyceride levels in excess of the normal range triglyceride levels were positively related to isotretinoin blood concentrations.

A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer.

PubMed

Dy, Grace K; Bruzek, Laura M; Croghan, Gary A; Mandrekar, Sumithra; Erlichman, Charles; Peethambaram, Prema; Pitot, Henry C; Hanson, Lorelei J; Reid, Joel M; Furth, Alfred; Cheng, Shinta; Martell, Robert E; Kaufmann, Scott H; Adjei, Alex A

2005-03-01

This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors. Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662. Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m(2)), paclitaxel (225 mg/m(2)) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (> 4 cycles) occurred in eight other patients. The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.

Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis.

PubMed

Sandborn, W J; Bhandari, B R; Fogel, R; Onken, J; Yen, E; Zhao, X; Jiang, Z; Ge, D; Xin, Y; Ye, Z; French, D; Silverman, J A; Kanwar, B; Subramanian, G M; McHutchison, J G; Lee, S D; Shackelton, L M; Pai, R K; Levesque, B G; Feagan, B G

2016-07-01

Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors.

PubMed

Krick, Erika L; Sorenmo, Karin U; Rankin, Shelley C; Cheong, Ian; Kobrin, Barry; Thornton, Katherine; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin; Diaz, Luis A

2012-01-01

To establish the maximum tolerated dose of Clostridium novyi-NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. 6 client-owned dogs. A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C. novyi-NT spores i.v.. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C. novyi-NT infection; both required surgical intervention. Clostridium novyi-NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Results indicated that C. novyi-NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology.

Portal Hypertension in Children With Wilms' Tumor: A Report From the National Wilms' Tumor Study Group

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warwick, Anne B., E-mail: awarwick@mcw.ed; Kalapurakal, John A.; Ou, San-San

Purpose: This analysis was undertaken to determine the cumulative risk of and risk factors for portal hypertension (PHTN) in patients with Wilms' tumor (WT). Methods and Materials: Medical records were reviewed to identify cases of PHTN identified with late liver/spleen/gastric toxicities in a cohort of 5,195 patients treated with National Wilms' Tumor Studies (NWTS) protocols 1 to 4. A nested case control study (5 controls/case) was conducted to determine relationships among doxorubicin, radiation therapy (RT) dose to the liver, patient gender, and PHTN. Conditional logistic regression was used to estimate adjusted hazard ratios (HR) of PHTN associated with these factors.more » Results: Cumulative risk of PHTN at 6 years from WT diagnosis was 0.7% for patients with right-sided tumors vs. 0.1% for those with left-sided tumors (p = 0.002). Seventeen of 19 cases were evaluable for RT. The majority of cases (16/17 [94%]) received right-flank RT either alone or as part of whole-abdomen RT and received >15 Gy to the liver. Fifteen of 17 (88%) patients received a higher dose to the liver than they would have with modern WT protocols. Controlling for RT dose, the HR was 3.0 for patients who received doxorubicin (p = 0.32) and 2.8 for females (p = 0.15). Controlling for doxorubicin, the 95% lower confidence bound on the HR associating PHTN with a minimum liver RT dose of >15 Gy vs. <=15 Gy was 2.5 (p = 0.001); it was 2.4 for a maximum liver dose of >15 Gy vs. <=15 Gy (p = 0.001). Conclusions: There was a strong association between higher doses of liver RT (>15 Gy) and the development of PHTN among WT patients.« less

Comparison of testicular dose delivered by intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) in patients with prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martin, Jeffrey M.; Handorf, Elizabeth A.; Price, Robert A.

A small decrease in testosterone level has been documented after prostate irradiation, possibly owing to the incidental dose to the testes. Testicular doses from prostate external beam radiation plans with either intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) were calculated to investigate any difference. Testicles were contoured for 16 patients being treated for localized prostate cancer. For each patient, 2 plans were created: 1 with IMRT and 1 with VMAT. No specific attempt was made to reduce testicular dose. Minimum, maximum, and mean doses to the testicles were recorded for each plan. Of the 16 patients, 4 receivedmore » a total dose of 7800 cGy to the prostate alone, 7 received 8000 cGy to the prostate alone, and 5 received 8000 cGy to the prostate and pelvic lymph nodes. The mean (range) of testicular dose with an IMRT plan was 54.7 cGy (21.1 to 91.9) and 59.0 cGy (25.1 to 93.4) with a VMAT plan. In 12 cases, the mean VMAT dose was higher than the mean IMRT dose, with a mean difference of 4.3 cGy (p = 0.019). There was a small but statistically significant increase in mean testicular dose delivered by VMAT compared with IMRT. Despite this, it unlikely that there is a clinically meaningful difference in testicular doses from either modality.« less

Mumijo attenuates chemically induced inflammatory pain in mice.

PubMed

Malekzadeh, Golnaz; Dashti-Rahmatabadi, Mohammad Hossein; Zanbagh, Samira; Akhavi Mirab-bashii, Atefehsadat

2015-01-01

Mumijo (shilajit) has been well known in traditional medicine as a remedy for a number of diseases, such as bone fractures, wounds, inflammation, and headache. It is also widely used as an analgesic agent in folk medicine, but no scientific documentation exists concerning that effect. The current study was conducted to evaluate the ability of mumijo to reduce sensitivity to painful stimuli when compared with morphine sulfate and sodium diclofenac. A total of 176 animals were randomly and equally divided into 2 groups with 88 mice each-one for formalin test and the other for writhing test. For each test, the animals were allocated into 10 equal groups, based on the dosage of the analgesic, plus a negative control group, with 8 mice in each group. The analgesic effect of mumijo extract in doses of 0.75, 7.5, 75, and 750 mg/kg was assessed and compared witha group receiving distilled water-the negative control group, and that for groups receiving 1, 2, or 4 mg/kg of morphine sulfate or 10, 20, or 30 mg/kg of sodium diclofenac-the positive control groups. The results showed a significant decrease in pain intensity for all mice receiving doses of mumijo extract during a 1-h formalin test when compared with the distilled water group. For all the mumijo groups except the one receiving 750 mg/kg, the analgesic effect was significantly lower than that for the morphine sulfate group receiving 4 mg/kg. No significant differences existed between all mumijo and all diclofenac groups. In a writhing test, a significant inhibition of the pain response induced by acetic acid also occurred in all 4 mumijo-administered groups as opposed to the group receiving distilled water. No significant differences existed between the writhing response in groups receiving 75 and 750 mg/kg of mumijo and any doses of diclofenac or morphine. The comparison among the different doses of mumijo in the formalin test did not show any significant differences, but in the writhing test, the maximum dose showed a more effective analgesic action. The findings indicated a significant analgesic effect for mumijo extract on chronic pain in mice, occurring in a dose-independent manner.

Pediatric 131I-MIBG Therapy for Neuroblastoma: Whole-Body 131I-MIBG Clearance, Radiation Doses to Patients, Family Caregivers, Medical Staff, and Radiation Safety Measures.

PubMed

Willegaignon, José; Crema, Karin Paola; Oliveira, Nathaliê Canhameiro; Pelissoni, Rogério Alexandre; Coura-Filho, George Barberio; Sapienza, Marcelo Tatit; Buchpiguel, Carlos Alberto

2018-06-19

I-metaiodobenzylguanidine (I-MIBG) has been used in the diagnosis and therapy of neuroblastoma in adult and pediatric patients for many years. In this study, we evaluated whole-body I-MIBG clearance and radiation doses received by patients, family caregivers, and medical staff to establish appropriate radiation safety measures to be used in therapy applications. Research was focused on 23 children and adolescents with metastatic neuroblastoma, with ages ranging from 1.8 to 13 years, being treated with I-MIBG. Based on measured external dose rates from patients, dosimetric data to patients, family members, and others were calculated. The mean ± SD I-MIBG activity administered was 8.55 ± 1.69 GBq. Percent whole-body retention rates of I-MIBG at 24, 48, and 72 hours after administration were 48% ± 7%, 23% ± 7%, and 12% ± 6%, with a whole-body I-MIBG effective half-life of 23 ± 5 hours for all patients. The mean doses for patients were 0.234 ± 0.096 mGy·MBq to red-marrow and 0.251 ± 0.101 mGy·MBq to whole body. The maximum potential radiation doses transmitted by patients to others at 1.0 m was estimated to be 11.9 ± 3.4 mSv, with 97% of this dose occurring over 120 hours after therapy administration. Measured mean dose received by the 22 family caregivers was 1.88 ± 1.85 mSv, and that received by the 19 pediatric physicians was 43 ± 51 μSv. In this study, we evaluated the whole-body clearance of I-MIBG in 23 pediatric patients, and the radiation doses received by family caregivers and medical staff during these therapy procedures, thus facilitating the establishment of radiation safety measures to be applied in pediatric therapy.

Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
.

PubMed

Schultze-Mosgau, Marcus-Hillert; Schuett, Barbara; Hafner, Frank-Thorsten; Zollmann, Frank; Kaiser, Andreas; Hoechel, Joachim; Rohde, Beate

2017-01-01

Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)md/AUC(0-24)sd ratios: 1.9 to 3.2). The ratio AUC(0-24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg). Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.
.

SU-G-BRC-02: A Novel Multi-Criteria Optimization Approach to Generate Deliverable Intensity-Modulated Radiation Therapy (IMRT) Treatment Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirlik, G; D’Souza, W; Zhang, H

2016-06-15

Purpose: To present a novel multi-criteria optimization (MCO) solution approach that generates treatment plans with deliverable apertures using column generation. Methods: We demonstrate our method with 10 locally advanced head-and-neck cancer cases retrospectively. In our MCO formulation, we defined an objective function for each structure in the treatment volume. This resulted in 9 objective functions, including 3 distinct objectives for primary target volume, high-risk and low-risk target volumes, 5 objectives for each of the organs-at-risk (OARs) (two parotid glands, spinal cord, brain stem and oral cavity), and one for the non-target non-OAR normal tissue. Conditional value-at-risk (CVaR) constraints were utilizedmore » to ensure at least certain fraction of the target volumes receiving the prescription doses. To directly generate deliverable plans, column generation algorithm was embedded within our MCO approach for aperture shape generation. Final dose distributions for all plans were generated using a Monte Carlo kernel-superposition dose calculation. We compared the MCO plans with the clinical plans, which were created by clinicians. Results: At least 95% target coverage was achieved by both MCO plans and clinical plans. However, the average conformity indices of clinical plans and the MCO plans were 1.95 and 1.35, respectively (31% reduction, p<0.01). Compared to the conventional clinical plan, the proposed MCO method achieved average reductions in left parotid mean dose of 5% (p=0.06), right parotid mean dose of 18% (p<0.01), oral cavity mean dose of 21% (p=0.03), spinal cord maximum dose of 20% (p<0.01), brain stem maximum dose of 61% (p<0.01), and normal tissue maximum dose of 5% (p<0.01), respectively. Conclusion: We demonstrated that the proposed MCO method was able to obtain deliverable IMRT treatment plans while achieving significant improvements in dosimetric plan quality.« less

Patient awareness, knowledge and use of colchicine: an exploratory qualitative study in the Counties Manukau region, Auckland, New Zealand.

PubMed

Rebello, Caraliese; Thomson, Maree; Bassett-Clarke, Deborah; Martini, Nataly

2016-06-01

INTRODUCTION Treatment of gout, specifically with colchicine, varies globally. Colchicine can be fatal due to its narrow therapeutic index and potential for interactions. In New Zealand, cases of intentional and unintentional colchicine overdose have been documented. AIMS To explore patients' knowledge on the use of gout medicines, and in particular their awareness of the maximum dose of colchicine, the dangers of colchicine overdose, and their opinions on restricting colchicine dispensing. The study also investigates where patients receive gout information. METHODS Thirty people with gout presenting to their regular gout clinic in Auckland currently or previously taking colchicine were invited to participate in a 30-min semi-structured interview. Data were analysed using a general inductive thematic approach. FINDINGS Overall, participants had a lack of knowledge regarding colchicine and used variable doses during an acute gout attack. Participants were unsure of the maximum dose of colchicine and several took more than prescribed. The prophylactic use of colchicine and allopurinol varied from 3 weeks to 15 years. Mixed views were reported on restricting colchicine supply. Most participants received gout information from their general practitioner (GP). CONCLUSION Poor understanding of colchicine contributed to inappropriate use and highlights the need for targeted patient education. Considerable inter-patient variability exists in the use of colchicine for acute gout, suggesting the efficacy of low dose regimens be explored. The length of adjunctive colchicine use, as part of a prophylaxis regimen, needs to be regularly reviewed and tailored to each patient. Further research is required on limiting the amount of colchicine dispensed.

Predicting Chest Wall Pain From Lung Stereotactic Body Radiotherapy for Different Fractionation Schemes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woody, Neil M.; Videtic, Gregory M.M.; Stephans, Kevin L.

Purpose: Recent studies with two fractionation schemes predicted that the volume of chest wall receiving >30 Gy (V30) correlated with chest wall pain after stereotactic body radiation therapy (SBRT) to the lung. This study developed a predictive model of chest wall pain incorporating radiobiologic effects, using clinical data from four distinct SBRT fractionation schemes. Methods and Materials: 102 SBRT patients were treated with four different fractionations: 60 Gy in three fractions, 50 Gy in five fractions, 48 Gy in four fractions, and 50 Gy in 10 fractions. To account for radiobiologic effects, a modified equivalent uniform dose (mEUD) model calculatedmore » the dose to the chest wall with volume weighting. For comparison, V30 and maximum point dose were also reported. Using univariable logistic regression, the association of radiation dose and clinical variables with chest wall pain was assessed by uncertainty coefficient (U) and C statistic (C) of receiver operator curve. The significant associations from the univariable model were verified with a multivariable model. Results: 106 lesions in 102 patients with a mean age of 72 were included, with a mean of 25.5 (range, 12-55) months of follow-up. Twenty patients reported chest wall pain at a mean time of 8.1 (95% confidence interval, 6.3-9.8) months after treatment. The mEUD models, V30, and maximum point dose were significant predictors of chest wall pain (p < 0.0005). mEUD improved prediction of chest wall pain compared with V30 (C = 0.79 vs. 0.77 and U = 0.16 vs. 0.11). The mEUD with moderate weighting (a = 5) better predicted chest wall pain than did mEUD without weighting (a = 1) (C = 0.79 vs. 0.77 and U = 0.16 vs. 0.14). Body mass index (BMI) was significantly associated with chest wall pain (p = 0.008). On multivariable analysis, mEUD and BMI remained significant predictors of chest wall pain (p = 0.0003 and 0.03, respectively). Conclusion: mEUD with moderate weighting better predicted chest wall pain than did V30, indicating that a small chest wall volume receiving a high radiation dose is responsible for chest wall pain. Independently of dose to the chest wall, BMI also correlated with chest wall pain.« less

SU-E-T-122: Anisotropic Analytical Algorithm (AAA) Vs. Acuros XB (AXB) in Stereotactic Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mynampati, D; Scripes, P Godoy; Kuo, H

2015-06-15

Purpose: To evaluate dosimetric differences between superposition beam model (AAA) and determinant photon transport solver (AXB) in lung SBRT and Cranial SRS dose computations. Methods: Ten Cranial SRS and ten Lung SBRT plans using Varian, AAA -11.0 were re-planned using Acuros -XB-11.0 with fixed MU. 6MV photon Beam model with HD120-MLC used for dose calculations. Four non-coplanar conformal arcs used to deliver 21Gy or 18Gy to SRS targets (0.4 to 6.2cc). 54Gy (3Fractions) or 50Gy (5Fractions) was planned for SBRT targets (7.3 to 13.9cc) using two VAMT non-coplanar arcs. Plan comparison parameters were dose to 1% PTV volume (D1), dosemore » to 99% PTV volume( D99), Target mean (Dmean), Conformity index (ratio of prescription isodose volume to PTV), Homogeneity Index [ (D2%-D98%)/Dmean] and R50 (ratio of 50% of prescription isodose volume to PTV). OAR parameters were Brain volume receiving 12Gy dose (V12Gy) and maximum dose (D0.03) to Brainstem for SRS. For lung SBRT, maximum dose to Heart and Cord, Mean lung dose (MLD) and volume of lung receiving 20Gy (V20Gy) were computed. PTV parameters compared by percentage difference between AXB and AAA parameters. OAR parameters and HI compared by absolute difference between two calculations. For analysis, paired t-test performed over the parameters. Results: Compared to AAA, AXB SRS plans have on average 3.2% lower D99, 6.5% lower CI and 3cc less Brain-V12. However, AXB SBRT plans have higher D1, R50 and Dmean by 3.15%, 1.63% and 2.5%. For SRS and SBRT, AXB plans have average HI 2 % and 4.4% higher than AAA plans. In both techniques, all other parameters vary within 1% or 1Gy. In both sets only two parameters have P>0.05. Conclusion: Even though t-test results signify difference between AXB and AAA plans, dose differences in dose estimations by both algorithms are clinically insignificant.« less

SU-E-T-395: Evaluation of Multiple Brain Metastases Stereotactic Treatment Planning in Cyberknife Versus Linac

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vikraman, S; Rajesh, Thiyagarajan; Karrthick, Kp

2015-06-15

Purpose: The purpose of this study was to evaluate multiple brain metastases stereotactic treatment planning of Cyberknife versus linac using dose volume based indices. Methods: Fifteen multiple brain metastases patients were taken for this study from Cyberknife Multiplan TPSv4.6.0. All these patients underwent stereotactic treatment in Cyberknife. For each patient VMAT stereotactic treatment plan was generated in MONACO TPSv5.0 using Elekta beam modulator MLC and matched the delivered plan. A median dose of 8.5Gy(range 7–12Gy) per fraction was prescribed. Tumor volume was in the range of 0.06–4.33cc. Treatment plan quality was critically evaluated by comparing DVH indices such as D98,more » D95, CI, and HI for target volumes. Maximum point doses and volume doses were evaluated for critical organs. Results: For each case, target coverage of D98 was achieved with 100% prescription dose with SD of 0.29% and 0.41% in Linac and Cyberknife respectively. The average conformity index(CI) of 1.26±0.0796 SD for Cyberknife and 1.92±0.60SD for linac were observed. Better homogeneity Index (HI) of 1.17±0.09SD was observed in linac as compared to Cyberknife HI of 1.24±0.05SD.All the critical organ doses were well within tolerance limit in both linac and Cyberknife plans. There is no significant difference of maximum point doses for brainstem and optic chiasm. Treatment time and number of monitor units are more in Cyberknife compared to linac. The average volume receiving 12Gy in whole brain was 6% and 12% for Cyberknife and linac respectively. 1000cc of whole brain received 60% lesser dose in Linac compared to Cyberknife in all cases. Conclusion: The study shows that dosimetrically comparable plans are achievable Cyberknife and Linac. However, a better conformity, target coverage, lesser OAR dose is achieved with Cyberknife due to greater degrees of freedom with robotic gantry and smaller collimator for multiple targets.« less

Predicting Rectal and Bladder Overdose During the Course of Prostate Radiotherapy Using Dose-Volume Data From Initial Treatment Fractions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murthy, Vedang, E-mail: vmurthy@actrec.gov.in; Shukla, Pragya; Adurkar, Pranjal

2012-09-01

Purpose: To evaluate whether information from the initial fractions can determine which patients are likely to consistently exceed their planning dose-volume constraints during the course of radiotherapy for prostate cancer. Methods and Materials: Ten patients with high-risk prostate cancer were treated with helical tomotherapy to a dose of 60 Gy in 20 fractions. The prostate, rectum, and bladder were recontoured on their daily megavoltage computed tomography scans and the dose was recalculated. The bladder and rectal volumes (in mL) receiving {>=}100% and {>=}70% of the prescribed dose in each fraction and in the original plans were recorded. A fraction formore » which the difference between planned and delivered was more than 2 mL was considered a volume failure. Similarly if the difference in the planned and delivered maximum dose (D{sub max}) was {>=}1% for the rectum and bladder, the fraction was considered a dose failure. Each patient's first 3 to 5 fractions were analyzed to determine if they correctly identified those patients who would consistently fail (i.e., {>=}20% of fractions) during the course of their radiotherapy. Results: Six parameters were studied; the rectal volume (RV) and bladder volumes (BV) (in mL) received {>=}100% and {>=}70% of the prescribed dose and maximum dose to 2 mL of the rectum and bladder. This was given by RV{sub 100}, RV{sub 70}, BV{sub 100}, BV{sub 70}, RD{sub max}, and BD{sub max}, respectively. When more than 1 of the first 3 fractions exceed the planning constraint as defined, it accurately predicts consistent failures through the course of the treatment. This method is able to correctly identify the consistent failures about 80% (RV{sub 70}, BV{sub 100}, and RV{sub 100}), 90% (BV{sub 70}), and 100% (RD{sub max} and BD{sub max}) of the times. Conclusions: This study demonstrates the feasibility of a method accurately identifying patients who are likely to consistently exceed the planning constraints during the course of their treatment, using information from the first 3 to 5 fractions.« less

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: Phase 1 trial in adults with malignant glioma

PubMed Central

Reardon, David A.; Desjardins, Annick; Vredenburgh, James J.; Sathornsumetee, Sith; Rich, Jeremy N.; Quinn, Jennifer A.; Lagattuta, Theodore F.; Egorin, Merrill J.; Gururangan, Sridharan; McLendon, Roger; Herndon, James E.; Friedman, Allan H.; Salvado, August J.; Friedman, Henry S.

2008-01-01

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150–200 mg/m2 per day on days 4–8 plus imatinib mesylate administered orally on days 1–8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n = 28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population. PMID:18359865

Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

A pilot study: dose adaptation of capecitabine using mobile phone toxicity monitoring - supporting patients in their homes.

PubMed

Weaver, Andrew; Love, Sharon B; Larsen, Mark; Shanyinde, Milensu; Waters, Rachel; Grainger, Lisa; Shearwood, Vanessa; Brooks, Claire; Gibson, Oliver; Young, Annie M; Tarassenko, Lionel

2014-10-01

Real-time symptom monitoring using a mobile phone is potentially advantageous for patients receiving oral chemotherapy. We therefore conducted a pilot study of patient dose adaptation using mobile phone monitoring of specific symptoms to investigate relative dose intensity of capecitabine, level of toxicity and perceived supportive care. Patients with breast or colorectal cancer receiving capecitabine completed a symptom, temperature and dose diary twice a day using a mobile phone application. This information was encrypted and automatically transmitted in real time to a secure server, with moderate levels of toxicity automatically prompting self-care symptom management messages on the screen of the patient's mobile phone or in severe cases, a call from a specialist nurse to advise on care according to an agreed protocol. Patients (n = 26) completed the mobile phone diary on 92.6 % of occasions. Twelve patients had a maximum toxicity grade of 3 (46.2 %). The average dose intensity for all patients as a percentage of standard dose was 90 %. In eight patients, the dose of capecitabine was reduced, and in eight patients, the dose of capecitabine was increased. Patients and healthcare professionals involved felt reassured by the novel monitoring system, in particular, during out of hours. It is possible to optimise the individual dose of oral chemotherapy safely including dose increase and to manage chemotherapy side effects effectively using real-time mobile phone monitoring of toxicity parameters entered by the patient.

SU-F-T-444: Quality Improvement Review of Radiation Therapy Treatment Planning in the Presence of Dental Implants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parenica, H; Ford, J; Mavroidis, P

Purpose: To quantify and compare the effect of metallic dental implants (MDI) on dose distributions calculated using Collapsed Cone Convolution Superposition (CCCS) algorithm or a Monte Carlo algorithm (with and without correcting for the density of the MDI). Methods: Seven previously treated patients to the head and neck region were included in this study. The MDI and the streaking artifacts on the CT images were carefully contoured. For each patient a plan was optimized and calculated using the Pinnacle3 treatment planning system (TPS). For each patient two dose calculations were performed, a) with the densities of the MDI and CTmore » artifacts overridden (12 g/cc and 1 g/cc respectively) and b) without density overrides. The plans were then exported to the Monaco TPS and recalculated using Monte Carlo dose calculation algorithm. The changes in dose to PTVs and surrounding Regions of Interest (ROIs) were examined between all plans. Results: The Monte Carlo dose calculation indicated that PTVs received 6% lower dose than the CCCS algorithm predicted. In some cases, the Monte Carlo algorithm indicated that surrounding ROIs received higher dose (up to a factor of 2). Conclusion: Not properly accounting for dental implants can impact both the high dose regions (PTV) and the low dose regions (OAR). This study implies that if MDI and the artifacts are not appropriately contoured and given the correct density, there is potential significant impact on PTV coverage and OAR maximum doses.« less

Dosimetry during intramedullary nailing of the tibia.

PubMed

Kirousis, George; Delis, Harry; Megas, Panagiotis; Lambiris, Elias; Panayiotakis, George

2009-10-01

Intramedullary nailing under fluoroscopic guidance is a common operation. We studied the intraoperative radiation dose received by both the patient and the personnel. 25 intramedullary nailing procedures of the tibia were studied. All patients suffered from tibial fractures and were treated using the Grosse-Kempf intramedullary nail, with free-hand technique for fixation of the distal screws, under fluoroscopic guidance. The exposure, at selected positions, was recorded using an ion chamber, while the dose area product (DAP) was measured with a DAP meter, attached to the tube head. Thermoluminescent dosimeters (TLDs) were used to derive the occupational dose to the personnel, and also to monitor the surface dose on the gonads of some of the patients. The mean operation time was 101 (48-240) min, with a mean fluoroscopic time of 72 seconds and a mean DAP value of 75 cGy x cm(2). The surface dose to the gonads of the patients was less than 8.8 mGy during any procedure, and thus cannot be considered to be a contraindication for the use of this technique. Occupational dose differed substantially between members of the operating personnel, the maximum dose recorded being to the operator of the fluoroscopic equipment (0.11 mSv). Our findings underscore the care required by the primary operator not to exceed the dose constraint of 10 mSv per year. The rest of the operating personnel, although they do not receive very high doses, should focus on the dose optimization of the technique.

Malfunctions of Implantable Cardiac Devices in Patients Receiving Proton Beam Therapy: Incidence and Predictors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gomez, Daniel R., E-mail: dgomez@mdanderson.org; Poenisch, Falk; Pinnix, Chelsea C.

2013-11-01

Purpose: Photon therapy has been reported to induce resets of implanted cardiac devices, but the clinical sequelae of treating patients with such devices with proton beam therapy (PBT) are not well known. We reviewed the incidence of device malfunctions among patients undergoing PBT. Methods and Materials: From March 2009 through July 2012, 42 patients with implanted cardiac implantable electronic devices (CIED; 28 pacemakers and 14 cardioverter-defibrillators) underwent 42 courses of PBT for thoracic (23, 55%), prostate (15, 36%), liver (3, 7%), or base of skull (1, 2%) tumors at a single institution. The median prescribed dose was 74 Gy (relativemore » biological effectiveness; range 46.8-87.5 Gy), and the median distance from the treatment field to the CIED was 10 cm (range 0.8-40 cm). Maximum proton and neutron doses were estimated for each treatment course. All CIEDs were checked before radiation delivery and monitored throughout treatment. Results: Median estimated peak proton and neutron doses to the CIED in all patients were 0.8 Gy (range 0.13-21 Gy) and 346 Sv (range 11-1100 mSv). Six CIED malfunctions occurred in 5 patients (2 pacemakers and 3 defibrillators). Five of these malfunctions were CIED resets, and 1 patient with a defibrillator (in a patient with a liver tumor) had an elective replacement indicator after therapy that was not influenced by radiation. The mean distance from the proton beam to the CIED among devices that reset was 7.0 cm (range 0.9-8 cm), and the mean maximum neutron dose was 655 mSv (range 330-1100 mSv). All resets occurred in patients receiving thoracic PBT and were corrected without clinical incident. The generator for the defibrillator with the elective replacement indicator message was replaced uneventfully after treatment. Conclusions: The incidence of CIED resets was about 20% among patients receiving PBT to the thorax. We recommend that PBT be avoided in pacing-dependent patients and that patients with any type of CIED receiving thoracic PBT be followed closely.« less

Effects of high doses of oxytetracycline on metacarpophalangeal joint kinematics in neonatal foals.

PubMed

Kasper, C A; Clayton, H M; Wright, A K; Skuba, E V; Petrie, L

1995-07-01

Thirteen clinically normal Belgian-type foals were used to study the effects of high doses of oxytetracycline on metacarpophalangeal joint kinematics. Seven foals (treatment group) received 2 doses of oxytetracycline (3 g, IV). The first dose was given when foals were 4 days old; the second dose was given 24 hours later. Six foals (control group) received 2 doses of saline (0.9% NaCl) solution (15 ml, IV) at equivalent time periods. All foals were videotaped at a walk twice: immediately prior to the first treatment and 24 hours after the second treatment. The tapes were digitized, and metacarpophalangeal joint angle was measured along the palmar surface of the limb during 3 strides. The angular data were normalized for time, and data from the 3 strides were averaged to describe a representative stride. Repeated measures ANOVA was used to test for differences between groups and within groups over time. Values for stride duration, stance phase percentage, and minimum metacarpophalangeal joint angle obtained before treatment were not significantly different from values obtained after treatment. Maximum metacarpophalangeal joint angle, which occurred during the stance phase of the stride, and range of joint motion were significantly increased for foals in the treatment group, compared with foals in the control group.

Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study.

PubMed

Horton, Terzah M; Blaney, Susan M; Langevin, Anne-Marie; Kuhn, John; Kamen, Barton; Berg, Stacey L; Bernstein, Mark; Weitman, Steven

2005-03-01

To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia. Raltitrexed was administered as a 15-minute infusion for 3 consecutive weeks every 5 weeks, at doses ranging from 1.3 to 2.8 mg/m(2). The first course was used to determine the dose-limiting toxicities and maximum tolerated dose. Correlative studies included an assessment of raltitrexed pharmacokinetics and measurement of plasma 2'-deoxyuridine concentrations, a surrogate measure of thymidylate synthase inhibition. Twenty-one children (18 evaluable) with refractory leukemia received 25 courses of raltitrexed. The dose-limiting toxicity was reversible elevation in liver transaminases at the 2.8-mg/m(2) dose level and the maximum tolerated dose was 2.1 mg/m(2) per dose. Pharmacokinetics were best characterized by a two-compartment model with a clearance of 139 mL/min/m(2) (8.3 L/h/m(2)), a 2.4-L volume of distribution, an initial half-life (t(1/2alpha)) of 6 minutes, and a terminal half-life (t(1/2beta)) of 45 minutes. There were three objective responses. Raltitrexed was well tolerated when administered as a single agent to children with recurrent or refractory leukemia. We observed preliminary evidence of antileukemia activity using this weekly dosing schedule and these observations support further evaluation of raltitrexed in this population.

Predictors of Acute Esophagitis in Lung Cancer Patients Treated With Concurrent Three-Dimensional Conformal Radiotherapy and Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodriguez, Nuria; Department of Medicine, Universitat Autonoma de Barcelona, Barcelona; Algara, Manuel

2009-03-01

Purpose: To evaluate the risk factors for acute esophagitis (AET) in lung cancer patients treated with concurrent 3D-CRT and chemotherapy. Methods and Materials: Data from 100 patients treated with concurrent chemoradiotherapy with a mean dose of 62.05 {+-} 4.64 Gy were prospectively evaluated. Esophageal toxicity was graded according to criteria of the Radiation Therapy Oncology Group. The following dosimetric parameters were analyzed: length and volume of esophagus in treatment field, percentage of esophagus volume treated to {>=}10, {>=}20, {>=}30, {>=}35, {>=}40, {>=}45, {>=}50, {>=}55, and {>=}60 Gy, and the maximum (D{sub max}) and mean doses (D{sub mean}) delivered to themore » esophagus. Also, we developed an esophagitis index (EI) to account the esophagitis grades over treatment time. Results: A total of 59 patients developed AET (Grade 1, 26 patients; Grade 2, 29 patients; and Grade 3, 4 patients). V50 was associated with AET duration (p = 0.017), AET Grade 1 duration (p = 0.016), maximum analgesia (p = 0.019), esophagitis index score (p = 0.024), and AET Grade {>=}1 (p = 0.058). If V50 is <30% there is a 47.3% risk of AET Grade {>=}1, which increases to 73.3% if V50 is {>=}30% (p = 0.008). The predictive abilities of models (sensitivity and specificity) were calculated by receiver operating characteristic curves. Conclusions: According to the receiver operating characteristic curve analysis, the 30% of esophageal volume receiving {>=}50 Gy was the most statistically significant factor associated with AET Grade {>=}1 and maximum analgesia (A{sub max}). There was an association with AET Grade {>=}2 but it did not achieve statistical significance (p = 0.076)« less

Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.

PubMed

Rodríguez, Núria; Algara, Manuel; Foro, Palmira; Lacruz, Marti; Reig, Anna; Membrive, Ismael; Lozano, Joan; López, José Luis; Quera, Jaime; Fernández-Velilla, Enric; Sanz, Xavier

2009-03-01

To evaluate the risk factors for acute esophagitis (AET) in lung cancer patients treated with concurrent 3D-CRT and chemotherapy. Data from 100 patients treated with concurrent chemoradiotherapy with a mean dose of 62.05 +/- 4.64 Gy were prospectively evaluated. Esophageal toxicity was graded according to criteria of the Radiation Therapy Oncology Group. The following dosimetric parameters were analyzed: length and volume of esophagus in treatment field, percentage of esophagus volume treated to >or=10, >or=20, >or=30, >or=35, >or=40, >or=45, >or=50, >or=55, and >or=60 Gy, and the maximum (D(max)) and mean doses (D(mean)) delivered to the esophagus. Also, we developed an esophagitis index (EI) to account the esophagitis grades over treatment time. A total of 59 patients developed AET (Grade 1, 26 patients; Grade 2, 29 patients; and Grade 3, 4 patients). V50 was associated with AET duration (p = 0.017), AET Grade 1 duration (p = 0.016), maximum analgesia (p = 0.019), esophagitis index score (p = 0.024), and AET Grade >or=1 (p = 0.058). If V50 is <30% there is a 47.3% risk of AET Grade >or=1, which increases to 73.3% if V50 is >or=30% (p = 0.008). The predictive abilities of models (sensitivity and specificity) were calculated by receiver operating characeristic curves. According to the receiver operating characeristic curve analysis, the 30% of esophageal volume receiving >or=50 Gy was the most statistically significant factor associated with AET Grade >or=1 and maximum analgesia (A(max)). There was an association with AET Grade >or=2 but it did not achieve statistical significance (p = 0.076).

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

2015-10-01

The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose levels higher than 51 mg/m(2). Additional phase II trials are recommended at 250 mg/m(2).

Real world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

PubMed

Mato, Anthony R; Thompson, Meghan; Allan, John N; Brander, Danielle M; Pagel, John M; Ujjani, Chaitra S; Hill, Brian T; Lamanna, Nicole; Lansigan, Frederick; Jacobs, Ryan; Shadman, Mazyar; Skarbnik, Alan P; Pu, Jeffrey J; Barr, Paul M; Sehgal, Alison R; Cheson, Bruce D; Zent, Clive S; Tuncer, Hande H; Schuster, Stephen J; Pickens, Peter V; Shah, Nirav N; Goy, Andre; Winter, Allison M; Garcia, Christine; Kennard, Kaitlin; Isaac, Krista; Dorsey, Colleen; Gashonia, Lisa M; Singavi, Arun K; Roeker, Lindsey E; Zelenetz, Andrew; Williams, Annalynn; Howlett, Christina; Weissbrot, Hanna; Ali, Naveed; Khajavian, Sirin; Sitlinger, Andrea; Tranchito, Eve; Rhodes, Joanna; Felsenfeld, Joshua; Bailey, Neil; Patel, Bhavisha; Burns, Timothy F; Yacur, Melissa; Malhotra, Mansi; Svoboda, Jakub; Furman, Richard R; Nabhan, Chadi

2018-06-07

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with CLL treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients , the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study. Copyright © 2018, Ferrata Storti Foundation.

Systemic Delivery of Atropine Sulfate by the MicroDose Dry-Powder Inhaler

PubMed Central

Venkataramanan, R.; Hoffman, R.M.; George, M.P.; Petrov, A.; Richards, T.; Zhang, S.; Choi, J.; Gao, Y.Y.; Oakum, C.D.; Cook, R.O.; Donahoe, M.

2013-01-01

Abstract Background Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). Methods The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses×0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen® auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. Results A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA=20.1±5.8, AUTO=23.7±4.9 ng hr/mL (means±SD); maximum concentration reached, DPIA=7.7±3.5, AUTO=11.0±3.8 ng/mL; time to reach maximum concentration, DPIA=0.25±0.47, AUTO=0.19±0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18±12, AUTO=23±13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16±0.22 L, AUTO=0.11±0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. Conclusions Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine. PMID:22691110

Systemic delivery of atropine sulfate by the MicroDose Dry-Powder Inhaler.

PubMed

Corcoran, T E; Venkataramanan, R; Hoffman, R M; George, M P; Petrov, A; Richards, T; Zhang, S; Choi, J; Gao, Y Y; Oakum, C D; Cook, R O; Donahoe, M

2013-02-01

Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses × 0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen® auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA=20.1±5.8, AUTO=23.7±4.9 ng hr/mL (means±SD); maximum concentration reached, DPIA=7.7±3.5, AUTO=11.0±3.8 ng/mL; time to reach maximum concentration, DPIA=0.25±0.47, AUTO=0.19±0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18±12, AUTO=23±13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16±0.22 L, AUTO=0.11±0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine.

Comparison of organ doses for patients undergoing balloon brachytherapy of the breast with HDR 192Ir or electronic sources using Monte Carlo simulations in a heterogeneous human phantom1

PubMed Central

Mille, Matthew M.; Xu, X. George; Rivard, Mark J.

2010-01-01

Purpose: Accelerated partial breast irradiation via interstitial balloon brachytherapy is a fast and effective treatment method for certain early stage breast cancers. The radiation can be delivered using a conventional high-dose rate (HDR) 192Ir gamma-emitting source or a novel electronic brachytherapy (eBx) source which uses lower energy x rays that do not penetrate as far within the patient. A previous study [A. Dickler, M. C. Kirk, N. Seif, K. Griem, K. Dowlatshahi, D. Francescatti, and R. A. Abrams, “A dosimetric comparison of MammoSite high-dose-rate brachytherapy and Xoft Axxent electronic brachytherapy,” Brachytherapy 6, 164–168 (2007)] showed that the target dose is similar for HDR 192Ir and eBx. This study compares these sources based on the dose received by healthy organs and tissues away from the treatment site. Methods: A virtual patient with left breast cancer was represented by a whole-body, tissue-heterogeneous female voxel phantom. Monte Carlo methods were used to calculate the dose to healthy organs in a virtual patient undergoing balloon brachytherapy of the left breast with HDR 192Ir or eBx sources. The dose-volume histograms for a few organs which received large doses were also calculated. Additional simulations were performed with all tissues in the phantom defined as water to study the effect of tissue inhomogeneities. Results: For both HDR 192Ir and eBx, the largest mean organ doses were received by the ribs, thymus gland, left lung, heart, and sternum which were close to the brachytherapy source in the left breast. eBx yielded mean healthy organ doses that were more than a factor of ∼1.4 smaller than for HDR 192Ir for all organs considered, except for the three closest ribs. Excluding these ribs, the average and median dose-reduction factors were ∼28 and ∼11, respectively. The volume distribution of doses in nearby soft tissue organs that were outside the PTV were also improved with eBx. However, the maximum dose to the closest rib with the eBx source was 5.4 times greater than that of the HDR 192Ir source. The ratio of tissue-to-water maximum rib dose for the eBx source was ∼5. Conclusions: The results of this study indicate that eBx may offer lower toxicity to most healthy tissues, except nearby bone. TG-43 methods have a tendency to underestimate dose to bone, especially the ribs. Clinical studies evaluating the negative health effects caused by irradiating healthy organs are needed so that physicians can better understand when HDR 192Ir or eBx might best benefit a patient. PMID:20229875

Measured and Calculated Neutron Spectra and Dose Equivalent Rates at High Altitudes; Relevance to SST Operations and Space Research

NASA Technical Reports Server (NTRS)

Foelsche, T.; Mendell, R. B.; Wilson, J. W.; Adams, R. R.

1974-01-01

Results of the NASA Langley-New York University high-altitude radiation study are presented. Measurements of the absorbed dose rate and of secondary fast neutrons (1 to 10 MeV energy) during the years 1965 to 1971 are used to determine the maximum radiation exposure from galactic and solar cosmic rays of supersonic transport (SST) and subsonic jet occupants. The maximum dose equivalent rates that the SST crews might receive turn out to be 13 to 20 percent of the maximum permissible dose rate (MPD) for radiation workers (5 rem/yr). The exposure of passengers encountering an intense giant-energy solar particle event could exceed the MPD for the general population (0.5 rem/yr), but would be within these permissible limits if in such rare cases the transport descends to subsonic altitude; it is in general less than 12 percent of the MPD. By Monte Carlo calculations of the transport and buildup of nucleons in air for incident proton energies E of 0.02 to 10 GeV, the measured neutron spectra were extrapolated to lower and higher energies and for galactic cosmic rays were found to continue with a relatively high intensity to energies greater than 400 MeV, in a wide altitude range. This condition, together with the measured intensity profiles of fast neutrons, revealed that the biologically important fast and energetic neutrons penetrate deep into the atmosphere and contribute approximately 50 percent of the dose equivalant rates at SST and present subsonic jet altitudes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kitabatake, T.; Kaneko, M.; Takagi, Y.

Dosimetry was used to estimate the radiation dose received by dertal patients and dentists in dental clinics in Japan, and the results were compared with those obtained by an enlargement technique. The phantom of paraffin used for measuring exposure doses was based on a whole-body plaster of panis cast of a Japanese of medium size. The lungs in the phantom were made of cork with a specific gravity of 0.2, and three holes were constructed in the oral cavity, lower abdomen (ovary region), and testicular region for insertion of a dosimeter. Since in most dental clinics in Japan the x-raymore » apparatus is installed in the corner of the treatment room without any Pb protection, dose distribution of scattered x rays was also surveyed. Four types of x-ray units were used, and measurement was performed at distances 50 to 200 cm at levels of 50 and 100 cm from the floor. The gonads received a dose of about 0.5 to 3 mr per exposure in males, and 0.03 to 1 mr in females. Patients received radiation doses of 10 to l000 mr per exposure at the eye lens, 1500 mr on the nasal apex, and 500 mr on the thyroid region. Not less than 100 mr of radiation was distributed in the regions of the pharynx and cervical spine. For dentists holding the film in the patient's mouth, about 1 to 3 r were received per exposure. They also received whole-body irradiation of scattered rays of about 500 to 2000 mr/hr. Since in Japan, even at present, the dentist usually holds the fllm in the patient's mouth during radiography, and if he conducts dental radiography 10 times a day, he should receive 10 to 30 r on his hands a day, or 3000 to 9000 r a year. Furthermore, the dentist standing near the patient is exposed to scattered rays of about 1.4 mr per exposure. Therefore 11 exposures per day give the upper limit of irradiation dose according to maximum permissible dose. The long-cone method, it is suggested, is of value not only for making enlargement radiograms but also for diminishing the exposure dose of dentists since it prevents the production of scattered rays. (BBB)« less

Tolerance of cranial nerves of the cavernous sinus to radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tishler, R.B.; Loeffler, J.S.; Alexander, E. III

1993-09-20

Stereotactic radiosurgery is becoming a more accepted treatment option for benign, deep seated intracranial lesions. However, little is known about the effects of large single fractions of radiation on cranial nerves. This study was undertaken to assess the effect of radiosurgery on the cranial nerves of the cavernous sinus. The authors examined the tolerance of cranial nerves (II-VI) following radiosurgery for 62 patients (42/62 with meningiomas) treated for lesions within or near the cavernous sinus. Twenty-nine patients were treated with a modified 6 MV linear accelerator (Joint Center for Radiation Therapy) and 33 were treated with the Gamma Knife (Universitymore » of Pittsburgh). Three-dimensional treatment plans were retrospectively reviewed and maximum doses were calculated for the cavernous sinus and the optic nerve and chiasm. Median follow-up was 19 months (range 3-49). New cranial neuropathies developed in 12 patients from 3-41 months following radiosurgery. Four of these complications involved injury to the optic system and 8 (3/8 transient) were the result of injury to the sensory or motor nerves of the cavernous sinus. There was no clear relationship between the maximum dose to the cavernous sinus and the development of complications for cranial nerves III-VI over the dose range used (1000-4000 cGy). For the optic apparatus, there was a significantly increased incidence of complications with dose. Four of 17 patients (24%) receiving greater than 800 cGy to any part of the optic apparatus developed visual complications compared with 0/35 who received less than 800 cGy (p = 0.009). Radiosurgery using tumor-controlling doses of up to 4000 cGy appears to be a relatively safe technique in treating lesions within or near the sensory and motor nerves (III-VI) of the cavernous sinus. The dose to the optic apparatus should be limited to under 800 cGy. 21 refs., 4 tabs.« less

Dosimetric comparison of peripheral NSCLC SBRT using Acuros XB and AAA calculation algorithms.

PubMed

Ong, Chloe C H; Ang, Khong Wei; Soh, Roger C X; Tin, Kah Ming; Yap, Jerome H H; Lee, James C L; Bragg, Christopher M

2017-01-01

There is a concern for dose calculation in highly heterogenous environments such as the thorax region. This study compares the quality of treatment plans of peripheral non-small cell lung cancer (NSCLC) stereotactic body radiation therapy (SBRT) using 2 calculation algorithms, namely, Eclipse Anisotropic Analytical Algorithm (AAA) and Acuros External Beam (AXB), for 3-dimensional conformal radiation therapy (3DCRT) and volumetric-modulated arc therapy (VMAT). Four-dimensional computed tomography (4DCT) data from 20 anonymized patients were studied using Varian Eclipse planning system, AXB, and AAA version 10.0.28. A 3DCRT plan and a VMAT plan were generated using AAA and AXB with constant plan parameters for each patient. The prescription and dose constraints were benchmarked against Radiation Therapy Oncology Group (RTOG) 0915 protocol. Planning parameters of the plan were compared statistically using Mann-Whitney U tests. Results showed that 3DCRT and VMAT plans have a lower target coverage up to 8% when calculated using AXB as compared with AAA. The conformity index (CI) for AXB plans was 4.7% lower than AAA plans, but was closer to unity, which indicated better target conformity. AXB produced plans with global maximum doses which were, on average, 2% hotter than AAA plans. Both 3DCRT and VMAT plans were able to achieve D95%. VMAT plans were shown to be more conformal (CI = 1.01) and were at least 3.2% and 1.5% lower in terms of PTV maximum and mean dose, respectively. There was no statistically significant difference for doses received by organs at risk (OARs) regardless of calculation algorithms and treatment techniques. In general, the difference in tissue modeling for AXB and AAA algorithm is responsible for the dose distribution between the AXB and the AAA algorithms. The AXB VMAT plans could be used to benefit patients receiving peripheral NSCLC SBRT. Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Population dose commitments due to radioactive releases from nuclear power plant sites in 1985

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commericial power reactors operating during 1985. Fifty-year dose commitments from a one-year exposure were calculated from both liquid and atmospheric releases for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each of 61 sites. This report tabulates the results of these calculations, showing the dose commitments for both liquid and airborne pathways for each age group and organ. Also included for each of the sites is a histogram showing the fraction of the total population within 2 to 80 km aroundmore » each site receiving various average dose commitments from the airborne pathways. The total dose commitments (from both liquid and airborne pathways) for each site ranged from a high of 73 person-rem to a low of 0.011 person-rem for the sites with plants operating throughout the year with an arithmetic mean of 3 person-rem. The total population dose for all sites was estimated at 200 person-rem for the 110 million people considered at risk. The site average individual dose commitment from all pathways ranged from a low of 5 /times/ 10/sup /minus/6/ mrem to a high of 0.02 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites.« less

Population dose commitments due to radioactive releases from nuclear power plant sites in 1984

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1984. Fifty-year dose commitments from a one-year exposure were calculated from both liquid and atmospheric releases for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each of 56 sites. This report tabulates the results of these calculations, showing the dose commitments for both liquid and airborne pathways for each age group and organ. Also included for each of the sites is a histogram showing the fraction of the total population within 2 to 80 km aroundmore » each site receiving various average dose commitments from the airborne pathways. The total dose commitments (from both liquid and airborne pathways) for each site ranged from a high of 110 person-rem to a low of 0.002 person-rem for the sites with plants operating throughout the year with an arithmetic mean of 5 person-rem. The total population dose for all sites was estimated at 280 person-rem for the 100 million people considered at risk. The site average individual dose commitment from all pathways ranged from a low of 6 x 10/sup -6/ mrem to a high of 0.04 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites.« less

Population dose commitments due to radioactive releases from nuclear power plant sites in 1986

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1986. Fifty-year dose commitments for a one-year exposure from both liquid and atmospheric releases were calculated for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each of 66 reactor sites. This report tabulates the results of these calculations, showing the dose commitments for both water and airborne pathways for each age group and organ. Also included for each of the sites is a histogram showing the fraction of the total population within 2 to 80 kmmore » around each site receiving various average dose commitments from the airborne pathways. The total dose commitments (from both liquid and airborne pathways) for each site ranged from a high of 31 person-rem to a low of 0.0007 person-rem for the sites with plants operating throughout the year with an arithmetic mean of 1.7 person-rem. The total population dose for all sites was estimated at 110 person-rem for the 140 million people considered at risk. The site average individual dose commitment from all pathways ranged from a low of 2 {times} 10{sup -6} mrem to a high of 0.02 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites. 12 refs.« less

Population dose commitments due to radioactive releases from nuclear power plant sites in 1982. Volume 4

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.; Peloquin, R.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1982. Fifty-year dose commitments from a one-year exposure were calculated from both liquid and atmospheric releases for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each of 51 sites. This report tabulates the results of these calculations, showing the dose commitments for both liquid and airborne pathways for each age group and organ. Also included for each site is a histogram showing the fraction of the total population within 2 to 80 km around each sitemore » receiving various average dose commitments from the airborne pathways. The total dose commitments from both liquid and airborne pathways ranged from a high of 30 person-rem to a low of 0.007 person-rem for the sites with plants operating throughout the year with an arithmetic mean of 3 person-rem. The total population dose for all sites was estimated at 130 person-rem for the 100 million people considered at risk. The average individual dose commitment from all pathways on a site basis ranged from a low of 6 x 10/sup -7/ mrem to a high of 0.06 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites.« less

Pharmacometrics-based dose selection of levofloxacin as a treatment for postexposure inhalational anthrax in children.

PubMed

Li, Fang; Nandy, Partha; Chien, Shuchean; Noel, Gary J; Tornoe, Christoffer W

2010-01-01

Levofloxacin was recently (May 2008) approved by the U.S. Food and Drug Administration as a treatment for children following inhalational exposure to anthrax. Given that no clinical trials to assess the efficacy of a chosen dose was conducted, the basis for the dose recommendation was based upon pharmacometric analyses. The objective of this paper is to describe the basis of the chosen pediatric dose recommended for the label. Pharmacokinetic (PK) data from 90 pediatric patients receiving 7 mg/kg of body weight levofloxacin and two studies of 47 healthy adults receiving 500 and 750 mg/kg levofloxacin were used for the pharmacometric analyses. Body weight was found to be a significant covariate for levofloxacin clearance and the volume of distribution. Consistently with developmental physiology, clearance also was found to be reduced in pediatric patients under 2 years of age due to immature renal function. Different dosing regimens were simulated to match adult exposure (area under the concentration-time curve from 0 to 24 h at steady state, maximum concentration of drug in serum at steady state, and minimum concentration of drug in serum at steady state) following the approved adult dose of 500 mg once a day. The recommended dose of 8 mg/kg twice a day was found to match the exposure of the dose approved for adults in a manner that permitted confidence that this dose in children would achieve efficacy comparable to that of adults.

Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study.

PubMed

Thamlikitkul, Lucksamon; Srimuninnimit, Vichien; Akewanlop, Charuwan; Ithimakin, Suthinee; Techawathanawanna, Sirisopa; Korphaisarn, Krittiya; Chantharasamee, Jomjit; Danchaivijitr, Pongwut; Soparattanapaisarn, Nopadol

2017-02-01

The purpose of this study is to determine the efficacy of ginger for reducing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving adriamycin and cyclophosphamide (AC) regimens. We enrolled breast cancer patients receiving AC who experienced moderate to severe nausea or vomiting during the first chemotherapy cycle. Subjects were randomized to receive a 500-mg ginger capsule or placebo twice a day for 5 days starting on the first day of the second AC cycle and were switched to the other treatment in the third cycle. All participants also received ondansetron and dexamethasone for CINV prophylaxis. Nausea severity was recorded once a day during the first 5 days of each cycle. The primary outcome was reduction in nausea score. Thirty-four subjects (68 cycles of AC) were enrolled. Mean (range) maximum nausea score in the first AC cycle was 58 (40-90). Thirty-three subjects (97 %) received the same AC doses in the second as in the third cycle. Mean (±standard error) maximum nausea scores in patients receiving ginger and placebo were 35.36 (±4.43) and 32.17 (±3.71), respectively. The difference in mean maximum nausea scores was 3 (95 % confidence interval, -3 to 9; P = 0.3). There were no significant differences between ginger and placebo in terms of vomiting incidence and severity, rescue medication use, chemotherapy compliance, and adverse events. Ginger (500 mg) twice daily was safe, but conferred no additional benefit in terms of reducing nausea severity in breast cancer patients receiving AC and ondansetron and dexamethasone for CINV prophylaxis.

Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.

PubMed

Dahan, A; Yassen, A; Bijl, H; Romberg, R; Sarton, E; Teppema, L; Olofsen, E; Danhof, M

2005-06-01

There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats. In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 microg kg(-1) (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 microg kg(-1) (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 microg kg(-1) and fentanyl 0, 50, 68 and 90 microg kg(-1). In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses > or = 2.9 microg kg(-1); buprenorphine caused depression of minute ventilation which levelled off at doses > or = 3.0 microg kg(-1) to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses > 1.4 microg kg(-1). The effect on PaCO2 was modest (maximum value measured, 5.5 kPa). Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Evaluation of Clostridium novyi–NT spores in dogs with naturally occurring tumors

PubMed Central

Krick, Erika L.; Sorenmo, Karin U.; Rankin, Shelley C.; Cheong, Ian; Kobrin, Barry; Thornton, Katherine; Kinzler, Kenneth W.; Vogelstein, Bert; Zhou, Shibin; Diaz, Luis A.

2015-01-01

Objective To establish the maximum tolerated dose of Clostridium novyi–NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. Animals 6 client-owned dogs. Procedures A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C novyi–NT spores IV. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. Results The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C novyi–NT infection; both required surgical intervention. Clostridium novyi–NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Conclusions and Clinical Relevance Results indicated that C novyi–NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology. PMID:22204296

Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelsey, Chris R., E-mail: christopher.kelsey@duke.edu; Das, Shiva; Gu, Lin

2015-12-01

Purpose: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT. Methods and Materials: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standardmore » 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT. Results: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6). Conclusions: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions.« less

Phase I dose-escalation study of afatinib, an ErbB family blocker, plus docetaxel in patients with advanced cancer.

PubMed

Marshall, John; Shapiro, Geoffrey I; Uttenreuther-Fischer, Martina; Ould-Kaci, Mahmoud; Stopfer, Peter; Gordon, Michael S

2013-02-01

To determine the maximum tolerated dose (MTD), safety and anti-tumor activity of afatinib combined with docetaxel in advanced cancer. The MTD was determined from dose-limiting toxicities in the first cycle. Thirty-one patients received 10, 20 and 30 mg oral afatinib, plus 60 and 75 mg/m(2) intravenous docetaxel (six cohorts; 3-week cycles). The MTD of afatinib was 20 mg/day (days 2-21) with 75 mg/m(2) docetaxel (day 1). Dose-limiting toxicities were grade 3/4 diarrhea (n = 3) and febrile neutropenia (n = 6). Most frequently occurring adverse events were diarrhea, neutropenia and rash. Disease stabilization occurred in 14 patients. Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile.

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma.

PubMed

Liu, Qi; Cai, Xu-Wei; Fu, Xiao-Long; Chen, Jun-Chao; Xiang, Jia-Qing

2015-10-13

To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study.

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma

PubMed Central

Fu, Xiao-Long; Chen, Jun-Chao; Xiang, Jia-Qing

2015-01-01

Purpose To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. Methods and Materials From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. Results The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. Conclusions The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study. PMID:26314958

Radiation dose produced by patients during radiopharmaceutical incorporation in nuclear medicine diagnostic procedures.

PubMed

Morán, V; Prieto, E; García-García, B; Barbés, B; Ribelles, M J; Richter, J Á; Martí-Climent, J M

2016-01-01

The aim of this study was to assess the dose received by members of the public due to close contact with patients undergoing nuclear medicine procedures during radiopharmaceutical incorporation, and comparing it with the emitted radiation dose when the test was complete, in order to establish recommendations. A prospective study was conducted on 194 patients. H*(10) dose rates were measured at 0.1, 0.5, and 1.0m after the radiopharmaceutical administration, before the image acquisition, and at the end of the nuclear medicine procedure. Effective dose for different close contact scenarios were calculated, according to 95th percentile value (bone scans) and the maximum value (remaining tests). During the radiopharmaceutical incorporation, a person who stays with another injected patient in the same waiting room may receive up to 0.59 mSv. If the patient had a medical appointment, or went to a restaurant or a coffee shop, members of the public could receive 23, 43, and 22 μSv, respectively. After finishing the procedure, these doses are reduced by a factor 3. In most of the studies, the use of private instead of public transport may reduce the dose by more than a factor 6. It is recommended to increase the distance between the patients during the radiopharmaceutical incorporation and to distribute them according to the diagnostic procedure. Patients should be encouraged to use private instead of public transport. Depending on the number of nuclear medicine outpatients per year attended by a physician, it could be necessary to apply restrictions. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

Evaluation of contralateral breast skin doses by thermoluminescent dosimeters of patients receiving adjuvant radiotherapy for breast cancer.

PubMed

Gorken, I B; Kentli, S; Alanyali, H; Karagüler, Z; Kinay, M

2002-01-01

It is reported that low dose radiation received by the contralateral breast (CLB) during adjuvant radiotherapy (RT) is carcinogenic. This trial was planned to evaluate the CLB skin doses received during adjuvant RT of breast carcinoma. Twenty-four breast carcinoma patients treated locally or locoregionally with adjuvant RT were included. RT was performed with only tangential fields (TA) in 6 patients whereas 9 patients had an extra internal mammary (IM) field (TAIM). The remaining 9 patients received 5-field locoregional RT (5FLR). All patients were treated with wedge filters except for 3 TA patients. Of 9 5FLR patients IM fields were treated with Co60 in 5 and with electrons in the remaining 4 patients. LiF(2)-based Ribbon type thermoluminescent dosimeters (TLD) were used for dose evaluation. An average of 10 TLD's, placed with 1 cm gaps beginning from the medial border of the treatment field along the central axis were used to obtain dose measurements. Median measure of TLD's between 2-8 cm and maximum dose point (MDP) values in the same range were used to evaluate the CLB dose. In TA patients the CLB skin received 6.3% of the total dose in patients treated with wedge filters and 7.13% with half-beam blocks. For 6 TAIM patients with IM fields treated with Co60, the CLB dose was 7.24%. In 5 of 9 5FLR patients, whose IM fields were treated with Co60 the CLB skin received 8.8% of the total dose, while for electron beam therapy the CLB dose was 5.44%. CLB median MDP values were as follows: 12.76% in TA patients treated with wedge filters and 11.45% with half-beam blocking; 11.89% in TAIM patients with IM fields treated with Co60 and 7.83% with electron beams; 12.29% in 5FLR patients of whose IM fields were treated with Co60 and 8.94% with electron beams. When compared to wedge filters, halfbeam blocks caused 13% increase in CLB doses. If IM fields were added, 27.5% and 62% increases at CLB doses were established with Co60 when compared to electron beam RT in 3-field and 5-field treatments, respectively. CLB doses increased by 15-40% with the increased number of treatment fields. MDP values were also found to be higher with IM fields treated with Co60, but the number of treatment fields and accessories used seemed to have no effect on MDP doses. We conclude that by using wedge filters instead of half-beam blocks and by increasing the number of fractions treated with electron energies for IM fields, apparent decreases in CLB doses can be obtained. Large number of cases is needed to statistically establish the significant differences between subgroups.

Single-dose pharmacokinetic properties of esomeprazole in children aged 1 - 11 years with endoscopically proven GERD: a randomized, open-label study.

PubMed

Youssef, Nader N; Tron, Eduardo; Tolia, Vasundhara; Hamer-Maansson, Jennifer E; Lundborg, Per; Illueca, Marta

2014-11-01

To assess the overall exposure after a single dose of esomeprazole in children with gastroesophageal reflux disease (GERD). Oral esomeprazole administered as an intact capsule with 30 - 180 mL of water, or as an opened capsule mixed with as much as 1 tablespoon of applesauce followed by 30 - 180 mL of water. In this randomized, open-label study of children aged 1 - 11 years with endoscopically proven GERD, patients weighing 8 - < 20 kg were randomized to a single 5- or 10-mg oral dose of esomeprazole, and patients weighing >= 20 kg were randomized to a single 10- or 20-mg oral dose of esomeprazole. Esomeprazole exposure (AUC(0-∞)), AUC from zero to last measurable concentration (AUC(0-t)), maximum plasma concentration (C(max)), time to C(max) (t(max)), terminal-phase half-life, apparent oral clearance, and apparent volume of distribution were determined. 28 patients were randomized to receive esomeprazole: 14 patients weighing 8 to < 20 kg received esomeprazole 5 mg (n = 7) or 10 mg (n = 7), and 14 patients weighing ≥20 kg received esomeprazole 10 mg (n = 6) or 20 mg (n = 8). Children weighing 8 - < 20 kg had a 1.8-fold higher exposure with the 10-mg vs. 5-mg dose (AUC(0-∞), 1.32 vs. 0.73 μmol·h/L, respectively); children weighing ≥ 20 kg had a 4.4-fold higher exposure with the 20-mg vs. 10-mg dose (AUC(0-∞), 3.06 vs. 0.69 μmol·h/L). C(max) was 2.2-fold higher for the 10-mg vs. 5-mg dose (8 to < 20 kg) and 2.4-fold higher for the 20-mg vs.10-mg dose (>= 20 kg). The pharmacokinetics of single-dose esomeprazole were dose-dependent in children weighing >= 20 kg but not in children weighing 8 to < 20 kg.

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

PubMed

Atkins, Michael B; Plimack, Elizabeth R; Puzanov, Igor; Fishman, Mayer N; McDermott, David F; Cho, Daniel C; Vaishampayan, Ulka; George, Saby; Olencki, Thomas E; Tarazi, Jamal C; Rosbrook, Brad; Fernandez, Kathrine C; Lechuga, Mariajose; Choueiri, Toni K

2018-03-01

Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). Pfizer Inc. Copyright © 2018 Elsevier Ltd. All rights reserved.

Platelet Aggregation Inhibitory Effects and Pharmacokinetics of Prasugrel Used in Combination With Aspirin in Healthy Japanese Subjects.

PubMed

Umemura, Kazuo; Ikeda, Yasuhiko; Matsushima, Nobuko; Kondo, Kazunao

2017-07-01

We evaluated the pharmacokinetics and pharmacodynamics of prasugrel used in combination with aspirin in healthy Japanese subjects. All subjects received aspirin 100 mg/day. Subsequently, in the single-administration study, 23 subjects also received prasugrel 20 or 30 mg, and in the multiple-administration study, 20 subjects received a loading dose of prasugrel 20 or 30 mg on day 1, followed by a maintenance dose of prasugrel 5 or 7.5 mg/day, respectively, on days 2-5. In both studies, the plasma concentration of the active metabolite of prasugrel, R-138727, reached a maximum 0.5 hours after administration and rapidly decreased within 4 hours. In the single-administration study, the inhibitory effect on adenosine diphosphate-induced platelet aggregation was significantly higher in the prasugrel 20- and 30-mg groups than in the placebo group at all times (1-144 hours) after administration. In the multiple-administration study, a similar antiplatelet effect was found after both the loading dose and the maintenance dose and was maintained for 3-6 days after the last administration. There were study drug-related adverse events; however, all were mild, and none was clinically significant. © 2016 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turley, Jessica; Claridge Mackonis, Elizabeth

To evaluate in-field megavoltage (MV) imaging of simultaneously integrated boost (SIB) breast fields to determine its feasibility in treatment verification for the SIB breast radiotherapy technique, and to assess whether the current-imaging protocol and treatment margins are sufficient. For nine patients undergoing SIB breast radiotherapy, in-field MV images of the SIB fields were acquired on days that regular treatment verification imaging was performed. The in-field images were matched offline according to the scar wire on digitally reconstructed radiographs. The offline image correction results were then applied to a margin recipe formula to calculate safe margins that account for random andmore » systematic uncertainties in the position of the boost volume when an offline correction protocol has been applied. After offline assessment of the acquired images, 96% were within the tolerance set in the current department-imaging protocol. Retrospectively performing the maximum position deviations on the Eclipse™ treatment planning system demonstrated that the clinical target volume (CTV) boost received a minimum dose difference of 0.4% and a maximum dose difference of 1.4% less than planned. Furthermore, applying our results to the Van Herk margin formula to ensure that 90% of patients receive 95% of the prescribed dose, the calculated CTV margins were comparable to the current departmental procedure used. Based on the in-field boost images acquired and the feasible application of these results to the margin formula the current CTV-planning target volume margins used are appropriate for the accurate treatment of the SIB boost volume without additional imaging.« less

SU-E-T-284: Dose Plan Optimization When Using Hydrogel Prostate-Rectum Spacer: A Single Institution Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rajecki, M; Thurber, A; Catalfamo, F

2015-06-15

Purpose: To describe rectal dose reduction achieved and techniques used to take advantage of the increased peri-rectal spacing provided by injected polyethylene-glycol. Methods: Thirty prostate cancer patents were 2:1 randomized during a clinical trial to evaluate the effectiveness of injected poly-ethylene glycol hydrogel (SpaceOAR System) in creating space between the prostate and the anterior rectal wall. All patients received a baseline CT/MR scan and baseline IMRT treatment plan. Patients were randomized to receive hydrogel injection (n=20) or Control (n=10), followed by another CT/MR scan and treatment plan (single arc VMAT, 6 MV photons, 79.2 Gy, 44 fractions). Additional optimization structuresmore » were employed to constrain the dose to the rectum; specifically an avoidance structure to limit V75 <15%, and a control structure to limit the maximum relative dose <105% in the interface region of the anterior rectal wall and the prostate planning target volume. Dose volumetric data was analyzed for rectal volumes receiving 60 through 80 Gy. Results: Rectal dose reduction was observed in all patients who received the hydrogel. Volumetric analysis indicates a median rectal volume and (reduction from baseline plan) following spacer application of 4.9% (8.9%) at V60Gy, 3.8% (8.1%) at V65Gy, 2.5% (7.2%) at V70Gy, 1.6% (5.8%) at V75Gy, and 0.5% (2.5%) at V80Gy. Conclusion: Relative to planning without spacers, rectal dose constraints of 5%, 4%, 3%, 2%, 1% for V60, V65, V70, V75, and V80, should be obtainable when peri-rectal spacers are used. The combined effect of increased peri-rectal space provided by the hydrogel, with strict optimization objectives, resulted in reduced dose to the rectum. To maximize benefit, strict optimization objectives and reduced rectal dose constraints should be employed when creating plans for patients with perirectal spacers. Clinical Trial for SpaceOAR product conducted by Augmenix,Inc. The research site was paid to be a participating site.« less

Technical Note: Dosimetric evaluation of Monte Carlo algorithm in iPlan for stereotactic ablative body radiotherapy (SABR) for lung cancer patients using RTOG 0813 parameters.

PubMed

Pokhrel, Damodar; Badkul, Rajeev; Jiang, Hongyu; Kumar, Pravesh; Wang, Fen

2015-01-08

For stereotactic ablative body radiotherapy (SABR) in lung cancer patients, Radiation Therapy Oncology Group (RTOG) protocols currently require radiation dose to be calculated using tissue heterogeneity corrections. Dosimetric criteria of RTOG 0813 were established based on the results obtained from non-Monte Carlo (MC) algorithms, such as superposition/convolutions. Clinically, MC-based algorithms are now routinely used for lung SABR dose calculations. It is essential to confirm that MC calculations in lung SABR meet RTOG guidelines. This report evaluates iPlan MC plans for SABR in lung cancer patients using dose-volume histogram normalization per current RTOG 0813 compliance criteria. Eighteen Stage I-II non-small cell lung cancer (NSCLC) patients with centrally located tumors, who underwent MC-based lung SABR with heterogeneity correction using X-ray Voxel Monte Carlo (XVMC) algorithm (BrainLAB iPlan version 4.1.2), were analyzed. Total dose of 60 Gy in 5 fractions was delivered to planning target volume (PTV) with at least V100% = 95%. Internal target volumes (ITVs) were delineated on maximum intensity projection (MIP) images of 4D CT scans. PTV (ITV + 5 mm margin) volumes ranged from 10.0 to 99.9 cc (mean = 36.8 ± 20.7 cc). Organs at risk (OARs) were delineated on average images of 4D CT scans. Optimal clinical MC SABR plans were generated using a combination of non-coplanar conformal arcs and beams for the Novalis-TX consisting of high definition multileaf collimators (MLCs) and 6 MV-SRS (1000 MU/min) mode. All plans were evaluated using the RTOG 0813 high and intermediate dose spillage criteria: conformity index (R100%), ratio of 50% isodose volume to the PTV (R50%), maximum dose 2 cm away from PTV in any direction (D2 cm), and percent of normal lung receiving 20 Gy (V20) or more. Other organs-at-risk (OARs) doses were tabulated, including the volume of normal lung receiving 5 Gy (V5), maximum cord dose, dose to < 15 cc of heart, and dose to <5 cc of esophagus. Only six out of 18 patients met all RTOG 0813 compliance criteria. Eight of 18 patients had minor deviations in R100%, four in R50%, and nine in D2 cm. However, only one patient had minor deviation in V20. All other OARs doses, such as maximum cord dose, dose to < 15 cc of heart, and dose to < 5 cc of esophagus, were satisfactory for RTOG criteria, except for one patient, for whom the dose to < 15 cc of heart was higher than RTOG guidelines. The preliminary results for our limited iPlan XVMC dose calculations indicate that the majority (i.e., 2/3) of our patients had minor deviations in the dosimetric guidelines set by RTOG 0813 protocol in one way or another. When using an exclusive highly sophisticated XVMC algorithm, the RTOG 0813 dosimetric compliance criteria such as R100% and D2 cm may need to be revisited. Based on our limited number of patient datasets, in general, about 6% for R100% and 9% for D2 cm corrections could be applied to pass the RTOG 0813 compliance criteria in most of those patients. More patient plans need to be evaluated to make recommendation for R50%. No adjustment is necessary for OAR dose tolerances, including normal lung V20. In order to establish new MC specific dose parameters, further investigation with a large cohort of patients including central, as well as peripheral lung tumors, is anticipated and strongly recommended.

Soft-tissue allografts terminally sterilized with an electron beam are biomechanically equivalent to aseptic, nonsterilized tendons.

PubMed

Elenes, Egleide Y; Hunter, Shawn A

2014-08-20

Allograft safety is contingent on effective sterilization. However, current sterilization methods have been associated with decreased biomechanical strength and higher failure rates of soft-tissue allografts. In this study, electron beam (e-beam) sterilization was explored as an alternative sterilization method to preserve biomechanical integrity. We hypothesized that e-beam sterilization would not significantly alter the biomechanical properties of tendon allograft compared with aseptic, nonsterilized controls and gamma-irradiated grafts. Separate sets of forty fresh-frozen tibialis tendon allografts (four from each of ten donors) and forty bisected bone-patellar tendon-bone (BTB) allografts (four from each of ten donors) were randomly assigned to four study groups. One group received a 17.1 to 21.0-kGy gamma radiation dose; two other groups were sterilized with an e-beam at either a high (17.1 to 21.0-kGy) or low (9.2 to 12.2-kGy) dose. A fourth group served as nonsterilized controls. Each graft was cyclically loaded to 200 N of tension for 2000 cycles at a frequency of 2 Hz, allowed to relax for five minutes, and then tested in tension until failure at a 100%/sec strain rate. One-way analysis of variance testing was used to identify significant differences. Tibialis tendons sterilized with both e-beam treatments and with gamma irradiation exhibited values for cyclic tendon elongation, maximum load, maximum displacement, stiffness, maximum stress, maximum strain, and elastic modulus that were not significantly different from those of nonsterilized controls. BTB allografts sterilized with the high e-beam dose and with gamma irradiation were not significantly different in cyclic tendon elongation, maximum load, maximum displacement, stiffness, maximum stress, maximum strain, and elastic modulus from nonsterilized controls. BTB allografts sterilized with the e-beam at the lower dose were significantly less stiff than nonsterilized controls (p = 0.014) but did not differ from controls in any other properties. The difference in stiffness likely resulted from variations in tendon size rather than the treatments, as the elastic moduli of the groups were similar. The biomechanical properties of tibialis and BTB allografts sterilized with use of an e-beam at a dose range of 17.1 to 21.0 kGy were not different from those of aseptic, nonsterilized controls or gamma-irradiated allografts. E-beam sterilization can be a viable method to produce safe and biomechanically uncompromised soft-tissue allografts. Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.

Radiation exposure during scoliosis screening radiography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nottage, W.M.; Waugh, T.R.; McMaster, W.C.

Screening programs to detect scoliosis in the adolescent population are active in most communities. Two percent of children screened will be referred for treatment or observation. Increasing concern has been voiced regarding the amount of the potential effects of the radiation administered in such screening programs. Radiation dosage was directly measured on 19 children participating in an established school scoliosis screening program, using lithium fluoride thermoluminescence dosimeters. The mean gonadal doses are measured to be 19 mrem in males and estimated at a maximum 95 mrem in females. The mean entrance skin dose was 174 mrem. A lack of uniformitymore » in the radiographic techniques employed by individual technician was identified. The measured doses were within established acceptable limits and are comparable or below the average dose of 100 mrem received annually by the general public from the environment.« less

Dosimetry during intramedullary nailing of the tibia

PubMed Central

2009-01-01

Background Intramedullary nailing under fluoroscopic guidance is a common operation. We studied the intraoperative radiation dose received by both the patient and the personnel. Patients and methods 25 intramedullary nailing procedures of the tibia were studied. All patients suffered from tibial fractures and were treated using the Grosse-Kempf intramedullary nail, with free-hand technique for fixation of the distal screws, under fluoroscopic guidance. The exposure, at selected positions, was recorded using an ion chamber, while the dose area product (DAP) was measured with a DAP meter, attached to the tube head. Thermoluminescent dosimeters (TLDs) were used to derive the occupational dose to the personnel, and also to monitor the surface dose on the gonads of some of the patients. Results The mean operation time was 101 (48–240) min, with a mean fluoroscopic time of 72 seconds and a mean DAP value of 75 cGy·cm2. The surface dose to the gonads of the patients was less than 8.8 mGy during any procedure, and thus cannot be considered to be a contraindication for the use of this technique. Occupational dose differed substantially between members of the operating personnel, the maximum dose recorded being to the operator of the fluoroscopic equipment (0.11 mSv). Interpretation Our findings underscore the care required by the primary operator not to exceed the dose constraint of 10 mSv per year. The rest of the operating personnel, although they do not receive very high doses, should focus on the dose optimization of the technique. PMID:19916691

SU-E-T-558: Assessing the Effect of Inter-Fractional Motion in Esophageal Sparing Plans.

PubMed

Williamson, R; Bluett, J; Niedzielski, J; Liao, Z; Gomez, D; Court, L

2012-06-01

To compare esophageal dose distributions in esophageal sparing IMRT plans with predicted dose distributions which include the effect of inter-fraction motion. Seven lung cancer patients were used, each with a standard and an esophageal sparing plan (74Gy, 2Gy fractions). The average max dose to esophagus was 8351cGy and 7758cGy for the standard and sparing plans, respectively. The average length of esophagus for which the total circumference was treated above 60Gy (LETT60) was 9.4cm in the standard plans and 5.8cm in the sparing plans. In order to simulate inter-fractional motion, a three-dimensional rigid shift was applied to the calculated dose field. A simulated course of treatment consisted of a single systematic shift applied throughout the treatment as well a random shift for each of the 37 fractions. Both systematic and random shifts were generated from Gaussian distributions of 3mm and 5mm standard deviation. Each treatment course was simulated 1000 times to obtain an expected distribution of the delivered dose. Simulated treatment dose received by the esophagus was less than dose seen in the treatment plan. The average reduction in maximum esophageal dose for the standard plans was 234cGy and 386cGY for the 3mm and 5mm Gaussian distributions, respectively. The average reduction in LETT60 was 0.6cm and 1.7cm, for the 3mm and 5mm distributions respectively. For the esophageal sparing plans, the average reduction in maximum esophageal dose was 94cGy and 202cGy for 3mm and 5mm Gaussian distributions, respectively. The average change in LETT60 for the esophageal sparing plans was smaller, at 0.1cm (increase) and 0.6cm (reduction), for the 3mm and 5mm distributions, respectively. Interfraction motion consistently reduced the maximum doses to the esophagus for both standard and esophageal sparing plans. © 2012 American Association of Physicists in Medicine.

The effect of intraoperative administration of dexamethasone for PONV prophylaxis on perioperative blood glucose level in obese and normal weight children.

PubMed

Gnatzy, Richard; Hempel, Gunther; Kaisers, Udo X; Höhne, Claudia

2015-11-01

The incidence of postoperative nausea and vomiting (PONV) can be reduced by dexamethasone. Single-dose administration may cause elevated blood glucose levels in obese adults. No data are available for children. The aim was to evaluate perioperative blood glucose changes related to body weight in children who received dexamethasone. This prospective observational study included 62 children. All patients received total intravenous anesthesia and a single dose of dexamethasone (0.15 mg/kg, maximum 8 mg). Blood glucose levels were measured up to 6 h. Standard deviation scores (SDS) were calculated using age- and gender-specific body mass index (BMI) percentiles, p<0.05. A total of 62 children (11.5±2.9 years, median SDS 0.43, 29% overweight/obese) were included. Blood glucose levels increased from 5.52±0.52 to 6.74±0.84 mmol/L 6 h after dexamethasone without correlation to the BMI-SDS. This study showed an increase of perioperative blood glucose (normoglycemic ranges) after single dose of dexamethasone, but no BMI-dependent effect was observed in children. Therefore, low-dose dexamethasone may be used in obese children for PONV prophylaxis.

Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers.

PubMed

Rice, David; Heil, Justin W; Biernat, Lukasz

2017-03-01

Liposomal bupivacaine is indicated for administration into the surgical site to produce post-surgical analgesia. The objectives of this study were to characterize the pharmacokinetic and safety profiles of liposomal bupivacaine following a repeated dose in healthy volunteers. Healthy adults were assigned to receive liposomal bupivacaine via subcutaneous infiltration in a single 266 mg dose (cohort 1) or in two 266 mg doses, with the second dose given immediately, 24, 48, or 72 h after the first dose (cohorts 2-5). Pharmacokinetic parameters were estimated from blood samples collected up to day 14. Subjects were monitored for adverse events and assessed for neurologic function, cardiac function, and infiltration area abnormalities. Twelve subjects were assigned to each cohort. The mean ± standard deviation maximum observed plasma concentration (C max ) of bupivacaine after a single dose was 129 ± 47 ng/mL. The mean C max after the second dose was higher, but always less than double the C max for cohort 1. The highest individual C max (589 ng/mL) was observed in a subject who received the second dose 24 h after the first dose (cohort 4), but was well below the reported thresholds for neurotoxicity and cardiac toxicity (2000 and 4000 ng/mL, respectively). A single and repeated dose were well-tolerated, and there were no clinically meaningful findings regarding neurologic examinations and electrocardiography. The mean C max following a repeated dose of liposomal bupivacaine remained well below accepted values for central nervous system and cardiac toxicity. Liposomal bupivacaine was well-tolerated and revealed no clinically important safety signals. CLINICALTRIALS. NCT02210247.

Inadvertent Intruder Analysis For The Portsmouth On-Site Waste Disposal Facility (OSWDF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Frank G.; Phifer, Mark A.

2014-01-22

The inadvertent intruder analysis considers the radiological impacts to hypothetical persons who are assumed to inadvertently intrude on the Portsmouth OSWDF site after institutional control ceases 100 years after site closure. For the purposes of this analysis, we assume that the waste disposal in the OSWDF occurs at time zero, the site is under institutional control for the next 100 years, and inadvertent intrusion can occur over the following 1,000 year time period. Disposal of low-level radioactive waste in the OSWDF must meet a requirement to assess impacts on such individuals, and demonstrate that the effective dose equivalent to anmore » intruder would not likely exceed 100 mrem per year for scenarios involving continuous exposure (i.e. chronic) or 500 mrem for scenarios involving a single acute exposure. The focus in development of exposure scenarios for inadvertent intruders was on selecting reasonable events that may occur, giving consideration to regional customs and construction practices. An important assumption in all scenarios is that an intruder has no prior knowledge of the existence of a waste disposal facility at the site. Results of the analysis show that a hypothetical inadvertent intruder at the OSWDF who, in the worst case scenario, resides on the site and consumes vegetables from a garden established on the site using contaminated soil (chronic agriculture scenario) would receive a maximum chronic dose of approximately 7.0 mrem/yr during the 1000 year period of assessment. This dose falls well below the DOE chronic dose limit of 100 mrem/yr. Results of the analysis also showed that a hypothetical inadvertent intruder at the OSWDF who, in the worst case scenario, excavates a basement in the soil that reaches the waste (acute basement construction scenario) would receive a maximum acute dose of approximately 0.25 mrem/yr during the 1000 year period of assessment. This dose falls well below the DOE acute dose limit of 500 mrem/yr. Disposal inventory constraints based on the intruder analysis are well above conservative estimates of the OSWDF inventory and, based on intruder disposal limits; about 7% of the disposal capacity is reached with the estimated OSWDF inventory.« less

Total target volume is a better predictor of whole brain dose from gamma stereotactic radiosurgery than the number, shape, or location of the lesions

PubMed Central

Narayanasamy, Ganesh; Smith, Adam; Van Meter, Emily; McGarry, Ronald; Molloy, Janelle A.

2013-01-01

Purpose: To assess the hypothesis that the volume of whole brain that receives a certain dose level is primarily dependent on the treated volume rather than on the number, shape, or location of the lesions. This would help a physician validate the suitability of GammaKnife® based stereotactic radiosurgery (GKSR) prior to treatment. Methods: Simulation studies were performed to establish the hypothesis for both oblong and spherical shaped lesions of various numbers and sizes. Forty patients who underwent GKSR [mean age of 54 years (range 7–80), mean number of lesions of 2.5 (range 1–6), and mean lesion volume of 4.4 cm3 (range 0.02–22.2 cm3)] were also studied retrospectively. Following recommendations of QUANTEC, the volume of brain irradiated by the 12 Gy (VB12) isodose line was measured and a power-law based relation is proposed here for estimating VB12 from the known tumor volume and the prescription dose. Results: In the simulation study on oblong, spherical, and multiple lesions, the volume of brain irradiated by 50%, 10%, and 1% of maximum dose was found to have linear, linear, and exponentially increasing dependence on the volume of the treated region, respectively. In the retrospective study on 40 GKSR patients, a similar relationship was found to predict the brain dose with a Spearman correlation coefficient >0.9. In both the studies, the volume of brain irradiated by a certain dose level does not have a statistically significant relationship (p ≥ 0.05) with the number, shape, or position of the lesions. The measured VB12 agrees with calculation to within 1.7%. Conclusions: The results from the simulation and the retrospective clinical studies indicate that the volume of whole brain that receives a certain percentage of the maximum dose is primarily dependent on the treated volume and less on the number, shape, and location of the lesions. PMID:24007147

Single-Dose and Multiple-Dose Pharmacokinetics of Nicotine 6 mg Gum.

PubMed

Hansson, Anna; Rasmussen, Thomas; Kraiczi, Holger

2017-04-01

Under-dosing is a recognized problem with current nicotine replacement therapy (NRT). Therefore, a new 6mg nicotine gum has been developed. To compare the nicotine uptake from the 6mg gum versus currently available NRT products, two pharmacokinetic studies were performed. In one randomized crossover study, 44 healthy adult smokers received single doses of 6, 4, and 2mg nicotine gum, and 4mg nicotine lozenge on separate occasions. In a separate randomized crossover multiple-dose study over 11 hours, 50 healthy adult smokers received one 6mg gum every hour and 90 minutes, respectively, one 4mg gum every hour, and one 4mg lozenge every hour. In both studies, blood samples were collected over 12 hours to determine single-dose and multiple-dose pharmacokinetic variables. In the single-dose study, the amount of nicotine released from the 2, 4, and 6mg gums (1.44, 3.36, and 4.94mg) as well as the resulting maximum concentration and area under the curve (5.9, 10.1, and 13.8ng/mL, and 17.1, 30.7, 46.2ng/mL × h, respectively) increased with dose. The maximum concentration and area under the curve of the 6mg gum were 44% and 30% greater, respectively, than those for 4mg lozenge. Upon hourly administration, the steady-state average plasma nicotine concentration with 6mg gum (37.4ng/mL) was significantly higher than those for 4mg lozenge (28.3ng/mL) and 4mg gum (27.1ng/mL). Nicotine delivery via the 6mg gum results in higher plasma nicotine concentrations after a single dose and at steady state than with currently available oral NRT. Under-dosing is a recognized problem with current NRT. Therefore, a new 6mg nicotine gum has been developed. Our studies show that upon single-dose and multiple-dose administration, the 6mg gum releases and delivers more nicotine to the systemic circulation than 2mg gum, 4mg gum, and 4mg lozenge. Thus, each 6mg nicotine gum provides a higher degree of nicotine substitution and/or lasts for a longer period of time than currently available nicotine gums and lozenges. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Occupational exposures in two industrial plants devoted to the production of ammonium phosphate fertilisers.

PubMed

Bolívar, J P; García-Tenorio, R; Mosqueda, F; Gázquez, M J; López-Coto, I; Adame, J A; Vaca, F

2013-03-01

In order to fill a gap in the open literature, occupational exposures and activity concentrations have been assessed in two NORM industrial plants, located in the south-west of Spain, devoted to the production of mono-ammonium phosphate (MAP) and di-ammonium phosphate (DAP) fertilisers. The annual effective doses received by the workers from these plants are clearly below 1 mSv yr(-1) and the contribution due to external radiation is similar to that due to inhalation. The contribution to the maximum effective doses due to inhalation of particulate matter has been estimated to be about 0.12 mSv yr(-1), while the (222)Rn concentrations inside the plants are of no concern. Consequently, no additional actions or radiological protection measures need to be taken to decrease the natural radiation received by the workers in these facilities.

Effect of dose timing in relation to food intake on systemic exposure to blonanserin.

PubMed

Saruwatari, Junji; Yasui-Furukori, Norio; Inoue, Yoshimasa; Kaneko, Sunao

2010-09-01

Blonanserin is a novel potent dopamine D(2) and serotonin 5-HT(2) antagonist for treating schizophrenia. The aim of this study was to investigate prandial effects on systemic exposure to blonanserin in healthy volunteers, with particular attention paid to the effect of dose timing relative to meal intake. Volunteers received a single 2-mg oral dose of blonanserin under the following conditions: fasting, 30 min before eating a standard meal; or 30 min or 2 or 4 h after eating the meal. Plasma concentrations of blonanserin were measured using validated high-performance liquid chromatography coupled with tandem mass spectrometry. Ratios and 90% confidence intervals of the geometric means compared with the fasting condition indicated that the maximum concentrations of blonanserin (C(max)) significantly increased with dosing 30 min before meal intake, and 30 min and 2 and 4 h after meal intake, yielding by 330%, 239%, 272%, and 138%, respectively. The truncated area under the concentration-time curve (AUC(last)) also increased by 386%, 201%, 256%, and 155%, respectively. There was no difference in values of the time to reach maximum concentration between the fasting and the four fed states. Food intake increased the systemic exposure to blonanserin for all time intervals investigated in this study. The marked effect of food on the bioavailability of blonanserin should be taken into account in its dosing schedules.

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PubMed Central

Merchant, Melinda S.; Geller, James I.; Baird, Kristin; Chou, Alexander J.; Galli, Susana; Charles, Ava; Amaoko, Martha; Rhee, Eunice H.; Price, Anita; Wexler, Leonard H.; Meyers, Paul A.; Widemann, Brigitte C.; Tsokos, Maria; Mackall, Crystal L.

2012-01-01

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. PMID:23071222

Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers.

PubMed

Rueangweerayut, Ronnatrai; Bancone, Germana; Harrell, Emma J; Beelen, Andrew P; Kongpatanakul, Supornchai; Möhrle, Jörg J; Rousell, Vicki; Mohamed, Khadeeja; Qureshi, Ammar; Narayan, Sushma; Yubon, Nushara; Miller, Ann; Nosten, François H; Luzzatto, Lucio; Duparc, Stephan; Kleim, Jörg-Peter; Green, Justin A

2017-09-01

Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol 487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects ( N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [ N = 3]) and primaquine (-1.25 to -3.0 g/dL [ N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% ( N = 2) and > 80% ( N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer.

PubMed

Daga, Haruko; Takeda, Koji; Okada, Hideaki; Miyazaki, Masaki; Ueda, Shinya; Kaneda, Hiroyasu; Okamoto, Isamu; Yoh, Kiyotaka; Goto, Koichi; Konishi, Koichi; Sarashina, Akiko; Tanaka, Tetsuya; Kaiser, Rolf; Nakagawa, Kazuhiko

2015-12-01

This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After ≥4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was <33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade ≥3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.

Implications of free breathing motion assessed by 4D-computed tomography on the delivered dose in radiotherapy for esophageal cancer.

PubMed

Duma, Marciana Nona; Berndt, Johannes; Rondak, Ina-Christine; Devecka, Michal; Wilkens, Jan J; Geinitz, Hans; Combs, Stephanie Elisabeth; Oechsner, Markus

2015-01-01

The aim of this study was to assess the effect of breathing motion on the delivered dose in esophageal cancer 3-dimensional (3D)-conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). We assessed 16 patients with esophageal cancer. All patients underwent 4D-computed tomography (4D-CT) for treatment planning. For each of the analyzed patients, 1 3D-CRT, 1 IMRT, and 1 VMAT (RapidArc-RA) plan were calculated. Each of the 3 initial plans was recalculated on the 4D-CT (for the maximum free inspiration and maximum free expiration) to assess the effect of breathing motion. We assessed the minimum dose (Dmin) and mean dose (Dmean) to the esophagus within the planning target volume, the volume changes of the lungs, the Dmean and the total lung volume receiving at least 40Gy (V40), and the V30, V20, V10, and V5. For the heart we assessed the Dmean and the V25. Over all techniques and all patients the change in Dmean as compared with the planned Dmean (planning CT [PCT]) to the esophagus was 0.48% in maximum free inspiration (CT_insp) and 0.55% in maximum free expiration (CT_exp). The Dmin CT_insp change was 0.86% and CT_exp change was 0.89%. The Dmean change of the lungs (heart) was in CT_insp 1.95% (2.89%) and 3.88% (2.38%) in CT_exp. In all, 4 patients had a clinically relevant change of the dose (≥ 5% Dmean to the heart and the lungs) between inspiration and expiration. These patients had a very cranially or caudally situated tumor. There are no relevant differences in the delivered dose to the regions of interest among the 3 techniques. Breathing motion management could be considered to achieve a better sparing of the lungs or heart in patients with cranially or caudally situated tumors. Copyright © 2015 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Implications of free breathing motion assessed by 4D-computed tomography on the delivered dose in radiotherapy for esophageal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duma, Marciana Nona, E-mail: Marciana.Duma@mri.tum.de; Berndt, Johannes; Rondak, Ina-Christine

2015-01-01

The aim of this study was to assess the effect of breathing motion on the delivered dose in esophageal cancer 3-dimensional (3D)-conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). We assessed 16 patients with esophageal cancer. All patients underwent 4D-computed tomography (4D-CT) for treatment planning. For each of the analyzed patients, 1 3D-CRT, 1 IMRT, and 1 VMAT (RapidArc—RA) plan were calculated. Each of the 3 initial plans was recalculated on the 4D-CT (for the maximum free inspiration and maximum free expiration) to assess the effect of breathing motion. We assessed the minimum dose (D{sub min})more » and mean dose (D{sub mean}) to the esophagus within the planning target volume, the volume changes of the lungs, the D{sub mean} and the total lung volume receiving at least 40 Gy (V{sub 40}), and the V{sub 30}, V{sub 20}, V{sub 10}, and V{sub 5}. For the heart we assessed the D{sub mean} and the V{sub 25}. Over all techniques and all patients the change in D{sub mean} as compared with the planned D{sub mean} (planning CT [PCT]) to the esophagus was 0.48% in maximum free inspiration (CT-insp) and 0.55% in maximum free expiration (CT-exp). The D{sub min} CT-insp change was 0.86% and CT-exp change was 0.89%. The D{sub mean} change of the lungs (heart) was in CT-insp 1.95% (2.89%) and 3.88% (2.38%) in CT-exp. In all, 4 patients had a clinically relevant change of the dose (≥ 5% D{sub mean} to the heart and the lungs) between inspiration and expiration. These patients had a very cranially or caudally situated tumor. There are no relevant differences in the delivered dose to the regions of interest among the 3 techniques. Breathing motion management could be considered to achieve a better sparing of the lungs or heart in patients with cranially or caudally situated tumors.« less

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Single-Dose, Open-Label Study of the Pharmacokinetics, Safety, and Tolerability of Lisdexamfetamine Dimesylate in Individuals With Normal and Impaired Renal Function

PubMed Central

Ermer, James; Corcoran, Mary; Lasseter, Kenneth; Marbury, Thomas; Yan, Brian

2016-01-01

Background: Lisdexamfetamine (LDX) and d-amphetamine pharmacokinetics were assessed in individuals with normal and impaired renal function after a single LDX dose; LDX and d-amphetamine dialyzability was also examined. Methods: Adults (N = 40; 8/group) were enrolled in 1 of 5 renal function groups [normal function, mild impairment, moderate impairment, severe impairment/end-stage renal disease (ESRD) not requiring hemodialysis, and ESRD requiring hemodialysis] as estimated by glomerular filtration rate (GFR). Participants with normal and mild to severe renal impairment received 30 mg LDX; blood samples were collected predose and serially for 96 hours. Participants with ESRD requiring hemodialysis received 30 mg LDX predialysis and postdialysis separated by a washout period of 7–14 days. Predialysis blood samples were collected predose, serially for 72 hours, and from the dialyzer during hemodialysis; postdialysis blood samples were collected predose and serially for 48 hours. Pharmacokinetic end points included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from time 0 to infinity (AUC0–∞) or to last assessment (AUClast). Results: Mean LDX Cmax, AUClast, and AUC0–∞ in participants with mild to severe renal impairment did not differ from those with normal renal function; participants with ESRD had higher mean Cmax and AUClast than those with normal renal function. d-amphetamine exposure (AUClast and AUC0–∞) increased and Cmax decreased as renal impairment increased. Almost no LDX and little d-amphetamine were recovered in the dialyzate. Conclusions: There seems to be prolonged d-amphetamine exposure after 30 mg LDX as renal impairment increases. In individuals with severe renal impairment (GFR: 15 ≤ 30 mL·min−1·1.73 m−2), the maximum LDX dose is 50 mg/d; in patients with ESRD (GFR: <15 mL·min−1·1.73 m−2), the maximum LDX dose is 30 mg/d. Neither LDX nor d-amphetamine is dialyzable. PMID:26926668

Planning comparison between intensity modulated radiation therapy and intensity modulated proton therapy in a case of head and neck cancer

NASA Astrophysics Data System (ADS)

Nguyen, T. T. C.; Nguyen, B. T.; Mai, N. V.

2018-03-01

In this work, we made the comparison between IMRT plan and IMPT plan for a head and neck case. We used Prowess Panther to perform IMRT plan and LAP- CERR for IMPT plan. The result showed that IMPT plan had better coverage than IMRT plan. In the IMRT plan, normal structures received higher dose with higher volume. Especially, the maximum dose of spinal cord is 31.5 Gy (RBE) using IMRT technique compared to 13.5 Gy (RBE) using IMPT technique. These results showed that IMPT is beneficial for head and neck cancer compared to IMRT technique.

SU-F-T-188: A Robust Treatment Planning Technique for Proton Pencil Beam Scanning Cranial Spinal Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, M; Mehta, M; Badiyan, S

2016-06-15

Purpose: To propose a proton pencil beam scanning (PBS) cranial spinal irradiation (CSI) treatment planning technique robust against patient roll, isocenter offset and proton range uncertainty. Method: Proton PBS plans were created (Eclipse V11) for three previously treated CSI patients to 36 Gy (1.8 Gy/fractions). The target volume was separated into three regions: brain, upper spine and lower spine. One posterior-anterior (PA) beam was used for each spine region, and two posterior-oblique beams (15° apart from PA direction, denoted as 2PO-15) for the brain region. For comparison, another plan using one PA beam for the brain target (denoted as 1PA)more » was created. Using the same optimization objectives, 98% CTV was optimized to receive the prescription dose. To evaluate plan robustness against patient roll, the gantry angle was increased by 3° and dose was recalculated without changing the proton spot weights. On the re-calculated plan, doses were then calculated using 12 scenarios that are combinations of isocenter shift (±3mm in X, Y, and Z directions) and proton range variation (±3.5%). The worst-case-scenario (WCS) brain CTV dosimetric metrics were compared to the nominal plan. Results: For both beam arrangements, the brain field(s) and upper-spine field overlap in the T2–T5 region depending on patient anatomy. The maximum monitor unit per spot were 48.7%, 47.2%, and 40.0% higher for 1PA plans than 2PO-15 plans for the three patients. The 2PO-15 plans have better dose conformity. At the same level of CTV coverage, the 2PO-15 plans have lower maximum dose and higher minimum dose to the CTV. The 2PO-15 plans also showed lower WCS maximum dose to CTV, while the WCS minimum dose to CTV were comparable between the two techniques. Conclusion: Our method of using two posterior-oblique beams for brain target provides improved dose conformity and homogeneity, and plan robustness including patient roll.« less

Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia.

PubMed

van der Westhuizen, J; Kuo, P Y; Reed, P W; Holder, K

2011-03-01

Gastric absorption of oral paracetamol (acetaminophen) may be unreliable perioperatively in the starved and stressed patient. We compared plasma concentrations of parenteral paracetamol given preoperatively and oral paracetamol when given as premedication. Patients scheduled for elective ear; nose and throat surgery or orthopaedic surgery were randomised to receive either oral or intravenous paracetamol as preoperative medication. The oral dose was given 30 minutes before induction of anaesthesia and the intravenous dose given pre-induction. All patients were given a standardised anaesthetic by the same specialist anaesthetist who took blood for paracetamol concentrations 30 minutes after the first dose and then at 30 minute intervals for 240 minutes. Therapeutic concentrations of paracetamol were reached in 96% of patients who had received the drug parenterally, and 67% of patients who had received it orally. Maximum median plasma concentrations were 19 mg.l(-1) (interquartile range 15 to 23 mg.l(-1)) and 13 mg.l(-1) (interquartile range 0 to 18 mg.l(-1)) for the intravenous and oral group respectively. The difference between intravenous and oral groups was less marked after 150 minutes but the intravenous preparation gave higher plasma concentrations throughout the study period. It can be concluded that paracetamol gives more reliable therapeutic plasma concentrations when given intravenously.

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.

PubMed

Vogl, Dan T; Martin, Thomas G; Vij, Ravi; Hari, Parameswaran; Mikhael, Joseph R; Siegel, David; Wu, Ka Lung; Delforge, Michel; Gasparetto, Cristina

2017-08-01

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m 2 . Dose-limiting toxicities (DLTs) at 2.4 mg/m 2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.

Antihyperlipidemic Effect of Different Fractions Obtained from Teucrium polium Hydroalcoholic Extract in Rats.

PubMed

Safaeian, Leila; Ghanadian, Mustafa; Shafiee-Moghadam, Zahra

2018-01-01

This study was aimed to screen the antihyperlipidemic effect of different fractions of Teucrium polium to obtain the most efficient herbal fraction for isolation of bioactive constituents responsible for hypolipidemic activity. Chloroform, butanol, and aqueous fractions were obtained from hydroalcoholic extract of T. polium aerial parts using partitioning process. To induce hyperlipidemia, dexamethasone (Dex) was injected 10 mg/kg/day (s.c.) for 8 days. In the test groups, animals received 50, 100 and 150 mg/kg of T. polium hydroalcoholic extract and different fractions orally simultaneously with Dex. Serum lipid profile and hepatic marker enzymes were evaluated using biochemical kits. All treatments, especially chloroform and aqueous fractions, reversed serum lipid markers in hyperlipidemic rats. Maximum reduction in triglyceride (60.2%, P < 0.001) and maximum elevation in high-density lipoprotein (HDL) (35.0%, P < 0.01) was observed for chloroform fraction. Maximum cholesterol-lowering effect (29.0%, P < 0.001) and maximum reduction in low-density lipoprotein were found for hydroalcoholic extract (72.9%, P < 0.001). Aqueous fraction improved all lipid markers at the highest dose. Butanol fraction decreased triglyceride at the lowest dose (43.9%, P < 0.001) and increased HDL (33%, P < 0.05) at the highest dose. There was a significant increase in alanine aminotransferase and aspartate aminotransferase levels in all tested groups compared to normal group ( P < 0.001). This study showed strong antihyperlipidemic effect of various fractions derived from hydroalcoholic extract of T. polium . Chloroform and aqueous fractions may be worthy candidates for isolation of bioactive hypolipidemic constituents. However, possible hepatotoxicity should be considered for clinical application.

Simulation of Dose to Surrounding Normal Structures in Tangential Breast Radiotherapy Due to Setup Error

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prabhakar, Ramachandran; Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi; Department of Radiology, All India Institute of Medical Sciences, New Delhi

Setup error plays a significant role in the final treatment outcome in radiotherapy. The effect of setup error on the planning target volume (PTV) and surrounding critical structures has been studied and the maximum allowed tolerance in setup error with minimal complications to the surrounding critical structure and acceptable tumor control probability is determined. Twelve patients were selected for this study after breast conservation surgery, wherein 8 patients were right-sided and 4 were left-sided breast. Tangential fields were placed on the 3-dimensional-computed tomography (3D-CT) dataset by isocentric technique and the dose to the PTV, ipsilateral lung (IL), contralateral lung (CLL),more » contralateral breast (CLB), heart, and liver were then computed from dose-volume histograms (DVHs). The planning isocenter was shifted for 3 and 10 mm in all 3 directions (X, Y, Z) to simulate the setup error encountered during treatment. Dosimetric studies were performed for each patient for PTV according to ICRU 50 guidelines: mean doses to PTV, IL, CLL, heart, CLB, liver, and percentage of lung volume that received a dose of 20 Gy or more (V20); percentage of heart volume that received a dose of 30 Gy or more (V30); and volume of liver that received a dose of 50 Gy or more (V50) were calculated for all of the above-mentioned isocenter shifts and compared to the results with zero isocenter shift. Simulation of different isocenter shifts in all 3 directions showed that the isocentric shifts along the posterior direction had a very significant effect on the dose to the heart, IL, CLL, and CLB, which was followed by the lateral direction. The setup error in isocenter should be strictly kept below 3 mm. The study shows that isocenter verification in the case of tangential fields should be performed to reduce future complications to adjacent normal tissues.« less

Radiation Dose-Volume Effects in the Stomach and Small Bowel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kavanagh, Brian D., E-mail: Brian.Kavanagh@ucdenver.ed; Pan, Charlie C.; Dawson, Laura A.

2010-03-01

Published data suggest that the risk of moderately severe (>=Grade 3) radiation-induced acute small-bowel toxicity can be predicted with a threshold model whereby for a given dose level, D, if the volume receiving that dose or greater (VD) exceeds a threshold quantity, the risk of toxicity escalates. Estimates of VD depend on the means of structure segmenting (e.g., V15 = 120 cc if individual bowel loops are outlined or V45 = 195 cc if entire peritoneal potential space of bowel is outlined). A similar predictive model of acute toxicity is not available for stomach. Late small-bowel/stomach toxicity is likely relatedmore » to maximum dose and/or volume threshold parameters qualitatively similar to those related to acute toxicity risk. Concurrent chemotherapy has been associated with a higher risk of acute toxicity, and a history of abdominal surgery has been associated with a higher risk of late toxicity.« less

Evaluation of serum theophylline concentrations following administration of sustained-release beads in applesauce to asthmatic preschool children.

PubMed

Leeder, J S; Robertson, C; Correia, J; Isles, A F; Levison, H; Macleod, S M

1986-02-01

A sustained-release theophylline preparation (Theo-Dur Sprinkle) was evaluated in young asthmatic patients aged 1 to 6 years and receiving a daily dose of 23.4 +/- 2.0 mg/kg (mean +/- SD) to determine, on the basis of serial serum concentrations obtained over a 12-hour dosing interval at steady state, the suitability of such a product in patients likely to metabolize the drug very rapidly. Peak theophylline concentrations of 15.1 +/- 4.1 mg/L were achieved 5.5 +/- 1.5 hours after dosing. The mean maximum to minimum concentration difference was 6.9 +/- 2.2 mg/L for the dosing interval studied. Fluctuations in theophylline concentration less than 100% were achieved in nine of the 12 study patients. Use of the "sprinkle-technique" with Theo-Dur Sprinkle appears to be a simple and effective method of maintaining acceptable fluctuations in serum theophylline concentrations in preschool asthmatic children.

SU-F-T-204: A Preliminary Approach of Reducing Contralateral Breast and Heart Dose in Left Sided Whole Breast Cancer Patients Utilizing Proton Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Islam, M; Algan, O; Jin, H

Purpose: To investigate the plan quality and feasibility of a hybrid plan utilizing proton and photon fields for superior coverage in the internal mammary (IM) and supraclavicular (S/C) regions while minimizing heart and contralateral breast dose for the left-sided whole breast cancer patient treatment. Methods: This preliminary study carried out on single left-sided intact breast patient involved IM and S/C nodes. The IM and S/C node fields of the 5-Field 3DCRT photon-electron base plan were replaced by two proton fields. These two along with two Field-in-Field tangential photon fields were optimized for comparable dose coverage. The treatment plans were donemore » using Eclipse TPS for the total dose of 46Gy in 23 fractions with 95% of the prescription dose covering 95% of the RTOG PTV. The 3DCRT photon-electron and 4-Field photon-proton hybrid plans were compared for the PTV dose coverage as well as dose to OARs. Results: The overall RTOG PTV coverage for proton-hybrid and 3DCRT plan was comparable (95% of prescription dose covers 95% PTV volume). In proton-hybrid plan, 99% of IM volume received 100% dose whereas in 3DCRT only 77% received 100% dose. For S/C regions, 97% and 77% volume received 100% prescription dose in proton-hybrid and 3DCRT plans, respectively. The heart mean dose, V3Gy(%), and V5Gy(%) was 2.2Gy, 14.4%, 9.8% for proton-hybrid vs. 4.20 Gy, 21.5%, and 39% for 3DCRT plan, respectively. The maximum dose to the contralateral breast was 39.75Gy for proton-hybrid while 56.87Gy for 3DCRT plan. The mean total lung dose, V20Gy(%), and V30Gy(%) was 5.68Gy, 11.3%, 10.5% for proton-hybrid vs. 5.90Gy, 9.8%, 7.2% for 3DCRT, respectively. Conclusion: The protonhybrid plan can offer better dose coverage to the involved lymphatic tissues while lower doses to the heart and contralateral breast. More treatment plans are currently in progress before being implemented clinically.« less

Low dose creatine supplementation enhances sprint phase of 400 meters swimming performance.

PubMed

Anomasiri, Wilai; Sanguanrungsirikul, Sompol; Saichandee, Pisut

2004-09-01

This study demonstrated the effect of low dose creatine supplement (10 g. per day) on the sprinting time in the last 50 meters of 400 meters swimming competition, as well as the effect on exertion. Nineteen swimmers in the experimental group received creatine monohydrate 5 g with orange solution 15 g, twice per day for 7 days and nineteen swimmers in the control group received the same quantity of orange solution. The results showed that the swimmers who received creatine supplement lessened the sprinting time in the last 50 meters of 400 meters swimming competition than the control group. (p<0.05). The results of Wingate test (anaerobic power, anaerobic capacity and fatigue index) compared between pre and post supplementation. There was significant difference at p<0.05 in the control group from training effect whereas there was significant difference at p<0.000 from training effect and creatine supplement in the experiment group. Therefore, the creatine supplement in amateur swimmers in the present study enhanced the physical performance up to the maximum capacity.

Intensity-modulated radiation therapy for pancreatic and prostate cancer using pulsed low–dose rate delivery techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Jie; Lang, Jinyi; Wang, Pei

2014-01-01

Reirradiation of patients who were previously treated with radiotherapy is vastly challenging. Pulsed low–dose rate (PLDR) external beam radiotherapy has the potential to reduce normal tissue toxicities while providing significant tumor control for recurrent cancers. This work investigates treatment planning techniques for intensity-modulated radiation therapy (IMRT)-based PLDR treatment of various sites, including cases with pancreatic and prostate cancer. A total of 20 patients with clinical recurrence were selected for this study, including 10 cases with pancreatic cancer and 10 with prostate cancer. Large variations in the target volume were included to test the ability of IMRT using the existing treatmentmore » planning system and optimization algorithm to deliver uniform doses in individual gantry angles/fields for PLDR treatments. Treatment plans were generated with 10 gantry angles using the step-and-shoot IMRT delivery technique, which can be delivered in 3-minute intervals to achieve an effective low dose rate of 6.7 cGy/min. Instead of dose constraints on critical structures, ring structures were mainly used in PLDR-IMRT optimization. In this study, the PLDR-IMRT plans were compared with the PLDR-3-dimensional conformal radiation therapy (3DCRT) plans and the PLDR-RapidArc plans. For the 10 cases with pancreatic cancer that were investigated, the mean planning target volume (PTV) dose for each gantry angle in the PLDR-IMRT plans ranged from 17.6 to 22.4 cGy. The maximum doses ranged between 22.9 and 34.8 cGy. The minimum doses ranged from 8.2 to 17.5 cGy. For the 10 cases with prostate cancer that were investigated, the mean PTV doses for individual gantry angles ranged from 18.8 to 22.6 cGy. The maximum doses per gantry angle were between 24.0 and 34.7 cGy. The minimum doses per gantry angle ranged from 4.4 to 17.4 cGy. A significant reduction in the organ at risk (OAR) dose was observed with the PLDR-IMRT plan when compared with that using the PLDR-3DCRT plan. The volume receiving an 18-Gy (V{sub 18}) dose for the left and right kidneys was reduced by 10.6% and 12.5%, respectively, for the pancreatic plans. The volume receiving a 45-Gy (V{sub 45}) dose for the small bowel decreased from 65.3% to 45.5%. For the cases with prostate cancer, the volume receiving a 40-Gy (V{sub 40}) dose for the bladder and the rectum was reduced significantly by 25.1% and 51.2%, respectively. When compared with the RapidArc technique, the volume receiving a 30-Gy (V{sub 30}) dose for the left and the right kidneys was lower in the IMRT plans. For most OARs, no significant differences were observed between the PLDR-IMRT and the PLDR-RapidArc plans. These results clearly demonstrated that the PLDR-IMRT plan was suitable for PLDR pancreatic and prostate cancer treatments in terms of the overall plan quality. A significant reduction in the OAR dose was achieved with the PLDR-IMRT plan when compared with that using the PLDR-3DCRT plan. For most OARs, no significant differences were observed between the PLDR-IMRT and the PLDR-RapidArc plans. When compared with the PLDR-3DCRT plan, the PLDR-IMRT plan could provide superior target coverage and normal tissue sparing for PLDR reirradiation of recurrent pancreatic and prostate cancers. The PLDR-IMRT plan is an effective treatment choice for recurrent cancers in most cancer centers.« less

Population dose commitments due to radioactive releases from nuclear power plant sites in 1988

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1988. Fifty-year commitments for a one-year exposure from both liquid and atmospheric releases were calculated for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each of 71 reactor sites. This report tabulates the results of these calculations, showing the dose commitments for both water and airborne pathways for each age group and organ. Also included for each of the sites is a histogram showing the fraction of the total population within 2 to 80 km aroundmore » each site receiving various average dose commitments from the airborne pathways. The total collective dose commitments (from both liquid and airborne pathways) for each site ranged from a high of 16 person-rem to a low of 0.0011 person-rem for the sites with plants operating throughout the year with an arithmetic mean of 1.1 person-rem. The total population dose for all sites was estimated at 75 person-rem for the 150 million people considered at risk. The site average individual dose commitment from all pathways ranged from a low of 3 {times} 10{sup {minus}7} mrem to a high of 0.02 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites. However, licensee calculation of doses to the maximally exposed individual at some sites indicated values of up to approximately 100 times average individual doses (on the order of a few millirem per year).« less

Population dose commitments due to radioactive releases from nuclear power plant sites in 1988. Volume 10

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, D.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1988. Fifty-year commitments for a one-year exposure from both liquid and atmospheric releases were calculated for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each of 71 reactor sites. This report tabulates the results of these calculations, showing the dose commitments for both water and airborne pathways for each age group and organ. Also included for each of the sites is a histogram showing the fraction of the total population within 2 to 80 km aroundmore » each site receiving various average dose commitments from the airborne pathways. The total collective dose commitments (from both liquid and airborne pathways) for each site ranged from a high of 16 person-rem to a low of 0.0011 person-rem for the sites with plants operating throughout the year with an arithmetic mean of 1.1 person-rem. The total population dose for all sites was estimated at 75 person-rem for the 150 million people considered at risk. The site average individual dose commitment from all pathways ranged from a low of 3 {times} 10{sup {minus}7} mrem to a high of 0.02 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites. However, licensee calculation of doses to the maximally exposed individual at some sites indicated values of up to approximately 100 times average individual doses (on the order of a few millirem per year).« less

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

PubMed Central

Cui, Yimin; Song, Yan; Wang, Jessie; Yu, Zhigang; Schuster, Alan; Barrett, Yu Chen; Frost, Charles

2013-01-01

Background The pharmacokinetics (PK), pharmacodynamics (PD), and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study. Subjects and methods Eighteen subjects 18–45 years of age were randomly assigned (2:1 ratio) to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9). The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations. Results PK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported. Conclusion Apixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race. PMID:24353445

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

PubMed Central

Estlin, E. J.; Lashford, L.; Ablett, S.; Price, L.; Gowing, R.; Gholkar, A.; Kohler, J.; Lewis, I. J.; Morland, B.; Pinkerton, C. R.; Stevens, M. C.; Mott, M.; Stevens, R.; Newell, D. R.; Walker, D.; Dicks-Mireaux, C.; McDowell, H.; Reidenberg, P.; Statkevich, P.; Marco, A.; Batra, V.; Dugan, M.; Pearson, A. D.

1998-01-01

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted. Images Figure 5 p658-b Figure 6 p659-b PMID:9744506

Dosimetric and delivery efficiency investigation for treating hepatic lesions with a MLC-equipped robotic radiosurgery-radiotherapy combined system.

PubMed

Jin, Lihui; Price, Robert A; Wang, Lu; Meyer, Joshua; Fan, James Jiajin; Ma, Chang Ming Charlie

2016-02-01

The CyberKnife M6 (CK-M6) Series introduced a multileaf collimator (MLC) for extending its capability from stereotactic radiosurgery/stereotactic radiotherapy (SBRT) to conventionally fractionated radiotherapy. This work is to investigate the dosimetric quality of plans that are generated using MLC-shaped beams on the CK-M6, as well as their delivery time, via comparisons with the intensity modulated radiotherapy plans that were clinically used on a Varian Linac for treating hepatic lesions. Nine patient cases were selected and divided into three groups with three patients in each group: (1) the group-one patients were treated conventionally (25 fractions); (2) the group-two patients were treated with SBRT-like hypofractionation (5 fractions); and (3) the group-three patients were treated similar to group-one patients, but with two planning target volumes (PTVs) and two different prescription dose levels correspondingly. The clinically used plans were generated on the eclipse treatment planning system (TPS) and delivered on a Varian Linac (E-V plans). The multiplan (MP) TPS was used to replan these clinical cases with the MLC as the beam device for the CK-M6 (C-M plans). After plans were normalized to the same PTV dose coverage, comparisons between the C-M and E-V plans were performed based on D(99%) (percentage of prescription dose received by 99% of the PTV), D(0.1cm(3)) (the percentage of prescription dose to 0.1 cm(3) of the PTV), and doses received by critical structures. Then, the delivery times for the C-M plans will be obtained, which are the MP TPS generated estimations assuming having an imaging interval of 60 s. The difference in D(99%) between C-M and E-V plans is +0.6% on average (+ or - indicating a higher or lower dose from C-M plans than from E-V plans) with a range from -4.1% to +3.8%, and the difference in D(0.1cm(3)) was -1.0% on average with a range from -5.1% to +2.9%. The PTV conformity index (CI) for the C-M plans ranges from 1.07 to 1.29 with a mean of 1.19, slightly inferior to the E-V plans, in which the CI ranges from 1.00 to 1.15 with a mean of 1.07. Accounting for all nine patients in three groups, 45% of the critical structures received a lower mean dose for the C-M plans as compared with the E-V plans, and similarly, 48% received a lower maximum dose. Furthermore, the average difference of the mean critical structure dose between the C-M and E-V plans over all critical structures for all patients showed only +2.10% relative to the prescription dose and the similar comparison finds the average difference of the maximum critical structure dose of only +1.24%. The estimated delivery times for the C-M plans on the CK-M6 range from 18 to 24 minutes while they are from 7 to 13.7 min for the E-V plans on the Varian Linac. For treating hepatic lesions, for the C-M plans that are comparable to E-V plans in quality, the times needed to deliver these C-M plans on the CK-M6 are longer than the delivery time for the E-V plans on the Varian Linac, but may be clinically acceptable.

Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke.

PubMed

Campbell, Bruce C V; Mitchell, Peter J; Churilov, Leonid; Yassi, Nawaf; Kleinig, Timothy J; Dowling, Richard J; Yan, Bernard; Bush, Steven J; Dewey, Helen M; Thijs, Vincent; Scroop, Rebecca; Simpson, Marion; Brooks, Mark; Asadi, Hamed; Wu, Teddy Y; Shah, Darshan G; Wijeratne, Tissa; Ang, Timothy; Miteff, Ferdinand; Levi, Christopher R; Rodrigues, Edrich; Zhao, Henry; Salvaris, Patrick; Garcia-Esperon, Carlos; Bailey, Peter; Rice, Henry; de Villiers, Laetitia; Brown, Helen; Redmond, Kendal; Leggett, David; Fink, John N; Collecutt, Wayne; Wong, Andrew A; Muller, Claire; Coulthard, Alan; Mitchell, Ken; Clouston, John; Mahady, Kate; Field, Deborah; Ma, Henry; Phan, Thanh G; Chong, Winston; Chandra, Ronil V; Slater, Lee-Anne; Krause, Martin; Harrington, Timothy J; Faulder, Kenneth C; Steinfort, Brendan S; Bladin, Christopher F; Sharma, Gagan; Desmond, Patricia M; Parsons, Mark W; Donnan, Geoffrey A; Davis, Stephen M

2018-04-26

Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin-specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion. We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage. Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group. Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND-IA TNK ClinicalTrials.gov number, NCT02388061 .).

Dose-related difference in progression rates of cytomegalovirus retinopathy during foscarnet maintenance therapy. AIDS Clinical Trials Group Protocol 915 Team.

PubMed

Holland, G N; Levinson, R D; Jacobson, M A

1995-05-01

A previous dose-ranging study of foscarnet maintenance therapy for cytomegalovirus retinopathy showed a positive relationship between dose and survival but could not confirm a relationship between dose and time to first progression. This retrospective analysis of data from that study was undertaken to determine whether there was a relationship between dose and progression rates, which reflects the amount of retina destroyed when progression occurs. Patients were randomly given one of two foscarnet maintenance therapy doses (90 mg/kg of body weight/day [FOS-90 group] or 120 mg/kg of body weight/day [FOS-120 group] after induction therapy. Using baseline and follow-up photographs and pre-established definitions and methodology in a masked analysis, posterior progression rates and foveal proximity rates for individual lesions, selected by prospectively defined criteria, were calculated in each patient. Rates were compared between groups. The following median rates were greater for the FOS-90 group (N = 8) than for the FOS-120 group (N = 10): greatest maximum rate at which lesions enlarged in a posterior direction (43.5 vs 12.5 microns/day; P = .002); posterior progression rate for lesions closest to the fovea (42.8 vs 5.5 microns/day; P = .010); and maximum foveal proximity rate for either eye (32.3 vs 3.4 microns/day; P = .031). Patients receiving higher doses of foscarnet have slower rates of progression and therefore less retinal tissue damage during maintenance therapy. A foscarnet maintenance therapy dose of 120 mg/kg of body weight/day instead of 90 mg/kg of body weight/day may help to preserve vision in patients with cytomegalovirus retinopathy.

Phase I study of the c-raf-1 antisense oligonucleotide ISIS 5132 in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.

PubMed

Fidias, Panos; Pennell, Nathan A; Boral, Anthony L; Shapiro, Geoffrey I; Skarin, Arthur T; Eder, Joseph P; Kwoh, T Jesse; Geary, Richard S; Johnson, Bruce E; Lynch, Thomas J; Supko, Jeffrey G

2009-09-01

A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC). Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m(2) and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC(fp)) of 5 mg . min/ml (dose level 1). The carboplatin dose was then increased to AUC(fp) 6 mg . min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m(2) (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion. Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC(fp) 6 mg . min/ml, paclitaxel 175 mg/m(2), and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum. ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study.

A phase 1 trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma.

PubMed

Nabors, Louis B; Fiveash, John B; Markert, James M; Kekan, Manasi S; Gillespie, George Y; Huang, Zhi; Johnson, Martin J; Meleth, Sreelatha; Kuo, Huichien; Gladson, Candece L; Fathallah-Shaykh, Hassan M

2010-03-01

To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. Phase 1 dose-escalation clinical trial. Comprehensive Cancer Center, University of Alabama at Birmingham. Patients A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed. There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells

PubMed Central

Rosenthal, Mark; McArthur, Grant A.; Pattison, Scott T.; Pattison, Stacey L.; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Scott, Andrew M.

2015-01-01

Background We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors. Methodology Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity. Principal Findings Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response. Conclusions/Significance This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000672257 PMID:26659127

SU-E-T-556: Dosimetric Comparison of the Bladder and Rectum Based On Daily CBCT for Prostate IMRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gill, S; Pearson, D; Dalhart, A

2014-06-01

Purpose: With the use of CBCT, delivered dose can be calculated by transferring the planned beams onto the CBCT. Bladder and rectum volumetric doses were calculated and correlated to the daily bladder and rectum fullness. Methods: Patients for this study underwent hypofractionated prostate IMRT to 70 Gy in 28 fractions. Daily CBCT was utilized for image guidance. A clinically acceptable plan was created using a CTV to PTV margin of 5mm. Image fusion was performed to transfer the bladder and rectum contours onto each CBCT. Contours were then edited to match the anatomy of each CBCT. Using the daily treatmentmore » isocenter, the planned beams were transferred onto the CBCT and daily and cumulative DVHs calculated. Results: At the time of planning the bladder volume was 470.66cc. The mean, minimum and maximum bladder volume from the 28 CBCTs was 230.57cc, 76.16 cc and 380.8 cc, respectively. Planned bladder V70Gy was 0.98%. Actual bladder V70Gy, as calculated from the CBCTs was 2.46±1.36%. Similarly, planned V60Gy, V50Gy and V40Gy were 2.55%, 4.15% and 6.35% of the total bladder volume. The observed volumes receiving 60Gy, 50Gy and 40Gy were 5.18±2.53%, 4 to 8.21±3.76% and 6 to 12.93±5.60%, respectively. On the planning CT the rectum volume was 41.5cc. The observed mean, minimum and maximum rectum volumes were 58.09cc, 93.52 and 47.50cc. The planned rectum V70Gy was 6.02% while the observed cumulative rectum V70Gy was 13.68±3.39%. Rectum V60Gy, V50Gy and V40Gy changed from 13.61% to 22.5±3.86%, 19.15% to 28.68±4.45 and 25.56% to 34.75±5.15%. Conclusion: Bladder and rectum volumes changes during treatment have an affect on the cumulative dose received by these organs. It was observed that volumetric dose received by bladder decreases as volume of the bladder increases. There is no particular trend observed between volumetric dose and rectal volume.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levin, J.

A case is reported of a 39-yr-old dentist who realized that his dental x- ray machine had been on for about 90 min. During this time he was near the machine constantly, with his back usually toward the source of radiation. The estimated dose to the back of his head and upper torso was 180 r. The dentist saffered some anxiety, but no acute symptoms of radiation sickness. Physical examination gave negative results. There was no evidence of acute radiation damage. Study of temporal scalp hair revealed an estimated maximum dose received by the hair follicles of approximates 50 tomore » 75 r. The direct technical cause of the accident was a loose washer in the timer mechanism, making contact and completing the switching circuit, thereby causing the unit to go on. It is suggested that dentists and their assistants should wear radiation exposure badges at all times. In addition, equipment shouid be systcmatically and regularly checked so that maximum operating efficiency can be combined with minimum exposure. (P.C.H.)« less

SU-G-TeP1-01: A Simulation Study to Investigate Maximum Allowable Deformations of Implant Geometry Before Plan Objectives Are Violated in Prostate HDR Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Babier, A; Joshi, C; Cancer Center of Southeastern Ontario, Kingston General Hospital, Kingston, Ontario

Purpose: In prostate HDR brachytherapy dose distributions are highly sensitive to changes in prostate volume and catheter displacements. We investigate the maximum deformations in implant geometry before planning objectives are violated. Methods: A typical prostate Ir-192 HDR brachytherapy reference plan was calculated on the Oncentra planning system, which used CT images from a tissue equivalent prostate phantom (CIRS Model 053S) embedded inside a pelvis wax phantom. The prostate was deformed and catheters were displaced in simulations using a code written in MATLAB. For each deformation dose distributions were calculated, based on TG43 methods, using the MATLAB code. The calculations weremore » validated through comparison with Oncentra calculations for the reference plan, and agreed within 0.12%SD and 0.3%SD for dose and volume, respectively. Isotropic prostate volume deformations of up to +34% to −27% relative to its original volume, and longitudinal catheter displacements of 7.5 mm in superior and inferior directions were simulated. Planning objectives were based on American Brachytherapy Society guidelines for prostate and urethra volumes. A plan violated the planning objectives when less than 90% of the prostate volume received the prescribed dose or higher (V{sub 100}), or the urethral volume receiving 125% of prescribed dose or higher was more than 1 cc (U{sub 125}). Lastly, the dose homogeneity index (DHI=1-V{sub 150}/V{sub 100}) was evaluated; a plan was considered sub-optimal when the DHI fell below 0.62. Results and Conclusion: Planning objectives were violated when the prostate expanded by 10.7±0.5% or contracted by 11.0±0.2%; objectives were also violated when catheters were displaced by 4.15±0.15 mm and 3.70±0.15 mm in the superior and inferior directions, respectively. The DHI changes did not affect the plan optimality, except in the case of prostate compression. In general, catheter displacements have a significantly larger impact on plan optimality than prostate volume changes.« less

High-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in locally advanced non-small-cell lung cancer: a feasibility study.

PubMed

Liu, Yue-E; Lin, Qiang; Meng, Fan-Jie; Chen, Xue-Ji; Ren, Xiao-Cang; Cao, Bin; Wang, Na; Zong, Jie; Peng, Yu; Ku, Ya-Jun; Chen, Yan

2013-08-11

Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer (NSCLC) and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear. The purpose of this study was to evaluate the feasibility of utilizing high-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for the treatment of local advanced NSCLC. Untreated patients with unresectable stage IIIA/IIIB NSCLC or patients with a recurrence of NSCLC received accelerated hypofractionated three-dimensional conformal radiotherapy. The total dose was greater than or equal to 60 Gy. The accelerated hypofractionated radiotherapy was conducted once daily at 3 Gy/fraction with 5 fractions per week, and the radiotherapy was completed in 5 weeks. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP. A total of 26 patients (19 previously untreated cases and 7 cases of recurrent disease) received 60Gy-75Gy radiotherapy with concurrent chemotherapy. All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis (88.5%) and radiation pneumonitis (42.3%). The percentages of grade III acute radiation esophagitis and grade III radiation pneumonitis were 15.4% and 7.7%, respectively. Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Two patients received high dose of 75 Gy had grade III late esophageal toxicity, and none had grade IV and above. Grade III and above late lung toxicity did not occur. High-dose accelerated hypofractionated three-dimensional conformal radiotherapy with a dose of 60 Gy or greater with concurrent NVB and CBP chemotherapy might be feasible. However esophagus toxicity needs special attention. A phase I trial is recommended to obtain the maximum tolerated radiation dose of accelerated hypofractionated radiotherapy with concurrent chemotherapy.

High-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in locally advanced non-small-cell lung cancer: a feasibility study

PubMed Central

2013-01-01

Background Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer (NSCLC) and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear. The purpose of this study was to evaluate the feasibility of utilizing high-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for the treatment of local advanced NSCLC. Methods Untreated patients with unresectable stage IIIA/IIIB NSCLC or patients with a recurrence of NSCLC received accelerated hypofractionated three-dimensional conformal radiotherapy. The total dose was greater than or equal to 60 Gy. The accelerated hypofractionated radiotherapy was conducted once daily at 3 Gy/fraction with 5 fractions per week, and the radiotherapy was completed in 5 weeks. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP. Results A total of 26 patients (19 previously untreated cases and 7 cases of recurrent disease) received 60Gy-75Gy radiotherapy with concurrent chemotherapy. All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis (88.5%) and radiation pneumonitis (42.3%). The percentages of grade III acute radiation esophagitis and grade III radiation pneumonitis were 15.4% and 7.7%, respectively. Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Two patients received high dose of 75 Gy had grade III late esophageal toxicity, and none had grade IV and above. Grade III and above late lung toxicity did not occur. Conclusion High-dose accelerated hypofractionated three-dimensional conformal radiotherapy with a dose of 60 Gy or greater with concurrent NVB and CBP chemotherapy might be feasible. However esophagus toxicity needs special attention. A phase I trial is recommended to obtain the maximum tolerated radiation dose of accelerated hypofractionated radiotherapy with concurrent chemotherapy. PMID:23937855

Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study.

PubMed

Bussel, James B; de Miguel, Purificación Garcia; Despotovic, Jenny M; Grainger, John D; Sevilla, Julián; Blanchette, Victor S; Krishnamurti, Lakshmanan; Connor, Philip; David, Michèle; Boayue, Koh B; Matthews, Dana C; Lambert, Michele P; Marcello, Lisa M; Iyengar, Malini; Chan, Geoffrey W; Chagin, Karen D; Theodore, Dickens; Bailey, Christine K; Bakshi, Kalpana K

2015-08-01

The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia. PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1-17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 10(9) per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12-17, 6-11, and 1-5 years. We established patients' starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6-17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing <27 kg) and patients aged 1-5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1-5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12-17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6-11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1-5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 10(9) per L or more at least once from weeks 1-6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037. Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12-17 years, 19 aged 6-11 years, and ten aged 1-5 years) and 22 to receive placebo (eight children aged 12-17 years, nine aged 6-11 years, and five aged 1-5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 10(9) per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39-13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase. Our results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults. GlaxoSmithKline. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dosimetric considerations and early clinical experience of accelerated partial breast irradiation using multi-lumen applicators in the setting of breast augmentation.

PubMed

Akhtari, Mani; Pino, Ramiro; Scarboro, Sarah B; Bass, Barbara L; Miltenburg, Darlene M; Butler, E Brian; Teh, Bin S

2015-12-01

Accelerated partial breast irradiation (APBI) is an accepted treatment option in breast-conserving therapy for early stage breast cancer. However, data regarding outcomes of patients treated with multi-lumen catheter systems who have existing breast implants is limited. The purpose of this study was to report treatment parameters, outcomes, and possible dosimetric correlation with cosmetic outcome for this population of patients at our institution. We report the treatment and outcome of seven consecutive patients with existing breast implants and early stage breast cancer who were treated between 2009 and 2013 using APBI following lumpectomy. All patients were treated twice per day for five days to a total dose of 34 Gy using a high-dose-rate (192)Ir source. Cosmetic outcomes were evaluated using the Harvard breast cosmesis scale, and late toxicities were reported using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity schema. After a mean follow-up of 32 months, all patients have remained cancer free. Six out of seven patients had an excellent or good cosmetic outcome. There were no grade 3 or 4 late toxicities. The average total breast implant volume was 279.3 cc, received an average mean dose of 12.1 Gy, and a maximum dose of 234.1 Gy. The average percentage of breast implant volume receiving 50%, 75%, 100%, 150%, and 200% of the prescribed dose was 15.6%, 7.03%, 4.6%, 1.58%, and 0.46%, respectively. Absolute volume of breast implants receiving more than 50% of prescribed dose correlated with worse cosmetic outcomes. Accelerated partial breast irradiation using a multi-lumen applicator in patients with existing breast implants can safely be performed with promising early clinical results. The presence of the implant did not compromise the ability to achieve dosimetric criteria; however, dose to the implant and the irradiated implant volume may be related with worse cosmetic outcomes.

Dosimetric considerations and early clinical experience of accelerated partial breast irradiation using multi-lumen applicators in the setting of breast augmentation

PubMed Central

Akhtari, Mani; Pino, Ramiro; Scarboro, Sarah B.; Bass, Barbara L.; Miltenburg, Darlene M.; Butler, E. Brian

2015-01-01

Purpose Accelerated partial breast irradiation (APBI) is an accepted treatment option in breast-conserving therapy for early stage breast cancer. However, data regarding outcomes of patients treated with multi-lumen catheter systems who have existing breast implants is limited. The purpose of this study was to report treatment parameters, outcomes, and possible dosimetric correlation with cosmetic outcome for this population of patients at our institution. Material and methods We report the treatment and outcome of seven consecutive patients with existing breast implants and early stage breast cancer who were treated between 2009 and 2013 using APBI following lumpectomy. All patients were treated twice per day for five days to a total dose of 34 Gy using a high-dose-rate 192Ir source. Cosmetic outcomes were evaluated using the Harvard breast cosmesis scale, and late toxicities were reported using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity schema. Results After a mean follow-up of 32 months, all patients have remained cancer free. Six out of seven patients had an excellent or good cosmetic outcome. There were no grade 3 or 4 late toxicities. The average total breast implant volume was 279.3 cc, received an average mean dose of 12.1 Gy, and a maximum dose of 234.1 Gy. The average percentage of breast implant volume receiving 50%, 75%, 100%, 150%, and 200% of the prescribed dose was 15.6%, 7.03%, 4.6%, 1.58%, and 0.46%, respectively. Absolute volume of breast implants receiving more than 50% of prescribed dose correlated with worse cosmetic outcomes. Conclusions Accelerated partial breast irradiation using a multi-lumen applicator in patients with existing breast implants can safely be performed with promising early clinical results. The presence of the implant did not compromise the ability to achieve dosimetric criteria; however, dose to the implant and the irradiated implant volume may be related with worse cosmetic outcomes. PMID:26816499

Prospective, open, multicentre Phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma.

PubMed

Ma, Hong-Bing; Di, Zheng-Li; Wen, Jiao; Ke, Yue; Sun, Xiaodong; Ren, Juan

2015-02-01

Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy. Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints. Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2. Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Experience of micromultileaf collimator linear accelerator based single fraction stereotactic radiosurgery: Tumor dose inhomogeneity, conformity, and dose fall off

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Linda X.; Garg, Madhur; Lasala, Patrick

2011-03-15

Purpose: Sharp dose fall off outside a tumor is essential for high dose single fraction stereotactic radiosurgery (SRS) plans. This study explores the relationship among tumor dose inhomogeneity, conformity, and dose fall off in normal tissues for micromultileaf collimator (mMLC) linear accelerator (LINAC) based cranial SRS plans. Methods: Between January 2007 and July 2009, 65 patients with single cranial lesions were treated with LINAC-based SRS. Among them, tumors had maximum diameters {<=}20 mm: 31; between 20 and 30 mm: 21; and >30 mm: 13. All patients were treated with 6 MV photons on a Trilogy linear accelerator (Varian Medical Systems,more » Palo Alto, CA) with a tertiary m3 high-resolution mMLC (Brainlab, Feldkirchen, Germany), using either noncoplanar conformal fixed fields or dynamic conformal arcs. The authors also created retrospective study plans with identical beam arrangement as the treated plan but with different tumor dose inhomogeneity by varying the beam margins around the planning target volume (PTV). All retrospective study plans were normalized so that the minimum PTV dose was the prescription dose (PD). Isocenter dose, mean PTV dose, RTOG conformity index (CI), RTOG homogeneity index (HI), dose gradient index R{sub 50}-R{sub 100} (defined as the difference between equivalent sphere radius of 50% isodose volume and prescription isodose volume), and normal tissue volume (as a ratio to PTV volume) receiving 50% prescription dose (NTV{sub 50}) were calculated. Results: HI was inversely related to the beam margins around the PTV. CI had a ''V'' shaped relationship with HI, reaching a minimum when HI was approximately 1.3. Isocenter dose and mean PTV dose (as percentage of PD) increased linearly with HI. R{sub 50}-R{sub 100} and NTV{sub 50} initially declined with HI and then reached a plateau when HI was approximately 1.3. These trends also held when tumors were grouped according to their maximum diameters. The smallest tumor group (maximum diameters {<=}20 mm) had the most HI dependence for dose fall off. For treated plans, CI averaged 2.55{+-}0.79 with HI 1.23{+-}0.06; the average R{sub 50}-R{sub 100} was 0.41{+-}0.08, 0.55{+-}0.10, and 0.65{+-}0.09 cm, respectively, for tumors {<=}20 mm, between 20 and 30 mm, and >30 mm. Conclusions: Tumor dose inhomogeneity can be used as an important and convenient parameter to evaluate mMLC LINAC-based SRS plans. Sharp dose fall off in the normal tissue is achieved with sufficiently high tumor dose inhomogeneity. By adjusting beam margins, a homogeneity index of approximately 1.3 would provide best conformity for the authors' SRS system.« less

Safety of an i.v. β-adrenergic blockade protocol for heart rate optimization before coronary CT angiography.

PubMed

Kassamali, Rahil H; Kim, Daniel H; Patel, Hiten; Raichura, Nitin; Hoey, Edward T D; Hodson, James; Hussain, Shahid

2014-10-01

The purpose of this study was to assess the safety of heart rate optimization by use of β-adrenergic blockade solely by the i.v. route before coronary CT angiography. The records of 679 patients undergoing CT coronary angiography after receiving i.v. β-adrenergic blockade were retrospectively analyzed. Health screening was completed before scanning, and heart rate was optimized by administration of i.v. metoprolol titrated to a maximum of 70 mg to achieve a heart rate less than 65 beats/min. The median i.v. dose was 20 mg (range, 5-70 mg). The 679 patients analyzed had a total of 10 complications (1.47%). Major complications, defined as not resolving with observation and analgesia alone, occurred in only three patients (0.44%). These complications included a second-degree atrioventricular block. A total of 299 patients (44.0%) needed more than 20 mg of i.v. metoprolol to achieve target heart rate. Only three patients needed the maximum i.v. dose of 70 mg metoprolol. Target heart rate was reached successfully in 666 patients (98.1%) with doses of less than 70 mg. This study did not show a statistically significant association between increasing complication frequency and increasing dose. This study showed that high doses of i.v. metoprolol can be used effectively and with a low rate of major complications to control heart rate before coronary CT angiography in correctly screened patients.

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

PubMed

Doi, Toshihiko; Shitara, Kohei; Naito, Yoichi; Shimomura, Akihiko; Fujiwara, Yasuhiro; Yonemori, Kan; Shimizu, Chikako; Shimoi, Tatsunori; Kuboki, Yasutoshi; Matsubara, Nobuaki; Kitano, Atsuko; Jikoh, Takahiro; Lee, Caleb; Fujisaki, Yoshihiko; Ogitani, Yusuke; Yver, Antoine; Tamura, Kenji

2017-11-01

Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater. The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg. Daiichi Sankyo Co, Ltd. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of contrast media on megavoltage photon beam dosimetry.

PubMed

Rankine, Ashley W; Lanzon, Peter J; Spry, Nigel A

2008-01-01

The purpose of this study was to quantify changes in photon beam dosimetry caused by using contrast media during computed tomography (CT) simulation and determine if the resulting changes are clinically significant. The effect of contrast on dosimetry was first examined for a single 6-MV photon beam incident on a plane phantom with a structure of varying electron densities (rho(e)) and thickness. Patient studies were then undertaken in which CT data sets were collected with and without contrast for 6 typical patients. Three patients received IV contrast (Optiray-240) only and 3 received IV plus oral (Gastrograffin) contrast. Each patient was planned using conformal multifield techniques in accordance with the department standards. Two methods were used to compare the effect of contrast on dosimetry for each patient. The phantom analysis showed that the change in dose at the isocenter for a single 10 x 10 cm2 6-MV photon beam traversing 10 cm of a contrast-enhanced structure with rho(e) 1.22 was 7.0% (1.22 was the highest average rho(e) observed in the patient data). As a result of using contrast, increases in rho(e) were observed in structures for the 6 patients studied. Consequently, when using contrast-enhanced CT data for multifield planning, increases in dose at the isocenter and in critical structures were observed up to 2.1% and 2.5%, respectively. Planning on contrast-enhanced CT images may result in an increase in dose of up to 2.1% at the isocenter, which would generally be regarded as clinically insignificant. If, however, a critical organ is in close proximity to the planning target volume (PTV) and is planned to receive its maximum allowable dose, planning on contrast-enhanced CT images may result in that organ receiving dose beyond the recommended tolerance. In these instances, pre-contrast CT data should be used for dosimetry.

A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours.

PubMed

Venugopal, B; Awada, A; Evans, T R J; Dueland, S; Hendlisz, A; Rasch, W; Hernes, K; Hagen, S; Aamdal, S

2015-10-01

CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.

Treatment of tumor-bearing dogs with actinomycin D.

PubMed

Hammer, A S; Couto, C G; Ayl, R D; Shank, K A

1994-01-01

Fifty dogs with advanced malignancies were treated with actinomycin D at doses ranging from 0.5 to 1.1 mg/m2 every 3 weeks. The greatest number of responses was noted in dogs with lymphoma, including dogs that had received prior chemotherapy. Other responding tumor types included anal sac adenocarcinoma, perianal adenocarcinoma, squamous cell carcinoma, thyroid carcinoma, and transitional cell carcinoma. The median time to maximum response for dogs with lymphoma was 7 days, with a median duration of 42 days. Gastrointestinal toxicity was the most frequently observed side effect. A dose of 0.6 to 0.7 mg/m2 appears to be appropriate for treating various malignancies in dogs.

1989 Environmental monitoring report, Sandia National Laboratories, Albuquerque, New Mexico

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, S.; Chavez, G.; Phelan, J.

1990-05-01

This 1989 report contains monitoring data from routine radiological and nonradiological environmental surveillance activities. Summaries of significant environmental compliance programs in progress such as National Environmental Policy Act documentation, environmental permits, environmental restoration, and various waste management programs for Sandia National Laboratories in Albuquerque (SNL, Albuquerque) are included. The maximum offsite dose impact was calculated to be 8.8 {times} 10{sup {minus}4} mrem. The total Albuquerque population received a collective dose of 0.097 person-rem during 1989 from SNL, Albuquerque, operations. As in the previous year, SNL, Albuquerque, operations in 1989 had no adverse impact on the general public or on themore » environment. 46 refs., 20 figs., 31 tabs.« less

Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

PubMed

Pan, Xiaoyun Lucy; Nordstrom, Beth L; MacLachlan, Sharon; Lin, Junji; Xu, Hairong; Sharma, Anjali; Chandler, David; Li, Xiaoyan Shawn

2017-01-01

Objectives To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. Study design This is a retrospective cohort study using a proprietary outpatient oncology database. Methods Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. Results Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. Conclusion The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

Investigation of new dyes for chromovitrectomy: preclinical biocompatibility of trisodium, orangell and methyl violet.

PubMed

Badaro, Emmerson; Souza-Lima, Rodrigo A; Novais, Eduardo A; Maia, Mauricio; Hirai, Flávio; Meyer, Carsten H; Farah, Michel Eid; Rodrigues, Eduardo B

2015-01-01

To investigate the retinal toxicity by electroretinography (ERG), clinical examination and histology after intravitreal injection of biological stains in two concentrations: Trisodium (0.50 g/L and 1.00 g/L), Orangell (0.25 g/L and 1.00 g/L) and Methyl Violet (0.50 g/L and 1.00 g/L). Eighteen New-Zealand albinos rabbits were assigned in six groups (n = 3 in each group). The animals in group 1 received Trisodium in the dose of 0.50 g/L and group 2 received 1.00 g/L; Group 3 received Orangell in the dose of 0.25 g/L and group 4 received 1.00 g/L; Group 5 received Methyl Violet in the dose of 1.00 g/L and group 6 received 0.50 g/L. A volume of 0.05 mL of dye was injected in the right eyes, whereas the left eyes received the same volume of balanced salt solution (BSS) as control. ERG recordings and clinical examination were performed at baseline and seven days after intravitreal injection. The ERG responses at one week after injection were compared with baseline levels. A decrease in the post-injection amplitude of more than 50% was considered remarkable. After the 7-day follow-up, rabbits were euthanized and eye enucleated for light microscopy (LM) histological evaluation. At clinical examination by indirect ophthalmoscopy seven days after dye injection, all eyes were negative for cataract, hemorrhage, retinal detachment, and intraocular opacities. Amplitude analysis of maximum scotopic b-wave showed no significant reduction in either dye injected or control eyes. Neither dye nor BSS caused significant retinal alteration on LM at doses tested. Trisodium, Orangell and Methyl Violet can be applied in future studies in order to prove the capacity to stain preretinal tissues and vitreous without toxicity. The three dyes did not induce significant ERG amplitude reduction or LM alterations in this preliminary experimental research. Trisodium, Orangell and Methyl Violet may be potentially useful vital dyes for ocular surgery, and deserve further investigation.

Esophageal Dose Tolerance to Hypofractionated Stereotactic Body Radiation Therapy: Risk Factors for Late Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stephans, Kevin L., E-mail: stephak@ccf.org; Djemil, Toufik; Diaconu, Claudiu

2014-09-01

Purpose: To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT). Methods and Materials: This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria. Results: The median esophageal point dose andmore » 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents. Conclusions: Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus.« less

Esophageal dose tolerance to hypofractionated stereotactic body radiation therapy: risk factors for late toxicity.

PubMed

Stephans, Kevin L; Djemil, Toufik; Diaconu, Claudiu; Reddy, Chandana A; Xia, Ping; Woody, Neil M; Greskovich, John; Makkar, Vinit; Videtic, Gregory M M

2014-09-01

To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT). This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria. The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents. Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison of Cognitive Performance Tests for Promethazine Pharmacodynamics in Human Subjects

NASA Technical Reports Server (NTRS)

Vaksman, Z.; Boyd, J. L.; Wang, Z.; Putcha, L.

2005-01-01

The objective of this study is to compare cognitive function tests, Automated Neurological Assessment Metrics (ANAM) based Readiness Evaluation System (ARES(Registered TradeMark)) on a Palm Pilot and Windows based Spaceflight Cognitive Assessment Tool (WinSCAT(Registered TradeMark)) on a personal computer (PC) to assess performance effects of promethazine (PMZ) after administration to human subjects. In a randomized placebo-controlled cross-over design, subjects received 12.5, 25, and 50 mg intramuscular (IM) PMZ or a placebo and completed 14 sessions with WinSCAT(Registered TradeMark) (v. 1.26) and ARES(Registered TradeMark) (v. 1.27) consecutively for 72 h post dose. Maximum plasma concentrations (4.25, 6.25 and 13.33 ng/ml) were linear with dose and were achieved by 0.75, 8, and 24 h after dosing for the three doses, respectively. No significant differences in cognitive function after PMZ dosing were detected using WinSCAT(Registered TradeMark), however, tests from ARES(Registered TradeMark) demonstrated concentration dependent decrements in reaction time associated with PMZ dose.

Occupational dose reduction in cardiac catheterisation laboratory: a randomised trial using a shield drape placed on the patient.

PubMed

Ordiales, J M; Nogales, J M; Vano, E; López-Mínguez, J R; Alvarez, F J; Ramos, J; Martínez, G; Sánchez, R M

2017-04-25

The aim of this study was to evaluate the occupational radiation dose in interventional cardiology by using a shielding drape on the patient. A random study with and without the protective material was conducted. The following control parameters were registered: demographic data, number of stents, contrast media volume, fluoroscopy time, number of cine images, kerma-area product and cumulative air kerma. Occupational dose data were obtained by electronic active dosemeters. No statistically significant differences in the analysed control parameters were registered. The median dose value received by the interventional cardiologist was 50% lower in the group with a shielding drape with a statistically significant p-value <0.001. In addition, the median value of the maximum scatter radiation dose was 31% lower in this group with a statistically significant p-value <0.001. This study showed that a shielding drape is a useful tool for reducing the occupational radiation dose in a cardiac catheterisation laboratory. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Status Epilepticus due to Intraperitoneal Injection of Vehicle Containing Propylene Glycol in Sprague Dawley Rats

PubMed Central

Meade, Seth M.; Smith, Cara S.; Chen, Keying; Kleinman, Nanette; Capadona, Jeffrey R.

2017-01-01

Published reports of status epilepticus due to intraperitoneal injection containing propylene glycol in rats are sparse. In fact, there are no reports specifying a maximum safe dose of propylene glycol through intraperitoneal administration. We report here a case of unexpected seizures in Sprague Dawley rats after receiving an intraperitoneal injection containing propylene glycol. Nine-week-old, 225–250 gram male rats were reported to experience tremor progressing to seizures within minutes after given injections of resveratrol (30 mg/kg) dissolved in a 40 : 60 propylene glycol/corn oil vehicle solution by direct intraperitoneal (IP) slow bolus injection or via a preplaced intraperitoneal catheter. The World Health Organization suggests a maximum dose of 25 mg/kg/day of propylene glycol taken orally and no more than 25 mg/dL in blood serum, whereas the animals used in our study got a calculated maximum 0.52 g/kg (25 times lower dose). Blood tests from the seizing rat support a diagnosis of hemolysis and lactic acidosis which may have led to the seizures, all of which appeared to be a consequence of the propylene glycol administration. These findings are consistent with oral and intravenous administration of propylene glycol toxicity as previously reported in other species, including humans. To our knowledge, this report represents the first published case of status epilepticus due to an IP injection containing propylene glycol. PMID:28785508

Status Epilepticus due to Intraperitoneal Injection of Vehicle Containing Propylene Glycol in Sprague Dawley Rats.

PubMed

Ereifej, Evon S; Meade, Seth M; Smith, Cara S; Chen, Keying; Kleinman, Nanette; Capadona, Jeffrey R

2017-01-01

Published reports of status epilepticus due to intraperitoneal injection containing propylene glycol in rats are sparse. In fact, there are no reports specifying a maximum safe dose of propylene glycol through intraperitoneal administration. We report here a case of unexpected seizures in Sprague Dawley rats after receiving an intraperitoneal injection containing propylene glycol. Nine-week-old, 225-250 gram male rats were reported to experience tremor progressing to seizures within minutes after given injections of resveratrol (30 mg/kg) dissolved in a 40 : 60 propylene glycol/corn oil vehicle solution by direct intraperitoneal (IP) slow bolus injection or via a preplaced intraperitoneal catheter. The World Health Organization suggests a maximum dose of 25 mg/kg/day of propylene glycol taken orally and no more than 25 mg/dL in blood serum, whereas the animals used in our study got a calculated maximum 0.52 g/kg (25 times lower dose). Blood tests from the seizing rat support a diagnosis of hemolysis and lactic acidosis which may have led to the seizures, all of which appeared to be a consequence of the propylene glycol administration. These findings are consistent with oral and intravenous administration of propylene glycol toxicity as previously reported in other species, including humans. To our knowledge, this report represents the first published case of status epilepticus due to an IP injection containing propylene glycol.

Pharmacokinetics and Safety of MP-376 (Levofloxacin Inhalation Solution) in Cystic Fibrosis Subjects▿

PubMed Central

Geller, David E.; Flume, Patrick A.; Griffith, David C.; Morgan, Elizabeth; White, Dan; Loutit, Jeffery S.; Dudley, Michael N.

2011-01-01

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single- and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (Cmax) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50- and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean Cmax for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin Cmax ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development. PMID:21444699

Use Dose Bricks Concept to Implement Nasopharyngeal Carcinoma Treatment Planning

PubMed Central

Wu, Jia-Ming; Yu, Tsan-Jung; Yeh, Shyh-An; Chao, Pei-Ju; Huang, Chih-Jou

2014-01-01

Purpose. A “dose bricks” concept has been used to implement nasopharyngeal carcinoma treatment plan; this method specializes particularly in the case with bell shape nasopharyngeal carcinoma case. Materials and Methods. Five noncoplanar fields were used to accomplish the dose bricks technique treatment plan. These five fields include (a) right superior anterior oblique (RSAO), (b) left superior anterior oblique (LSAO), (c) right anterior oblique (RAO), (d) left anterior oblique (LAO), and (e) superior inferior vertex (SIV). Nondivergence collimator central axis planes were used to create different abutting field edge while normal organs were blocked by multileaf collimators in this technique. Results. The resulting 92% isodose curves encompassed the CTV, while maximum dose was about 115%. Approximately 50% volume of parotid glands obtained 10–15% of total dose and 50% volume of brain obtained less than 20% of total dose. Spinal cord receives only 5% from the scatter dose. Conclusions. Compared with IMRT, the expenditure of planning time and costing, “dose bricks” may after all be accepted as an optional implementation in nasopharyngeal carcinoma conformal treatment plan; furthermore, this method also fits the need of other nonhead and neck lesions if organ sparing and noncoplanar technique can be executed. PMID:24967395

Guaifenesin Pharmacokinetics Following Single‐Dose Oral Administration in Children Aged 2 to 17 Years

PubMed Central

Thompson, Gary A.; Solomon, Gail; Albrecht, Helmut H.; Reitberg, Donald P.

2016-01-01

Abstract This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age‐based doses of 100‐400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography‐tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo) and terminal volume of distribution (Vz/F) increased with age. Due to a larger increase in Vz/F than CLo, an increase in terminal exponential half‐life was also observed. Allometric scaling indicated no maturation‐related changes in CLo and Vz/F. PMID:26632082

High lenticular tolerance to ultraviolet radiation-B by pigmented guinea-pig; application of a safety limit strategy for UVR-induced cataract.

PubMed

Mody, Vino C; Kakar, Manoj; Söderberg, Per G; Löfgren, Stefan

2012-05-01

The purpose of this study was to determine a threshold measure, maximum tolerable dose (MTD), for avoidance of UVR-B-induced cataract in the pigmented guinea-pig. Thirty pupil-dilated anesthetized young female guinea-pigs, divided into five equal groups, received between 0 and 84.9 kJ/m(2) unilateral UVR-B. Lens extraction and in vitro lens photography occurred 24 hr after exposure. Measurement of intensity of lens light scattering served as quantifying tool for the degree of cataract. Data analysis included regression, using a second order polynomial model. The applied MTD concept was based on the UVR-B dose-response curve obtained for the pigmented guinea-pig. A smaller number of pigmented guinea-pigs, pigmented rats and albino rats underwent morphometric analysis of the anterior segment geometry. All eyes exposed to UVR-B developed cataract in the anterior subcapsular region. MTD for avoidance of UVR-B-induced cataract was 69.0 kJ/m(2) in the pigmented guinea-pig. Iris was considerably thicker in the guinea-pig than in the rats. Lens blockage by the dilated iris was lowest in the guinea-pig. Maximum tolerable dose for avoidance of UVR-B-induced cataract in the pigmented guinea-pig was 69.0 kJ/m(2), over 10-fold higher than the threshold 5 kJ/m(2) obtained by Pitts et al. in the pigmented rabbit. Maximum tolerable dose is an appropriate method for estimation of toxicity for UVR-B-induced cataract in the guinea-pig. The pigmented guinea-pig is significantly less sensitive to UVR-B exposure than the pigmented rabbit and pigmented rat. © 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.

PubMed

Roberts, Andrew W; Davids, Matthew S; Pagel, John M; Kahl, Brad S; Puvvada, Soham D; Gerecitano, John F; Kipps, Thomas J; Anderson, Mary Ann; Brown, Jennifer R; Gressick, Lori; Wong, Shekman; Dunbar, Martin; Zhu, Ming; Desai, Monali B; Cerri, Elisa; Heitner Enschede, Sari; Humerickhouse, Rod A; Wierda, William G; Seymour, John F

2016-01-28

New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

Parotid Gland Sparing With Helical Tomotherapy in Head-and-Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Voordeckers, Mia, E-mail: mia.voordeckers@uzbrussel.be; Farrag, Ashraf; Assiut University

Purpose: This study evaluated the ability of helical tomotherapy to spare the function of the parotid glands in patients with head-and-neck cancer by analyzing dose-volume histograms, salivary gland scintigraphy, and quality of life assessment. Methods and Materials: Data from 76 consecutive patients treated with helical tomotherapy (Hi-Art Tomotherapy) at University Hospital Brussel were analyzed. During planning, priority was given to planning target volume (PTV) coverage: {>=}95% of the dose must be delivered to {>=}95% of the PTV. Elective nodal regions received 54 Gy (1.8 Gy/fraction). A dose of 70.5 Gy (2.35 Gy/fraction) was prescribed to the primary tumor and pathologicmore » lymph nodes (simultaneous integrated boost scheme). Objective scoring of salivary excretion was performed by salivary gland scintigraphy. Subjective scoring of salivary gland function was evaluated by the European Organization for Research and Treatment of Cancer quality of life questionnaires Quality of Life Questionnaire-C30 (QLQ-C30) and Quality of Life Questionnaire-Head and Neck 35 (H and N35). Results: Analysis of dose-volume histograms (DVHs) showed excellent coverage of the PTV. The volume of PTV receiving 95% of the prescribed dose (V95%) was 99.4 (range, 96.3-99.9). DVH analysis of parotid gland showed a median value of the mean parotid dose of 32.1 Gy (range, 17.5-70.3 Gy). The median parotid volume receiving a dose <26 Gy was 51.2%. Quality of life evaluation demonstrated an initial deterioration of almost all scales and items in QLQ-C30 and QLQ-H and N35. Most items improved in time, and some reached baseline values 18 months after treatment. Conclusion: DVH analysis, scintigraphic evaluation of parotid function, and quality of life assessment of our patient group showed that helical tomotherapy makes it possible to preserve parotid gland function without compromising disease control. We recommend mean parotid doses of <34 Gy and doses <26 Gy to a maximum 47% of the parotid volume as planning goals. Intensity-modulated radiotherapy should be considered as standard treatment in patients with head-and-neck cancer.« less

SU-E-T-25: A Dosimetric Comparison of Three-Dimension Conformal and Intensity-Modulated Radiation Therapy in Esophageal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gallardo, N; Maneru, F; Fuentemilla, N

2015-06-15

Purpose: dosimetric comparison of 3DCRT and IMRT in 9 esophageal cancer. The aim of this paper is to know which of these two techniques is dosimetrically more favorable dosimetrically at both the CTV coverage and dose obtained in the relevant organs at risk, in this case, lungs and heart, as the spinal cord received in all cases below 45 Gy. Methods: we chose 9 patients from our center (CHN) with the same type of esophageal cancer and in which the prescribed dose was the same, 54 Gy. For these treatments we have used the same fields and the same anglesmore » (AP (0 °), OPD (225°–240°) and OPI (125°–135°)).All plans have been implemented using Eclipse (version 11.0) with AAA( Analytical Anisotropic Algorithm )(Version 11.0.31). Results: To analyze the coverage of the CTV, we have evaluated the D99% and found that the average dose received by 99% of CTV with IMRT is 53.8 ± 0.4 Gy (99.6% of the prescribed dose) and the mean value obtained with 3DCRT is 52.3 ± 0.6 Gy (96.8% of the prescribed dose).The last data analyzed was the D2% of PTV, a fact that gives us information on the maximum dose received by our PTV. D2% of the PTV for IMRT planning is 55.4 ± 0.4 Gy (102.6% of the prescribed dose) and with 3DCRT is 56.8 ± 0.7 Gy (105.2% of the prescribed dose).All parameters analyzed at risk organs (V30, V40, V45 and V50 for the case of heart and V5, V10, V15 and V20 for the case of the lungs) provide us irradiated volume percentages lower in IMRT than 3DCRT. Conclusion: IMRT provides a considerable improvement in the coverage of the CTV and the doses to organs at risk.« less

Hypofractionated Image-Guided IMRT in Advanced Pancreatic Cancer With Simultaneous Integrated Boost to Infiltrated Vessels Concomitant With Capecitabine: A Phase I Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Passoni, Paolo, E-mail: passoni.paolo@hsr.it; Reni, Michele; Cattaneo, Giovanni M.

2013-12-01

Purpose: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. Methods and Materials: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2.more » Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m{sup 2} daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. Results: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2{sup nd} dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. Conclusions: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.« less

Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

PubMed

Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

2017-02-01

Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max ) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2 ) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC 0-last ), and maximum plasma concentration (C max ) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors.

PubMed

LoRusso, Patricia M; Infante, Jeffrey R; Kim, Kevin B; Burris, Howard A; Curt, Gregory; Emeribe, Ugochi; Clemett, Delyth; Tomkinson, Helen K; Cohen, Roger B

2017-03-06

The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors. This study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m 2 or dacarbazine 1000 mg/m 2 administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A. A total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity [DLT] events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine. The combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors. ClinicalTrials.gov NCT00600496; registered 8 July 2009.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giantsoudi, D; Adams, J; MacDonald, S

Purpose: In proton radiation therapy of posterior fossa tumors, to spare other sensitive structures, the preferred beam geometry results in placing the treatment field distal edge within or just beyond the brainstem, including in at least partially in the treatment volume. Concerns for brainstem toxicity are increased and a controversy exists as to weather the beam’s distal edge should be placed within the brainstem or beyond it, to avoid elevated linear energy transfer (LET) and relative biological effectiveness (RBE) within the brainstem. The dosimetric efficacy of these techniques was examined, accounting for LET- and dose-dependent variable RBE distributions. Methods: Threemore » treatment planning techniques were applied in six ependymoma cases: (a) three-field dose-sparing, with beams’ distal edge within the brainstem; (b) three-field LET-sparing, using same beam directions as (a) but extended field ranges beyond the brainstem; (c) two-posterior-oblique LET-sparing, with extended ranges as (b). Monte Carlo calculated dose, LET and RBE-weighted dose distributions were compared. Results: Lower LET values in the brainstem were accompanied by higher median dose: 53.7 Gy[RBE] and 54.3 Gy[RBE] for techniques (b) and (c) versus 52.1 Gy[RBE] for (a). Accounting for variable RBE, a 15% increase of the brainstem volume receiving at least 60 Gy[RBE] was observed for technique (c) versus (a). Maximum variable-RBE-weighted brainstem dose was comparable for all techniques. Conclusion: Extending the treatment beam range beyond the brainstem, significantly increased its volume receiving high dose radiation, even when accounting for the decreased LET values. The dosimetric benefits of techniques limiting the brainstem dose may outweigh the impact of LET reduction achieved through this technique, especially since clinical consequences of increased LET at the end of range have not been proven yet.« less

Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics.

PubMed

Freise, Kevin J; Hu, Beibei; Salem, Ahmed Hamed

2018-04-01

Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2. Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (C max ) 2.3- to 2.4-fold compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax C max and AUC, respectively. Administration of 50 mg ritonavir daily saturated CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 mg ritonavir was offset by ritonavir CYP3A induction, resulting in a limited net increase in CYP3A inhibition with multiple doses. After completion of the dose ramp-up, venetoclax dose reductions of at least 75% are recommended when administered concomitantly with strong CYP3A inhibitors to maintain venetoclax exposures within the established therapeutic window for CLL treatment.

A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors

PubMed Central

Rini, Brian I.; Garcia, Jorge A.; Cooney, Matthew M.; Elson, Paul; Tyler, Allison; Beatty, Kristi; Bokar, Joseph; Mekhail, Tarek; Bukowski, R.M.; Budd, G. Thomas; Triozzi, Pierre; Borden, Ernest; Ivy, Percy; Chen, Helen X.; Dolwati, Afshin; Dreicer, Robert

2009-01-01

Purpose Bevacizumab is an antibody against vascular endothelial growth factor (VEGF); sunitinib is an inhibitor of VEGF and related receptors. The safety and maximum tolerated dose (MTD) of sunitinib plus bevacizumab was assessed in this phase I trial. Experimental Design Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level 5 mg/kg) on days 1, 15 and 29 of a 42-day cycle. Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. Results Thirty-eight patients were enrolled. Pts received a median of 3 cycles of treatment (range, 1–17+). There was one DLT (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed RECIST-defined PR (18%; 95% confidence interval: 8–34%). Nineteen of the 32 patients with a post-baseline scan (59%) had at least some reduction in overall tumor burden (median 32%, range 3–73%). Conclusions The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Anti-tumor activity was observed across multiple solid tumors. PMID:19773375

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs: A pilot study

PubMed Central

Larson, Jeanne C.; Allstadt, Sara D.; Fan, Timothy M.; Khanna, Chand; Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.; Legendre, Alfred M.; Galyon, Gina D.; LeBlanc, Amy K.; Martin-Jimenez, Tomas

2017-01-01

Objective To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. Animals 5 healthy purpose-bred hounds. Procedures The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and non-compartmental analyses. Results Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. Conclusions and Clinical Relevance Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in ng/mL. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, needs to be determined. PMID:26709938

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs.

PubMed

Larson, Jeanne C; Allstadt, Sara D; Fan, Timothy M; Khanna, Chand; Lunghofer, Paul J; Hansen, Ryan J; Gustafson, Daniel L; Legendre, Alfred M; Galyon, Gina D; LeBlanc, Amy K; Martin-Jimenez, Tomas

2016-01-01

To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. 5 healthy purpose-bred hounds. The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental analyses. Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined.

A triplet combination with capecitabine/oxaliplatin/irinotecan (XELOXIRI) plus cetuximab as first-line therapy for patients with metastatic colorectal cancer: a dose escalation study.

PubMed

Sato, Yasushi; Hirakawa, Masahiro; Ohnuma, Hiroyuki; Takahashi, Minoru; Okamoto, Tetsuro; Okamoto, Koichi; Miyamoto, Hiroshi; Muguruma, Naoki; Furuhata, Tomohisa; Takemasa, Ichiro; Kato, Junji; Takayama, Tetsuji

2017-12-01

The addition of cetuximab to triplet chemotherapy can increase treatment efficacy for patients with metastatic colorectal cancer (mCRC). We explored the dose-limiting toxicity and feasibility of a triweekly capecitabine, oxaliplatin, irinotecan, plus cetuximab (XELOXIRI plus cetuximab) regimen in patients with wild-type KRAS mCRC. Patients received oxaliplatin (100 mg/m 2 , day 1), capecitabine (1700 mg/m 2 per day from day 2 to 15), irinotecan (100, 120, and 150 mg/m 2 for dose levels 1, 2, 3, respectively, on day 1), and cetuximab (400 mg/m 2 , day 1 and, thereafter, 250 mg/m 2 every week), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first 2 treatment cycles to determine the maximum tolerated dose (MTD) and the recommended dose (RD). Twelve patients received a median of 7 cycles of therapy (range 2-10). The DLT was grade 4 neutropenia, observed in 1 of 6 patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m 2 . Most common grade ≥ 3 toxicities were neutropenia (50%), diarrhea (17%), and febrile neutropenia (8%). The response rate was 83% (complete and partial response: 1 and 9 patient(s), respectively), including 4 conversion cases. The combination of XELOXIRI and cetuximab is feasible and has an acceptable toxicity profile; neutropenia was the DLT. The RD of irinotecan is 150 mg/m 2 . The observed response rate was promising and warrants further investigation.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

PubMed

Pasi, K John; Rangarajan, Savita; Georgiev, Pencho; Mant, Tim; Creagh, Michael D; Lissitchkov, Toshko; Bevan, David; Austin, Steve; Hay, Charles R; Hegemann, Inga; Kazmi, Rashid; Chowdary, Pratima; Gercheva-Kyuchukova, Liana; Mamonov, Vasily; Timofeeva, Margarita; Soh, Chang-Heok; Garg, Pushkal; Vaishnaw, Akshay; Akinc, Akin; Sørensen, Benny; Ragni, Margaret V

2017-08-31

Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robertson, John M., E-mail: jrobertson@beaumont.ed; Soehn, Matthias; Yan Di

Purpose: Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Methods and Materials: Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to developmore » a cutoff-dose normal tissue complication probability (NTCP) model. Results: There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). Conclusion: The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.« less

Monte Carlo simulations of the secondary neutron ambient and effective dose equivalent rates from surface to suborbital altitudes and low Earth orbit

NASA Astrophysics Data System (ADS)

El-Jaby, Samy; Richardson, Richard B.

2015-07-01

Occupational exposures from ionizing radiation are currently regulated for airline travel (<20 km) and for missions to low-Earth orbit (∼300-400 km). Aircrew typically receive between 1 and 6 mSv of occupational dose annually, while aboard the International Space Station, the area radiation dose equivalent measured over just 168 days was 106 mSv at solar minimum conditions. It is anticipated that space tourism vehicles will reach suborbital altitudes of approximately 100 km and, therefore, the annual occupational dose to flight crew during repeated transits is expected to fall somewhere between those observed for aircrew and astronauts. Unfortunately, measurements of the radiation environment at the high altitudes reached by suborbital vehicles are sparse, and modelling efforts have been similarly limited. In this paper, preliminary MCNPX radiation transport code simulations are developed of the secondary neutron flux profile in air from surface altitudes up to low Earth orbit at solar minimum conditions and excluding the effects of spacecraft shielding. These secondary neutrons are produced by galactic cosmic radiation interacting with Earth's atmosphere and are among the sources of radiation that can pose a health risk. Associated estimates of the operational neutron ambient dose equivalent, used for radiation protection purposes, and the neutron effective dose equivalent that is typically used for estimates of stochastic health risks, are provided in air. Simulations show that the neutron radiation dose rates received at suborbital altitudes are comparable to those experienced by aircrew flying at 7 to 14 km. We also show that the total neutron dose rate tails off beyond the Pfotzer maximum on ascension from surface up to low Earth orbit.

Monte Carlo simulations of the secondary neutron ambient and effective dose equivalent rates from surface to suborbital altitudes and low Earth orbit.

PubMed

El-Jaby, Samy; Richardson, Richard B

2015-07-01

Occupational exposures from ionizing radiation are currently regulated for airline travel (<20 km) and for missions to low-Earth orbit (∼300-400 km). Aircrew typically receive between 1 and 6 mSv of occupational dose annually, while aboard the International Space Station, the area radiation dose equivalent measured over just 168 days was 106 mSv at solar minimum conditions. It is anticipated that space tourism vehicles will reach suborbital altitudes of approximately 100 km and, therefore, the annual occupational dose to flight crew during repeated transits is expected to fall somewhere between those observed for aircrew and astronauts. Unfortunately, measurements of the radiation environment at the high altitudes reached by suborbital vehicles are sparse, and modelling efforts have been similarly limited. In this paper, preliminary MCNPX radiation transport code simulations are developed of the secondary neutron flux profile in air from surface altitudes up to low Earth orbit at solar minimum conditions and excluding the effects of spacecraft shielding. These secondary neutrons are produced by galactic cosmic radiation interacting with Earth's atmosphere and are among the sources of radiation that can pose a health risk. Associated estimates of the operational neutron ambient dose equivalent, used for radiation protection purposes, and the neutron effective dose equivalent that is typically used for estimates of stochastic health risks, are provided in air. Simulations show that the neutron radiation dose rates received at suborbital altitudes are comparable to those experienced by aircrew flying at 7 to 14 km. We also show that the total neutron dose rate tails off beyond the Pfotzer maximum on ascension from surface up to low Earth orbit. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

SU-F-T-113: Inherent Functional Dependence of Spinal Cord Doses of Variable Irradiated Volumes in Spine SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, L; Braunstein, S; Chiu, J

2016-06-15

Purpose: Spinal cord tolerance for SBRT has been recommended for the maximum point dose level or at irradiated volumes such as 0.35 mL or 10% of contoured volumes. In this study, we investigated an inherent functional relationship that associates these dose surrogates for irradiated spinal cord volumes of up to 3.0 mL. Methods: A hidden variable termed as Effective Dose Radius (EDR) was formulated based on a dose fall-off model to correlate dose at irradiated spinal cord volumes ranging from 0 mL (point maximum) to 3.0 mL. A cohort of 15 spine SBRT cases was randomly selected to derive anmore » EDR-parameterized formula. The mean prescription dose for the studied cases was 21.0±8.0 Gy (range, 10–40Gy) delivered in 3±1 fractions with target volumes of 39.1 ± 70.6 mL. Linear regression and variance analysis were performed for the fitting parameters of variable EDR values. Results: No direct correlation was found between the dose at maximum point and doses at variable spinal cord volumes. For example, Pearson R{sup 2} = 0.643 and R{sup 2}= 0.491 were obtained when correlating the point maximum dose with the spinal cord dose at 1 mL and 3 mL, respectively. However, near perfect correlation (R{sup 2} ≥0.99) was obtained when corresponding parameterized EDRs. Specifically, Pearson R{sup 2}= 0.996 and R{sup 2} = 0.990 were obtained when correlating EDR (maximum point dose) with EDR (dose at 1 mL) and EDR(dose at 3 mL), respectively. As a result, high confidence level look-up tables were established to correlate spinal cord doses at the maximum point to any finite irradiated volumes. Conclusion: An inherent functional relationship was demonstrated for spine SBRT. Such a relationship unifies dose surrogates at variable cord volumes and proves that a single dose surrogate (e.g. point maximum dose) is mathematically sufficient in constraining the overall spinal cord dose tolerance for SBRT.« less

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus.

PubMed

Vajda, Eric G; Logan, Douglas; Lasseter, Kenneth; Armas, Danielle; Plotkin, Diane J; Pipkin, J D; Li, Yong-Xi; Zhou, Rong; Klein, David; Wei, Xiaoxiong; Dilzer, Stacy; Zhi, Lin; Marschke, Keith B

2017-01-01

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD-6972, in healthy subjects and subjects with type 2 diabetes (T2DM). In the single ascending dose study, LGD-6972 (2-480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD-6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD-6972 daily for 14 days. LGD-6972 had linear plasma pharmacokinetics consistent with once-daily dosing that was comparable in healthy and T2DM subjects. Dose-dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD-6972 also reduced plasma glucose in the postprandial state. Dose-dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD-6972 was well tolerated at the doses tested without dose-related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia. Inhibition of glucagon action by LGD-6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

TH-A-9A-04: Incorporating Liver Functionality in Radiation Therapy Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, V; Epelman, M; Feng, M

2014-06-15

Purpose: Liver SBRT patients have both variable pretreatment liver function (e.g., due to degree of cirrhosis and/or prior treatments) and sensitivity to radiation, leading to high variability in potential liver toxicity with similar doses. This work aims to explicitly incorporate liver perfusion into treatment planning to redistribute dose to preserve well-functioning areas without compromising target coverage. Methods: Voxel-based liver perfusion, a measure of functionality, was computed from dynamic contrast-enhanced MRI. Two optimization models with different cost functions subject to the same dose constraints (e.g., minimum target EUD and maximum critical structure EUDs) were compared. The cost functions minimized were EUDmore » (standard model) and functionality-weighted EUD (functional model) to the liver. The resulting treatment plans delivering the same target EUD were compared with respect to their DVHs, their dose wash difference, the average dose delivered to voxels of a particular perfusion level, and change in number of high-/low-functioning voxels receiving a particular dose. Two-dimensional synthetic and three-dimensional clinical examples were studied. Results: The DVHs of all structures of plans from each model were comparable. In contrast, in plans obtained with the functional model, the average dose delivered to high-/low-functioning voxels was lower/higher than in plans obtained with its standard counterpart. The number of high-/low-functioning voxels receiving high/low dose was lower in the plans that considered perfusion in the cost function than in the plans that did not. Redistribution of dose can be observed in the dose wash differences. Conclusion: Liver perfusion can be used during treatment planning potentially to minimize the risk of toxicity during liver SBRT, resulting in better global liver function. The functional model redistributes dose in the standard model from higher to lower functioning voxels, while achieving the same target EUD and satisfying dose limits to critical structures. This project is funded by MCubed and grant R01-CA132834.« less

SU-F-T-35: Optimization of Bladder and Rectal Doses Using a Multi-Lumen Intracavitary Applicator for Gynecological Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laoui, S; Dietrich, S; Sehgal, V

2016-06-15

Purpose: Radiation dose delivery for endometrial cancer using HDR techniques is limited by dose to bladder and rectum. A dosimetric study was performed using Varian Capri vaginal brachytherapy applicator to determine the optimal channel configuration which minimizes dose to bladder and rectum, while providing good target coverage. Methods: A total of 17 patients, 63 plans clinically delivered, and 252 simulated plans using Varian BrachyVision planning system were generated to investigate optimal channel configuration which results in minimum dose to bladder and rectum while providing adequate target coverage. The Capri applicator consists of 13 lumens arranged in two concentric rings, onemore » central lumen and six lumens per ring. Manual dose shaping is invariably required to lower the dose to critical organs. Three-dimensional plans were simulated for 4 channel arrangements, all 13 channels, channel 12 o’clock (close to bladder) and 6 o’clock (close to rectum) deactivated, central channel deactivated, and central channel in addition to 12 o’clock and 6 o’clock deactivated. A relationship between V100, the volume that receives the prescribed dose, and the amount of curie-seconds required to deliver it, was established. Results: Using all 13 channels results in maximum dose to bladder and rectum. Deactivating central channel in addition to 12 o’clock and 6 o’clock resulted in minimizing bladder and rectum doses but compromised target coverage. The relationship between V100, the volume that receives the prescribed dose, and the curie seconds was found to be linear. Conclusion: Deactivating channels 12 o’clock and 6 o’clock was shown to be the optimal configuration leading to minimum dose to bladder and rectum without compromising target coverage. The linear relationship between V100 and the curie- seconds can be used as a verification parameter.« less

Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors.

PubMed

Moore, Kathleen N; Borghaei, Hossein; O'Malley, David M; Jeong, Woondong; Seward, Shelly M; Bauer, Todd M; Perez, Raymond P; Matulonis, Ursula A; Running, Kelli L; Zhang, Xiaoyan; Ponte, Jose F; Ruiz-Soto, Rodrigo; Birrer, Michael J

2017-08-15

Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors. Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity. In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response. IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society. © 2017 American Cancer Society.

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis.

PubMed

Ogura, Takashi; Taniguchi, Hiroyuki; Azuma, Arata; Inoue, Yoshikazu; Kondoh, Yasuhiro; Hasegawa, Yoshinori; Bando, Masashi; Abe, Shinji; Mochizuki, Yoshiro; Chida, Kingo; Klüglich, Matthias; Fujimoto, Tsuyoshi; Okazaki, Kotaro; Tadayasu, Yusuke; Sakamoto, Wataru; Sugiyama, Yukihiko

2015-05-01

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. Copyright ©ERS 2015.

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

PubMed Central

Moore, Kenneth Todd; Byra, William; Vaidyanathan, Seema; Natarajan, Jaya; Ariyawansa, Jay; Salih, Hiba; Turner, Kenneth C

2015-01-01

Aims The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives. Methods An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban. Results During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax) for INR after co-administration was 2.79–4.15 (mean PT Emax 41.0–62.7 s), compared with 1.41–1.74 (mean PT Emax 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug. Conclusions The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR. PMID:25475601

Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer.

PubMed

Satoh, Taroh; Yamada, Yasuhide; Muro, Kei; Hayashi, Hidetoshi; Shimada, Yasuhiro; Takahari, Daisuke; Taku, Keisei; Nakajima, Takako Eguchi; Shi, Xiaojin; Brown, Kathryn H; Boku, Narikazu

2012-02-01

The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer. Patients received continuous, once-daily oral doses of cediranib 20 mg in combination with either cisplatin (60 mg/m(2) iv day 1) plus S-1 (40-60 mg bid, days 1-21) every 5 weeks for a maximum of eight cycles [Arm A]; or cisplatin (80 mg/m(2) iv, day 1) plus capecitabine (1,000 mg/m(2) bid, days 1-14) every 3 weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21 days of cycle 1. Fourteen patients (Arm A, n = 6; Arm B, n = 8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n = 13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n = 1; Arm B, n = 2) partial responses that were ongoing at data cut-off. Cediranib 20 mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.

Enhancement of natural background gamma-radiation dose around uranium microparticles in the human body.

PubMed

Pattison, John E; Hugtenburg, Richard P; Green, Stuart

2010-04-06

Ongoing controversy surrounds the adverse health effects of the use of depleted uranium (DU) munitions. The biological effects of gamma-radiation arise from the direct or indirect interaction between secondary electrons and the DNA of living cells. The probability of the absorption of X-rays and gamma-rays with energies below about 200 keV by particles of high atomic number is proportional to the third to fourth power of the atomic number. In such a case, the more heavily ionizing low-energy recoil electrons are preferentially produced; these cause dose enhancement in the immediate vicinity of the particles. It has been claimed that upon exposure to naturally occurring background gamma-radiation, particles of DU in the human body would produce dose enhancement by a factor of 500-1000, thereby contributing a significant radiation dose in addition to the dose received from the inherent radioactivity of the DU. In this study, we used the Monte Carlo code EGSnrc to accurately estimate the likely maximum dose enhancement arising from the presence of micrometre-sized uranium particles in the body. We found that although the dose enhancement is significant, of the order of 1-10, it is considerably smaller than that suggested previously.

Dose conformation to the spine during palliative treatments using dynamic wedges

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ormsby, Matthew A., E-mail: Matthew.Ormsby@usoncology.com; Herndon, R. Craig; Kaczor, Joseph G.

2013-07-01

Radiation therapy is commonly used to alleviate pain associated with metastatic disease of the spine. Often, isodose lines are manipulated using dynamic or physical wedges to encompass the section of spine needing treatment while minimizing dose to normal tissue. We will compare 2 methods used to treat the entire thoracic spine. The first method treats the thoracic spine with a single, nonwedged posterior-anterior (PA) field. Dose is prescribed to include the entire spine. Isodose lines tightly conform to the top and bottom vertebrae, but vertebrae between these 2 received more than enough coverage. The second method uses a combination ofmore » wedges to create an isodose line that mimics the curvature of the thoracic spine. This “C”-shaped curvature is created by overlapping 2 fields with opposing dynamic wedges. Machine constraints limit the treatment length and therefore 2 isocenters are used. Each of the 2 PA fields contributes a portion of the total daily dose. This technique creates a “C”-shaped isodose line that tightly conforms to the thoracic spine, minimizing normal tissue dose. Spinal cord maximum dose is reduced, as well as mean dose to the liver, esophagus, and heart.« less

Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmacokinetics.

PubMed

Moschetti, Viktoria; Schlecker, Christina; Wind, Sven; Goetz, Sophia; Schmitt, Holger; Schultz, Armin; Liesenfeld, Karl-Heinz; Wunderlich, Glen; Desch, Michael

2018-05-30

Schizophrenia and Alzheimer's disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate receptor hypofunction. Glycine is an N-methyl-D-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-D-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers. Part 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4-14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening. Pharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0-4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed. Pharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses. CLINICALTRIALS. NCT02337283.

Dose painting to treat single-lobe prostate cancer with hypofractionated high-dose radiation using targeted external beam radiation: Is it feasible?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amini, Arya; Westerly, David C.; Waxweiler, Timothy V.

Targeted focal therapy strategies for treating single-lobe prostate cancer are under investigation. In this planning study, we investigate the feasibility of treating a portion of the prostate to full-dose external beam radiation with reduced dose to the opposite lobe, compared with full-dose radiation delivered to the entire gland using hypofractionated radiation. For 10 consecutive patients with low- to intermediate-risk prostate cancer, 2 hypofractionated, single-arc volumetric-modulated arc therapy (VMAT) plans were designed. The first plan (standard hypofractionation regimen [STD]) included the entire prostate gland, treated to 70 Gy delivered in 28 fractions. The second dose painting plan (DP) encompassed the involvedmore » lobe treated to 70 Gy delivered in 28 fractions, whereas the opposing, uninvolved lobe received 50.4 Gy in 28 fractions. Mean dose to the opposing neurovascular bundle (NVB) was considerably lower for DP vs STD, with a mean dose of 53.9 vs 72.3 Gy (p < 0.001). Mean penile bulb dose was 18.6 Gy for DP vs 19.2 Gy for STD (p = 0.880). Mean rectal dose was 21.0 Gy for DP vs 22.8 Gy for STD (p = 0.356). Rectum V{sub 70} (the volume receiving ≥70 Gy) was 2.01% for DP vs 2.74% for STD (p = 0.328). Bladder V{sub 70} was 1.69% for DP vs 2.78% for STD (p = 0.232). Planning target volume (PTV) maximum dose points were 76.5 and 76.3 Gy for DP and STD, respectively (p = 0.760). This study demonstrates the feasibility of using VMAT for partial-lobe prostate radiation in patients with prostate cancer involving 1 lobe. Partial-lobe prostate plans appeared to spare adjacent critical structures including the opposite NVB.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, M; Sura, S

Purpose: To evaluate dosimetric impact of two axillary nodes (AX) boost techniques: (1) posterior-oblique optimized field boost (POB), (2) traditional posterior-anterior boost (PAB) with field optimization (O-PAB), for a postmastectomy breast patient with positive axillary lymph nodes. Methods: Five patients, 3 left and 2 right chest walls, were included in this study. All patients were simulated in 5mm CT slice thickness. Supraclavicular (SC) and level I/II/III AX were contoured based on the RTOG atlas guideline. Five treatment plans, (1) tangential chest wall, (2) oblique SC including AX, (3) PAB, O-PAB and POB, were created for each patient. Three plan sumsmore » (PS) were generated by sum one of (3) plan with plan (1) and (2). The field optimization was done through PS dose distribution, which included a field adjustment, a fractional dose, a calculation location and a gantry angle selection for POB. A dosimetric impact was evaluated by comparing a SC and AX coverage, a PS maximum dose, an irradiated area percentage volume received dose over 105% prescription dose (V105), an ipsi-laterial mean lung dose (MLD), an ipsi-laterial mean humeral head dose (MHHD), a mean heart dose (MHD) (for left case only) and their DVH amount these three technique. Results: O-PAB, POB and PAB dosimetric results showed that there was no significant different on SC and AX coverage (p>0.43) and MHD (p>0.16). The benefit of sparing lung irradiation from PAB to O-PAB to POB was significant (p<0.004). PAB showed a highest PS maximum dose (p<0.005), V105 (p<0.023) and MLD (compared with OPAB, p=0.055). MHHD showed very sensitive to the patient arm positioning and anatomy. O-PAB convinced a lower MHHD than PAB (p=0.03). Conclusion: 3D CT contouring plays main role in accuracy radiotherapy. Dosimetric advantage of POB and O-PAB was observed for a better normal tissue irradiation sparing.« less

Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors.

PubMed

Strauss, Julius; Heery, Christopher R; Schlom, Jeffrey; Madan, Ravi A; Cao, Liang; Kang, Zhigang; Lamping, Elizabeth; Marté, Jennifer L; Donahue, Renee N; Grenga, Italia; Cordes, Lisa; Christensen, Olaf; Mahnke, Lisa; Helwig, Christoph; Gulley, James L

2018-03-15

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ "trap." Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Results: Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287-95. ©2018 AACR . ©2018 American Association for Cancer Research.

SU-E-T-317: The Development of a DIBH Technique for Left Sided Breast Patients Undergoing Radiation Therapy Utilizing Varians RPM System in a Community Hospital

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hasson, B; Young, M; Workie, D

2014-06-01

Purpose: To develop and implement a Deep Inhalation Breath Hold program (DIBH) for treatment of patients with Left-sided breast cancer in a community hospital. Methods: All patients with left sided breast cancer underwent a screening free breathing CT. Evaluation of the conventional tangent treatment fields and the heart was conducted. If the heart would not be excluded using tangents, the patient then received DIBH breathe coaching. The patients returned for a 4D CT simulation. The patients breathing cycle was monitored using the Varian Real-Time position ManagementTM (RPM) system to assess duration of DIBH, amplitude, phase and recovery time to normalmore » breathing. Then a DIBH CT was obtained at the desired amplitude. Duplicate plans were developed for both free breathing and DIBH on the Eclipse planning system and comparison DVH's were created. The plan that provided the prescribed treatment coverage and the least doses to the OAR (heart, Lt. Lung) was determined. Those patients selected to receive treatment with DIBH were set up for treatment, and breathing was monitored using the RPM system. Practice trials were used to confirm that the amplitude, phase and recovery were consistent with findings from simulation. Results: 10 patients have been treated using the DIBH procedure in our clinic. The DIBH patients had an average increase of 80% lung volume on DIBH, decreased lung volume receiving 50% of the dose, and decreases in the V20 dose. Significant reduction in the maximum and mean dose to the heart, as well as the dose to 1CC of the volume for the DIBH plans. Conclusion: Using the RPM system already available in the clinic, staff training, and patient coaching a simple DIBH program was setup. The use of DIBH has shown promise in reducing doses to the critical organs while maintaining PTV coverage for left sided breast treatments.« less

Quantitatively Excessive Normal Tissue Toxicity and Poor Target Coverage in Postoperative Lung Cancer Radiotherapy Meta-analysis.

PubMed

Abuodeh, Yazan; Naghavi, Arash O; Echevarria, Michelle; DeMarco, MaryLou; Tonner, Brian; Feygelman, Vladimir; Stevens, Craig W; Perez, Bradford A; Dilling, Thomas J

2018-01-01

A previous meta-analysis (MA) found postoperative radiotherapy (PORT) in lung cancer patients to be detrimental in N0/N1 patients and equivocal in the N2 setting. We hypothesized that treatment plans generated using MA protocols had worse dosimetric outcomes compared to modern plans. We retrieved plans for 13 patients who received PORT with modern planning. A plan was recreated for each patient using the 8 protocols included in MA. Dosimetric values were then compared between the modern and simulated MA plans. A total of 104 MA plans were generated. Median prescribed dose was 50.4 (range, 50-60) Gy in the modern plans and 53.2 (30-60) Gy in the MA protocols. Median planning volume coverage was 96% (93%-100%) in the modern plans, versus 58% (0%-100%) in the MA plans (P < .001). Internal target volume coverage was 100% (99%-100%) versus 65% (0%-100%), respectively (P < .001). Organs at risk received the following doses: spinal cord maximum dose, 36.8 (4.6-50.4) Gy versus 46.8 (2.9-74.0) Gy (P < .001); esophageal mean dose, 22.9 (5.5-35) Gy versus 30.5 (11.1-52.5) Gy (P = .003); heart V30 (percentage of volume of an organ receiving at least a dose of 30 Gy), 16% (0%-45%) versus 35% (0%-79%) (P = .047); mean lung dose, 12.4 (3.4-24.3) Gy versus 14.8 (4.1-27.4) Gy (P = .008); and lung V20, 18% (4%-34%) versus 25% (8%-67%) (P = .023). We quantitatively confirm the inferiority of the techniques used in the PORT MA. Our analysis showed a lower therapeutic ratio in the MA plans, which may explain the poor outcomes in the MA. The findings of the MA are not relevant in the era of modern treatment planning. Copyright © 2017 Elsevier Inc. All rights reserved.

Radon activity concentrations and effective doses in ancient Egyptian tombs of the Valley of the Kings.

PubMed

Hafez, A F; Hussein, A S

2001-09-01

Radon concentrations and equilibrium factors were measured in three pharaonic tombs during the year 1998. The tombs, which are open to the public are located in a limestone wadi on the West Bank of the River Nile at Luxor, 650 km south of Cairo. The radon activity concentration and equilibrium factor were measured monthly by two-integral nuclear track detectors (bare and diffusion detectors). Seasonal variation of radon concentrations, with summer maximum and winter minimum were observed in all tombs investigated. The yearly mean radon activity concentrations insidc the tombs ranged from 540 to 3115 Bq m(-3). The mean equilibrium factor over a year was found to be 0.25 and 0.32 inside and at the entrance, respectively. Estimated annual effective doses to tour guides ranged from 0.33 to 1.90 mSv, visitors receive doses from 0.65 to 3.80 microSv per visit. The effective dose to tomb workers did not exceed the 20 mSv yr(-1) limit.

Effect of Single-dose Rifampin on the Pharmacokinetics of Warfarin in Healthy Volunteers

PubMed Central

Frymoyer, A; Shugarts, S; Browne, M; Wu, AHB; Frassetto, L; Benet, LZ

2011-01-01

Based on in vitro rat and human hepatocyte uptake studies showing inhibition of warfarin uptake in the presence of the non-specific organic anion transporting polypeptide (OATP) inhibitor rifampin, a clinical study was conducted in 10 healthy volunteers. In a randomized, single-dose, two-period, crossover design, subjects received a 7.5 mg dose of warfarin alone or immediately following a 600 mg intravenous dose of rifampin. Rifampin did not significantly alter R- or S- warfarin area under the concentration-time curve (AUC) from 0–12 hours (period of hepatic OATP inhibition by rifampin) or Cmax (maximum plasma concentration). AUC0–∞ was decreased on rifampin days for both R- (25% reduction; p < 0.001) and S-warfarin (15% reduction; p < 0.05). No differences were seen on the area under the INR-time curve. Our study suggests hepatic uptake via OATPs may not be clinically important in the pharmacokinetics of warfarin. PMID:20703222

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer: report of a phase I/II dose-escalating study.

PubMed

Thomas, A L; Cox, G; Sharma, R A; Steward, W P; Shields, F; Jeyapalan, K; Muller, S; O'Byrne, K J

2000-12-01

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis.

A population-based study of dosing and persistence with anti-dementia medications.

PubMed

Brewer, Linda; Bennett, Kathleen; McGreevy, Cora; Williams, David

2013-07-01

Cholinesterase inhibitors and memantine are the mainstay of pharmacological intervention for the cognitive symptoms of Alzheimer's disease (AD). This study assessed the adequacy of dosing and persistence with AD medications and the predictors of these variables in the 'real world' (outside the clinical trial setting). The Health Service Executive-Primary Care Reimbursement Services prescription claims database in the Republic of Ireland contains prescription information for 1.6 million people. Patients aged >70 years who received at least two prescriptions for donepezil, rivastigmine, galantamine and memantine between January 2006 and December 2010 were included in the study. Rates of dose-maximisation were recorded by examining the initiation dose of each AD drug commenced during the study period and any subsequent dose titrations. Non-persistence was defined by a gap in prescribing of more than 63 consecutive days. Predictors of dose-maximisation and non-persistence were also analysed. Between January 2006 and December 2010, 20,729 patients aged >70 years received a prescription for an AD medication. Despite most patients on donepezil and memantine receiving a prescription for the maximum drug dose, this dose was maintained for 2 consecutive months in only two-thirds of patients. Patients were significantly more likely to have their doses of donepezil and memantine maximised if prescribed in more recent years (2010 vs. 2007). Rates of non-persistence were 30.1 % at 6 months and 43.8 % at 12 months. Older age [75+ vs. <75 years; hazards ratio (HR) 1.16, 95 % confidence interval (CI) 1.06-1.27] and drug type (rivastigmine vs. donepezil; HR 1.15, 95 % CI 1.03-1.27) increased the risk of non-persistence. Non-persistence was lower for those commencing therapy in more recent years (2010 vs. 2007; HR 0.81, 95 % CI 0.73-0.89, p < 0.001) and for those on multiple anti-dementia medications (HR 0.59, 95 % CI 0.54-0.65, p < 0.001). Persistence was significantly higher when memantine was co-prescribed with donepezil (p < 0.0001). Future studies should explore the reasons underlying non-persistence and failure to maintain dose-maximisation in patients on AD medications. There may be scope to improve the dosing and persistence with these medications in the community.

Effect of heterogeneity correction on dosimetric parameters of radiotherapy planning for thoracic esophageal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakayama, Masao, E-mail: naka2008@med.kobe-u.ac.jp; Yoshida, Kenji; Nishimura, Hideki

2014-04-01

The present study aimed to investigate the effect of heterogeneity correction (HC) on dosimetric parameters in 3-dimensional conformal radiotherapy planning for patients with thoracic esophageal cancer. We retrospectively analyzed 20 patients. Two treatment plans were generated for each patient using a superposition algorithm on the Xio radiotherapy planning system. The first plan was calculated without HC. The second was a new plan calculated with HC, using identical beam geometries and maintaining the same number of monitor units as the first. With regard to the planning target volume (PTV), the overall mean differences in the prescription dose, maximum dose, mean dose,more » and dose that covers 95% of the PTV between the first and second plans were 1.10 Gy (1.8%), 1.35 Gy (2.2%), 1.10 Gy (1.9%), and 0.56 Gy (1.0%), respectively. With regard to parameters related to the organs at risk (OARs), the mean differences in the absolute percentages of lung volume receiving greater than 5, 10, 20, and 30 Gy (lung V{sub 5}, V{sub 10}, V{sub 20}, and V{sub 30}) between the first and second plans were 7.1%, 2.7%, 0.4%, and 0.5%, respectively. These results suggest that HC might have a more pronounced effect on the percentages of lung volume receiving lower doses (e.g., V{sub 5} and V{sub 10}) than on the dosimetric parameters related to the PTV and other OARs.« less

Ondansetron versus granisetron in the prevention of chemotherapy induced nausea and vomiting in children with acute lymphoblastic leukemia.

PubMed

Siddique, R; Hafiz, M G; Rokeya, B; Jamal, C Y; Islam, A

2011-10-01

Effect of ondansetron and granisetron were evaluated in sixty (60) children (age 4-11 years) irrespective of sex, diagnosed case of acute lymphoblastic leukemia (ALL) who received high dose methotrexate and did not receive any antiemetic 24 hours prior to HDMTX. This was a prospective, randomized, double-blind, single center study. Of 60 children, 30 received oral ondansetron (4mg) and rest 30 granisetron (1mg) half an hour before therapy. Drugs were randomly allocated with appropriate code. The patients were followed up from day 1 to day 5 of therapy. Episodes of nausea and vomiting were recorded and scorings was done every 24 hours following chemotherapy. No significant difference was found between two groups according to acute emesis (Day-1) (p=0.053). In day two and day three it was significant (p<0.05). In day four it was significant (p=0.002). Early chemotherapy induced nausea and vomiting (CINV) were controlled 90% in children who received granisetron and 70% in children who received ondansetron. Delayed (Day 2-4) CINV were controlled in 80% of children who received granisetron and 43.4% who received ondansetron (p<0.05). Granisetron group required additional doses only 3.3% cases and ondanseton group 30% cases on the second day (p<0.05). Result was significant between two groups. About 36.7% patients had episodes of nausea on day four of chemotherapy in ondansetron group and it was only 3.3% in granisetron group due to adverse effects of antiemetic drug itself (p=0.001). Maximum episodes of vomiting were found on the second day in ondansetron group 33.3% and in granisetron group 3.3% (p=0.003). Though adverse effects like headache, constipation, abdominal pain and loose motion were common in both group of children but their number was much less in children who received granisetron. On second day of therapy score of nausea and vomiting was maximum in ondansetron and minimum in granisetron treated on day 4 and the result was significant. So, to prevent acute and delayed CINV in children with ALL, oral graniseteron can be considered as more effective and well tolerated with minimum adverse effects compared with ondansetrons.

TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): Study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic disability after stroke.

PubMed

Nagpal, Anjali; Kremer, Karlea L; Hamilton-Bruce, Monica A; Kaidonis, Xenia; Milton, Austin G; Levi, Christopher; Shi, Songtao; Carey, Leeanne; Hillier, Susan; Rose, Miranda; Zacest, Andrew; Takhar, Parabjit; Koblar, Simon A

2016-07-01

Stroke represents a significant global disease burden. As of 2015, there is no chemical or biological therapy proven to actively enhance neurological recovery during the chronic phase post-stroke. Globally, cell-based therapy in stroke is at the stage of clinical translation and may improve neurological function through various mechanisms such as neural replacement, neuroprotection, angiogenesis, immuno-modulation, and neuroplasticity. Preclinical evidence in a rodent model of middle cerebral artery ischemic stroke as reported in four independent studies indicates improvement in neurobehavioral function with adult human dental pulp stem cell therapy. Human adult dental pulp stem cells present an exciting potential therapeutic option for improving post-stroke disability. TOOTH (The Open study Of dental pulp stem cell Therapy in Humans) will investigate the use of autologous stem cell therapy for stroke survivors with chronic disability, with the following objectives: (a) determine the maximum tolerable dose of autologous dental pulp stem cell therapy; (b) define that dental pulp stem cell therapy at the maximum tolerable dose is safe and feasible in chronic stroke; and (c) estimate the parameters of efficacy required to design a future Phase 2/3 clinical trial. TOOTH is a Phase 1, open-label, single-blinded clinical trial with a pragmatic design that comprises three stages: Stage 1 will involve the selection of 27 participants with middle cerebral artery ischemic stroke and the commencement of autologous dental pulp stem cell isolation, growth, and testing in sequential cohorts (n = 3). Stage 2 will involve the transplantation of dental pulp stem cell in each cohort of participants with an ascending dose and subsequent observation for a 6-month period for any dental pulp stem cell-related adverse events. Stage 3 will investigate the neurosurgical intervention of the maximum tolerable dose of autologous dental pulp stem cell followed by 9 weeks of intensive task-specific rehabilitation. Advanced magnetic resonance and positron emission tomography neuro-imaging, and clinical assessment will be employed to probe any change afforded by stem cell therapy in combination with rehabilitation. Nine participants will step-wise progress in Stage 2 to a dose of up to 10 million dental pulp stem cell, employing a cumulative 3 + 3 statistical design with low starting stem cell dose and subsequent dose escalation, assuming that an acceptable probability of dose-limiting complications is between 1 in 6 (17%) and 1 in 3 (33%) of patients. In Stage 3, another 18 participants will receive an intracranial injection with the maximum tolerable dose of dental pulp stem cell. The primary outcomes to be measured are safety and feasibility of intracranial administration of autologous human adult DPSC in patients with chronic stroke and determination of the maximum tolerable dose in human subjects. Secondary outcomes include estimation of the measures of effectiveness required to design a future Phase 2/3 clinical trial. © 2016 World Stroke Organization.

Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer.

PubMed

Narayan, Vivek; Mamtani, Ronac; Keefe, Stephen; Guzzo, Thomas; Malkowicz, S Bruce; Vaughn, David J

2016-07-01

We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) planned for radical cystectomy. Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of six patients were enrolled. The initial four patients received gemcitabine 1,000 mg/m(2) intravenously on days 1 and 8 and cisplatin 70 mg/m(2) intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug-delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%). The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens.

Phase I Study of Oral S-1 Plus Cisplatin With Concurrent Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaira, Kyoichi; Sunaga, Noriaki; Yanagitani, Noriko

Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: S-1 was administered orally twice daily for 14 days and cisplatin on Days 1 and 8 of each cycle; this was repeated every 3 weeks. Doses of each drug were planned as follows: level 0, 50/40; level 1, 60/40; level 2, 70/40; level 3, 80/40 (S-1 [mg/m{sup -2}/day{sup -1}]/cisplatin [mg/m{sup -2}/day{sup -1}]). Thoracic radiation therapy was administered in 2 Gy fractions five times weekly to amore » total dose of 60 Gy. Results: Ten patients were enrolled in this study. All patients received 60 Gy of thoracic radiotherapy and 7 (70%) patients received four cycles of chemotherapy. At level 1, 2 of 3 patients experienced a delay exceeding 10 days in the cisplatin administration of Day 29. Grade 4 neutropenia and Grade 3 fever occurred in 1 and 1 patients, respectively. Nonhematologic toxicities were mild. None developed {>=}Grade 3 esophagitis or lung toxicity. At level 0, 2 of 7 patients developed dose-limiting toxicity. Thus, level 1 was considered the MTD and Level 0 was selected as the RD. Objective responses were seen in all patients. Conclusions: The RD is the level 0 dose, and this regimen is a feasible and well-tolerated regimen for the treatment of patients with Stage III NSCLC.« less

Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia

PubMed Central

Carpenter, Thomas O.; Imel, Erik A.; Ruppe, Mary D.; Weber, Thomas J.; Klausner, Mark A.; Wooddell, Margaret M.; Kawakami, Tetsuyoshi; Ito, Takahiro; Zhang, Xiaoping; Humphrey, Jeffrey; Insogna, Karl L.; Peacock, Munro

2014-01-01

Background. X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Methods. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003–0.3 mg/kg i.v. or 0.1–1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. Results. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P < 0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8–15 days) compared with that seen with i.v. dosing (0.5–4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8–12 days after i.v. administration and 13–19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. Conclusion. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc. PMID:24569459

SU-F-BRA-14: Optimization of Dosimetric Guidelines for Accelerated Partial Breast Irradiation (APBI) Using the Strut-Adjusted Volume Implant (SAVI)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mooney, K; Altman, M; Garcia-Ramirez, J

Purpose: Treatment planning guidelines for accelerated partial breast irradiation (ABPI) using the strut-adjusted volume implant (SAVI) are inconsistent between the manufacturer and NSABP B-39/RTOG 0413 protocol. Furthermore neither set of guidelines accounts for different applicator sizes. The purpose of this work is to establish guidelines specific to the SAVI that are based on clinically achievable dose distributions. Methods: Sixty-two consecutive patients were implanted with a SAVI and prescribed to receive 34 Gy in 10 fractions twice daily using high dose-rate (HDR) Ir-192 brachytherapy. The target (PTV-EVAL) was defined per NSABP. The treatments were planned and evaluated using a combination ofmore » dosimetric planning goals provided by the NSABP, the manufacturer, and our prior clinical experience. Parameters evaluated included maximum doses to skin and ribs, and volumes of PTV-EVAL receiving 90%, 95%, 100%, 150%, and 200% of the prescription (V90, etc). All target parameters were evaluated for correlation with device size using the Pearson correlation coefficient. Revised dosimetric guidelines for target coverage and heterogeneity were determined from this population. Results: Revised guidelines for minimum target coverage (ideal in parentheses): V90≥95%(97%), V95≥90%(95%), V100≥88%(91%). The only dosimetric parameters that were significantly correlated (p<0.05) with device size were V150 and V200. Heterogeneity criteria were revised for the 6–1 Mini/6-1 applicators to V150≤30cc and V200≤15cc, and unchanged for the other sizes. Re-evaluation of patient plans showed 90% (56/62) met the revised minimum guidelines and 76% (47/62) met the ideal guidelines. All and 56/62 patients met our institutional guidelines for maximum skin and rib dose, respectively. Conclusions: We have optimized dosimetric guidelines for the SAVI applicators, and found that implementation of these revised guidelines for SAVI treatment planning yielded target coverage exceeding that required by existing guidelines while preserving heterogeneity constraints and minimizing dose to organs at risk.« less

The effects of Dalmane /flurazepam hydrochloride/ on human EEG characteristics.

NASA Technical Reports Server (NTRS)

Frost, J. D., Jr.; Carrie, J. R. G.; Borda, R. P.; Kellaway, P.

1973-01-01

Evaluation of the changes in the waking EEGs of six healthy male subjects who received 30 mg daily oral doses of flurazepam hydrochloride for two weeks. A placebo was then substituted for flurazepam for another two weeks. An increase in beta activity with a maximum in fronto-central leads was observed during the test period. A small increase in the mean wavelength of the alpha and theta activities in the central-occipital derivations was also apparent in the subjects during the period.

Double-Blind Comparison of Iodamide and Diatrizoate for Excretory Urography 1

PubMed Central

Rosenfield, Arthur T.; Putman, Charles E.; Ulreich, Sidney; Koss, Neal

1977-01-01

A double-blind comparison of meglumine iodamide and Renografin 60 (52% meglumine diatrizoate and 8% sodium diatrizoate) for bolus excretory urography was performed. Doses of 0.8 cc/kg. to a maximum of 55 cc were administered to fifty patients, twenty-five receiving each drug. There is a suggestion that iodamide may be superior to diatrizoate in pyelocalyceal opacification while being equal to diatrizoate in parenchymal opacification and in types and severity of side-effects. PMID:345632

MRI-Based Evaluation of the Vaginal Cuff in Brachytherapy Planning: Are We Missing the Target?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chapman, Christina Hunter; Prisciandaro, Joann I.; Maturen, Katherine E.

2016-06-01

Purpose: Although recurrences and toxicity occur after vaginal cuff (VC) brachytherapy, little is known about dosimetry due to the inability to clearly visualize the VC on computed tomography (CT). T2-weighted (T2W) magnetic resonance imaging (MRI) is superior to CT in this setting, and we hypothesized that it could provide previously unascertainable dosimetric information. Methods and Materials: In a cohort of 32 patients who underwent cylinder-based brachytherapy for endometrial cancer with available MR simulation images, the VC was retrospectively contoured on T2W images, and cases were replanned to treat the upper VC to a dose of 7 Gy/fraction prescribed to 5 mm. Relevantmore » dose-volume parameters for the VC were calculated. Results: T2W MRI identified significant underdosing not observed on CT or T1-weighted imaging. Over two-thirds (69%) of patients had at least 1 cm{sup 3} of VC that received less than 75% of the prescription dose and half (50%) of patients had a least 1 cm{sup 3} of VC that received less than 50% of the prescription dose. The mean minimum point dose to the VC was 2.4 Gy, or 34% of the intended prescription dose (range: 0.53-6.4 Gy). Conclusions: We identified previously unreported VC underdosing in over two-thirds of our patients, with most of these patients having volumes of undistended VC that received less than half of the prescription dose. The maximum dimension was along the craniocaudal axis in some patients or left-right/anterior-posterior axis in others, suggesting that suture material may be restricting access to the vaginal apex and that alternative applicators may be needed when the diameter of the apex is larger than the introitus. Additional follow-up will be needed to determine whether underdosing is associated with isolated VC failure or whether low failure rates across the cohort suggest that some patients are being exposed to excessive dose and unnecessary risk of toxicity.« less

Pharmacokinetics and effect on the corrected QT interval of single-dose escitalopram in healthy elderly compared with younger adults.

PubMed

Chung, Hyewon; Kim, Anhye; Lim, Kyoung Soo; Park, Sang-In; Yu, Kyung-Sang; Yoon, Seo Hyun; Cho, Joo-Youn; Chung, Jae-Yong

2017-01-01

Escitalopram is the (S)-enantiomer of citalopram that has a potential QT prolonging effect. In this study, 12 healthy elderly individuals received a single oral dose of escitalopram (20 mg), and their pharmacokinetics and QT effect data were compared with data from 33 younger adults obtained in a previous study. Serial blood samples for pharmacokinetic analysis were collected and ECG was performed up to 48 h postdose. The elderly and younger adults showed similar pharmacokinetic profiles. The geometric mean ratios (90% confidence interval) of the elderly compared with the younger adults were 1.02 (0.89-1.17) and 1.01 (0.86-1.17) for the maximum plasma concentration and area under the concentration-time curve, respectively. The mean baseline-adjusted QT (dQT) time profiles were similar and the mean values of maximum dQT were not significantly different between the elderly and the younger adults. The linear mixed-effect model indicated a weak but positive relationship between the escitalopram concentration and dQT, with an estimated coefficient of concentration of 0.43-0.54. In conclusion, the pharmacokinetics and QT effect of a single dose of escitalopram observed in the elderly without comorbidities and younger adults were generally similar.

Optimizing drug-dose alerts using commercial software throughout an integrated health care system.

PubMed

Saiyed, Salim M; Greco, Peter J; Fernandes, Glenn; Kaelber, David C

2017-11-01

All default electronic health record and drug reference database vendor drug-dose alerting recommendations (single dose, daily dose, dose frequency, and dose duration) were silently turned on in inpatient, outpatient, and emergency department areas for pediatric-only and nonpediatric-only populations. Drug-dose alerts were evaluated during a 3-month period. Drug-dose alerts fired on 12% of orders (104 098/834 911). System-level and drug-specific strategies to decrease drug-dose alerts were analyzed. System-level strategies included: (1) turning off all minimum drug-dosing alerts, (2) turning off all incomplete information drug-dosing alerts, (3) increasing the maximum single-dose drug-dose alert threshold to 125%, (4) increasing the daily dose maximum drug-dose alert threshold to 125%, and (5) increasing the dose frequency drug-dose alert threshold to more than 2 doses per day above initial threshold. Drug-specific strategies included changing drug-specific maximum single and maximum daily drug-dose alerting parameters for the top 22 drug categories by alert frequency. System-level approaches decreased alerting to 5% (46 988/834 911) and drug-specific approaches decreased alerts to 3% (25 455/834 911). Drug-dose alerts varied between care settings and patient populations. © The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Levetiracetam for Treatment of Neonatal Seizures

PubMed Central

Abend, Nicholas S.; Gutierrez-Colina, Ana M.; Monk, Heather M.; Dlugos, Dennis J.; Clancy, Robert R.

2011-01-01

Neonatal seizures are often refractory to treatment with initial antiseizure medications. Consequently, clinicians turn to alternatives such as levetiracetam, despite the lack of published data regarding its safety, tolerability, or efficacy in the neonatal population. We report a retrospectively identified cohort of 23 neonates with electroencephalographically confirmed seizures who received levetiracetam. Levetiracetam was considered effective if administration was associated with a greater than 50% seizure reduction within 24 hours. Levetiracetam was initiated at a mean conceptional age of 41 weeks. The mean initial dose was 16 ± 6 mg/kg and the mean maximum dose was 45 ± 19 mg/kg/day. No respiratory or cardiovascular adverse effects were reported or detected. Levetiracetam was associated with a greater than 50% seizure reduction in 35% (8 of 23), including seizure termination in 7. Further study is warranted to determine optimal levetiracetam dosing in neonates and to compare efficacy with other antiseizure medications. PMID:21233461

1992 Environmental monitoring report, Sandia National Laboratories, Albuquerque, New Mexico

DOE Office of Scientific and Technical Information (OSTI.GOV)

Culp, T.; Cox, W.; Hwang, H.

1993-09-01

This 1992 report contains monitoring data from routine radiological and nonradiological environmental surveillance activities. summaries of significant environmental compliance programs in progress, such as National Environmental Policy Act documentation, environmental permits, envirorunental restoration, and various waste management programs for Sandia National Laboratories in Albuquerque, New Mexico, are included. The maximum offsite dose impact was calculated to be 0.0034 millirem. The total population within a 50-mile radius of Sandia National Laboratories/New Mexico received an estimated collective dose of 0.019 person-rem during 1992 from the laboratories` operations. As in the previous year, the 1992 operations at Sandia National Laboratories/New Mexico had nomore » discernible impact on the general public or on the environment.« less

1991 Environmental monitoring report Sandia National Laboratories, Albuquerque, New Mexico

DOE Office of Scientific and Technical Information (OSTI.GOV)

Culp, T.; Cox, W.; Hwang, S.

1992-11-01

This 1991 report contains monitoring data from routine radiological and nonradiological environmental surveillance activities. Summaries of significant environmental compliance programs in progress such as National Environmental Policy Act (NEPA) documentation, environmental permits, environmental restoration (ER), and various waste management programs for Sandia National Laboratories in Albuquerque (SNL, Albuquerque) are included. The maximum offsite dose impact was calculated to be 1.3 {times} 10{sup {minus}3} mrem. The total population within a 50-mile radius of SNL, Albuquerque, received a collective dose of 0.53 person-rem during 1991 from SNL, Albuquerque, operations. As in the previous year, the 1991 operations at SNL, Albuquerque, had nomore » discernible impact on the general public or on the environment.« less

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

PubMed Central

Flaherty, Keith T.; Puzanov, Igor; Kim, Kevin B.; Ribas, Antoni; McArthur, Grant A.; Sosman, Jeffrey A.; O'Dwyer, Peter J.; Lee, Richard J.; Grippo, Joseph F.; Nolop, Keith; Chapman, Paul B.

2013-01-01

Background The identification of somatic mutations in the gene encoding the serine–threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease. Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.) PMID:20818844

Phase I Trial of Neoadjuvant Preoperative Chemotherapy With S-1 and Irinotecan Plus Radiation in Patients With Locally Advanced Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sato, Takeo; Kokuba, Yukihito; Koizumi, Wasaburo

Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with preoperative chemoradiotherapy with S-1 in patients with locally advanced rectal cancer. Patients and Methods: We gave preoperative radiotherapy (total dose, 45 Gy) to 23 patients with locally advanced (T3/T4) rectal cancer. Concurrently, S-1 was given orally at a fixed dose of 80 mg/m{sup 2}/day on Days 1-5, 8-12, 22-26, and 29-33, and irinotecan was given as a 90-min continuous i.v. infusion on Days 1, 8, 22, and 29. The dose of irinotecan was initially 40 mg/m{sup 2}/day and gradually increased to determine the MTDmore » and RD of this regimen. Results: Among the 4 patients who received 90 mg/m{sup 2} irinotecan, 2 had Grade 4 neutropenia and 1 had Grade 3 diarrhea. Because dose-limiting toxicity (DLT) occurred in 3 of the 4 patients, 90 mg/m{sup 2} irinotecan was designated as the MTD. Consequently, 80 mg/m{sup 2} irinotecan was given to 7 additional patients, with no DLT, and this was considered the RD. Of the patients who received irinotecan at the RD or lower doses, 6 (31.6%) had a complete pathologic response (Grade 3) and 9 (47.4%) underwent sphincter-preserving surgery. Conclusions: With our new regimen, the MTD of irinotecan was 90 mg/m{sup 2}, and the RD of irinotecan for Phase II studies was 80 mg/m{sup 2}. Although our results are preliminary, this new neoadjuvant chemoradiotherapy was considered safe and active, meriting further investigation in Phase II studies.« less

Brachial Plexus-Associated Neuropathy After High-Dose Radiation Therapy for Head-and-Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Allen M., E-mail: allen.chen@ucdmc.ucdavis.edu; Hall, William H.; Li, Judy

2012-09-01

Purpose: To identify clinical and treatment-related predictors of brachial plexus-associated neuropathies after radiation therapy for head-and-neck cancer. Methods and Materials: Three hundred thirty patients who had previously completed radiation therapy for head-and-neck cancer were prospectively screened using a standardized instrument for symptoms of neuropathy thought to be related to brachial plexus injury. All patients were disease-free at the time of screening. The median time from completion of radiation therapy was 56 months (range, 6-135 months). One-hundred fifty-five patients (47%) were treated by definitive radiation therapy, and 175 (53%) were treated postoperatively. Radiation doses ranged from 50 to 74 Gy (median,more » 66 Gy). Intensity-modulated radiation therapy was used in 62% of cases, and 133 patients (40%) received concurrent chemotherapy. Results: Forty patients (12%) reported neuropathic symptoms, with the most common being ipsilateral pain (50%), numbness/tingling (40%), motor weakness, and/or muscle atrophy (25%). When patients with <5 years of follow-up were excluded, the rate of positive symptoms increased to 22%. On univariate analysis, the following factors were significantly associated with brachial plexus symptoms: prior neck dissection (p = 0.01), concurrent chemotherapy (p = 0.01), and radiation maximum dose (p < 0.001). Cox regression analysis confirmed that both neck dissection (p < 0.001) and radiation maximum dose (p < 0.001) were independently predictive of symptoms. Conclusion: The incidence of brachial plexus-associated neuropathies after radiation therapy for head-and-neck cancer may be underreported. In view of the dose-response relationship identified, limiting radiation dose to the brachial plexus should be considered when possible.« less

Thyroid V50 Highly Predictive of Hypothyroidism in Head-and-Neck Cancer Patients Treated With Intensity-modulated Radiotherapy (IMRT).

PubMed

Sachdev, Sean; Refaat, Tamer; Bacchus, Ian D; Sathiaseelan, Vythialinga; Mittal, Bharat B

2017-08-01

Radiation-induced hypothyroidism affects a significant number of patients with head-and-neck squamous cell cancer (HNSCC). We examined detailed dosimetric and clinical parameters to better determine the risk of hypothyroidism in euthyroid HNSCC patients treated with intensity-modulated radiation therapy (IMRT). From 2006 to 2010, 75 clinically euthyroid patients with HNSCC were treated with sequential IMRT. The cohort included 59 men and 16 females with a median age of 55 years (range, 30 to 89 y) who were treated to a median dose of 70 Gy (range, 60 to 75 Gy) with concurrent chemotherapy in nearly all (95%) cases. Detailed thyroid dosimetric parameters including maximum dose, mean dose, and other parameters (eg, V50-percent volume receiving at least 50 Gy) were obtained. Freedom from hypothyroidism was evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using Cox regression. After a median follow-up period of 50 months, 25 patients (33%) became hypothyroid. On univariate analysis, thyroid V50 was highly correlated with developing hypothyroidism (P=0.035). Other dosimetric paramaters including mean thyroid dose (P=0.11) and maximum thyroid dose (P=0.39) did not reach statistical significance. On multivariate analysis incorporating patient, tumor, and treatment variables, V50 remained highly statistically significant (P=0.037). Regardless of other factors, for V50>60%, the odds ratio of developing hypothyroidism was 6.76 (P=0.002). In HNSCC patients treated with IMRT, thyroid V50 highly predicts the risk of developing hypothyroidism. V50>60% puts patients at a significantly higher risk of becoming hypothyroid. This can be a useful dose constraint to consider during treatment planning.

Single and multidose ocular kinetics and stability analysis of extemporaneous formulation of topical voriconazole in humans.

PubMed

Senthilkumari, Srinivasan; Lalitha, Prajna; Prajna, Namperumalsamy Venkatesh; Haripriya, Aravind; Nirmal, Jeyabalan; Gupta, Pankaj; Velpandian, Thirumurthy

2010-11-01

The purpose of the present study was to evaluate the kinetics of single and multiple doses of topical, non-preserved voriconazole (VZ) in human eyes. For single dose kinetics, 119 patients undergoing cataract surgery were divided into group I and group II and each group received a single drop (30 µl) of either 1% or 0.1% VZ formulation. Aqueous humor was collected at designated time intervals. For multidose kinetics, a single drop of 1% VZ was instilled 5 times either hourly or every 2 hr. The aqueous humor was tested for VZ at the 5th hr and 9th hr, respectively, after initial instillation. The stability and efficacy of the reconstituted VZ formulations were also evaluated after 30 days. Single dose ocular kinetics of 1% VZ resulted in a maximum mean aqueous concentration of 3.333 ± 1.61 µg/ml in 30 min whereas 0.1% showed a maximum mean aqueous concentration of 0.817 ±.36 µg/ml. In the multidose kinetic study, hourly and bi-hourly dosing resulted in mean aqueous concentrations of 7.47 ± 2.14 µg/ml and 4.69 ± 2.7 µg/ml, respectively. The reconstituted VZ formulations were stable at all studied temperatures, and their efficacy was maintained throughout the study period. The present study showed that the achieved mean concentration of VZ in both single dose and multi dose kinetic studies satisfactorily met the MIC(90) for almost all causative fungal organisms. The frequency of instillation may be designed for an "every 2 hr regimen" to maintain a therapeutic concentration for successful therapy.

A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

PubMed

Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

2018-02-01

Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity.

PubMed

Awada, Ahmad; Dumez, Herlinde; Aftimos, Philippe G; Costermans, Jo; Bartholomeus, Sylvie; Forceville, Kathleen; Berghmans, Thierry; Meeus, Marie-Anne; Cescutti, Jessica; Munzert, Gerd; Pilz, Korinna; Liu, Dan; Schöffski, Patrick

2015-06-01

This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6). Sequential patient cohorts (3 + 3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m(2)) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n = 30) or volasertib/carboplatin (n = 31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively. The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m(2) and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively. Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.

Chromosome translocations in turtles: a biomarker in a sentinel animal for ecological dosimetry.

PubMed

Ulsh, B A; Mühlmann-Díaz, M C; Whicker, F W; Hinton, T G; Congdon, J D; Bedford, J S

2000-06-01

Nonhuman organisms are being exposed to ionizing radiations at radionuclide-contaminated sites around the world. Direct methods are seldom available for measuring biologically relevant doses received by these organisms. Here we extend biological dosimetry techniques, which are much better developed for humans and a few other mammalian species, to a nonmammalian species. Turtles were chosen because a long-lived animal would best serve the need for low-level, chronic exposure conditions. We chose the yellow-bellied slider turtle (Trachemys scripta), which is known to have a maximum life span of at least 22 years. As reported elsewhere, we first isolated an embryonic fibroblast cell line and constructed whole-chromosome-specific DNA libraries for chromosome 1 by microdissection and PCR. A FISH painting probe was prepared and used to establish a dose-response curve for ionizing radiation-induced chromosome interchange aberrations in turtle fibroblasts. This was compared to the dose response for human fibroblasts treated under similar conditions in our laboratory. With respect to induction of chromosome interchange aberrations, human fibroblasts were approximately 1.7 times more sensitive than the T. scripta fibroblasts. To the extent that symmetrical interchanges are persistent over long periods, this approach could eventually provide a measure of the integrated lifetime dose these organisms receive from radionuclides in their environment and give a measure of the extent of relevant genetic damage over that time.

In vivo dosimetry and acute toxicity in breast cancer patients undergoing intraoperative radiotherapy as boost

PubMed Central

Lee, Jason Joon Bock; Choi, Jinhyun; Ahn, Sung Gwe; Jeong, Joon; Lee, Ik Jae; Park, Kwangwoo; Kim, Kangpyo; Kim, Jun Won

2017-01-01

Purpose To report the results of a correlation analysis of skin dose assessed by in vivo dosimetry and the incidence of acute toxicity. This is a phase 2 trial evaluating the feasibility of intraoperative radiotherapy (IORT) as a boost for breast cancer patients. Materials and Methods Eligible patients were treated with IORT of 20 Gy followed by whole breast irradiation (WBI) of 46 Gy. A total of 55 patients with a minimum follow-up of 1 month after WBI were evaluated. Optically stimulated luminescence dosimeter (OSLD) detected radiation dose delivered to the skin during IORT. Acute toxicity was recorded according to the Common Terminology Criteria for Adverse Events v4.0. Clinical parameters were correlated with seroma formation and maximum skin dose. Results Median follow-up after IORT was 25.9 weeks (range, 12.7 to 50.3 weeks). Prior to WBI, only one patient developed acute toxicity. Following WBI, 30 patients experienced grade 1 skin toxicity and three patients had grade 2 skin toxicity. Skin dose during IORT exceeded 5 Gy in two patients: with grade 2 complications around the surgical scar in one patient who received 8.42 Gy. Breast volume on preoperative images (p = 0.001), ratio of applicator diameter and breast volume (p = 0.002), and distance between skin and tumor (p = 0.003) showed significant correlations with maximum skin dose. conclusions IORT as a boost was well-tolerated among Korean women without severe acute complication. In vivo dosimetry with OSLD can help ensure safe delivery of IORT as a boost. PMID:28712278

In vivo dosimetry and acute toxicity in breast cancer patients undergoing intraoperative radiotherapy as boost.

PubMed

Lee, Jason Joon Bock; Choi, Jinhyun; Ahn, Sung Gwe; Jeong, Joon; Lee, Ik Jae; Park, Kwangwoo; Kim, Kangpyo; Kim, Jun Won

2017-06-01

To report the results of a correlation analysis of skin dose assessed by in vivo dosimetry and the incidence of acute toxicity. This is a phase 2 trial evaluating the feasibility of intraoperative radiotherapy (IORT) as a boost for breast cancer patients. Eligible patients were treated with IORT of 20 Gy followed by whole breast irradiation (WBI) of 46 Gy. A total of 55 patients with a minimum follow-up of 1 month after WBI were evaluated. Optically stimulated luminescence dosimeter (OSLD) detected radiation dose delivered to the skin during IORT. Acute toxicity was recorded according to the Common Terminology Criteria for Adverse Events v4.0. Clinical parameters were correlated with seroma formation and maximum skin dose. Median follow-up after IORT was 25.9 weeks (range, 12.7 to 50.3 weeks). Prior to WBI, only one patient developed acute toxicity. Following WBI, 30 patients experienced grade 1 skin toxicity and three patients had grade 2 skin toxicity. Skin dose during IORT exceeded 5 Gy in two patients: with grade 2 complications around the surgical scar in one patient who received 8.42 Gy. Breast volume on preoperative images (p = 0.001), ratio of applicator diameter and breast volume (p = 0.002), and distance between skin and tumor (p = 0.003) showed significant correlations with maximum skin dose. IORT as a boost was well-tolerated among Korean women without severe acute complication. In vivo dosimetry with OSLD can help ensure safe delivery of IORT as a boost.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Son, Christina H.; Law, Ethel; Oh, Jung Hun

Purpose: Although vaginal stenosis (VS) is a recognized toxicity in women who receive pelvic radiation therapy (RT), the relationship between RT dose and the volume and extent of toxicity has not been analyzed. We modeled this relationship to identify predictors of VS. Methods and Materials: We evaluated 54 women, aged 29 to 78 years, who underwent pelvic RT for rectal or anal cancer during 2008 to 2011 and were enrolled in a prospective study evaluating vaginal dilator use. Maximum dilator size was measured before RT (baseline) and 1 month and 12 months after RT. Dilator use was initiated at 1 month. The difference (D)more » in dilator size before and after RT was recorded. Those with D ≤−1 were classified as having VS (n=35); those with D ≥0 were classified as having no VS (n=19 at 1 month). Dose-volume parameters were extracted, and the generalized equivalent uniform dose (gEUD) was used to build a predictive model. Results: The mean vaginal doses were 50.0 Gy and 36.8 Gy for anal and rectal cancer patients, respectively. One month after RT, a gEUD model using a wide range of a values suggests that sparing of vaginal volume to a low dose may be important. When gEUD (a = −1) was <35 Gy and the mean vaginal dose was <43 Gy, severe VS was reduced (P=.02). A 1-year analysis suggests increasingly negative D values with increasing mean dose. However, patients with compliance <40% were more likely to have toxicity. Conclusions: Vaginal stenosis is influenced by multiple RT dose-volume characteristics. Mean dose and gEUD constraints together may reduce the risk of severe VS. Patients receiving higher mean vaginal doses should have greater compliance with dilator therapy to minimize risk of toxicity. Further validation with independent datasets is needed.« less

Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule

PubMed Central

Awada, A; Punt, C J A; Piccart, M J; Tellingen, O Van; Manen, L Van; Kerger, J; Groot, Y; Wanders, J; Verweij, J; Wagener, D J Th

1999-01-01

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min IV infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1–5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 μg m−2. According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 μg m−2, the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 μg m−2. From the dose level 170 μg m−2, the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 μg m−2. The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml−1) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values. © 1999 Cancer Research Campaign PMID:10188890

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

PubMed

Reynolds, Kerry Lynn; Bedard, Philippe L; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue

2017-09-12

Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Thaker, Premal H.; Brady, William E.; Lankes, Heather A.; Odunsi, Kunle; Bradley, William H.; Moore, Kathleen N.; Muller, Carolyn Y.; Anwer, Khursheed; Schilder, Russell J.; Alvarez, Ronald D.; Fracasso, Paula M.

2017-01-01

Objective The study’s purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). Methods Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3 + 3 phase I dose escalation design with patients receiving intravenous PLD 40 mg/m2 (dose level 1 and 2) or 50 mg/m2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m2 (dose level 1) or 36 mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28 day cycle. Cycles were repeated every 28 days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. Results Sixteen evaluable patients received a median of 4 cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. Conclusions GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1. PMID:28802766

An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy subjects

PubMed Central

Round, Patrick; Priestley, Anthony; Robinson, Jan

2011-01-01

AIMS XEN-D0501, a novel TRPV1 antagonist, is being developed to treat overactive bladder. This study investigated the safety and pharmacokinetics of repeat-dose XEN-D0501 in healthy subjects. METHODS The study was conducted in two parts. Part 1 was a double-blind, randomized, placebo-controlled, two-way crossover study in three cohorts of 12 young male subjects. Each subject received XEN-D0501 and placebo (in random order) twice daily for 13 days, with a final single dose on day 14. Doses of 1, 2.5 and 5 mg XEN-D0501 were investigated. Part 2 was an open-label, randomized, two-way crossover study in male and female subjects (45 to 65 years). Subjects received single doses of 5 mg XEN-D0501 under fasted and fed conditions in random order. Blood sampling and safety assessments were conducted throughout the study. RESULTS XEN-D0501 was rapidly absorbed (tmax generally 0.5–4 h post dose). XEN-D0501 exposure increased less than proportionally to dose over the range studied and exhibited minimal accumulation with twice daily dosing. Food had no clinically relevant effects on the pharmacokinetics of XEN-D0501. There were no severe or serious adverse events and all doses were well tolerated. A dose-related increase in body temperature was seen with XEN-D0501 which attenuated over time. Differences from placebo in mean maximum core body temperatures were 0.22°C, 0.5°C and 0.74°C following 1 mg, 2.5 mg and 5 mg twice daily XEN-D0501. The observed increase in body temperature was not considered to be of clinical concern. CONCLUSIONS XEN-D0501 appeared safe and well tolerated at doses up to 5 mg twice daily for 14 days in healthy subjects. PMID:21676011

Measurement of doses to the extremities of nuclear medicine staff

NASA Astrophysics Data System (ADS)

Shousha, Hany A.; Farag, Hamed; Hassan, Ramadan A.

2010-01-01

Medical uses of ionizing radiation now represent>95% of all man-made radiation exposure, and is the largest single radiation source after natural background radiation. Therefore, it is important to quantify the amount of radiation received by occupational individuals to optimize the working conditions for staff, and further, to compare doses in different departments to ensure compatibility with the recommended standards. For some groups working with unsealed sources in nuclear medicine units, the hands are more heavily exposed to ionizing radiation than the rest of the body. A personal dosimetry service runs extensively in Egypt. But doses to extremities have not been measured to a wide extent. The purpose of this study was to investigate the equivalent radiation doses to the fingers for five different nuclear medicine staff occupational groups for which heavy irradiation of the hands was suspected. Finger doses were measured for (1) nuclear medicine physicians, (2) technologists, (3) nurses and (4) physicists. The fifth group contains three technicians handling 131I, while the others handled 99mTc. Each staff member working with the radioactive material wore two thermoluminescent dosimeters (TLDs) during the whole testing period, which lasted from 1 to 4 weeks. Staff performed their work on a regular basis throughout the month, and mean annual doses were calculated for these groups. Results showed that the mean equivalent doses to the fingers of technologist, nurse and physicist groups were 30.24±14.5, 30.37±17.5 and 16.3±7.7 μSv/GBq, respectively. Equivalent doses for the physicians could not be calculated per unit of activity because they did not handle the radiopharmaceuticals directly. Their doses were reported in millisieverts (mSv) that accumulated in one week. Similarly, the dose to the fingers of individuals in Group 5 was estimated to be 126.13±38.2 μSv/GBq. The maximum average finger dose, in this study, was noted in the technologists who handled therapeutic 131I (2.5 mSv). In conclusion, the maximum expected annual dose to extremities is less than the annual limit (500 mSv/y).

Bioavailability of oral and intramuscular molindone hydrochloride in schizophrenic patients.

PubMed

Zetin, M; Cramer, M; Garber, D; Plon, L; Paulshock, M; Hoffman, H E; Schary, W L

1985-01-01

This study was designed to assess the bioequivalence of intramuscular molindone hydrochloride and marketed oral molindone. Ten schizophrenic patients (mean age, 30.2 years) received oral molindone in single daily doses of 100 or 150 mg for four to eight days followed by intramuscular molindone in single daily doses of 50 or 75 mg for four days. On the last day each molindone formulation was given, plasma samples were collected at baseline and at 0.5, 1, 2, 4, 6, 8, and 12 hours after administration. The pharmacokinetic measures of area under the curve and maximum concentration show that intramuscular molindone is 1.49 to 1.67 times more bioavailable than oral molindone. This finding indicates that once a patient's acute psychotic episode has been stabilized with intramuscular molindone, therapy can continue without interruption by substituting 1.5 mg of oral molindone for every 1 mg of intramuscular molindone. The time to maximum concentration occurred significantly earlier (P = 0.05) with intramuscular molindone (0.6 hours) than with oral molindone (1.1 hours). Elimination half-life values were approximately two hours for both formulations.

[Estimation of Maximum Entrance Skin Dose during Cerebral Angiography].

PubMed

Kawauchi, Satoru; Moritake, Takashi; Hayakawa, Mikito; Hamada, Yusuke; Sakuma, Hideyuki; Yoda, Shogo; Satoh, Masayuki; Sun, Lue; Koguchi, Yasuhiro; Akahane, Keiichi; Chida, Koichi; Matsumaru, Yuji

2015-09-01

Using radio-photoluminescence glass dosimeter, we measured the entrance skin dose (ESD) in 46 cases and analyzed the correlations between maximum ESD and angiographic parameters [total fluoroscopic time (TFT); number of digital subtraction angiography (DSA) frames, air kerma at the interventional reference point (AK), and dose-area product (DAP)] to estimate the maximum ESD in real time. Mean (± standard deviation) maximum ESD, dose of the right lens, and dose of the left lens were 431.2 ± 135.8 mGy, 33.6 ± 15.5 mGy, and 58.5 ± 35.0 mGy, respectively. Correlation coefficients (r) between maximum ESD and TFT, number of DSA frames, AK, and DAP were r=0.379 (P<0.01), r=0.702 (P<0.001), r=0.825 (P<0.001), and r=0.709 (P<0.001), respectively. AK was identified as the most useful parameter for real-time prediction of maximum ESD. This study should contribute to the development of new diagnostic reference levels in our country.

Excel-Based Tool for Pharmacokinetically Guided Dose Adjustment of Paclitaxel.

PubMed

Kraff, Stefanie; Lindauer, Andreas; Joerger, Markus; Salamone, Salvatore J; Jaehde, Ulrich

2015-12-01

Neutropenia is a frequent and severe adverse event in patients receiving paclitaxel chemotherapy. The time above a paclitaxel threshold concentration of 0.05 μmol/L (Tc > 0.05 μmol/L) is a strong predictor for paclitaxel-associated neutropenia and has been proposed as a target pharmacokinetic (PK) parameter for paclitaxel therapeutic drug monitoring and dose adaptation. Up to now, individual Tc > 0.05 μmol/L values are estimated based on a published PK model of paclitaxel by using the software NONMEM. Because many clinicians are not familiar with the use of NONMEM, an Excel-based dosing tool was developed to allow calculation of paclitaxel Tc > 0.05 μmol/L and give clinicians an easy-to-use tool. Population PK parameters of paclitaxel were taken from a published PK model. An Alglib VBA code was implemented in Excel 2007 to compute differential equations for the paclitaxel PK model. Maximum a posteriori Bayesian estimates of the PK parameters were determined with the Excel Solver using individual drug concentrations. Concentrations from 250 patients were simulated receiving 1 cycle of paclitaxel chemotherapy. Predictions of paclitaxel Tc > 0.05 μmol/L as calculated by the Excel tool were compared with NONMEM, whereby maximum a posteriori Bayesian estimates were obtained using the POSTHOC function. There was a good concordance and comparable predictive performance between Excel and NONMEM regarding predicted paclitaxel plasma concentrations and Tc > 0.05 μmol/L values. Tc > 0.05 μmol/L had a maximum bias of 3% and an error on precision of <12%. The median relative deviation of the estimated Tc > 0.05 μmol/L values between both programs was 1%. The Excel-based tool can estimate the time above a paclitaxel threshold concentration of 0.05 μmol/L with acceptable accuracy and precision. The presented Excel tool allows reliable calculation of paclitaxel Tc > 0.05 μmol/L and thus allows target concentration intervention to improve the benefit-risk ratio of the drug. The easy use facilitates therapeutic drug monitoring in clinical routine.

Equivalent dose and effective dose from stray radiation during passively scattered proton radiotherapy for prostate cancer

NASA Astrophysics Data System (ADS)

Fontenot, Jonas; Taddei, Phillip; Zheng, Yuanshui; Mirkovic, Dragan; Jordan, Thomas; Newhauser, Wayne

2008-03-01

Proton therapy reduces the integral therapeutic dose required for local control in prostate patients compared to intensity-modulated radiotherapy. One proposed benefit of this reduction is an associated decrease in the incidence of radiogenic secondary cancers. However, patients are also exposed to stray radiation during the course of treatment. The purpose of this study was to quantify the stray radiation dose received by patients during proton therapy for prostate cancer. Using a Monte Carlo model of a proton therapy nozzle and a computerized anthropomorphic phantom, we determined that the effective dose from stray radiation per therapeutic dose (E/D) for a typical prostate patient was approximately 5.5 mSv Gy-1. Sensitivity analysis revealed that E/D varied by ±30% over the interval of treatment parameter values used for proton therapy of the prostate. Equivalent doses per therapeutic dose (HT/D) in specific organs at risk were found to decrease with distance from the isocenter, with a maximum of 12 mSv Gy-1 in the organ closest to the treatment volume (bladder) and 1.9 mSv Gy-1 in the furthest (esophagus). Neutrons created in the nozzle predominated effective dose, though neutrons created in the patient contributed substantially to the equivalent dose in organs near the proton field. Photons contributed less than 15% to equivalent doses.

Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

PubMed

Thompson, Gary A; Solomon, Gail; Albrecht, Helmut H; Reitberg, Donald P; Guenin, Eric

2016-07-01

This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age-based doses of 100-400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo ) and terminal volume of distribution (Vz /F) increased with age. Due to a larger increase in Vz /F than CLo , an increase in terminal exponential half-life was also observed. Allometric scaling indicated no maturation-related changes in CLo and Vz /F. © 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Radical radiotherapy incorporating a brachytherapy boost for the treatment of carcinoma of the thoracic oesophagus: results from a cohort of patients and review of the literature.

PubMed

Churn, M; Jones, B; Myint, A Sun

2002-04-01

The optimal treatment for potentially curable carcinoma of the oesophagus unsuitable for surgical resection is unresolved. An intraluminal brachytherapy boost (ILBT) can be used following external beam radiotherapy (EBRT) with or without concurrent chemotherapy (CRT). ILBT increases the dose to the tumour volume substantially while reducing the lung dose but the corresponding high dose to the oesophageal wall may cause increased complications. We report the outcomes of 32 consecutive patients treated with radical radiotherapy. A dose of 45-55 Gy in 20-25 fractions with external beam radiotherapy (EBRT) followed by an ILBT boost. Earlier in the series a low dose rate (LDR) brachytherapy technique using 125Iodine seeds delivering a dose of 20-22 Gy at 25-40 cGy/h was used. This was later superseded by high dose rate (HDR) treatments delivering 8.5-10 Gy in one fraction at 1 cm from the catheter. Patients of age below 76 years, of good performance status and with no other medical contraindication were considered for concurrent chemotherapy (CRT) using a planned regime of cisplatin (80 mg/m2 day 1) and 5-flurouracil (1 g/m2 days 1 to 4) in the first and last weeks of radiotherapy (13 patients). The EBRT and ILBT were well tolerated but 8/13 (62%) patients had dose modifications of chemotherapy in one or both cycles due to advanced age, co-morbidity or toxicity. The median follow-up period of surviving patients was 37 months (range 35-39) and the median overall survival for the whole group was 9 months. The overall survival at 1 year was 34.4% (17.6-51.2%), 15.6% (2.8-28.4%) at 2 and 3 years. Local recurrence-free survival at 1 year was 35.3% (15.9-54.7%) and 24.5% (8.3-44.6%) at 2 and 3 years (Fig. 2). Though symptom relief was good there were six cases of ulceration, six of stricture and two fistulae. Biological equivalent for tumour response (BED Gy,10) and late radiation effects (BED Gy3) were calculated for the different radiotherapy regimens using equations derived from the linear quadratic model. In this series no advantage was found in terms of local control or survival for patients receiving radiotherapy doses resulting in a BED Gy10 greater than 75% of the maximum. Similarly, no significant increase in complications was noted in those patients receiving doses resulting in a BED Gy3 > 75% of the maximum. The merits and hazards of the ILBT boost used in radical radiotherapy are discussed and the relevant literature reviewed.

Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design.

PubMed

Tevaarwerk, Amye; Wilding, George; Eickhoff, Jens; Chappell, Rick; Sidor, Carolyn; Arnott, Jamie; Bailey, Howard; Schelman, William; Liu, Glenn

2012-06-01

MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.

In HFREF patients, sacubitril/valsartan, given at relatively low doses, does not lead to increased mortality or hospitalization : A retrospective cohort study.

PubMed

De Vecchis, R; Ariano, C; Di Biase, G; Noutsias, M

2018-03-08

In heart failure with reduced left ventricular ejection fraction (HFREF) patients, the dosage of sacubitril/valsartan is modulated according to a gradual increase regimen. Nevertheless, if patients exhibit tolerability problems, a provisional reduction of the dose of sacubitril/valsartan or even its interruption are recommended. This study provides estimates of respective proportions of patients receiving minimum or intermediate doses of sacubitril/valsartan. In addition, a comparison was made to detect possible differences regarding all-cause mortality and heart failure hospitalization in patients treated with the recommended optimum dose compared to those receiving submaximum maintenance doses of sacubitril/valsartan. Patients treated with sacubitril/valsartan in addition to beta-blocker and mineralocorticoid receptor blocker were 68. Among them, 20 patients (29.4%), were identified as having clinical features that were contraindications to the administration of sacubitril/valsartan at full dose. The subsequent decision was to maintain an intermediate dose in 11 patients and to reduce the dose to the minimum level allowed, i.e., 24 mg/26 mg twice daily in nine patients. After a median follow-up of 5.25 months, no differences were found concerning the risk of all-cause death by comparing patients treated with reduced versus those subjected to target doses of sacubitril/valsartan (odds ratio [OR] = 1.666; 95% confidence interval [CI] = 0.256-10.823; p = 0.6266). Patients taking reduced doses had a similar risk of heart failure hospitalizations when compared to patients treated with the target dose (OR = 0.789; 95% CI: 0.077-8.0808; p = 1.00). During a median follow-up of 5.25 months, in the group of patients who had proven to be intolerant to the maximum dose of sacubitril/valsartan, use of reduced doses of the drug did not result in increased all-cause mortality or heart failure hospitalization compared to patients treated with sacubitril/valsartan at the target dose.

Fractional model for pharmacokinetics of high dose methotrexate in children with acute lymphoblastic leukaemia

NASA Astrophysics Data System (ADS)

Popović, Jovan K.; Spasić, Dragan T.; Tošić, Jela; Kolarović, Jovanka L.; Malti, Rachid; Mitić, Igor M.; Pilipović, Stevan; Atanacković, Teodor M.

2015-05-01

The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4-19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2-5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post's and Newton's method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

Evaluation of the Pharmacokinetic Interaction between Venetoclax, a Selective BCL-2 Inhibitor, and Warfarin in Healthy Volunteers.

PubMed

Salem, Ahmed Hamed; Hu, Beibei; Freise, Kevin J; Agarwal, Suresh K; Sidhu, Dilraj S; Wong, Shekman L

2017-03-01

Venetoclax is a selective, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. In vitro data indicated weak cytochrome P450 (CYP) 2C9 inhibition by venetoclax; however, it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. A Phase 1 study was conducted in healthy volunteers to evaluate the effect of venetoclax on warfarin pharmacokinetics. Subjects received a single oral dose of 5 mg warfarin on day 1 of both periods 1 and 2, separated by a 14 days washout. On day 1 of period 2, subjects concomitantly received a single 400 mg oral dose of venetoclax. Blood samples for warfarin concentration determination were collected after each dose administration for up to 9 days. Modest increases of 18 to 28% were observed in the maximum observed plasma concentration (C max ) and area under the curve from time zero to infinity (AUC ∞ ) of both R- and S-warfarin. Due to the narrow therapeutic window of warfarin, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving venetoclax and warfarin. Since similar increases in exposure were observed for both enantiomers, even though CYP2C9 is only involved in the metabolism of the S-enantiomer, and the half-life of both enantiomers remained the same, the interaction does not appear to be mediated via CYP2C9.

Dose Calculation For Accidental Release Of Radioactive Cloud Passing Over Jeddah

NASA Astrophysics Data System (ADS)

Alharbi, N. D.; Mayhoub, A. B.

2011-12-01

For the evaluation of doses after the reactor accident, in particular for the inhalation dose, a thorough knowledge of the concentration of the various radionuclide in air during the passage of the plume is required. In this paper we present an application of the Gaussian Plume Model (GPM) to calculate the atmospheric dispersion and airborne radionuclide concentration resulting from radioactive cloud over the city of Jeddah (KSA). The radioactive cloud is assumed to be emitted from a reactor of 10 MW power in postulated accidental release. Committed effective doses (CEDs) to the public at different distance from the source to the receptor are calculated. The calculations were based on meteorological condition and data of the Jeddah site. These data are: pasquill atmospheric stability is the class B and the wind speed is 2.4m/s at 10m height in the N direction. The residence time of some radionuclides considered in this study were calculated. The results indicate that, the values of doses first increase with distance, reach a maximum value and then gradually decrease. The total dose received by human is estimated by using the estimated values of residence time of each radioactive pollutant at different distances.

Assessment of individual organ doses in a realistic human phantom from neutron and gamma stimulated spectroscopy of the breast and liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Belley, Matthew D.; Segars, William Paul; Kapadia, Anuj J., E-mail: anuj.kapadia@duke.edu

2014-06-15

Purpose: Understanding the radiation dose to a patient is essential when considering the use of an ionizing diagnostic imaging test for clinical diagnosis and screening. Using Monte Carlo simulations, the authors estimated the three-dimensional organ-dose distribution from neutron and gamma irradiation of the male liver, female liver, and female breasts for neutron- and gamma-stimulated spectroscopic imaging. Methods: Monte Carlo simulations were developed using the Geant4 GATE application and a voxelized XCAT human phantom. A male and a female whole body XCAT phantom was voxelized into 256 × 256 × 600 voxels (3.125 × 3.125 × 3.125 mm{sup 3}). A monoenergeticmore » rectangular beam of 5.0 MeV neutrons or 7.0 MeV photons was made incident on a 2 cm thick slice of the phantom. The beam was rotated at eight different angles around the phantom ranging from 0° to 180°. Absorbed dose was calculated for each individual organ in the body and dose volume histograms were computed to analyze the absolute and relative doses in each organ. Results: The neutron irradiations of the liver showed the highest organ dose absorption in the liver, with appreciably lower doses in other proximal organs. The dose distribution within the irradiated slice exhibited substantial attenuation with increasing depth along the beam path, attenuating to ∼15% of the maximum value at the beam exit side. The gamma irradiation of the liver imparted the highest organ dose to the stomach wall. The dose distribution from the gammas showed a region of dose buildup at the beam entrance, followed by a relatively uniform dose distribution to all of the deep tissue structures, attenuating to ∼75% of the maximum value at the beam exit side. For the breast scans, both the neutron and gamma irradiation registered maximum organ doses in the breasts, with all other organs receiving less than 1% of the breast dose. Effective doses ranged from 0.22 to 0.37 mSv for the neutron scans and 41 to 66 mSv for the gamma scans. Conclusions: Neutron and gamma irradiation of a primary target organ was found to impart the majority of the total dose to the primary target organ (and other large organs) within the beam plane and considerably lower dose to proximal organs outside of the beam. These results also indicate that despite the use of a highly scattering particle such as a neutron, the dose from neutron stimulated emission computed tomography scans is on par with other clinical imaging techniques such as x-ray computed tomography (x-ray CT). Given the high nonuniformity in the dose across an organ during the neutron scan, care must be taken when computing average doses from neutron irradiations. The effective doses from neutron scanning were found to be comparable to x-ray CT. Further technique modifications are needed to reduce the effective dose levels from the gamma scans.« less

Stereotactic Fractionated Radiotherapy and LINAC Radiosurgery in the Treatment of Vestibular Schwannoma-Report About Both Stereotactic Methods From a Single Institution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kopp, Christine, E-mail: Christine.Kopp@lrz.tu-muenchen.de; Fauser, Claudius; Mueller, Axel

2011-08-01

Purpose: To evaluate tumor control and side effects associated with radiosurgery (RS) and stereotactic fractionated radiotherapy (SFR) for vestibular schwannomas (VSs) in a group of patients treated at the same institution. Methods and Materials: Between May 1997 and June 2007, 115 consecutive cases of VS were treated in our department. The SFR group (47 patients), including larger tumors (maximum diameter >1.5 cm), received a total dose of 54 Gy at 1.8 Gy per fraction. The RS group (68 patients, maximum diameter <1.5 cm) received a total dose of 12 Gy at the 100% isodose. Evaluation included serial imaging tests (magneticmore » resonance imaging) and neurologic and functional hearing examinations. Results: The tumor control rate was 97.9% in the SFR group for a mean follow-up time of 32.1 months and 98.5% in the RS group for a mean follow-up time of 30.1 months. Hearing function was preserved after RS in 85% of the patients and after SFR in 79%. Facial and trigeminal nerve function remained mostly unaffected after SFR. After RS, new trigeminal neuropathy occurred in 9 of 68 patients (13%). Conclusions: A high tumor control rate and low number of side effects are registered after SFR and RS of VS. These results confirm that considering tumor diameter, both RS and SFR are good treatment modalities for VS.« less

First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy.

PubMed

Belderbos, José S A; De Jaeger, Katrien; Heemsbergen, Wilma D; Seppenwoolde, Yvette; Baas, Paul; Boersma, Liesbeth J; Lebesque, Joos V

2003-02-01

To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy. The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status or=grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications). Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4. Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group.

Dose Calculations for [131I] Meta-Iodobenzylguanidine-Induced Bystander Effects

PubMed Central

Gow, M. D.; Seymour, C. B.; Boyd, M.; Mairs, R. J.; Prestiwch, W. V.; Mothersill, C. E.

2014-01-01

Targeted radiotherapy is a potentially useful treatment for some cancers and may be potentiated by bystander effects. However, without estimation of absorbed dose, it is difficult to compare the effects with conventional external radiation treatment. Methods: Using the Vynckier – Wambersie dose point kernel, a model for dose rate evaluation was created allowing for calculation of absorbed dose values to two cell lines transfected with the noradrenaline transporter (NAT) gene and treated with [131I]MIBG. Results: The mean doses required to decrease surviving fractions of UVW/NAT and EJ138/NAT cells, which received medium from [131I]MIBG-treated cells, to 25 – 30% were 1.6 and 1.7 Gy respectively. The maximum mean dose rates achieved during [131I]MIBG treatment were 0.09 – 0.75 Gy/h for UVW/NAT and 0.07 – 0.78 Gy/h for EJ138/NAT. These were significantly lower than the external beam gamma radiation dose rate of 15 Gy/h. In the case of control lines which were incapable of [131I]MIBG uptake the mean absorbed doses following radiopharmaceutical were 0.03 – 0.23 Gy for UVW and 0.03 – 0.32 Gy for EJ138. Conclusion: [131I]MIBG treatment for ICCM production elicited a bystander dose-response profile similar to that generated by external beam gamma irradiation but with significantly greater cell death. PMID:24659931

Dosimetric and delivery efficiency investigation for treating hepatic lesions with a MLC-equipped robotic radiosurgery–radiotherapy combined system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin, Lihui, E-mail: lihui.jin@fccc.edu; Price, Robert A.; Wang, Lu

Purpose: The CyberKnife M6 (CK-M6) Series introduced a multileaf collimator (MLC) for extending its capability from stereotactic radiosurgery/stereotactic radiotherapy (SBRT) to conventionally fractionated radiotherapy. This work is to investigate the dosimetric quality of plans that are generated using MLC-shaped beams on the CK-M6, as well as their delivery time, via comparisons with the intensity modulated radiotherapy plans that were clinically used on a Varian Linac for treating hepatic lesions. Methods: Nine patient cases were selected and divided into three groups with three patients in each group: (1) the group-one patients were treated conventionally (25 fractions); (2) the group-two patients weremore » treated with SBRT-like hypofractionation (5 fractions); and (3) the group-three patients were treated similar to group-one patients, but with two planning target volumes (PTVs) and two different prescription dose levels correspondingly. The clinically used plans were generated on the ECLIPSE treatment planning system (TPS) and delivered on a Varian Linac (E-V plans). The multiplan (MP) TPS was used to replan these clinical cases with the MLC as the beam device for the CK-M6 (C-M plans). After plans were normalized to the same PTV dose coverage, comparisons between the C-M and E-V plans were performed based on D{sub 99%} (percentage of prescription dose received by 99% of the PTV), D{sub 0.1cm{sup 3}} (the percentage of prescription dose to 0.1 cm{sup 3} of the PTV), and doses received by critical structures. Then, the delivery times for the C-M plans will be obtained, which are the MP TPS generated estimations assuming having an imaging interval of 60 s. Results: The difference in D{sub 99%} between C-M and E-V plans is +0.6% on average (+ or − indicating a higher or lower dose from C-M plans than from E-V plans) with a range from −4.1% to +3.8%, and the difference in D{sub 0.1cm{sup 3}} was −1.0% on average with a range from −5.1% to +2.9%. The PTV conformity index (CI) for the C-M plans ranges from 1.07 to 1.29 with a mean of 1.19, slightly inferior to the E-V plans, in which the CI ranges from 1.00 to 1.15 with a mean of 1.07. Accounting for all nine patients in three groups, 45% of the critical structures received a lower mean dose for the C-M plans as compared with the E-V plans, and similarly, 48% received a lower maximum dose. Furthermore, the average difference of the mean critical structure dose between the C-M and E-V plans over all critical structures for all patients showed only +2.10% relative to the prescription dose and the similar comparison finds the average difference of the maximum critical structure dose of only +1.24%. The estimated delivery times for the C-M plans on the CK-M6 range from 18 to 24 minutes while they are from 7 to 13.7 min for the E-V plans on the Varian Linac. Conclusions: For treating hepatic lesions, for the C-M plans that are comparable to E-V plans in quality, the times needed to deliver these C-M plans on the CK-M6 are longer than the delivery time for the E-V plans on the Varian Linac, but may be clinically acceptable.« less

Preoperative single fraction partial breast radiotherapy for early-stage breast cancer.

PubMed

Palta, Manisha; Yoo, Sua; Adamson, Justus D; Prosnitz, Leonard R; Horton, Janet K

2012-01-01

Several recent series evaluating external beam accelerated partial breast irradiation (PBI) have reported adverse cosmetic outcomes, possibly related to large volumes of normal tissue receiving near-prescription doses. We hypothesized that delivery of external beam PBI in a single fraction to the preoperative tumor volume would be feasible and result in a decreased dose to the uninvolved breast compared with institutional postoperative PBI historical controls. A total of 17 patients with unifocal Stage T1 breast cancer were identified. Contrast-enhanced subtraction magnetic resonance images were loaded into an Eclipse treatment planning system and used to define the target volumes. A "virtual plan" was created using four photon beams in a noncoplanar beam arrangement and optimized to deliver 15 Gy to the planning target volume. The median breast volume was 1,713 cm(3) (range: 1,014-2,140), and the median clinical target volume was 44 cm(3) (range: 26-73). In all cases, 100% of the prescription dose covered 95% of the clinical target volume. The median conformity index was 0.86 (range: 0.70-1.12). The median percentage of the ipsilateral breast volume receiving 100% and 50% of the prescribed dose was 3.8% (range: 2.2-6.9) and 13.3% (range: 7.5-20.8) compared with 18% (range: 3-42) and 53% (range: 24-65) in the institutional historical controls treated with postoperative external beam PBI (p = .002). The median maximum skin dose was 9 Gy. The median dose to 1 and 10 cm(3) of skin was 6.7 and 4.9 Gy. The doses to the heart and ipsilateral lung were negligible. Preoperative PBI resulted in a substantial reduction in ipsilateral breast tissue dose compared with postoperative PBI. The skin dose appeared reasonable, given the small volumes. A prospective Phase I trial evaluating this technique is ongoing. Copyright © 2012 Elsevier Inc. All rights reserved.

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group.

PubMed

Chuk, Meredith K; Widemann, Brigitte C; Minard, Charles G; Liu, Xiaowei; Kim, AeRang; Bernhardt, Melanie Brooke; Kudgus, Rachel A; Reid, Joel M; Voss, Stephan D; Blaney, Susan; Fox, Elizabeth; Weigel, Brenda J

2018-04-25

We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m 2 /day. At 40 mg/m 2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m 2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m 2 /day. A phase 2 study of cabozantinib is being conducted. © 2018 Wiley Periodicals, Inc.

Analysis of esophageal-sparing treatment plans for patients with high-grade esophagitis.

PubMed

Niedzielski, Joshua; Bluett, Jaques B; Williamson, Ryan T; Liao, Zhongxing; Gomez, Daniel R; Court, Laurence E

2013-07-08

We retrospectively generated IMRT plans for 14 NSCLC patients who had experienced grade 2 or 3 esophagitis (CTCAE version 3.0). We generated 11-beam and reduced esophagus dose plan types to compare changes in the volume and length of esophagus receiving doses of 50, 55, 60, 65, and 70 Gy. Changes in planning target volume (PTV) dose coverage were also compared. If necessary, plans were renormalized to restore 95% PTV coverage. The critical organ doses examined were mean lung dose, mean heart dose, and volume of spinal cord receiving 50 Gy. The effect of interfractional motion was determined by applying a three-dimensional rigid shift to the dose grid. For the esophagus plan, the mean reduction in esophagus V50, V55, V60, V65, and V70 Gy was 2.8, 4.1, 5.9, 7.3, and 9.5 cm(3), respectively, compared with the clinical plan. The mean reductions in LE50, LE55, LE60, LE65, and LE70 Gy were 2.0, 3.0, 3.8, 4.0, and 4.6 cm, respectively. The mean heart and lung dose decreased 3.0 Gy and 2.4 Gy, respectively. The mean decreases in 90% and 95% PTV coverage were 1.7 Gy and 2.8 Gy, respectively. The normalized plans' mean reduction of esophagus V50, V55, V60, V65, and V70 Gy were 1.6, 2.0, 2.9, 3.9, and 5.5 cm(3), respectively, compared with the clinical plans. The normalized plans' mean reductions in LE50, LE55, LE60, LE65, and LE70 Gy were 4.9, 5.2, 5.4, 4.9, and 4.8 cm, respectively. The mean reduction in maximum esophagus dose with simulated interfractional motion was 3.0 Gy and 1.4 Gy for the clinical plan type and the esophagus plan type, respectively. In many cases, the esophagus dose can be greatly reduced while maintaining critical structure dose constraints. PTV coverage can be restored by increasing beam output, while still obtaining a dose reduction to the esophagus and maintaining dose constraints.

Analysis of esophageal‐sparing treatment plans for patients with high‐grade esophagitis

PubMed Central

Bluett, Jaques B.; Williamson, Ryan T.; Liao, Zhongxing; Gomez, Daniel R.; Court, Laurence E.

2013-01-01

We retrospectively generated IMRT plans for 14 NSCLC patients who had experienced grade 2 or 3 esophagitis (CTCAE version 3.0). We generated 11‐beam and reduced esophagus dose plan types to compare changes in the volume and length of esophagus receiving doses of 50, 55, 60, 65, and 70 Gy. Changes in planning target volume (PTV) dose coverage were also compared. If necessary, plans were renormalized to restore 95% PTV coverage. The critical organ doses examined were mean lung dose, mean heart dose, and volume of spinal cord receiving 50 Gy. The effect of interfractional motion was determined by applying a three‐dimensional rigid shift to the dose grid. For the esophagus plan, the mean reduction in esophagus V50, V55, V60, V65, and V70 Gy was 2.8, 4.1, 5.9, 7.3, and 9.5 cm3, respectively, compared with the clinical plan. The mean reductions in LE50, LE55, LE60, LE65, and LE70 Gy were 2.0, 3.0, 3.8, 4.0, and 4.6 cm, respectively. The mean heart and lung dose decreased 3.0 Gy and 2.4 Gy, respectively. The mean decreases in 90% and 95% PTV coverage were 1.7 Gy and 2.8 Gy, respectively. The normalized plans’ mean reduction of esophagus V50, V55, V60, V65, and V70 Gy were 1.6, 2.0, 2.9, 3.9, and 5.5 cm3, respectively, compared with the clinical plans. The normalized plans’ mean reductions in LE50, LE55, LE60, LE65, and LE70 Gy were 4.9, 5.2, 5.4, 4.9, and 4.8 cm, respectively. The mean reduction in maximum esophagus dose with simulated interfractional motion was 3.0 Gy and 1.4 Gy for the clinical plan type and the esophagus plan type, respectively. In many cases, the esophagus dose can be greatly reduced while maintaining critical structure dose constraints. PTV coverage can be restored by increasing beam output, while still obtaining a dose reduction to the esophagus and maintaining dose constraints. PACS number: 87.53 Tf PMID:23835390

Pharmacokinetic profile and clinical efficacy of a once-daily ondansetron suppository in cyclophosphamide-induced emesis: a double blind comparative study with ondansetron tablets.

PubMed Central

de Wit, R.; Beijnen, J. H.; van Tellingen, O.; Schellens, J. H.; de Boer-Dennert, M.; Verweij, J.

1996-01-01

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available oral formulation. PMID:8688345

Pharmacokinetic profile and clinical efficacy of a once-daily ondansetron suppository in cyclophosphamide-induced emesis: a double blind comparative study with ondansetron tablets.

PubMed

de Wit, R; Beijnen, J H; van Tellingen, O; Schellens, J H; de Boer-Dennert, M; Verweij, J

1996-07-01

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available oral formulation.

SU-F-J-223: Patterns of Failure for Laryngeal Cancer Patients Treated with Definitive IMRT: Comparing Two Different Methods for Determining the Origin of Recurrence From Follow-Up PET/CT Scans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brodin, P; Guha, C; Tome, W

Purpose: To determine patterns of failure in laryngeal cancer treated with definitive IMRT by comparing two different methods for identifying the recurrence epicenter on follow-up PET/CT. Methods: We identified 20 patients treated for laryngeal squamous cell carcinoma with definitive IMRT who had loco-regional recurrence diagnosed on PET/CT. Recurrence PET/CT scans were co-registered with the original treatment planning CT using deformable image registration with the VoxAlign deformation engine in MIM Software. Recurrence volumes were delineated on co-registered follow-up scans using a semi-automatic PETedge tool and two separate methods were used to identify the recurrence point of origin: a) Finding the pointmore » within the recurrence volume for which the maximum distance to the surface of the surrounding recurrence volume is smaller than for any other point. b) Finding the point within the recurrence volume with the maximum standardized uptake value (SUVmax), without geometric restrictions.For each method the failure pattern was determined as whether the recurrence origin fell within the original high-dose target volumes GTV70, CTV70, PTV70 (receiving 70Gy), intermediate-risk PTV59 (receiving 59.4Gy) or low-risk PTV54 (receiving 54.1Gy), in the original treatment planning CT. Results: 23 primary/nodal recurrences from the 20 patients were analyzed. The three-dimensional distance between the two different origins was on average 10.5mm (std.dev. 10mm). Most recurrences originated in the high-dose target volumes for both methods with 13 (57%) and 11 (48%) in the GTV70 and 20 (87%) and 20 (87%) in the PTV70 for method a) and b), respectively. There was good agreement between the two methods in classifying the origin target volumes with 69% concordance for GTV70, 89% for CTV70 and 100% for PTV70. Conclusion: With strong agreement in patterns of failure between two separate methods for determining recurrence origin, we conclude that most recurrences occurred within the high-dose treatment region, which influences potential risk-adaptive treatment strategies.« less

Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.

PubMed

Robinson, Jennifer G; Farnier, Michel; Krempf, Michel; Bergeron, Jean; Luc, Gérald; Averna, Maurizio; Stroes, Erik S; Langslet, Gisle; Raal, Frederick J; El Shahawy, Mahfouz; Koren, Michael J; Lepor, Norman E; Lorenzato, Christelle; Pordy, Robert; Chaudhari, Umesh; Kastelein, John J P

2015-04-16

Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).

[Therapeutic failure in scabies: An observational study].

PubMed

De Sainte Marie, B; Mallet, S; Gaudy-Marqueste, C; Baumstarck, K; Bentaleb, N; Loundou, A; Hesse, S; Monestier, S; Grob, J-J; Richard, M-A

2016-01-01

Several sources suggest an escalation of scabies in France. To describe a population of patients continuing to present with scabies despite multiple treatments in order to identify factors associated with persistence of infection. A descriptive cross-sectional study in adults and children consulting for persistent scabies despite at least one previous treatment. A standardized questionnaire explored potential sources of treatment failure. Thirty-one patients were analyzed. Initial symptoms were noted to have started between two and 52 weeks earlier (mean: 19 weeks). The mean number of prior consultations with a general practitioner was 3.1 (0-10) and 1.7 with a dermatologist (0-7). The mean number of patients per household was 3.5 (1-9). At least one dose of oral ivermectin (maximum of 6 doses per household) was prescribed for 84 % of patients (29 % of whom were not fasted at the time). Further, 74 % of patients received at least one local application of esdepallethrin and piperonyl butoxide (maximum: 5 courses), four received benzyl benzoate and two received permethrin; however, 58 % did not reapply the substance after hand washing. All households bought the prescribed treatments despite the costs. Close contacts of patients were treated in 58 % of households. Decontamination of bedding and clothing was carried out properly in 90 % of households. Persistence of infection appears to be linked to: (1) insufficient treatment of close contacts; (2) absence of a second treatment between days 7 and 14; (3) insufficient efficacy of the available treatments, doubtless due to multiple factors (intrinsic resistance of Sarcoptes, failure to repeat treatment, poor explanation of methods for dosing and application, and oral intake of treatments). Access to non-reimbursed treatments was not identified as a problem and decontamination of bedding and clothing was correctly performed in most cases. Though certain fundamental aspects of scabies treatment must be better known, longer consultations and provision of efficacious treatments are also a priority. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A retrospective cohort study of long-term immediate-release hydrocodone/acetaminophen use and acetaminophen dosing above the Food and Drug Administration recommended maximum daily limit among commercially insured individuals in the United States (2008-2013).

PubMed

DeVeaugh-Geiss, Angela; Kadakia, Aditi; Chilcoat, Howard; Alexander, Louis; Coplan, Paul

2015-06-01

Immediate-release (IR) hydrocodone/acetaminophen is the most prescribed opioid in the United States; however, patterns of use, including long-term treatment and dose, are not well described. Duration of use, including the percentage of patients on long-term treatment (>90 days of continuous use), was assessed for patients newly prescribed IR hydrocodone/acetaminophen compared to other opioid analgesics in a national commercial insurance database (January 2008-September 2013). Though only a small percentage of IR hydrocodone/acetaminophen patients continued treatment long-term (1.7%), the number was large (104,839) and was nearly 5 times the number receiving extended-release (ER) morphine (n = 22,338) and nearly 4 times the number receiving ER oxycodone (n = 26,946) long-term. Using a less conservative allowable gap in treatment increased the number of patients meeting the criteria for long-term use (approximately 160,000 for IR hydrocodone/acetaminophen vs <30,000 for ER morphine and ER oxycodone). Most patients meeting these criteria received IR hydrocodone doses between >20 and ≤60 mg/d (n = 56,220, 53.6%) in month 4; 5.5% (n = 5,743) received doses >60 mg/d. Moreover, approximately 15% of IR hydrocodone/acetaminophen patients (n > 900,000) were prescribed total daily acetaminophen doses exceeding 4 g (the limit recommended by the U.S. Food and Drug Administration) at their initial IR hydrocodone/acetaminophen prescription or any time during therapy. Although most patients were prescribed IR hydrocodone/acetaminophen for acute pain, the number of patients prescribed long-term therapy exceeds the number of patients prescribed ER opioids. It is important to consider the benefits and risks inherent with long-term opioid therapy, whether with IR or ER opioids, to ensure safe use of these products. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Phenobarbitone versus phenytoin for treatment of neonatal seizures: an open-label randomized controlled trial.

PubMed

Pathak, Garima; Upadhyay, Amit; Pathak, Umesh; Chawla, Deepak; Goel, Sneh P

2013-08-01

To compare the efficacy of phenobarbitone and phenytoin for treatment of neonatal seizures in term and near-term neonates. Open labeled randomized controlled trial. Neonatal intensive care unit of a level II unit from India, from November 2008 to September 2009. All term and late pre-term neonates admitted with clinically apparent seizures and not having any transient metabolic disorders (hypoglycemia or hypocalcemia) were randomly assigned. Phenobarbitone (n=54) or phenytoin (n=55) intravenously 20 mg/kg/dose over 20-30 min. Neonates whose seizures were not controlled by the assigned drug were then crossed over to be treated with other drug in same dose. Clinical control of seizures (seizure free period of 24 hours after giving anticonvulsant). Baseline characteristics including mean birthweight, gestation age and sex were comparable in both groups. Seizures were controlled in 8 of the 55 (14.5%) neonates who received phenytoin, as compared to 39 of 54 (72.2%) neonates who received phenobarbitone (P <0.001). In babies not responding to assigned drugs, after cross-over to the other drug, seizure control was achieved in 44/55 (80%) of the neonates assigned to receive phenytoin first as compared to 49/54 (91%) of those assigned to receive phenobarbitone first (P=0.014). After maximum dose of phenobarbitone seizures were controlled in 49/55(89%) in phenytoin group and 52/54 (96%) in phenobarbitone group (P<0.05). Phenobarbitone is more efficacious than phenytoin in control of clinical seizures in term or near-term neonates, irrespective of etiology. To evaluate serum vascular endothelial growth factor (VEGF) levels in children with acute lymphoblastic leukemia (ALL) during the induction phase of chemotherapy.

Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program.

PubMed

Payne, Roxanne; Glenn, Lyn; Hoen, Helena; Richards, Beverley; Smith, John W; Lufkin, Robert; Crocenzi, Todd S; Urba, Walter J; Curti, Brendan D

2014-01-01

High-dose interleukin-2 (IL-2) has been FDA-approved for over 20 years, but it is offered only at a small number of centers with expertise in its administration. We analyzed the outcomes of patients receiving high-dose IL-2 in relation to the severity of toxicity to ascertain if response or survival were adversely affected. A retrospective analysis of the outcomes of 500 patients with metastatic renal cell carcinoma (RCC) (n = 186) or melanoma (n = 314) treated with high-dose IL-2 between 1997 and 2012 at Providence Cancer Center was performed. IL-2 was administered at a dose of 600,000 international units per kg by IV bolus every 8 hours for up to 14 doses. A second cycle was administered 16 days after the first and patients with tumor regression could receive additional cycles. Survival and anti-tumor response were analyzed by diagnosis, severity of toxicity, number of IL-2 cycles and subsequent therapy. The objective response rate in melanoma was 28% (complete 12% and partial 16%), and in RCC was 24% (complete 7% and partial 17%). The 1-, 2- and 3-year survivals were 59%, 41% and 31%, for melanoma and 75%, 56% and 44%, for RCC, respectively. The proportion of patients with complete or partial response in both melanoma and RCC was higher in patients who a) required higher phenylephrine doses to treat hypotension (p < 0.003), b) developed acidosis (bicarbonate < 19 mmol (p < 0.01)), or c) thrombocytopenia (<50, 50-100, >100,000 platelets; p < 0.025). The proportion achieving a complete or partial response was greater in patients with melanoma who received 5 or more compared with 4 or fewer IL-2 cycles (p < 0.0001). The incidence of death from IL-2 was less than 1% and was not higher in patients who required phenylephrine. High-dose IL-2 can be administered safely; severe toxicity including hypotension is reversible and can be managed in a community hospital. The tumor response and survival reported here are superior to the published literature and support treating patients to their individualized maximum tolerated dose. IL-2 should remain part of the treatment paradigm in selected patients with melanoma and RCC.

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate.

PubMed

Yap, B S; McCredie, K B; Benjamin, R S; Bodey, G P; Freireich, E J

1978-09-16

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m(2) methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m(2). Seven days later intravenous methotrexate, 120 mg/m(2) was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m(2) with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m(2) (median 200 mg/m(2)). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m(2) caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.

Comparison of the extent of hippocampal sparing according to the tilt of a patient's head during WBRT using linear accelerator-based IMRT and VMAT.

PubMed

Moon, Sun Young; Yoon, Myonggeun; Chung, Mijoo; Chung, Weon Kuu; Kim, Dong Wook

2016-05-01

In this paper, we report the results of our investigation into whole brain radiotherapy (WBRT) using linear accelerator-based intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) in lung cancer patients with a high risk of metastasis to the brain. Specifically, we assessed the absorbed dose and the rate of adverse effects for several organs at risk (OAR), including the hippocampus, according to the tilt of a patient's head. We arbitrarily selected five cases where measurements were made with the patients' heads tilted forward and five cases without such tilt. We set the entire brain as the planning target volume (PTV), and the hippocampi, the lenses, the eyes, and the cochleae as the main OAR, and formulated new plans for IMRT (coplanar, non-coplanar) and VMAT (coplanar, non-coplanar). Using the dose-volume histogram (DVH), we calculated and compared the effective uniform dose (EUD), normal tissue complication probability (NTCP) of the OAR and the mean and the maximum doses of hippocampus. As a result, if the patient tilted the head forward when receiving the Linac-based treatment, for the same treatment effect in the PTV, we confirmed that a lower dose entered the OAR, such as the hippocampus, eye, lens, and cochlea. Moreover, the damage to the hippocampus was expected to be the least when receiving coplanar VMAT with the head tilted forward. Accordingly, if patients tilt their heads forward when undergoing Linac-based WBRT, we anticipate that a smaller dose would be transmitted to the OAR, resulting in better quality of life following treatment. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Comparison of arterial input functions measured from ultra-fast dynamic contrast enhanced MRI and dynamic contrast enhanced computed tomography in prostate cancer patients

NASA Astrophysics Data System (ADS)

Wang, Shiyang; Lu, Zhengfeng; Fan, Xiaobing; Medved, Milica; Jiang, Xia; Sammet, Steffen; Yousuf, Ambereen; Pineda, Federico; Oto, Aytekin; Karczmar, Gregory S.

2018-02-01

The purpose of this study was to evaluate the accuracy of arterial input functions (AIFs) measured from dynamic contrast enhanced (DCE) MRI following a low dose of contrast media injection. The AIFs measured from DCE computed tomography (CT) were used as ‘gold standard’. A total of twenty patients received CT and MRI scans on the same day. Patients received 120 ml Iohexol in DCE-CT and a low dose of (0.015 mM kg-1) of gadobenate dimeglumine in DCE-MRI. The AIFs were measured in the iliac artery and normalized to the CT and MRI contrast agent doses. To correct for different temporal resolution and sampling periods of CT and MRI, an empirical mathematical model (EMM) was used to fit the AIFs first. Then numerical AIFs (AIFCT and AIFMRI) were calculated based on fitting parameters. The AIFMRI was convolved with a ‘contrast agent injection’ function (AIFMRICON ) to correct for the difference between MRI and CT contrast agent injection times (~1.5 s versus 30 s). The results show that the EMMs accurately fitted AIFs measured from CT and MRI. There was no significant difference (p  >  0.05) between the maximum peak amplitude of AIFs from CT (22.1  ±  4.1 mM/dose) and MRI after convolution (22.3  ±  5.2 mM/dose). The shapes of the AIFCT and AIFMRICON were very similar. Our results demonstrated that AIFs can be accurately measured by MRI following low dose contrast agent injection.

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

PubMed Central

Trippett, Tanya M.; Herzog, Cynthia; Whitlock, James A.; Wolff, Johannes; Kuttesch, John; Bagatell, Rochelle; Hunger, Stephen P.; Boklan, Jessica; Smith, Amy A.; Arceci, Robert J.; Katzenstein, Howard M.; Harbison, Christopher; Zhou, Xiaofei; Lu, Haolan; Langer, Christiane; Weber, Martin; Gore, Lia

2009-01-01

Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen. PMID:19770383

Effect of heterogeneity correction on dosimetric parameters of radiotherapy planning for thoracic esophageal cancer.

PubMed

Nakayama, Masao; Yoshida, Kenji; Nishimura, Hideki; Miyawaki, Daisuke; Uehara, Kazuyuki; Okamoto, Yoshiaki; Okayama, Takanobu; Sasaki, Ryohei

2014-01-01

The present study aimed to investigate the effect of heterogeneity correction (HC) on dosimetric parameters in 3-dimensional conformal radiotherapy planning for patients with thoracic esophageal cancer. We retrospectively analyzed 20 patients. Two treatment plans were generated for each patient using a superposition algorithm on the Xio radiotherapy planning system. The first plan was calculated without HC. The second was a new plan calculated with HC, using identical beam geometries and maintaining the same number of monitor units as the first. With regard to the planning target volume (PTV), the overall mean differences in the prescription dose, maximum dose, mean dose, and dose that covers 95% of the PTV between the first and second plans were 1.10Gy (1.8%), 1.35Gy (2.2%), 1.10Gy (1.9%), and 0.56Gy (1.0%), respectively. With regard to parameters related to the organs at risk (OARs), the mean differences in the absolute percentages of lung volume receiving greater than 5, 10, 20, and 30Gy (lung V5, V10, V20, and V30) between the first and second plans were 7.1%, 2.7%, 0.4%, and 0.5%, respectively. These results suggest that HC might have a more pronounced effect on the percentages of lung volume receiving lower doses (e.g., V5 and V10) than on the dosimetric parameters related to the PTV and other OARs. © 2013 Published by American Association of Medical Dosimetrists on behalf of American Association of Medical Dosimetrists.

A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma.

PubMed

Rothe, Achim; Sasse, Stephanie; Topp, Max S; Eichenauer, Dennis A; Hummel, Horst; Reiners, Katrin S; Dietlein, Markus; Kuhnert, Georg; Kessler, Joerg; Buerkle, Carolin; Ravic, Miroslav; Knackmuss, Stefan; Marschner, Jens-Peter; Pogge von Strandmann, Elke; Borchmann, Peter; Engert, Andreas

2015-06-25

AFM13 is a bispecific, tetravalent chimeric antibody construct (TandAb) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase 1 dose-escalation study, 28 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7 mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, antitumor activity, and pharmacodynamics. Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. Pharmacokinetics assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin-refractory patients. In 13 patients who received doses of ≥1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571. © 2015 by The American Society of Hematology.

Opioid needs of patients with advanced cancer and the morphine dose-limiting law in Egypt.

PubMed

Alsirafy, Samy A; El-Mesidi, Salah M; El-Sherief, Wesam A; Galal, Khaled M; Abou-Elela, Enas N; Aklan, Nahla A

2011-01-01

Morphine is the drug of choice for moderate to severe cancer pain management. The Egyptian Narcotics Control Law limits the amount of morphine prescribed in a single prescription to a maximum of 420 mg for tablets and 60 mg for ampoules. The usual practice in Egypt is to provide that limited amount of morphine on a weekly basis. The aim of this study is to estimate the extent to which Egyptian patients may be undertreated because of this law. We reviewed the medical records of advanced cancer patients referred to the first palliative care unit in Egypt over a seven-month period. Cancer pain was managed following the WHO guidelines. After modifying the internal institutional policy, patients received adequate amounts of the available opioids without any violations of the law. From 117 eligible advanced cancer patients, 58 (50%) patients required strong opioids, 32 (27%) required weak opioids, and 27 (23%) required no regular opioids. The mean last prescribed opioid dose for those who required strong opioids was 194 mg of oral morphine equivalent/24 h (± 180). For this group of patients, a single weekly prescription would supply enough oral morphine for only 26% of them. In the case of parenteral morphine, none of these patients would receive an adequate supply. In view of the current morphine dose-limiting law and practices in Egypt, the majority of patients suffering severe cancer pain would not have access to adequate morphine doses. That dose-limiting law and other restrictive regulations represent an obstacle to cancer pain control in Egypt and should be revised urgently.

A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma

PubMed Central

Rothe, Achim; Sasse, Stephanie; Topp, Max S.; Eichenauer, Dennis A.; Hummel, Horst; Reiners, Katrin S.; Dietlein, Markus; Kuhnert, Georg; Kessler, Joerg; Buerkle, Carolin; Ravic, Miroslav; Knackmuss, Stefan; Marschner, Jens-Peter; Pogge von Strandmann, Elke; Borchmann, Peter

2015-01-01

AFM13 is a bispecific, tetravalent chimeric antibody construct (TandAb) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase 1 dose-escalation study, 28 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7 mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, antitumor activity, and pharmacodynamics. Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. Pharmacokinetics assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin–refractory patients. In 13 patients who received doses of ≥1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571. PMID:25887777

Antiviral Activity, Safety, and Exposure-Response Relationships of GSK3532795, a Second-Generation Human Immunodeficiency Virus Type 1 Maturation Inhibitor, Administered as Monotherapy or in Combination With Atazanavir With or Without Ritonavir in a Phase 2a Randomized, Dose-Ranging, Controlled Trial (AI468002).

PubMed

Hwang, Carey; Schürmann, Dirk; Sobotha, Christian; Boffito, Marta; Sevinsky, Heather; Ray, Neelanjana; Ravindran, Palanikumar; Xiao, Hong; Keicher, Christian; Hüser, Andreas; Krystal, Mark; Dicker, Ira B; Grasela, Dennis; Lataillade, Max

2017-08-01

GSK3532795 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor that targets HIV-1 Gag, inhibiting the final protease cleavage between capsid protein p24 and spacer protein-1, producing immature, noninfectious virions. This was a phase 2a, randomized, dose-ranging multipart trial. In part A, subtype B-infected subjects received 5-120 mg GSK3532795 (or placebo) once daily for 10 days. In part B, subtype B-infected subjects received 40 mg or 80 mg GSK3532795 once daily with atazanavir (ATV) with or without (±) ritonavir (RTV) or standard of care (SOC) (tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and ATV/RTV 300 mg/100 mg) for 28 days. In part C, subtype C-infected subjects received 40 mg or 120 mg GSK3532795 once daily (or placebo) for 10 days. Endpoints included change in HIV-1 RNA from baseline on day 11 (parts A/C) or day 29 (part B). A >1 log10 median decline in HIV-1 RNA was achieved by day 11 in parts A and C and day 29 in part B at GSK3532795 doses ≥40 mg; part B subjects receiving GSK3532795 and ATV ± RTV achieved similar declines to those receiving SOC. Median of the maximum declines in HIV-1 RNA were similar for the 40-120 mg once-daily dose groups regardless of baseline Gag polymorphisms. There were no deaths, adverse events leading to discontinuation, or serious adverse events. GSK3532795 demonstrated potent antiviral activity against subtype B (monotherapy or with ATV ± RTV) and subtype C, and was generally well tolerated, which supported continued development of GSK3532795 in subjects with HIV-1 subtype B or subtype C. NCT01803074. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Performance of toxicity probability interval based designs in contrast to the continual reassessment method

PubMed Central

Horton, Bethany Jablonski; Wages, Nolan A.; Conaway, Mark R.

2016-01-01

Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for Phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both the mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. PMID:27435150

Enhancement of natural background gamma-radiation dose around uranium microparticles in the human body

PubMed Central

Pattison, John E.; Hugtenburg, Richard P.; Green, Stuart

2010-01-01

Ongoing controversy surrounds the adverse health effects of the use of depleted uranium (DU) munitions. The biological effects of gamma-radiation arise from the direct or indirect interaction between secondary electrons and the DNA of living cells. The probability of the absorption of X-rays and gamma-rays with energies below about 200 keV by particles of high atomic number is proportional to the third to fourth power of the atomic number. In such a case, the more heavily ionizing low-energy recoil electrons are preferentially produced; these cause dose enhancement in the immediate vicinity of the particles. It has been claimed that upon exposure to naturally occurring background gamma-radiation, particles of DU in the human body would produce dose enhancement by a factor of 500–1000, thereby contributing a significant radiation dose in addition to the dose received from the inherent radioactivity of the DU. In this study, we used the Monte Carlo code EGSnrc to accurately estimate the likely maximum dose enhancement arising from the presence of micrometre-sized uranium particles in the body. We found that although the dose enhancement is significant, of the order of 1–10, it is considerably smaller than that suggested previously. PMID:19776147

Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.

PubMed

Edelman, Alison B; Cherala, Ganesh; Blue, Steven W; Erikson, David W; Jensen, Jeffrey T

2016-07-01

To determine if differences exist in the pharmacokinetics (PK) of levonorgestrel-based emergency contraception (LNG-EC) in obese and normal body mass index (BMI) users and test whether doubling the dose of LNG-EC in obese women increases total and free (active) LNG serum concentrations. Healthy, reproductive-age women with obese and normal BMIs received 1.5mg LNG orally (ECx1) and then in a subsequent menstrual cycle, the obese group also received 3mg LNG (ECx2). Dosing occurred during the follicular phase. Total and free LNG PK parameters were obtained via serum samples through an indwelling catheter at 0, 0.5, 1, 1.5, 2, and 2.5h. The primary outcome was the difference in total and free LNG concentration maximum (Cmax) between ECx1 and ECx2 in the obese group. A total of 10 women enrolled and completed the study (normal BMI=5, median 22.8kg/m(2), range 20.8-23.7; obese BMI=5, 39.5kg/m(2), range 35.9-46.7). The total LNG Cmax for obese subjects following ECx1 (5.57±2.48ng/mL) was significantly lower than the level observed in normal BMI women (10.30±2.47, p=.027). Notably, ECx2 increased the Cmax significantly (10.52±2.76, p=.002); approximating the level in normal BMI subjects receiving ECx1. Free LNG Cmax followed a similar pattern. Obesity adversely impacts both the total and free Cmax levels of LNG EC and this likely explains its lack of efficacy in obese women. Doubling the dose appears to correct the obesity-related PK changes but additional research is needed to determine if this also improves EC effectiveness in obese women. This study demonstrates that obesity interferes with the pharmacokinetics of LNG EC, and that doubling the dose may be an effective strategy to improve its efficacy in obese women. Copyright © 2016 Elsevier Inc. All rights reserved.

Predictor of Severe Gastroduodenal Toxicity After Stereotactic Body Radiotherapy for Abdominopelvic Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bae, Sun Hyun; Kim, Mi-Sook, E-mail: mskim@kcch.re.kr; Cho, Chul Koo

2012-11-15

Purpose: To identify the predictors for the development of severe gastroduodenal toxicity (GDT) in patients treated with stereotactic body radiotherapy (SBRT) using 3 fractionations for abdominopelvic malignancies. Methods and Materials: From 2001 to 2011, 202 patients with abdominopelvic malignancies were treated with curative-intent SBRT. Among these patients, we retrospectively reviewed the clinical records of 40 patients with the eligibility criteria as follows: 3 fractionations, follow-up period {>=}1 year, absence of previous radiation therapy (RT) history or combination of external-beam RT and the presence of gastroduodenum (GD) that received a dose higher than 20% of prescribed dose. The median SBRT dosemore » was 45 Gy (range, 33-60 Gy) with 3 fractions. We analyzed the clinical and dosimetric parameters, including multiple dose-volume histogram endpoints: V{sub 20} (volume of GD that received 20 Gy), V{sub 25}, V{sub 30}, V{sub 35}, and D{sub max} (the maximum point dose). The grade of GDT was defined by the National Cancer Institute Common Toxicity Criteria version 4.0, and GDT {>=}grade 3 was defined as severe GDT. Results: The median time to the development of severe GDT was 6 months (range, 3-12 months). Severe GDT was found in 6 patients (15%). D{sub max} was the best dosimetric predictor for severe GDT. D{sub max} of 35 Gy and 38 Gy were respectively associated with a 5% and 10% probability of the development of severe GDT. A history of ulcer before SBRT was the best clinical predictor on univariate analysis (P=.0001). Conclusions: We suggest that D{sub max} is a valuable predictor of severe GDT after SBRT using 3 fractionations for abdominopelvic malignancies. A history of ulcer before SBRT should be carefully considered as a clinical predictor, especially in patients who receive a high dose to GD.« less

Combined Chemoradiation Therapy With Twice-Weekly Gemcitabine and Cisplatin for Organ Preservation in Muscle-Invasive Bladder Cancer: Long-Term Results of a Phase 1 Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Azria, David, E-mail: david.azria@icm.unicancer.fr; INSERM, U896, IRCM, Montpellier; Riou, Olivier

2014-03-15

Purpose: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. Methods and Materials: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabinemore » twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. Results: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. Conclusions: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.« less

Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers

PubMed Central

Rueangweerayut, Ronnatrai; Bancone, Germana; Harrell, Emma J.; Beelen, Andrew P.; Kongpatanakul, Supornchai; Möhrle, Jörg J.; Rousell, Vicki; Mohamed, Khadeeja; Qureshi, Ammar; Narayan, Sushma; Yubon, Nushara; Miller, Ann; Nosten, François H.; Luzzatto, Lucio; Duparc, Stephan; Kleim, Jörg-Peter; Green, Justin A.

2017-01-01

Abstract. Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40–60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose–response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (−2.65 to −2.95 g/dL [N = 3]) and primaquine (−1.25 to −3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61–80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days. PMID:28749773

Conditioning of the 4 Curies Radium-226 Sealed Radiation Source in Thailand

DOE Office of Scientific and Technical Information (OSTI.GOV)

Punnachaiya, M.; Sawangsri, T.; Wanabongse, P.

This paper describes the conditioning of the 4 curies Radium-226 (Ra-226) sealed radiation source using as a teletherapy unit for cancer treatment in Thailand. The conditioning was under the International Atomic Energy Agency (IAEA) supervision and budgetary supports, comprised of 6 operational steps: the surface dose rate and actual dimension of radium unit measurements, the appropriate lead shielding design with IAEA approval, confirmation of radioactive contamination before conditioning (smear test and radon gas leakage test), transfer of radium source unit into the designed shielding, confirmation of radioactive contamination and dose rate measurement after conditioning, and transportation of Ra-226 conditioning wastemore » package to OAP interim waste storage. The Ra-226 unit was taken out of OAP temporary waste storage for the surface dose rate and the actual dimension measurements behind the 12 inches thick heavy concrete shielding. The maximum measured surface dose rate was 70 R/hr. The special lead container was designed according to its surface dose rate along the source unit which the maximum permissible dose limit for surface dose rate of waste package after conditioning at 2 mSv/hr was applied. The IAEA approved container had total weight of 2.4 ton. After the confirmation of radioactive contamination, Ra-226 source unit was transferred and loaded in the designed lead shielding within 2 minutes. The results of smear test before and after conditioning including radon gas leakage test revealed that there was no radioactive contamination. After conditioning, the surface dose rate measured on the top, bottom were 15,10 mR/hr and varied from 6 - 50 mR/hr around lead container. The Ra-226 conditioning waste package was safely transported to store in OAP interim waste storage. Total working time including the time consumed for radon gas leakage test was 3.5 hours. The total radiation dose received by 16 operators, were ranged from 1 - 69.84 {mu}Sv and the operational team completed the conditioning safely within the effective dose limit for occupational exposure of 50 mSv/year (200 {mu}Sv/day). (authors)« less

Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63-9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties.

PubMed

Wensing, Georg; Haase, Claus; Brendel, Erich; Böttcher, Michael Friedrich

2007-12-01

BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study. 45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.25 mg, 0.5 mg, 1.2 mg, 2.5 mg and 5.0 mg. Pupil reaction (baseline pupil diameter (DIAM), constriction amplitude (CA)), body temperature, electroencephalography (EEG) and prolactin, cortisol and adrenocorticotrophic hormone (ACTH) served as pharmacodynamic measures and were monitored up to 24 h after drug intake. Safety, tolerability and plasma samples for determination of BAY 63-9044 were followed up to 72 h. Up to a dose of 2.5 mg, BAY 63-9044 was safe and well tolerated. Dose-limiting adverse events (nausea, vomiting, and dizziness) occurred in 5 out of 6 volunteers at the 5 mg dose. Adverse events resolved spontaneously in all but one volunteers who was treated with an antihistaminergic for vomiting. Dose-dependent changes of DIAM and CA were observed at doses higher than 0.5 mg and 1.2 mg, respectively. Body temperature showed a trend for reduction starting at C(max) in the highest two doses only. No clear effect was found on prolactin, cortisol and ACTH levels. The pharmacokinetics of BAY 63-9044 showed a dose-dependent increase with maximum plasma concentrations reached within 1 h. Plasma concentrations declined in a bi-phased manner with an apparent terminal half-life of 5.2-8.1 h. Up to the maximum tolerated dose (MTD) of 2.5 mg BAY 63-9044 was safe and well tolerated and showed predictable linear pharmacokinetics. Pupil reaction may serve as a non-invasive biomarker for pharmacodynamic effects of 5-HT(1A)-compounds with DIAM being the most sensitive parameter.

The dose-effect relationship of baclofen in alcohol dependence: A 1-year cohort study.

PubMed

Pignon, Baptiste; Labreuche, Julien; Auffret, Marine; Gautier, Sophie; Deheul, Sylvie; Simioni, Nicolas; Cottencin, Olivier; Bordet, Régis; Duhamel, Alain; Rolland, Benjamin

2017-07-01

Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence. Two hundred two patients with alcohol dependence, who received baclofen treatment for drinking reduction, were followed up for 1 year. For each patient-month of treatment, the maximum daily dose of baclofen (DDB) and average weekly alcohol consumption (AWAC) were calculated. We defined a favorable drinking outcome as an AWAC under 200 g/w for at least 2 consecutive months. We divided the DDB of each patient-month into 3 categories (low dose: <90 mg/d, medium dose: 90-150 mg/d, and high dose: >150 mg/d) and investigated the relationship between reaching a favorable outcome and the concurrent DDB category in a time-varying Cox regression analysis. Hazard ratios (HRs) were adjusted based on age, sex, and initial AWAC. One hundred forty subjects were followed during at least 1 month. Of these patients, 58 (41%) had a favorable drinking outcome. In comparison to low dose, medium dose was associated with a decreased rate of favorable drinking outcome (HR = 0.42; 95% CI [0.20, 0.88]), whereas no difference was found with high dose (HR = 1.31; 95% CI [0.65, 2.64]). The relationship between dose of baclofen and favorable drinking outcome was U-shaped, that is, was increased at low and high doses compared to medium doses. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of X-ray irradiation on human spermatogenesis

NASA Technical Reports Server (NTRS)

Thorslund, T. W.; Paulsen, C. A.

1972-01-01

Direct cell kill and inhibition of mitosis have been suggested as mechanisms to explain the occurrence of absolute sterility following the irradiation of the testes. In order to obtain information on the existence and dose dependency of the mechanisms for man, a controlled study was initiated. Sixty-four men received a single midorgan dose to both of their testes ranging from 7.5 to 400r (f = .95). It was deduced from resulting pre-sterile period and sterile period data that both cell kill and mitosis halting mechanisms were operating. The maximum observed sterile period was 501 days with eventual recovery observed in each individual where the follow-up was complete. Thus man appears to be highly radiosensitive in regard to temporary sterility but quite radioresistant in regard to permanent sterility.

In vivo imaging of human retinal microvasculature using adaptive optics scanning light ophthalmoscope fluorescein angiography

PubMed Central

Pinhas, Alexander; Dubow, Michael; Shah, Nishit; Chui, Toco Y.; Scoles, Drew; Sulai, Yusufu N.; Weitz, Rishard; Walsh, Joseph B.; Carroll, Joseph; Dubra, Alfredo; Rosen, Richard B.

2013-01-01

The adaptive optics scanning light ophthalmoscope (AOSLO) allows visualization of microscopic structures of the human retina in vivo. In this work, we demonstrate its application in combination with oral and intravenous (IV) fluorescein angiography (FA) to the in vivo visualization of the human retinal microvasculature. Ten healthy subjects ages 20 to 38 years were imaged using oral (7 and/or 20 mg/kg) and/or IV (500 mg) fluorescein. In agreement with current literature, there were no adverse effects among the patients receiving oral fluorescein while one patient receiving IV fluorescein experienced some nausea and heaving. We determined that all retinal capillary beds can be imaged using clinically accepted fluorescein dosages and safe light levels according to the ANSI Z136.1-2000 maximum permissible exposure. As expected, the 20 mg/kg oral dose showed higher image intensity for a longer period of time than did the 7 mg/kg oral and the 500 mg IV doses. The increased resolution of AOSLO FA, compared to conventional FA, offers great opportunity for studying physiological and pathological vascular processes. PMID:24009994

[Augmented antipsychotic therapy with pantogam active in patients with schizophrenia].

PubMed

Medvedev, V E; Frolova, V I; Gushanskaya, E V; Ter-Israelyan, A U

2015-01-01

to study the efficacy of the GABA-ergic drug pantogam active (D-, L-gopantenic acid) in patients with schizophrenia treated with typical neuroleptics and to assess the rate of treatment response and tolerability of the drug. A sample consisted of 70 patients with schizophrenia stratified into main (n=35) and control (n=35) groups. All patients received one of typical antipsychotics (haloperidol, zuclopenthixol, promazine or perphenazine). Patients of the main group received in addition pantogam active in dose of 1200-1800 mg daily. The maximum allowed dose of 1800 mg daily was used in 62.9% of the patients. The long-term combined therapy with the addition of D-, L-gopantenic acid (pantogam activ) allowed to achieve clinical improvement earlier (on 8th week in the main group versus 16th week in the control group). The frequency and severity of secondary negative symptoms associated with antipsychotic therapy were decreased as well. The high efficacy and tolerability of the combined therapy allow to improve quality of life in patients with schizophrenia and their compliance to treatment as well as to reduce costs of medical care.

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer.

PubMed

Moehler, Markus; Mahlberg, Rolf; Heinemann, Volker; Obermannová, Radka; Kubala, Eugen; Melichar, Bohuslav; Weinmann, Arndt; Scigalla, Paul; Tesařová, Marietta; Janda, Petr; Hédouin-Biville, Fabienne; Mansoor, Wasat

2017-03-01

This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m 2 followed by oxaliplatin 130 mg/m 2 (maximum 8 cycles) and then S-1 [20 mg/m 2 (cohort 1) or 25 mg/m 2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer. DLT was reported for two of the five patients in cohort 2, defining 20 mg/m 2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m 2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. The promising activity of EOS (S-1 dose level, 25 mg/m 2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites.

PubMed

Mahipal, Amit; Klapman, Jason; Vignesh, Shivakumar; Yang, Chung S; Neuger, Anthony; Chen, Dung-Tsa; Malafa, Mokenge P

2016-07-01

Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects. Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC. No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4-9.3 and 4.7-7.3 h, maximum concentration of 795.6-3742.6 and 493.3-3746 ng/mL, half-life of 1.7-5.9 and 2.3-6.9 h, and 0-12 h area under the curve of 4518.7-20,781.4 and 1987.7-22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30-60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed. Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.

Relative bioavailability and plasma paracetamol profiles of Panadol suppositories in children.

PubMed

Coulthard, K P; Nielson, H W; Schroder, M; Covino, A; Matthews, N T; Murray, R S; Van Der Walt, J H

1998-10-01

To determine the relative bioavailability and plasma paracetamol concentration profiles following administration of a proprietary formulation of paracetamol suppositories to postoperative children. Study A-eight children undergoing minor surgery had blood samples collected following the rectal administration of either a 250 mg or 500 mg paracetamol suppository on one day and an equivalent oral dose on the following day. A mean dose of 13 mg/kg gave a mean Cmax (Tmax) of 7.7 mg/L (1.6 h) and 4.9 mg/L (2.0 h) following oral and rectal administration, respectively. The mean relative rectal bioavailability was 78% (95% confidence interval of 55-101%). Study B-20 children undergoing tonsillectomy and/or adenoidectomy were randomly assigned to receive a postoperative dose of 500 mg of paracetamol either as 2 x 250 mg liquid filled or 1 x 500 mg hard wax Panadol suppository. A mean dose of 25 mg/kg produced mean maximum plasma paracetamol concentrations of 13.2 mg/L and 14.5 mg/L at 2.1 and 1.9 h for the hard and liquid filled suppository, respectively. The absorption rate constants and areas under the curves suggested no difference in the rate or extent of absorption between the two formulations. Absorption of paracetamol following rectal administration of Panadol suppositories to postoperative children is slower and reduced as compared to oral therapy. The hard wax and liquid filled products have similar absorption characteristics. The usually quoted antipyretic therapeutic range for paracetamol is 10-20 mg/L, although 5 mg/L may be effective. A single rectal dose of 25 mg/kg will obtain this lower concentration within 1 h of administration and maintain it for up to 6 h. When given in an appropriate dose for analgesia, maximum plasma paracetamol concentrations would be available in the immediate postoperative period if the rectal dose was given 2 h before the planned end of the procedure.

Sodium bicarbonate use and the risk of hypernatremia in thoracic aortic surgical patients with metabolic acidosis following deep hypothermic circulatory arrest

PubMed Central

Ghadimi, Kamrouz; Gutsche, Jacob T.; Ramakrishna, Harish; Setegne, Samuel L.; Jackson, Kirk R.; Augoustides, John G.; Ochroch, E. Andrew; Weiss, Stuart J.; Bavaria, Joseph E.; Cheung, Albert T.

2016-01-01

Objective: Metabolic acidosis after deep hypothermic circulatory arrest (DHCA) for thoracic aortic operations is commonly managed with sodium bicarbonate (NaHCO3). The purpose of this study was to determine the relationships between total NaHCO3 dose and the severity of metabolic acidosis, duration of mechanical ventilation, duration of vasoactive infusions, and Intensive Care Unit (ICU) or hospital length of stay (LOS). Methods: In a single center, retrospective study, 87 consecutive elective thoracic aortic operations utilizing DHCA, were studied. Linear regression analysis was used to test for the relationships between the total NaHCO3 dose administered through postoperative day 2, clinical variables, arterial blood gas values, and short-term clinical outcomes. Results: Seventy-five patients (86%) received NaHCO3. Total NaHCO3 dose averaged 136 ± 112 mEq (range: 0.0–535 mEq) per patient. Total NaHCO3 dose correlated with minimum pH (r = 0.41, P < 0.0001), minimum serum bicarbonate (r = −0.40, P < 0.001), maximum serum lactate (r = 0.46, P = 0.007), duration of metabolic acidosis (r = 0.33, P = 0.002), and maximum serum sodium concentrations (r = 0.29, P = 0.007). Postoperative hypernatremia was present in 67% of patients and peaked at 12 h following DHCA. Eight percent of patients had a serum sodium ≥ 150 mEq/L. Total NaHCO3 dose did not correlate with anion gap, serum chloride, not the duration of mechanical ventilator support, vasoactive infusions, ICU or hospital LOS. Conclusion: Routine administration of NaHCO3 was common for the management of metabolic acidosis after DHCA. Total dose of NaHCO3 was a function of the severity and duration of metabolic acidosis. NaHCO3 administration contributed to postoperative hypernatremia that was often severe. The total NaHCO3 dose administered was unrelated to short-term clinical outcomes. PMID:27397449

Phase I safety, pharmacokinetic, and pharmacodynamic study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced cancer.

PubMed

Hoekstra, Ronald; de Vos, Filip Y F L; Eskens, Ferry A L M; Gietema, Jourik A; van der Gaast, Ate; Groen, Harry J M; Knight, Raymond A; Carr, Robert A; Humerickhouse, Rod A; Verweij, Jaap; de Vries, Elisabeth G E

2005-08-01

ABT-510 is an angiogenesis inhibitor derived from thrombospondin-1, a naturally occurring inhibitor of angiogenesis. We investigated ABT-510, which was administered subcutaneously in patients with advanced solid malignancies, to assess safety, pharmacokinetics, and serum markers of angiogenesis. ABT-510 was administered subcutaneously as a continuous infusion (100 mg/24 h) and bolus injections (100, 200, and 260 mg once daily; 50 and 100 mg twice daily) in 28-day cycles. Thirty-nine patients received a total of 144 treatment cycles. Administration by continuous infusion was hampered by the onset of painful skin infiltrates at the injection site. In the bolus injection regimens, the most common toxicities observed were mild injection-site reactions and fatigue. Maximum-tolerated dose was not defined, but 260 mg was defined as the maximum clinically practical dose. ABT-510 pharmacokinetics were linear across the dosage ranges tested, and the potential therapeutic threshold (plasma concentrations > 100 ng/mL > 3 h/d) was achieved with all dose regimens. Median serum basic fibroblast growth factor (bFGF) levels decreased from 14.1 pg/mL (range, 0.5 to 77.7 pg/mL) at baseline to 3.2 pg/mL (range, 0.2 to 29.4 pg/mL) after 56 days of treatment (P = .003). No correlations with time on study or ABT-510 dose or exposure were observed for individual changes in bFGF. Stable disease lasting for six cycles or more was seen in six patients. ABT-510 demonstrated a favorable toxicity profile and linear and time-independent pharmacokinetics with biologically relevant plasma concentrations. The significant number of patients with prolonged stable disease and the convenient method of dosing merit further studies with this angiogenesis inhibitor.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munbodh, R; Ding, X; Yin, L

Purpose: To identify indicators of Late Grade 3 (LG3) toxicity, late vision and hearing changes in patients treated for primary brain tumors with photon (XRT) or proton radiotherapy (PRT). Methods: We retrospectively reviewed 102 patients who received brain XRT or PRT to doses of 54 or 59.6 Gy in daily fractions of 1.8–2 Gy. Of the 80 patients (34 XRT, 39 PRT and 7 both modalities) reviewed for indicators of LG3 toxicity, 25 developed LG3 toxicity 90 to 500 days after radiotherapy completion. 55 patients had less than LG3 toxicity > 500 days after treatment. In that time, late visionmore » and hearing changes were seen in 44 of 75 and 25 of 78 patients, respectively. The correlation between late toxicity and prescription dose, planning target volume (PTV) size, and doses to the brainstem, brain, optic chiasm, optic nerves, eyes and cochlea was evaluated. A two-tailed Fisher's exact test and Wilcoxon rank sum test were used for the statistical analysis for XRT, PRT and all patients combined. Results: Exceeding the 54 Gy-5% dose-volume brainstem constraint, but not the optic structure constraints, was significantly correlated (p < 0.05) with late vision changes in all three groups. Exceeding maximum and mean cochlear doses of 45 and 30 Gy, respectively, was a significant indicator of hearing changes (p < 0.05) in PRT patients and all patients combined. In a sub-group of 52 patients in whom the brain was contoured, the absolute brain volume receiving ≤ 50 Gy and > 60 Gy was significantly larger in patients with LG3 toxicity for all patients combined (p < 0.05). Prescription dose, brainstem dose and PTV volume were not correlated to LG3 toxicity. Conclusion: Our results indicate the importance of minimizing the brain volume irradiated, and brainstem and cochlea doses to reduce the risk of late toxicities following brain radiotherapy.« less

Intensity modulated radiotherapy and 3D conformal radiotherapy for whole breast irradiation: a comparative dosimetric study and introduction of a novel qualitative index for plan evaluation, the normal tissue index

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yim, Jackie; Suttie, Clare; Bromley, Regina

We report on a retrospective dosimetric study, comparing 3D conformal radiotherapy (3DCRT) and hybrid intensity modulated radiotherapy (hIMRT). We evaluated plans based on their planning target volume coverage, dose homogeneity, dose to organs at risk (OARs) and exposure of normal tissue to radiation. The Homogeneity Index (HI) was used to assess the dose homogeneity in the target region, and we describe a new index, the normal tissue index (NTI), to assess the dose in the normal tissue inside the tangent treatment portal. Plans were generated for 25 early-stage breast cancer patients, using a hIMRT technique. These were compared with themore » 3DCRT plans of the treatment previously received by the patients. Plan quality was evaluated using the HI, NTI and dose to OARs. The hIMRT technique was significantly more homogenous than the 3DCRT technique, while maintaining target coverage. The hIMRT technique was also superior at minimising the amount of tissue receiving D{sub 105%} and above (P < 0.0001). The ipsilateral lung and contralateral breast maximum were significantly lower in the hIMRT plans (P < 0.05 and P < 0.005), but the 3DCRT technique achieved a lower mean heart dose in left-sided breast cancer patients (P < 0.05). Hybrid intensity modulated radiotherapy plans achieved improved dose homogeneity compared to the 3DCRT plans and superior outcome with regard to dose to normal tissues. We propose that the addition of both HI and NTI in evaluating the quality of intensity modulated radiotherapy (IMRT) breast plans provides clinically relevant comparators which more accurately reflect the new paradigm of treatment goals and outcomes in the era of breast IMRT.« less

Tolerance of the Brachial Plexus to High-Dose Reirradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Allen M., E-mail: achen5@kumc.edu; Yoshizaki, Taeko; Velez, Maria A.

Purpose: To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. Methods and Materials: Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculatedmore » by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24 months (range, 3-144 months). Results: The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5 Gy to 150.1 Gy (median, 95.0 Gy). The cumulative mean (Dmean) dose ranged from 20.2 Gy to 111.5 Gy (median, 63.8 Gy). The 1-year freedom from brachial plexus–related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0 Gy, respectively (P=.05). The 1-year complication-free rate was 66% and 87%, for those reirradiated within and after 2 years from the initial course, respectively (P=.06). Conclusion: The development of brachial plexus–related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications.« less

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

PubMed

Yoh, Kiyotaka; Doi, Toshihiko; Ohmatsu, Hironobu; Kojima, Takashi; Takahashi, Hideaki; Zenke, Yoshitaka; Wacheck, Volker; Enatsu, Sotaro; Nakamura, Takashi; Turner, Kellie; Uenaka, Kazunori

2016-10-01

Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N = 3; 1400 mg, N = 3; 2000 mg, N = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib (N = 3) or gefitinib (N = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (Cmax) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

PubMed Central

Adjei, Alex A.; Cohen, Roger B.; Franklin, Wilbur; Morris, Clive; Wilson, David; Molina, Julian R.; Hanson, Lorelei J.; Gore, Lia; Chow, Laura; Leong, Stephen; Maloney, Lara; Gordon, Gilad; Simmons, Heidi; Marlow, Allison; Litwiler, Kevin; Brown, Suzy; Poch, Gregory; Kane, Katie; Haney, Jerry; Eckhardt, S. Gail

2009-01-01

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing. PMID:18390968

Estimation of the radiation dose from radiotherapy for skin haemangiomas in childhood: the ICTA software for epidemiology

NASA Astrophysics Data System (ADS)

Shamsaldin, A.; Lundell, M.; Diallo, I.; Ligot, L.; Chavaudra, J.; de Vathaire, F.

2000-12-01

Radium applicators and pure beta emitters have been widely used in the past to treat skin haemangioma in early childhood. A well defined relationship between the low doses received from these applicators and radiation-induced cancers requires accurate dosimetry. A human-based CT scan phantom has been used to simulate every patient and treatment condition and then to calculate the source-target distance when radium and pure beta applicators were used. The effective transmission factor ϕ(r) for the gamma spectrum emitted by the radium sources applied on the skin surface was modelled using Monte Carlo simulations. The well-known quantization approach was used to calculate gamma doses delivered from radium applicators to various anatomical points. For 32P, 90Sr/90Y applicators and 90Y needles we have used the apparent exponential attenuation equation. The dose calculation algorithm was integrated into the ICTA software (standing for a model that constructs an Individualized phantom based on CT slices and Auxological data), which has been developed for epidemiological studies of cohorts of patients who received radium and beta-treatments for skin haemangioma. The ϕ(r) values obtained for radium skin applicators are in good agreement with the available values in the first 10 cm but higher at greater distances. Gamma doses can be calculated with this algorithm at 165 anatomical points throughout the body of patients treated with radium applicators. Lung heterogeneity and air crossed by the gamma rays are considered. Comparison of absorbed doses in water from a 10 mg equivalent radium source simulated by ICTA with those measured at the Radiumhemmet, Karolinska Hospital (RAH) showed good agreement, but ICTA estimation of organ doses did not always correspond those estimated at the RAH. Beta doses from 32P, 90Sr/90Y applicators and 90Y needles are calculated up to the maximum beta range (11 mm).

Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients.

PubMed

Turner, Alice M; Stolk, Jan; Bals, Robert; Lickliter, Jason D; Hamilton, James; Christianson, Dawn R; Given, Bruce D; Burdon, Jonathan G; Loomba, Rohit; Stoller, James K; Teckman, Jeffery H

2018-03-21

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation in AAT (SERPINA1) results in mis-folded AAT protein (Z-AAT) accumulating in hepatocytes, leading to fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of AAT. Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (two placebo: four active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 patients with PiZZ (homozygous for Z-AAT) genotype AATD, who received up to 4.0 mg/kg of ARC-AAT or placebo. Patients with baseline FibroScan® >11 kPa or forced expiratory volume in one second (FEV1) <60% were excluded. Assessments included safety, pharmacokinetics, and change in serum AAT concentrations. A total of 36 HVs received ARC-AAT and 18 received placebo (part A). Seven PiZZ individuals received ARC-AAT and four received placebo (part B). A dose response in serum AAT reduction was observed at doses ≥4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. The time it took for serum AAT to return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. PiZZ patients and HVs responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated. Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with alpha-1 antitrypsin deficiency. NCT02363946. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The characteristics of dose at mass interface on lung cancer Stereotactic Body Radiotherapy (SBRT) simulation

NASA Astrophysics Data System (ADS)

Wulansari, I. H.; Wibowo, W. E.; Pawiro, S. A.

2017-05-01

In lung cancer cases, there exists a difficulty for the Treatment Planning System (TPS) to predict the dose at or near the mass interface. This error prediction might influence the minimum or maximum dose received by lung cancer. In addition to target motion, the target dose prediction error also contributes in the combined error during the course of treatment. The objective of this work was to verify dose plan calculated by adaptive convolution algorithm in Pinnacle3 at the mass interface against a set of measurement. The measurement was performed using Gafchromic EBT 3 film in static and dynamic CIRS phantom with amplitudes of 5 mm, 10 mm, and 20 mm in superior-inferior motion direction. Static and dynamic phantom were scanned with fast CT and slow CT before planned. The results showed that adaptive convolution algorithm mostly predicted mass interface dose lower than the measured dose in a range of -0,63% to 8,37% for static phantom in fast CT scanning and -0,27% to 15,9% for static phantom in slow CT scanning. In dynamic phantom, this algorithm was predicted mass interface dose higher than measured dose up to -89% for fast CT and varied from -17% until 37% for slow CT. This interface of dose differences caused the dose mass decreased in fast CT, except for 10 mm motion amplitude, and increased in slow CT for the greater amplitude of motion.

Osteoradionecrosis following treatment for head and neck cancer and the effect of radiotherapy dosimetry: the Guy's and St Thomas' Head and Neck Cancer Unit experience.

PubMed

De Felice, Francesca; Thomas, Christopher; Patel, Vinod; Connor, Steve; Michaelidou, Andriana; Sproat, Chris; Kwok, Jerry; Burke, Mary; Reilly, Damien; McGurk, Mark; Simo, Ricard; Lyons, Andrew; Oakley, Richard; Jeannon, Jean-Pierre; Lei, Mary; Urbano, Teresa Guerrero

2016-07-01

To analyze clinical features, dosimetric parameters, and outcomes of osteoradionecrosis (ORN). Thirty-six patients with ORN who had been previously treated with radiotherapy (RT) were retrospectively identified between January 2009 and April 2014. ORN volumes were contoured on planning computed tomography (CT) scans. Near maximum dose (D2%), minimum dose (Dmin), mean dose (Dmean), and percentage of bone volume receiving 50 Gy (V50) were examined. Clinical and dosimetric variables were considered to compare ORN resolution versus ORN persistence. Median interval time from end of RT to development of ORN was 6 months. Of the ORN cases, 61% were located in the mandible. Dmean to affected bone was 57.6 Gy, and 44% had a D2% 65 Gy or greater. Smoking was associated with ORN persistence on univariate analysis, but no factors were found to impact ORN resolution or progression on logistic regression. Prevention strategies for ORN development should be prioritized. Dose-volume parameters could have a role in preventing ORN. Copyright © 2016 Elsevier Inc. All rights reserved.

Solar UV radiation exposure of seamen - Measurements, calibration and model calculations of erythemal irradiance along ship routes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feister, Uwe; Meyer, Gabriele; Kirst, Ulrich

2013-05-10

Seamen working on vessels that go along tropical and subtropical routes are at risk to receive high doses of solar erythemal radiation. Due to small solar zenith angles and low ozone values, UV index and erythemal dose are much higher than at mid-and high latitudes. UV index values at tropical and subtropical Oceans can exceed UVI = 20, which is more than double of typical mid-latitude UV index values. Daily erythemal dose can exceed the 30-fold of typical midlatitude winter values. Measurements of erythemal exposure of different body parts on seamen have been performed along 4 routes of merchant vessels.more » The data base has been extended by two years of continuous solar irradiance measurements taken on the mast top of RV METEOR. Radiative transfer model calculations for clear sky along the ship routes have been performed that use satellite-based input for ozone and aerosols to provide maximum erythemal irradiance and dose. The whole data base is intended to be used to derive individual erythemal exposure of seamen during work-time.« less

SU-F-BRD-05: Dosimetric Comparison of Protocol-Based SBRT Lung Treatment Modalities: Statistically Significant VMAT Advantages Over Fixed- Beam IMRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Best, R; Harrell, A; Geesey, C

2014-06-15

Purpose: The purpose of this study is to inter-compare and find statistically significant differences between flattened field fixed-beam (FB) IMRT with flattening-filter free (FFF) volumetric modulated arc therapy (VMAT) for stereotactic body radiation therapy SBRT. Methods: SBRT plans using FB IMRT and FFF VMAT were generated for fifteen SBRT lung patients using 6 MV beams. For each patient, both IMRT and VMAT plans were created for comparison. Plans were generated utilizing RTOG 0915 (peripheral, 10 patients) and RTOG 0813 (medial, 5 patients) lung protocols. Target dose, critical structure dose, and treatment time were compared and tested for statistical significance. Parametersmore » of interest included prescription isodose surface coverage, target dose heterogeneity, high dose spillage (location and volume), low dose spillage (location and volume), lung dose spillage, and critical structure maximum- and volumetric-dose limits. Results: For all criteria, we found equivalent or higher conformality with VMAT plans as well as reduced critical structure doses. Several differences passed a Student's t-test of significance: VMAT reduced the high dose spillage, evaluated with conformality index (CI), by an average of 9.4%±15.1% (p=0.030) compared to IMRT. VMAT plans reduced the lung volume receiving 20 Gy by 16.2%±15.0% (p=0.016) compared with IMRT. For the RTOG 0915 peripheral lesions, the volumes of lung receiving 12.4 Gy and 11.6 Gy were reduced by 27.0%±13.8% and 27.5%±12.6% (for both, p<0.001) in VMAT plans. Of the 26 protocol pass/fail criteria, VMAT plans were able to achieve an average of 0.2±0.7 (p=0.026) more constraints than the IMRT plans. Conclusions: FFF VMAT has dosimetric advantages over fixed beam IMRT for lung SBRT. Significant advantages included increased dose conformity, and reduced organs-at-risk doses. The overall improvements in terms of protocol pass/fail criteria were more modest and will require more patient data to establish difference trends of more statistical significance.« less

Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects.

PubMed

Anderson, Matt S; Gilmartin, Jocelyn; Cilissen, Caroline; De Lepeleire, Inge; Van Bortel, Luc; Dockendorf, Marissa F; Tetteh, Ernestina; Ancona, June K; Liu, Rachael; Guo, Ying; Wagner, John A; Butterton, Joan R

2015-01-01

Doravirine is a novel non-nucleoside inhibitor of HIV-1 reverse transcriptase with potent activity against wild-type virus (95% inhibitory concentration 19 nM, 50% human serum). Doravirine has low potential to cause drug-drug interactions since it is primarily eliminated by oxidative metabolism and does not inhibit or significantly induce drug-metabolizing enzymes. The pharmacokinetics and safety of doravirine were investigated in two double-blind, dose-escalation studies in healthy males. Thirty-two subjects received single doses of doravirine (6-1,200 mg) or matching placebo tablets; 40 subjects received doravirine (30-750 mg) or matching placebo tablets once daily for 10 days. In addition, the effect of doravirine (120 mg for 14 days) on single-dose pharmacokinetics of the CYP3A substrate midazolam was evaluated (10 subjects). The maximum plasma concentration (Cmax) of doravirine was achieved within 1-5 h with an apparent terminal half-life of 12-21 h. Consistent with single-dose pharmacokinetics, steady state was achieved after approximately 7 days of once daily administration, with accumulation ratios (day 10/day 1) of 1.1-1.5 in the area under the plasma concentration-time curve during the dosing interval (AUC0-24 h), Cmax and trough plasma concentration (C24 h). All dose levels produced C24 h>19 nM. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC time zero to infinity (AUC0-∞) and C24 h with no change in Cmax. Midazolam AUC0-∞ was slightly reduced by coadministration of doravirine (geometric mean ratio 0.82, 90% CI 0.70, 0.97). There was no apparent relationship between adverse event frequency or intensity and doravirine dose. No rash or significant central nervous system events other than headache were reported. Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.

Correlation of dosimetric parameters obtained with the analytical anisotropic algorithm and toxicity of chest chemoradiation in lung carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cartier, Lysian; Auberdiac, Pierre; Khodri, Mustapha

The purpose of this study was to analyze and revisit toxicity related to chest chemoradiotherapy and to correlate these side effects with dosimetric parameters obtained using analytical anisotropic algorithm (AAA) in locally unresectable advanced lung cancer. We retrospectively analyzed data from 47 lung cancer patients between 2005 and 2008. All received conformal 3D radiotherapy using high-energy linear accelerator plus concomitant chemotherapy. All treatment planning data were transferred into Eclipse 8.05 (Varian Medical Systems, Palo Alto, CA) and dosimetric calculations were performed using AAA. Thirty-three patients (70.2%) developed acute pneumopathy after radiotherapy (grades 1 and 2). One patient (2.1%) presented withmore » grade 3 pneumopathy. Thirty-one (66%) presented with grades 1-2 lung fibrosis, and 1 patient presented with grade 3 lung fibrosis. Thirty-four patients (72.3%) developed grade 1-2 acute oesophagic toxicity. Four patients (8.5%) presented with grades 3 and 4 dysphagia, necessitating prolonged parenteral nutrition. Median prescribed dose was 64 Gy (range 50-74) with conventional fractionation (2 Gy per fraction). Dose-volume constraints were respected with a median V20 of 23.5% (maximum 34%) and a median V30 of 17% (maximum 25%). The median dose delivered to healthy contralateral lung was 13.1 Gy (maximum 18.1 Gy). At univariate analysis, larger planning target volume and V20 were significantly associated with the probability of grade {>=}2 radiation-induced pneumopathy (p = 0.022 and p = 0.017, respectively). No relation between oesophagic toxicity and clinical/dosimetric parameters could be established. Using AAA, the present results confirm the predictive value of the V20 for lung toxicity as already demonstrated with the conventional pencil beam convolution approach.« less

Lack of effect of lacosamide on the pharmacokinetic and pharmacodynamic profiles of warfarin.

PubMed

Stockis, Armel; van Lier, Jan Jaap; Cawello, Willi; Kumke, Thomas; Eckhardt, Klaus

2013-07-01

The aim of this study was to evaluate the effect of the antiepileptic drug lacosamide on the pharmacokinetics and pharmacodynamics of the anticoagulant warfarin. In this open-label, two-treatment crossover study, 16 healthy adult male volunteers were randomized to receive a single 25-mg dose of warfarin alone in one period and lacosamide 200 mg twice daily on days 1-9 with a single 25 mg dose of warfarin coadministered on day 3 in the other period. There was a 2-week washout between treatments. Pharmacokinetic end points were area under the plasma concentration-time curve (AUC(0,last) and AUC(0,∞) ) and maximum plasma concentration (Cmax ) for S- and R-warfarin. Pharmacodynamic end points were area under the international normalized ratio (INR)-time curve (AUCINR ), maximum INR (INRmax ), maximum prothrombin time (PTmax ) and area under the PT-time curve (AUCPT ). Following warfarin and lacosamide coadministration, Cmax and AUC of S- and R-warfarin, as well as peak value and AUC of PT and INR, were equivalent to those after warfarin alone. In particular, the AUC(0,∞) ratio (90% confidence interval) for coadministration of warfarin and lacosamide versus warfarin alone was 0.97 (0.94-1.00) for S-warfarin and 1.05 (1.02-1.09) for R-warfarin, and the AUCINR ratio was 1.04 (1.01-1.06). All participants completed the study. Coadministration of lacosamide 400 mg/day did not alter the pharmacokinetics of warfarin 25 mg or the anticoagulation level. These results suggest that there is no need for dose adjustment of warfarin when coadministered with lacosamide. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Randomized trial of standard pain control with or without gabapentin for pain related to radiation-induced mucositis in head and neck cancer.

PubMed

Kataoka, Tomoko; Kiyota, Naomi; Shimada, Takanobu; Funakoshi, Yohei; Chayahara, Naoko; Toyoda, Masanori; Fujiwara, Yutaka; Nibu, Ken-Ichi; Komori, Takahide; Sasaki, Ryohei; Mukohara, Toru; Minami, Hironobu

2016-12-01

Radiation-induced mucositis (RIM) in chemoradiotherapy (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance, QOL and outcome. Following retrospective reports, we conducted a randomized trial of the safety and efficacy of gabapentin for RIM-associated pain during CRT. HNC patients (pts) receiving CRT were randomized to standard pain control (SPC) with acetaminophen and opioids, or SPC plus gabapentin (SPC+G). Gabapentin was maintained at 900mg/day for 4 weeks after CRT. Primary endpoint was maximum visual analogue scale (VAS) score during CRT, and secondary endpoints were total opioid dose, changes in QOL (EORTC QLQ-C30 and QLQ-HN 35) from baseline to 4 weeks after CRT, and adverse events. Twenty-two eligible Stage III or IV pts were randomly assigned to SPC or SPC+G (n=11 each). Twelve were treated in a locally advanced setting and 10 in a postoperative setting. Median maximum VAS scores, median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT tended to be higher in the SPC+G arm (47 in SPC vs. 74 in SPC+G, p=0.517; 215mg vs. 745.3mg, p=0.880; and 1260mg vs. 1537.5mg, p=0.9438, respectively), without significance. QOL analysis showed significantly worse scores in the SPC+G arm for weight gain (p=0.005). Adverse events related to gabapentin were manageable. This pilot study is the first prospective randomized trial of gabapentin for RIM-related pain. Gabapentin had no apparent beneficial effect. Further research into agents for RIM-related pain is warranted. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

LDEF: Dosimetric measurement results (AO 138-7 experiment)

NASA Technical Reports Server (NTRS)

Bourrieau, J.

1992-01-01

One of the objectives of the AO 138-7 experiment on board the LDEF was a total dose measurement with Thermo Luminescent Detectors (TLD 100). Two identical cases, both including 5 TLDs inside various aluminum shields, are exposed to the space environment in order to obtain the absorbed dose profile induced. Radiation fluence received during the total mission length was computed, taking into account the trapped particles (solar maximum and solar minimum periods) and the cosmic rays; due to the magnetospheric shielding, the solar proton fluences are negligible on the LDEF orbit. The total dose induced by these radiations inside a semi-infinite plane shield of Al are computed with radiation transport codes. TLD reading are performed after flight; due to the mission duration increase, a post-flight calibration was necessary in order to cover the range of the flight induced dose. The results obtained, similar (+ or - 30 pct.) in both cases, are compared with the dose profile computation. In practice, these LDEF results, with less than a factor 1.4 between measurements and forecasts, reinforce the validity of the computation methods and models used for the long term evaluation of space radiation intensity on low inclination Earth orbits.

Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial.

PubMed

Frye, R E; Slattery, J; Delhey, L; Furgerson, B; Strickland, T; Tippett, M; Sailey, A; Wynne, R; Rose, S; Melnyk, S; Jill James, S; Sequeira, J M; Quadros, E V

2018-02-01

We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4  months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg -1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.

Desensitization to rituximab in a multidisciplinary setting.

PubMed

Amorós-Reboredo, Patrícia; Sánchez-López, Jaime; Bastida-Fernández, Carla; do Pazo-Oubiña, Fernando; Borràs-Maixenchs, Núria; Giné, Eva; Valero, Antonio; Creus-Baró, Natàlia

2015-10-01

The need to offer first-line therapy to the increasing number of patients who have suffered an hypersensitivity reaction has stimulated the use of rapid desensitization protocols. To present our experience working as a multidisciplinary team using a rituximab rapid desensitization scheme. Patient demographics, allergic reaction, skin tests to rituximab, number of desensitizations, reactions during the desensitization protocol and actions taken, number of administered and completed cycles, were retrospectively collected in patients who received at least one desensitization to rituximab. Number of desensitizations successfully managed. Between 2012 and June 2013 five patients received a total of 19 desensitizations to rituximab using a 12 step rapid desensitization protocol. All patients received the scheduled chemotherapeutic cycles as inpatients, with no delay in administration dates. Three patients presented a hypersensitivity reaction during the first desensitization and in one patient the event occurred again during the second treatment cycle. All reactions occurred in the last step, when the infusion rate reached the maximum speed. The developed protocol for rapid desensitization was successful in five patients receiving rituximab. Patients could receive the full intended dose.

Combined photon-electron beams in the treatment of the supraclavicular lymph nodes in breast cancer: A novel technique that achieves adequate coverage while reducing lung dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Salem, Ahmed, E-mail: ahmed.salem@doctors.org.uk; Mohamad, Issa; Dayyat, Abdulmajeed

2015-10-01

Radiation pneumonitis is a well-documented side effect of radiation therapy for breast cancer. The purpose of this study was to compare combined photon-electron, photon-only, and electron-only plans in the radiation treatment of the supraclavicular lymph nodes. In total, 13 patients requiring chest wall and supraclavicular nodal irradiation were planned retrospectively using combined photon-electron, photon-only, and electron-only supraclavicular beams. A dose of 50 Gy over 25 fractions was prescribed. Chest wall irradiation parameters were fixed for all plans. The goal of this planning effort was to cover 95% of the supraclavicular clinical target volume (CTV) with 95% of the prescribed dosemore » and to minimize the volume receiving ≥ 105% of the dose. Comparative end points were supraclavicular CTV coverage (volume covered by the 95% isodose line), hotspot volume, maximum radiation dose, contralateral breast dose, mean total lung dose, total lung volume percentage receiving at least 20 Gy (V{sub 20} {sub Gy}), heart volume percentage receiving at least 25 Gy (V{sub 25} {sub Gy}). Electron and photon energies ranged from 8 to 18 MeV and 4 to 6 MV, respectively. The ratio of photon-to-electron fractions in combined beams ranged from 5:20 to 15:10. Supraclavicular nodal coverage was highest in photon-only (mean = 96.2 ± 3.5%) followed closely by combined photon-electron (mean = 94.2 ± 2.5%) and lowest in electron-only plans (mean = 81.7 ± 14.8%, p < 0.001). The volume of tissue receiving ≥ 105% of the prescription dose was higher in the electron-only (mean = 69.7 ± 56.1 cm{sup 3}) as opposed to combined photon-electron (mean = 50.8 ± 40.9 cm{sup 3}) and photon-only beams (mean = 32.2 ± 28.1 cm{sup 3}, p = 0.114). Heart V{sub 25} {sub Gy} was not statistically different among the plans (p = 0.999). Total lung V{sub 20} {sub Gy} was lowest in electron-only (mean = 10.9 ± 2.3%) followed by combined photon-electron (mean = 13.8 ± 2.3%) and highest in photon-only plans (mean = 16.2 ± 3%, p < 0.001). As expected, photon-only plans demonstrated the highest target coverage and total lung V{sub 20} {sub Gy}. The superiority of electron-only beams, in terms of decreasing lung dose, is set back by the dosimetric hotspots associated with such plans. Combined photon-electron treatment is a feasible technique for supraclavicular nodal irradiation and results in adequate target coverage, acceptable dosimetric hotspot volume, and slightly reduced lung dose.« less

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials

PubMed Central

Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L.; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-01-01

Purpose The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. Patients and Methods We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. Results A total of 13,008 toxicities were captured: 46% of patients’ first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m2, the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. Conclusions When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. PMID:26926682

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.

PubMed

Lee, Shing M; Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-04-20

The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. © 2016 by American Society of Clinical Oncology.

Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ9-THC in cannabis users

PubMed Central

Lile, Joshua A.; Kelly, Thomas H.; Charnigo, Richard J.; Stinchcomb, Audra L.; Hays, Lon R.

2013-01-01

Oral Δ9-tetrahydrocannabinol (Δ9-THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40 mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioral effects of oral Δ9-THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral Δ9-THC, administered in ascending order in 15 mg increments across separate sessions, up to a maximum of 90 mg, was determined in seven cannabis users. Five subjects received all doses and two experienced untoward side effects at lower doses. Δ9-THC produced a constellation of effects consistent with previous clinical studies. Low cannabinoid concentrations were associated with significant effects on drug- sensitive measures, although progressively greater levels did not lead to proportionately larger drug effects. Considerable variability in Cmax and tmax was observed. Doses of oral Δ9-THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral Δ9-THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response. PMID:23754596

Phase I study of icotinib, an EGFR tyrosine kinase inhibitor combined with IMRT in nasopharyngeal carcinoma.

PubMed

Hu, Wei; Wang, Wei; Yang, Peinong; Zhou, Chao; Yang, Weifang; Wu, Bo; Lu, Hongsheng; Yang, Haihua

2015-01-01

Epidermal growth factor receptor (EGFR) is a new target for nasopharyngeal carcinoma (NPC) therapy. This prospective phase I study sought to determine the safety and recommended phase II dose of icotinib, a novel highly selective oral EGFR tyrosine kinase inhibitor, in combination with intensity-modulated radiotherapy (IMRT) in patients with NPC. Eligible patients with NPC received escalating doses of icotinib during IMRT. We treated six patients at a particular dose level until the maximum tolerated dose (MTD) was determined. The starting dose was 125 mg, once-daily and the dose was escalated to another level 125 mg, twice- and thrice- daily, until dose-limiting toxicity (DLT) occurred in two or more patients at a dose level. Expression and mutation analysis of EGFR were performed in all cases. A total of twelve patients were enrolled. Three patients experienced DLT (250 mg/day cohort) and MTD was 125 mg/day. Mucositis toxicity appears to be the major DLT. While EGFR expression in tumor tissue was detected in 75% (9/12) patients, EGFR mutation was detected in 16.67% (1/6) patients in 125 mg/day cohort, and 50% (3/6) in 250 mg/day cohort. The combination of icotinib (125 mg/day) and IMRT in patients with locally NPC had an acceptable safety profile and was well tolerated.

Georgia fishery study: implications for dose calculations. Revision 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turcotte, M.D.S.

Fish consumption will contribute a major portion of the estimated individual and population doses from L-Reactor liquid releases and Cs-137 remobilization in Steel Creek. It is therefore important that the values for fish consumption used in dose calculations be as realistic as possible. Since publication of the L-Reactor Environmental Information Document (EID), data have become available on sport fishing in the Savannah River. These data provide SRP with a site-specific sport fish harvest and consumption values for use in dose calculations. The Georgia fishery data support the total population fish consumption and calculated dose reported in the EID. The datamore » indicate, however, that both the EID average and maximum individual fish consumption have been underestimated, although each to a different degree. The average fish consumption value used in the EID is approximately 3% below the lower limit of the fish consumption range calculated using the Georgia data. Maximum fish consumption in the EID has been underestimated by approximately 60%, and doses to the maximum individual should also be recalculated. Future dose calculations should utilize an average adult fish consumption value of 11.3 kg/yr, and a maximum adult fish consumption value of 34 kg/yr. Consumption values for the teen and child age groups should be increased proportionally: (1) teen average = 8.5; maximum = 25.9 kg/yr; and (2) child average = 3.6; maximum = 11.2 kg/yr. 8 refs.« less

A simple LC-MS/MS method using HILIC chromatography for the determination of fosfomycin in plasma and urine: application to a pilot pharmacokinetic study in humans.

PubMed

Parker, Suzanne L; Lipman, Jeffrey; Roberts, Jason A; Wallis, Steven C

2015-02-01

A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, using hydrophilic interaction liquid chromatography (HILIC) chromatography for the analysis of fosfomycin in human plasma and urine, has been developed and validated. The plasma method uses a simple protein precipitation using a low volume sample (10 μL) and is suitable for the concentration range of 1 to 2000 μg/mL. The urine method involves a simple dilution of 10 μL of sample and is suitable for a concentration range of 0.1 to 10 mg/mL. The plasma and urine results, reported, respectively, are for recovery (68, 72%), inter-assay precision (≤9.1%, ≤8.1%) and accuracy (range -7.2 to 3.3%, -1.9 to 1.6%), LLOQ precision (4.7%, 3.1%) and accuracy (1.7% and 1.2%), and includes investigations into the linearity, stability and matrix effects. The method was used in a pilot pharmacokinetic study of a critically ill patient receiving i.v. fosfomycin, which measured a maximum and minimum plasma concentration of 222 μg/mL and 172 μg/mL, respectively, after the initial dose, and a maximum and minimum plasma concentration of 868 μg/mL and 591μg/mL, respectively, after the fifth dose. The urine concentration was 2.03 mg/mL after the initial dose and 0.29 mg/mL after the fifth dose. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory.

PubMed

Belley, Adam; Robson, Richard; Francis, John L; Adcock, Dorothy M; Tiefenbacher, Stefan; Rubino, Christopher M; Moeck, Greg; Sylvester, David; Dudley, Michael N; Loutit, Jeffery

2017-02-01

Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo, a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing. Copyright © 2017 American Society for Microbiology.

Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory

PubMed Central

Robson, Richard; Francis, John L.; Adcock, Dorothy M.; Tiefenbacher, Stefan; Rubino, Christopher M.; Moeck, Greg; Sylvester, David; Dudley, Michael N.; Loutit, Jeffery

2016-01-01

ABSTRACT Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo, a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing. PMID:27956417

An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder.

PubMed

Takahashi, Michihiro; Takita, Yasushi; Goto, Taro; Ichikawa, Hironobu; Saito, Kazuhiko; Matsumoto, Hideo; Tanaka, Yasuo

2011-02-01

The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was -15.0 (P<0.001). This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.

Phase I/II clinical trial of 2-Difluoromethylornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma

PubMed Central

Skorupski, Katherine A.; O'Brien, Thomas G.; Guerrero, Teri; Rodriguez, Carlos O.; Burns, Mark R.

2011-01-01

Polyamines are essential for cell proliferation. Their production is dysregulated in many cancers and polyamine depletion leads to tumor regression in mouse models of SCC. The purpose of this study was to determine the maximally tolerated dose of the polyamine transport inhibitor, MQT 1426, when combined with the ornithine decarboxylase inhibitor, DFMO, and to determine whether this therapy results in reduction in tumor polyamine levels. Thirteen cats with oral SCC received both drugs orally and serial tumor biopsies were obtained for polyamine measurement. Cats were monitored for response to therapy and toxicity. A maximum tolerated dose of MQT 1426 when combined with DFMO was determined. Dose limiting toxicity was vestibular in nature, but was fully reversible. Spermidine and total polyamine levels decreased significantly in tissues, 2 cats experienced objective tumor regression, and 6 cats had stable disease. These results suggest that further study of polyamine depletion therapies is warranted. PMID:22077408

WE-EF-BRA-03: Catheter- Free Ablation with External Photon Radiation: Treatment Planning, Delivery Considerations, and Correlation of Effects with Delivered Dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deisher, A; Anderson, S; Cusma, J

Purpose: To plan, target, and calculate delivered dose in atrioventricular node (AVN) ablation with volume-modulated arc therapy (VMAT) in an intact porcine model. Methods: Seven pigs underwent AVN irradiation, with prescription doses ranging between 25 and 55Gy in a single fraction. Cardiac CT scans were acquired at expiration. Two physicians contoured AVN targets on 10 phases, providing estimates of target motion and inter-physician variability. Treatment planning was conducted on a static phase-averaged CT. The volume designated to receive prescription dose covered the full extent of AVN cardiac motion, expanded by 4mm for setup uncertainty. Optimization limited doses to risk structuresmore » according to single-fraction tumor treatment protocols. Orthogonal kV images were used to align bony anatomy at time of treatment. Localization was further refined with respiratory-gated cone-beam CT, and range of cardiac motion was verified under fluoroscopy. Beam delivery was respiratory-gated for expiration with a mean efficiency of 60%. Deformable registration of the 10 cardiac CT phases was used to calculate actual delivered dose for comparison to electro-anatomical and visually evident lesions. Results: The mean [minimum,maximum] amplitude of AVN cardiac motion was LR 2.9 [1.7,3.9]mm, AP 6.6 [4.4,10.4]mm, and SI 5.6 [2.0,9.9]mm. Incorporating cardiac motion into the dose calculation showed the volume receiving full dose was 40–80% of the volume indicated on the static planning image, although the contoured AVN target received full dose in all animals. Initial results suggest the dimensions of the electro-anatomical lesion are correlated with the 40Gy isodose volume. Conclusion: Image-guidance techniques allow for accurate and precise delivery of VMAT for catheter-free arrhythmia ablation. An arsenal of advanced radiation planning, dose optimization, and image-guided delivery techniques was employed to assess and mitigate effects of cardiac and respiratory motion. Feasibility of delivery to the pulmonary veins and left ventricular myocardium will be investigated in future studies. D. Packer Disclosures: Abiomed, Biosense Webster, Inc., Boston Scientific Corp., CardioFocus, Inc., Johnson and Johnson, Excerpta Medica, Ortho-McNeil-Jannsen, Sanofi Aventis, CardioInsight Technologies, InfoBionic, SIEMENS, Medtronic, Inc., CardioDx, Inc., CardioInsight Technologies, FoxP2 Medica, Mediasphere Medical, Wiley-Blackwell, St. Jude Medical, Endosense, Thermedical, EP Advocate LLC, Hansen Medical, American Heart Association, EpiEP, NIH.« less

IMRT head and neck treatment planning with a commercially available Monte Carlo based planning system

NASA Astrophysics Data System (ADS)

Boudreau, C.; Heath, E.; Seuntjens, J.; Ballivy, O.; Parker, W.

2005-03-01

The PEREGRINE Monte Carlo dose-calculation system (North American Scientific, Cranberry Township, PA) is the first commercially available Monte Carlo dose-calculation code intended specifically for intensity modulated radiotherapy (IMRT) treatment planning and quality assurance. In order to assess the impact of Monte Carlo based dose calculations for IMRT clinical cases, dose distributions for 11 head and neck patients were evaluated using both PEREGRINE and the CORVUS (North American Scientific, Cranberry Township, PA) finite size pencil beam (FSPB) algorithm with equivalent path-length (EPL) inhomogeneity correction. For the target volumes, PEREGRINE calculations predict, on average, a less than 2% difference in the calculated mean and maximum doses to the gross tumour volume (GTV) and clinical target volume (CTV). An average 16% ± 4% and 12% ± 2% reduction in the volume covered by the prescription isodose line was observed for the GTV and CTV, respectively. Overall, no significant differences were noted in the doses to the mandible and spinal cord. For the parotid glands, PEREGRINE predicted a 6% ± 1% increase in the volume of tissue receiving a dose greater than 25 Gy and an increase of 4% ± 1% in the mean dose. Similar results were noted for the brainstem where PEREGRINE predicted a 6% ± 2% increase in the mean dose. The observed differences between the PEREGRINE and CORVUS calculated dose distributions are attributed to secondary electron fluence perturbations, which are not modelled by the EPL correction, issues of organ outlining, particularly in the vicinity of air cavities, and differences in dose reporting (dose to water versus dose to tissue type).

Antipsychotic medication and length of stay at a psychiatric maximum-security unit in Norway (1987-2000).

PubMed

Renkel, Sabine; Rasmussen, Kirsten

2006-01-01

The aim of this study was to evaluate psychopharmacological treatment and the length of stay (LOS) of patients with schizophrenia in a maximum-security psychiatric unit. Data were collected from the hospital files of 82 consecutively admitted patients with schizophrenia who were both admitted and discharged between the years 1987 and 2000. Psychotropic medication and LOS at the time of discharge were registered. Ninety-five per cent of the patients received antipsychotic medication. Zuclopenthixol was the most frequent medication, given to 43% of the patients. Antipsychotic polypharmacy was found in 20% of the cases. Twenty-seven per cent of the patients were medicated with doses above the recommended therapeutic dose range. During the study period, there was no change in the administration and number of psychotropics, but there was an increase in the dosage of antipsychotics. However, LOS was unchanged during the same time. This supports other findings, which suggest that there is no clinical benefit of higher antipsychotic dosage. It is suggested that an optimized medication practice could yield beneficiary effects, not only for schizophrenic symptoms, but also for violence in schizophrenic patients.

Harmful excipients in medicines for neonates in Spain.

PubMed

Garcia-Palop, Beatriz; Movilla Polanco, Emma; Cañete Ramirez, Carmen; Cabañas Poy, Maria Jose

2016-04-01

Neonates may respond differently from adults to drug components. Hence, ingredients that seem safe in adults may not be safe in this age group. To describe the content of harmful excipients in drugs used in our neonatal wards and compare the daily dose a neonate may receive with the accepted daily intake (ADI) in adults. All drugs included in the hospital's neonatal treatment guide were reviewed, using information from the package inserts or the summary of product characteristics. Those containing at least one harmful excipient (e.g., metabisulfite, sorbitol) were analyzed. Minimum and maximum usual daily drug doses were determined, and excipient exposure was estimated by extrapolation of the minimum and maximum of excipient referred to the active ingredient. These amounts were compared with ADIs for each excipient in adults. In total, 32 % of intravenous and 62 % of oral formulations used in neonates contained at least one harmful excipient. On quantitative analysis, 25 % of intravenous and 19 % of oral drugs contained harmful excipients exceeding the ADI in adults. Several drugs commonly used to treat neonates contain harmful excipients in amounts that may exceed the ADI in adults. Clinicians should be aware of this to prescribe appropriate treatment in this population.

Prospective multicenter observational study of 260 infants born to 259 opiate-dependent mothers on methadone or high-dose buprenophine substitution.

PubMed

Lejeune, Claude; Simmat-Durand, Laurence; Gourarier, Laurent; Aubisson, Sandrine

2006-05-20

Specialized prenatal care and substitution programs improve the perinatal prognoses of pregnant drug-abusers and their infants. Although methadone is well documented, little is known about high-dose buprenorphine (HDB). This prospective, multicenter (n = 35) observational study included 259 women on maintenance during pregnancy: 39% on methadone and 61% on HDB. Major findings were: 46% of them received good prenatal care; 62% had peridural analgesia; 12.3% delivered prematurely (<37 weeks); mean gestational age, 38.6 weeks; mean birth weight, 2822g. Three-quarters of the newborns developed neonatal abstinence syndrome (NAS) beginning at a mean age of 40h, with the mean maximum Lipsitz score of 9.1 at 72 h; half of them were treated, mainly with morphine hydrochloride. No baby died. Newborns were discharged with their mothers (96%) or placed in foster care (4%). Comparing methadone with HDB, respectively, mean age at the maximum Lipsitz score was 81 h versus 66 h (P = 0.066). The perinatal medical and social prognoses for these 259 drug addicts and their infants appeared to be improved by specialized prenatal care and was similar for methadone or BHD substitution during pregnancy.

External effective radiation dose to workers in the restricted area of the Fukushima Daiichi Nuclear Power Plant during the third year after the Great East Japan Earthquake

PubMed Central

Sakumi, Akira; Miyagawa, Ryu; Tamari, Yuki; Nawa, Kanabu; Sakura, Osamu; Nakagawa, Keiichi

2016-01-01

Since the Great East Japan Earthquake on 11 March 2011, Iitate Village has continued to be classified as a deliberate evacuation area, in which residents are estimated to receive an annual additional effective radiation dose of >20 mSv. Some companies still operate in Iitate Village, with a special permit from the Cabinet Office Team in Charge of Assisting the Lives of Disaster Victims. In this study, we measured the annual effective radiation dose to workers in Iitate Village from 15 January to 13 December 2013. The workers stayed in Iitate for 10 h and left the village for the remaining 14 h each working day. They worked for 5 days each week in Iitate Village, but stayed outside of the village for the remaining 2 days each week. We found that the effective radiation dose of 70% of the workers was <2 mSv, including natural radiation; the maximum dose was 3.6 mSv. We estimated the potential annual additional effective radiation dose if people returned full-time to Iitate. Our analysis supports the plan for people to return to their home village at the end of 2017. PMID:26661855

Non-linear relationship of cell hit and transformation probabilities in a low dose of inhaled radon progenies.

PubMed

Balásházy, Imre; Farkas, Arpád; Madas, Balázs Gergely; Hofmann, Werner

2009-06-01

Cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive bronchial epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or support of the linear-non-threshold (LNT) hypothesis. In this study, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors at bronchial airway bifurcations, expressed as the ratio of local to average deposition densities, were determined to characterise the inhomogeneity of deposition and to elucidate their effect on resulting hit probabilities. The results obtained suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high, even at low average doses. Assuming a uniform distribution of activity there are practically no multiple hits and the hit probability as a function of dose exhibits a linear shape in the low dose range. The results are quite the opposite in the case of hot spots revealed by realistic deposition calculations, where practically all cells receive multiple hits and the hit probability as a function of dose is non-linear in the average dose range of 10-100 mGy.

Comparison of carprofen and tramadol for postoperative analgesia in dogs undergoing enucleation.

PubMed

Delgado, Cherlene; Bentley, Ellison; Hetzel, Scott; Smith, Lesley J

2014-12-15

To compare analgesia provided by carprofen and tramadol in dogs after enucleation. Randomized, masked clinical trial. 43 dogs. Client-owned dogs admitted for routine enucleation were randomly assigned to receive either carprofen or tramadol orally 2 hours prior to surgery and 12 hours after the first dose. Dogs were scored for signs of pain at baseline (ie, before carprofen or tramadol administration) and at 0.25, 0.5, 1, 2, 4, 6, 8, 24, and 30 hours after extubation. Dogs received identical premedication and inhalation anesthesia regimens, including premedication with hydromorphone. If the total pain score was ≥ 9 (maximum possible score of 20), there was a score ≥ 3 in any of 5 behavioral categories (highest score possible per category was 3 or 4), or the visual analog scale (VAS) score was ≥ 35 (maximum possible score of 100) combined with a palpation score > 0, rescue analgesia (hydromorphone) was administered and treatment failure was recorded. No differences were found in age, sex, or baseline pain scores between groups. Significantly more dogs receiving tramadol required rescue analgesia (6/21), compared with dogs receiving carprofen (1/22). Pain and VAS scores decreased linearly over time. No significant differences were found in pain or VAS scores between groups at any time point (dogs were excluded from analysis after rescue). Results of this study suggested that carprofen, with opioid premedication, may provide more effective postoperative analgesia than tramadol in dogs undergoing enucleation.

Potential for reduced radiation‐induced toxicity using intensity‐modulated arc therapy for whole‐brain radiotherapy with hippocampal sparing

PubMed Central

Sood, Sumit; Lominska, Christopher; Kumar, Parvesh; Badkul, Rajeev; Jiang, Hongyu; Wang, Fen

2015-01-01

The purpose of this study was to retrospectively investigate the accuracy, plan quality, and efficiency of using intensity‐modulated arc therapy (IMAT) for whole brain radiotherapy (WBRT) patients with sparing not only the hippocampus (following RTOG 0933 compliance criteria) but also other organs at risk (OARs). A total of 10 patients previously treated with nonconformal opposed laterals whole‐brain radiotherapy (NC‐WBRT) were retrospectively replanned for hippocampal sparing using IMAT treatment planning. The hippocampus was volumetrically contoured on fused diagnostic T1‐weighted MRI with planning CT images and hippocampus avoidance zone (HAZ) was generated using a 5 mm uniform margin around the hippocampus. Both hippocampi were defined as one paired organ. Whole brain tissue minus HAZ was defined as the whole‐brain planning target volume (WB‐PTV). Highly conformal IMAT plans were generated in the Eclipse treatment planning system for Novalis TX linear accelerator consisting of high‐definition multileaf collimators (HD‐MLCs: 2.5 mm leaf width at isocenter) and 6 MV beam for a prescription dose of 30 Gy in 10 fractions following RTOG 0933 dosimetric criteria. Two full coplanar arcs with orbits avoidance sectors were used. In addition to RTOG criteria, doses to other organs at risk (OARs), such as parotid glands, cochlea, external/middle ear canals, skin, scalp, optic pathways, brainstem, and eyes/lens, were also evaluated. Subsequently, dose delivery efficiency and accuracy of each IMAT plan was assessed by delivering quality assurance (QA) plans with a MapCHECK device, recording actual beam‐on time and measuring planed vs. measured dose agreement using a gamma index. On IMAT plans, following RTOG 0933 dosimetric criteria, the maximum dose to WB‐PTV, mean WB‐PTV D2%, and mean WB‐PTV D98% were 34.9±0.3 Gy,33.2±0.4 Gy, and 26.0±0.4 Gy, respectively. Accordingly, WB‐PTV received the prescription dose of 30 Gy and mean V30 was 90.5%±0.5%. The D100%, and mean and maximum doses to hippocampus were 8.4±0.3 Gy,11.2±0.3 Gy, and 15.6±0.4 Gy, on average, respectively. The mean values of homogeneity index (HI) and conformity index (CI) were 0.23×0.02 and 0.96×0.02, respectively. The maximum point dose to WB‐PTV was 35.3 Gy, well below the optic pathway tolerance of 37.5 Gy. In addition, compared to NC‐WBRT, dose reduction of mean and maximum of parotid glands from IMAT were 65% and 50%, respectively. Ear canals mean and maximum doses were reduced by 26% and 12%, and mean and maximum scalp doses were reduced by 9 Gy (32%) and 2 Gy (6%), on average, respectively. The mean dose to skin was 9.7 Gy with IMAT plans compared to 16 Gy with conventional NC‐WBRT, demonstrating that absolute reduction of skin dose by a factor of 2. The mean values of the total number of monitor units (MUs) and actual beam on time were 719×44 and 2.34×0.14 min, respectively. The accuracy of IMAT QA plan delivery was (98.1±0.8) %, on average, with a 3%/3 mm gamma index passing rate criteria. All of these plans were considered clinically acceptable per RTOG 0933 criteria. IMAT planning provided highly conformal and homogenous plan with a fast and effective treatment option for WBRT patients, sparing not only hippocampi but also other OARs, which could potentially result in an additional improvement of the quality life (QoL). In the future, we plan to evaluate the clinical potential of IMAT planning and treatment option with hippocampal and other OARs avoidance in our patient's cohort and asses the QoL of the WBRT patients, as well as simultaneous integrated boost (SIB) for the brain metastases diseases. PACS number: 87 PMID:26699321

Effects of urine alkalization and activated charcoal on the pharmacokinetics of orally administered carprofen in dogs.

PubMed

Raekallio, Marja R; Honkavaara, Juhana M; Säkkinen, Mia S; Peltoniemi, S Marikki

2007-04-01

To investigate the effects of oral administration of activated charcoal (AC) and urine alkalinization via oral administration of sodium bicarbonate on the pharmacokinetics of orally administered carprofen in dogs. 6 neutered male Beagles. Each dog underwent 3 experiments (6-week interval between experiments). The dogs received a single dose of carprofen (16 mg/kg) orally at the beginning of each experiment; after 30 minutes, sodium bicarbonate (40 mg/kg, PO), AC solution (2.5 g/kg, PO), or no other treatments were administered. Plasma concentrations of unchanged carprofen were determined via high-performance liquid chromatography at intervals until 48 hours after carprofen administration. Data were analyzed by use of a Student paired t test or Wilcoxon matched-pairs rank test. Compared with the control treatment, administration of AC decreased plasma carprofen concentrations (mean +/- SD maximum concentration was 85.9 +/- 11.9 mg/L and 58.1 +/- 17.6 mg/L, and area under the time-concentration curve was 960 +/- 233 mg/L x h and 373 +/- 133 mg/L x h after control and AC treatment, respectively). The elimination half-life remained constant. Administration of sodium bicarbonate had no effect on plasma drug concentrations. After oral administration of carprofen in dogs, administration of AC effectively decreased maximum plasma carprofen concentration, compared with the control treatment, probably by decreasing carprofen absorption. Results suggest that AC can be used to reduce systemic carprofen absorption in dogs receiving an overdose of carprofen. Oral administration of 1 dose of sodium bicarbonate had no apparent impact on carprofen kinetics in dogs.

SU-E-T-393: Evaluation of Large Field IMRT Versus RapidArc Planning for Carcinoma Cervix with Para-Aotic Node Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raman, S Kothanda; Girigesh, Y; MISHRA, M

Purpose: The objective of this work is to evaluate and compare Large field IMRT and RapidArc planning for Carcinoma Cervix and Para-aotic node irradiation. Methods: In this study, ten patients of Cervix with para-aotic node have been selected with PTV length 35+2cm. All plans were generated in Eclipse TPS V10.0 with Dynamic IMRT and RapidArc technique using 6MV photon energy. In IMRT planning, 7 fields were chosen to get optimal plan and in RapidArc, double Full arc clockwise and counter clockwise were used for planning. All the plans were generated with single isocenter and calculated using AAA dose algorithm. Formore » all the cases the prescribed dose to PTV was same and the plan acceptance criteria is; 95% of the PTV volume should receive 100% prescribed dose. The tolerance doses for the OAR’s is also taken in to account. The evaluation criteria used for analysis are; 1) Homogeneity Index, 2) Conformity Index, 3) Mean Dose to OAR’s, 4)Total monitor units delivered. Results: DVH analysis were performed for both IMRT and RapidArc planning. In both the plans, 95% of PTV volume receives prescribed dose and maximum dose are less than 107%. The conformity index are same in both the techniques. The mean Homogeneity index are 1.036 and 1.053 for IMRT and RapidArc plan. The mean (mean + SD) dose of bladder and rectum in IMRT is 44.2+1.55, 42.05+2.52 and RapidArc is 46.66+1.6, 44.2+2.75 respectively. There is no significant difference found in Right Femoral head, Left Femoral head and Kidney doses. It is found that total MU’s are more in IMRT compared with RapidArc planning. Conclusion: In the case of cervix with Para-arotic node single isocenter irradiation, IMRT planning in large-field is better compared to RapidArc planning in terms of Homogeneity Index and mean dose of Bladder and Rectum.« less

Dose-Finding and Pharmacokinetic Study to Optimize the Dosing of Irinotecan According to the UGT1A1 Genotype of Patients With Cancer

PubMed Central

Innocenti, Federico; Schilsky, Richard L.; Ramírez, Jacqueline; Janisch, Linda; Undevia, Samir; House, Larry K.; Das, Soma; Wu, Kehua; Turcich, Michelle; Marsh, Robert; Karrison, Theodore; Maitland, Michael L.; Salgia, Ravi; Ratain, Mark J.

2014-01-01

Purpose The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes. Patients and Methods Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1. Results In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r2 = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r2 = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response. Conclusion The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan. PMID:24958824

Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial.

PubMed

Socinski, Mark A; Morris, David E; Halle, Jan S; Moore, Dominic T; Hensing, Thomas A; Limentani, Steven A; Fraser, Robert; Tynan, Maureen; Mears, Andrea; Rivera, M Patricia; Detterbeck, Frank C; Rosenman, Julian G

2004-11-01

Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non-small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival. Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m(2), and paclitaxel 175 mg/m(2) days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTV(I)) and boost clinical target volume (CTV(B)), respectively. The CTV(I) received 40 to 50 Gy; the CTV(B) received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose. Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% > or = 5% weight loss). Induction CIP was well tolerated (with filgrastim support) and active (partial response rate, 46.2%; stable disease, 53.8%; and early progression, 0%). The TCRT dose was escalated from 78 to 90 Gy without dose-limiting toxicity. The primary acute toxicity was esophagitis (16%, all grade 3). Late toxicity consisted of grade 2 esophageal stricture (n = 3), bronchial stenosis (n = 2), and fatal hemoptysis (n = 2). The overall response rate was 60%, with a median survival time and 1-year survival probability of 24 months and 0.73 (95% CI, 0.55 to 0.89), respectively. CONCLUSION Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.

FDA-sunlamp recommended Maximum Timer Interval And Exposure Schedule: consensus ISO/CIE dose equivalence.

PubMed

Dowdy, John C; Czako, Eugene A; Stepp, Michael E; Schlitt, Steven C; Bender, Gregory R; Khan, Lateef U; Shinneman, Kenneth D; Karos, Manuel G; Shepherd, James G; Sayre, Robert M

2011-09-01

The authors compared calculations of sunlamp maximum exposure times following current USFDA Guidance Policy on the Maximum Timer Interval and Exposure Schedule, with USFDA/CDRH proposals revising these to equivalent erythemal exposures of ISO/CIE Standard Erythema Dose (SED). In 2003, [USFDA/CDRH proposed replacing their unique CDRH/Lytle] erythema action spectrum with the ISO/CIE erythema action spectrum and revising the sunlamp maximum exposure timer to 600 J m(-2) ISO/CIE effective dose, presented as being biologically equivalent. Preliminary analysis failed to confirm said equivalence, indicating instead ∼38% increased exposure when applying these proposed revisions. To confirm and refine this finding, a collaboration of tanning bed and UV lamp manufacturers compiled 89 UV spectra representing a broad sampling of U.S. indoor tanning equipment. USFDA maximum recommended exposure time (Te) per current sunlamp guidance and CIE erythemal effectiveness per ISO/CIE standard were calculated. The CIE effective dose delivered per Te averaged 456 J(CIE) m(-2) (SD = 0.17) or ∼4.5 SED. The authors found that CDRH's proposed 600 J(CIE) m(-2) recommended maximum sunlamp exposure exceeds current Te erythemal dose by ∼33%. The current USFDA 0.75 MED initial exposure was ∼0.9 SED, consistent with 1.0 SED initial dose in existing international sunlamp standards. As no sunlamps analyzed exceeded 5 SED, a revised maximum exposure of 500 J(CIE) m(-2) (∼80% of CDRH's proposal) should be compatible with existing tanning equipment. A tanning acclimatization schedule is proposed beginning at 1 SED thrice-weekly, increasing uniformly stepwise over 4 wk to a 5 SED maximum exposure in conjunction with a tan maintenance schedule of twice-weekly 5 SED sessions, as biologically equivalent to current USFDA sunlamp policy.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eley, J; Mehta, M; Molitoris, J

Purpose: The purpose of this study was to propose a method to implement arc therapy that is compatible with existing particle therapy systems having gantries and pencil-beam scanning capacities. Furthermore, we sought to demonstrate expected benefits of this method for selected clival chordoma patients. Methods: We propose that a desired particle arc treatment plan can be discretized into a finite number of fixed beams and that only one (or a subset) of these beams be delivered in any single treatment fraction; the target should receive uniform dose during each fraction. For 3 clival-chordoma patients, robust-optimized, scanned proton beams were simulatedmore » to deliver 78 Gy (RBE) to clinical target volumes (CTVs), using either a single-field plan with a posterior-anterior (PA) beam or a discrete-arc plan with 16 beams that were equally spaced throughout a 360-degree axial arc. Dose-volume metrics were compared with emphasis on the brainstem, since risk of radiation necrosis there can often restrict application of tumoricidal doses for chordomas. Results: The mean volume of brainstem receiving a dose of 60 Gy (RBE) or higher (V60Gy) was 10.3±0.9 cm{sup 3} for the single-field plan and 4.7±1.8 cm{sup 3} for the discrete-arc plan, a reduction of 55% in favor of arcs. The mean dose to the brainstem was also reduced using arcs, by 18%, while the maximum dose was nearly identical for both methods. For the whole brain, V60Gy was reduced by 23%, in favor of arcs. Mean dose to the CTVs were nearly identical for both strategies, within 0.3%. Conclusion: Discrete arc treatments can be implemented using existing scanned particle-beam facilities. Aside from the physical advantages, the biological uncertainties of particle therapy, particularly high in the distal edge, can be reduced by arc therapy via rotational smearing, which may be of benefit for tumors near the brainstem.« less

Evaluation of Radiation Exposure to Staff and Environment Dose from [18F]-FDG in PET/CT and Cyclotron Center using Thermoluminescent Dosimetry

PubMed Central

Zargan, S.; Ghafarian, P.; Shabestani Monfared, A.; Sharafi, A.A.; Bakhshayeshkaram, M.; Ay, M.R.

2017-01-01

Background: PET/CT imaging using [18F]-FDG is utilized in clinical oncology for tumor detecting, staging and responding to therapy procedures. Essential consideration must be taken for radiation staff due to high gamma radiation in PET/CT and cyclotron center. The aim of this study was to assess the staff exposure regarding whole body and organ dose and to evaluate environment dose in PET/CT and cyclotron center. Materials and Methods: 80 patients participated in this study. Thermoluminescence, electronic personal dosimeter and Geiger-Muller dosimeter were also utilized for measurement purpose. Results: The mean annual equivalent organ dose for scanning operator with regard to lens of eyes, thyroid, breast and finger according to mean±SD value, were 0.262±0.044, 0.256±0.046, 0.257±0.040 and 0.316±0.118, respectively. The maximum and minimum estimated annual whole body doses were observed for injector and the chemist group with values of (3.98±0.021) mSv/yr and (1.64±0.014) mSv/yr, respectively. The observed dose rates were 5.67 µSv/h in uptake room at the distance of 0.5 meter from the patient whereas the value 4.94 and 3.08 µSv/h were recorded close to patient’s head in PET/CT room and 3.5 meter from the reception desk. Conclusion: In this study, the injector staff and scanning operator received the first high level and second high level of radiation. This study confirmed that low levels of radiation dose were received by all radiation staff during PET/CT procedure using 18F-FDG due to efficient shielding and using trained radiation staff in PET/CT and cyclotron center of Masih Daneshvari hospital. PMID:28451574

The maximum single dose of resistant maltodextrin that does not cause diarrhea in humans.

PubMed

Kishimoto, Yuka; Kanahori, Sumiko; Sakano, Katsuhisa; Ebihara, Shukuko

2013-01-01

The objective of the present study was to determine the maximum dose of resistant maltodextrin (Fibersol)-2, a non-viscous water-soluble dietary fiber), that does not induce transitory diarrhea. Ten healthy adult subjects (5 men and 5 women) ingested Fibersol-2 at increasing dose levels of 0.7, 0.8, 0.9, 1.0, and 1.1 g/kg body weight (bw). Each administration was separated from the previous dose by an interval of 1 wk. The highest dose level that did not cause diarrhea in any subject was regarded as the maximum non-effective level for a single dose. The results showed that no subject of either sex experienced diarrhea at dose levels of 0.7, 0.8, 0.9, or 1.0 g/kg bw. At the highest dose level of 1.1 g/kg bw, no female subject experienced diarrhea, whereas 1 male subject developed diarrhea with muddy stools 2 h after ingestion of the test substance. Consequently, the maximum non-effective level for a single dose of the resistant maltodextrin Fibersol-2 is 1.0 g/kg bw for men and >1.1 g/kg bw for women. Gastrointestinal symptoms were gurgling sounds in 4 subjects (7 events) and flatus in 5 subjects (9 events), although no association with dose level was observed. These symptoms were mild and transient and resolved without treatment.

1990 Environmental Monitoring Report, Sandia National Laboratories, Albuquerque, New Mexico

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, S.; Yeager, G.; Wolff, T.

1991-05-01

This 1990 report contains monitoring data from routine radiological and nonradiological environmental surveillance activities. Summaries of significant environmental compliance programs in progress such as National Environmental Policy Act (NEPA) documentation, environmental permits, environmental restoration, and various waste management programs for Sandia National Laboratories in Albuquerque (SNL, Albuquerque) are included. The maximum offsite dose impact was calculated to be 2.0 {times} 10{sup {minus}3} mrem. The total 50-mile population received a collective dose of 0.82 person-rem during 1990 from SNL, Albuquerque, operations. As in the previous year, the 1990 SNL operations had no adverse impact on the general public or on themore » environment. This report is prepared for the US Department of Energy in compliance with DOE Order 5400.1. 97 refs., 30 figs., 137 tabs.« less

Randomized Crossover Comparison of the Short-Term Efficacy and Safety of Single Half-Dose Silodosin and Tamsulosin Hydrochoride in Men With Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.

PubMed

Takeshita, Hideki; Moriyama, Shingo; Arai, Yoshiaki; Washino, Satoshi; Saito, Kimitoshi; Chiba, Koji; Horiuchi, Susumu; Noro, Akira

2016-01-01

To compare the efficacy and safety of single half-dose silodosin and single full-dose tamsulosin in Japanese men with lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). Japanese men aged ≥50 years with LUTS/BPH and an International Prostate Symptom Score (IPSS) of ≥8 were enrolled in the randomized crossover study and divided into silodosin-preceding (S-T) and tamsulosin-preceding (T-S) groups. The S-T group received 4 mg silodosin once daily for 4 weeks followed by 0.2 mg tamsulosin once daily for 4 weeks. The T-S group received the reverse treatment sequence. A washout period prior to drug crossover was not included. Subjective and objective efficacy parameters including IPSS, quality of life (QOL) index, uroflowmetry, and safety were compared between the two groups. Thirty of 34 men (S-T group n = 16; T-S group n = 14) completed the study. Both drugs significantly improved all IPSS items and QOL index in the first treatment period. Subjective improvement in nocturia by silodosin was observed in both the first and crossover treatment periods. Objective improvement in maximum flow rate by silodosin was only observed in the first treatment period. Adverse events occurred more frequently with silodosin than with tamsulosin; however, none of the adverse events required treatment discontinuation. Ejaculation disorders occurred in three participants (10%) and were associated with silodosin use. Single half-dose silodosin has a similar efficacy to full-dose tamsulosin in Japanese men with LUTS/BPH and thus, may represent an effective, safe, and affordable treatment option. © 2015 Wiley Publishing Asia Pty Ltd.

A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer.

PubMed

Cohen, Steven J; Zalupski, Mark M; Modiano, Manuel R; Conkling, Paul; Patt, Yehuda Z; Davis, Peg; Dorr, Robert T; Boytim, Michelle L; Hersh, Evan M

2010-07-01

Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m(2) intravenously (IV) over 30 min days 1-5, 15-19 and gemcitabine 800 or 1,000 mg/m(2) IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m(2) IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m(2) IV over 30 min on days 1, 8, and 15 every 28 days). One hundred five patients received 340 treatment cycles (median 2, range 1-16). median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. The recommended phase II dose of imexon is 875 mg/m(2) with gemcitabine 1,000 mg/m(2). DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.

Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

PubMed Central

Richardson, Paul G.; Weller, Edie; Jagannath, Sundar; Avigan, David E.; Alsina, Melissa; Schlossman, Robert L.; Mazumder, Amitabha; Munshi, Nikhil C.; Ghobrial, Irene M.; Doss, Deborah; Warren, Diane L.; Lunde, Laura E.; McKenney, Mary; Delaney, Carol; Mitsiades, Constantine S.; Hideshima, Teru; Dalton, William; Knight, Robert; Esseltine, Dixie-Lee; Anderson, Kenneth C.

2009-01-01

Purpose Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM. Patients and Methods Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination. Results Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months. Conclusion Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM. PMID:19786667

Identifying risk factors for L'Hermitte's sign after IMRT for head and neck cancer.

PubMed

Laidley, Hannah M; Noble, David J; Barnett, Gill C; Forman, Julia R; Bates, Amy M; Benson, Richard J; Jefferies, Sarah J; Jena, Rajesh; Burnet, Neil G

2018-05-04

L'Hermitte's sign (LS) after chemoradiotherapy for head and neck cancer appears related to higher spinal cord doses. IMRT plans limit spinal cord dose, but the incidence of LS remains high. One hundred seventeen patients treated with TomoTherapy™ between 2008 and 2015 prospectively completed a side-effect questionnaire (VoxTox Trial Registration: UK CRN ID 13716). Baseline patient and treatment data were collected. Radiotherapy plans were analysed; mean and maximum spinal cord dose and volumes receiving 10, 20, 30 and 40 Gy were recorded. Dose variation across the cord was examined. These data were included in a logistic regression model. Forty two patients (35.9%) reported LS symptoms. Concurrent weekly cisplatin did not increase LS risk (p = 0.70, OR = 1.23 {95% CI 0.51-2.34}). Of 13 diabetic participants (9 taking metformin), only 1 developed LS (p = 0.025, OR = 0.13 {95% CI 0.051-3.27}). A refined binary logistic regression model showed that patients receiving unilateral radiation (p = 0.019, OR = 2.06 {95% CI 0.15-0.84}) were more likely to develop LS. Higher V 40Gy (p = 0.047, OR = 1.06 {95% CI 1.00-1.12}), and younger age (mean age 56.6 vs 59.7, p = 0.060, OR = 0.96 {95% CI 0.92-1.00}) were associated with elevated risk of LS, with borderline significance. In this cohort, concomitant cisplatin did not increase risk, and LS incidence was lower in diabetic patients. Patient age and dose gradients across the spinal cord may be important factors.

A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer.

PubMed

Dy, Grace K; Thomas, James P; Wilding, George; Bruzek, Laura; Mandrekar, Sumithra; Erlichman, Charles; Alberti, Dona; Binger, Kim; Pitot, Henry C; Alberts, Steven R; Hanson, Lorelei J; Marnocha, Rebecca; Tutsch, Kendra; Kaufmann, Scott H; Adjei, Alex A

2005-05-01

To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.

TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study

PubMed Central

Bang, Yung-Jue; Takano, Toshimi; Lin, Chia-Chi; Fasanmade, Adedigbo; Yang, Huyuan; Danaee, Hadi; Asato, Takayuki; Kalebic, Thea; Wang, Hui; Doi, Toshihiko

2018-01-01

Purpose This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). Materials and Methods Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. Results Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. Conclusion TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose. PMID:28494535

(90)Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study.

PubMed

Chevallier, Patrice; Eugene, Thomas; Robillard, Nelly; Isnard, Françoise; Nicolini, Franck; Escoffre-Barbe, Martine; Huguet, Françoise; Hunault, Mathilde; Marcais, Antoine; Gaschet, Joelle; Cherel, Michel; Guillaume, Thierry; Delaunay, Jacques; Peterlin, Pierre; Eveillard, Marion; Thomas, Xavier; Ifrah, Norbert; Lapusan, Simona; Bodet-Milin, Caroline; Barbet, Jacques; Faivre-Chauvet, Alain; Ferrer, Ludovic; Bene, Marie C; Le Houerou, Claire; Goldenberg, David M; Wegener, William A; Kraeber-Bodéré, Françoise

2015-03-01

Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). (90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m(2) 1 week apart per cycle for phase 2 studies. Immunomedics and Direction de la Recherche Clinique of Nantes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of tetrastarch (hydroxyethyl starch 130/0.4) on plasma creatinine concentration in cats: a retrospective analysis (2010-2015).

PubMed

Yozova, Ivayla D; Howard, Judith; Adamik, Katja N

2017-10-01

Objectives The objective was to determine survival and changes in creatinine concentrations after administration of 6% tetrastarch (hydroxyethyl starch [HES] 130/0.4) vs crystalloids in critically ill cats. Methods The medical records were reviewed for cats admitted to the intensive care unit with at least two plasma creatinine measurements and initial concentrations not exceeding the upper reference interval. Cats were excluded if they had received HES prior to admission or if they had received fluid therapy for <24 h between initial and subsequent measurements. Changes in creatinine concentrations were evaluated as the percentage change from initial values to the maximum subsequent measurements. Cats receiving only crystalloids were assigned to the crystalloid group; cats receiving only HES or HES and crystalloids were assigned to the HES group. Results Ninety-three cats were included in the study (62 in the crystalloid group, 31 in the HES group). The total median cumulative HES dose was 94 ml/kg (range 26-422 ml/kg) and 24 ml/kg/day (range 16-42 ml/kg/day). No difference was detected between the groups for age, sex, body weight or mortality. The HES group had a significantly longer length of hospitalisation ( P = 0.012), lower albumin concentrations ( P <0.001), higher Acute Patient Physiologic and Laboratory Evaluation scores ( P = 0.037) and higher incidence of systemic inflammatory response syndrome ( P = 0.009) and sepsis ( P = 0.013). There was no significant difference in initial, maximum or maximum change in creatinine concentrations between the groups. Moreover, there was no significant difference in maximum change in creatinine concentrations in the subgroups of cats with systemic inflammatory response syndrome or sepsis. Conclusions and relevance In this population of cats, the administration of HES did not result in a significantly greater increase in creatinine from values measured on admission or higher mortality compared with administration of crystalloids. Further prospective studies are needed to assess both safety and efficacy of HES in cats before recommendations can be made.

[Efficacy of intravenous phenobarbital treatment for status epilepticus].

PubMed

Muramoto, Emiko; Mizobuchi, Masahiro; Sumi, Yoshihiro; Sako, Kazuya; Nihira, Atsuko; Takeuchi, Akiko; Nakamura, Hirohiko

2013-08-01

Intravenous phenobarbital (IV-PB) therapy was launched in Japan in October 2008. We retrospectively investigated its efficacy and tolerability in patients with status epilepticus. Forty-three consecutive patients received IV-PB for status epilepticus between June 2009 and April 2011. Among them, 39 patients had underlying diseases, which included acute diseases in 19 patients and chronic conditions in 20 patients. Although 18 patients had been taking antiepileptic drugs (AEDs) before the occurrence of status epilepticus, the blood AED concentrations in 8 patients was below the therapeutic levels. Before the administration of IV-PB, 39 patients were treated with intravenous benzodiazepine, 17 patients were treated with intravenous phenytoin, and 15 patients with intravenous infusion of lidocaine. The initial doses of IV-PB ranged from 125 to 1,250 mg (1.9-20.0 mg/kg). Additional doses of IV-PB were required in 12 patients. Seizures were controlled in 35 patients (81%) after IV-PB administration. Cessation of status epilepticus was attained in 24 patients after the initial dose and in 11 patients after additional doses. There were no serious adverse effects, although respiratory suppression was observed in 3 patients and drug eruption was observed in 1 patient. IV-PB is relatively safe and effective for controlling status epilepticus. If the first dose is not effective, additional doses are required up to the recommended maximum dose.

Surface dose measurements for highly oblique electron beams.

PubMed

Ostwald, P M; Kron, T

1996-08-01

Clinical applications of electrons may involve oblique incidence of beams, and although dose variations for angles up to 60 degrees from normal incidence are well documented, no results are available for highly oblique beams. Surface dose measurements in highly oblique beams were made using parallel-plate ion chambers and both standard LiF:Mg, Ti and carbon-loaded LiF Thermoluminescent Dosimeters (TLD). Obliquity factors (OBF) or surface dose at an oblique angle divided by the surface dose at perpendicular incidence, were obtained for electron energies between 4 and 20 MeV. Measurements were performed on a flat solid water phantom without a collimator at 100 cm SSD. Comparisons were also made to collimated beams. The OBFs of surface doses plotted against the angle of incidence increased to a maximum dose followed by a rapid dropoff in dose. The increase in OBF was more rapid for higher energies. The maximum OBF occurred at larger angles for higher-energy beams and ranged from 73 degrees for 4 MeV to 84 degrees for 20 MeV. At the dose maximum, OBFs were between 130% and 160% of direct beam doses, yielding surface doses of up to 150% of Dmax for the 20 MeV beam. At 2 mm depth the dose ratio was found to increase initially with angle and then decrease as Dmax moved closer to the surface. A higher maximum dose was measured at 2 mm depth than at the surface. A comparison of ion chamber types showed that a chamber with a small electrode spacing and large guard ring is required for oblique dose measurement. A semiempirical equation was used to model the dose increase at the surface with different energy electron beams.

Phase 1 first-in-human studies of the reactogenicity and immunogenicity of a recombinant meningococcal NspA vaccine in healthy adults.

PubMed

Halperin, Scott A; Langley, Joanne M; Smith, Bruce; Wunderli, Peter; Kaufman, Lisa; Kimura, Alan; Martin, Denis

2007-01-05

Neisserial surface protein A (NspA) is a highly conserved, surface-exposed outer membrane protein of Neisseria meningitidis that has been shown to induce a bactericidal immune response in animals against all pathogenic Neisserial serogroups. Healthy 18-50-year-old adults were assigned to receive, in a dose escalating manner, 3 doses of 1 of 5 formulations of an experimental, unfolded, recombinant NspA (rNspA) vaccine or placebo, or 1 dose of commercially available quadravalent (A, C, Y, W-135) meningococcal polysaccharide vaccine (Menomune((R))). Adverse events were collected during the first week post-immunization, prior to the next dose and 1 month after the last dose. Serum for measurement of hematological and biochemical parameters and antibodies by enzyme immunoassay and bactericidal assay were measured before the first dose, prior to the second dose and 1 month after the last dose of vaccine. The rNspA vaccine was well tolerated by recipients. Injection-site pain was reported more frequently by recipients of the three highest doses of rNspA compared to placebo but at similar rates to the licensed meningococcal polysaccharide vaccine. Adverse events were reported less frequently after subsequent doses in the three-dose series. An antibody rise measured by enzyme immunoassay was elicited with a dose-related increase that reached a maximum with the 125mug dose. Prolongation of the dosing interval between the second and third dose appeared to be associated with increased antibody levels. No bactericidal antibodies were detected after any of the rNspA formulations. The unfolded rNspA meningococcal vaccine was well tolerated and immunogenic in healthy adult volunteers but did not elicit bactericidal antibodies.

Uncertainties in estimating heart doses from 2D-tangential breast cancer radiotherapy.

PubMed

Lorenzen, Ebbe L; Brink, Carsten; Taylor, Carolyn W; Darby, Sarah C; Ewertz, Marianne

2016-04-01

We evaluated the accuracy of three methods of estimating radiation dose to the heart from two-dimensional tangential radiotherapy for breast cancer, as used in Denmark during 1982-2002. Three tangential radiotherapy regimens were reconstructed using CT-based planning scans for 40 patients with left-sided and 10 with right-sided breast cancer. Setup errors and organ motion were simulated using estimated uncertainties. For left-sided patients, mean heart dose was related to maximum heart distance in the medial field. For left-sided breast cancer, mean heart dose estimated from individual CT-scans varied from <1Gy to >8Gy, and maximum dose from 5 to 50Gy for all three regimens, so that estimates based only on regimen had substantial uncertainty. When maximum heart distance was taken into account, the uncertainty was reduced and was comparable to the uncertainty of estimates based on individual CT-scans. For right-sided breast cancer patients, mean heart dose based on individual CT-scans was always <1Gy and maximum dose always <5Gy for all three regimens. The use of stored individual simulator films provides a method for estimating heart doses in left-tangential radiotherapy for breast cancer that is almost as accurate as estimates based on individual CT-scans. Copyright © 2016. Published by Elsevier Ireland Ltd.

Beta-cell response during a meal test: a comparative study of incremental doses of repaglinide in type 2 diabetic patients.

PubMed

Cozma, Lawrence S; Luzio, Stephen D; Dunseath, Gareth J; Underwood, Paul M; Owens, David R

2005-05-01

To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal. Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA(1c) 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart. The insulinogenic index (DeltaI30/DeltaG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC(0-30)) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) < 9-mmol/l subgroup of subjects and not in the FPG >9-mmol/l subgroup. There was a significant dose-related increase in the late postprandial insulin secretion (insulin AUC(120-240)), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses. Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses.

HADOC: a computer code for calculation of external and inhalation doses from acute radionuclide releases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strenge, D.L.; Peloquin, R.A.

The computer code HADOC (Hanford Acute Dose Calculations) is described and instructions for its use are presented. The code calculates external dose from air submersion and inhalation doses following acute radionuclide releases. Atmospheric dispersion is calculated using the Hanford model with options to determine maximum conditions. Building wake effects and terrain variation may also be considered. Doses are calculated using dose conversion factor supplied in a data library. Doses are reported for one and fifty year dose commitment periods for the maximum individual and the regional population (within 50 miles). The fractional contribution to dose by radionuclide and exposure modemore » are also printed if requested.« less

Estimation of the total effective dose from low-dose CT scans and radiopharmaceutical administrations delivered to patients undergoing SPECT/CT explorations.

PubMed

Montes, Carlos; Tamayo, Pilar; Hernandez, Jorge; Gomez-Caminero, Felipe; García, Sofia; Martín, Carlos; Rosero, Angela

2013-08-01

Hybrid imaging, such as SPECT/CT, is used in routine clinical practice, allowing coregistered images of the functional and structural information provided by the two imaging modalities. However, this multimodality imaging may mean that patients are exposed to a higher radiation dose than those receiving SPECT alone. The study aimed to determine the radiation exposure of patients who had undergone SPECT/CT examinations and to relate this to the Background Equivalent Radiation Time (BERT). 145 SPECT/CT studies were used to estimate the total effective dose to patients due to both radiopharmaceutical administrations and low-dose CT scans. The CT contribution was estimated by the Dose-Length Product method. Specific conversion coefficients were calculated for SPECT explorations. The radiation dose from low-dose CTs ranged between 0.6 mSv for head and neck CT and 2.6 mSv for whole body CT scan, representing a maximum of 1 year of background radiation exposure. These values represent a decrease of 80-85% with respect to the radiation dose from diagnostic CT. The radiation exposure from radiopharmaceutical administration varied from 2.1 mSv for stress myocardial perfusion SPECT to 26 mSv for gallium SPECT in patients with lymphoma. The BERT ranged from 1 to 11 years. The contribution of low-dose CT scans to the total radiation dose to patients undergoing SPECT/CT examinations is relatively low compared with the effective dose from radiopharmaceutical administration. When a CT scan is only acquired for anatomical localization and attenuation correction, low-dose CT scan is justified on the basis of its lower dose.

Intubation conditions in young infants after propofol and remifentanil induction with and without low-dose rocuronium.

PubMed

Gelberg, J; Kongstad, L; Werner, O

2014-08-01

Bolus injections of intravenous propofol and remifentanil can be used in the tracheal intubation of infants and children, but relatively large doses are needed. We hypothesised that addition of a small bolus of rocuronium would ensure good intubation conditions when modest propofol and remifentanil doses were used. Seventy infants between 3 weeks and 4 months of age were randomised to receive either placebo or rocuronium. Anaesthesia was induced with IV propofol, 3 (3-5) mg/kg [median (range)]. Rocuronium (0.2 mg/kg) or placebo was then injected, followed 15 s later by 2 μg/kg remifentanil. One anaesthetist attempted tracheal intubation 1 min after the rocuronium/placebo injection and used the 'Copenhagen scoring system' to assess intubation conditions. The neuromuscular effect of 0.2 mg/kg rocuronium was recorded in another eight, already intubated, infants using thumb accelerometry during train-of-four stimulation of the ulnar nerve. Intubation conditions were classified as 'poor' in 14 of 34 (41%) patients given placebo and in 10 of 36 (28%) patients given rocuronium (P = 0.32). There were four failed first attempts at intubation in the placebo group and none in the rocuronium group (P = 0.051). Maximum neuromuscular depression occurred 4 (3-8) after injection of 0.2 mg/kg rocuronium. Intubation conditions were poor in almost one third of the patients receiving propofol-remifentanil. Adding a low-dose rocuronium did not significantly improve intubation conditions. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Air Pathway Dose Modeling for the E-Area Low-Level Waste Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dixon, K. L.; Minter, K. M.

2017-09-06

Dose-release factors (DRFs) were calculated for potential atmospheric releases of several radionuclides from the E-Area Low-Level Waste Facility (ELLWF). The ELLWF receives solid low-level radioactive waste from across the Savannah River Site (SRS) and offsite for disposal. These factors represent the maximum dose a receptor would receive if standing at either 100 m or 11,410 m (Site Boundary) from the edge of an ELLWF disposal unit which are points of assessment (POA) for Department of Energy (DOE) Order 435.1 performance assessments (PA). The DRFs were calculated for 1 Ci of the specified radionuclide being released from the ground surface tomore » the atmosphere (mrem per curie released). The calculation conservatively represented the ELLWF as a point source, and conservatively assumed the receptor was positioned at the center of the contaminant plume and continuously exposed for a period of one year. These DRFs can be refined to take into consideration disposal unit size, proximity and timing of peak dose to establish less conservative radionuclide specific disposal limits. DRFs were calculated for H-3 and C-14 in Revision 0 of this report. H-3 as HTO and C-14 as CO 2 were identified as volatile radionuclides of potential concern in earlier radionuclide screening studies. In Revision 1, DRFs were calculated for eight additional radionuclides identified by an updated screening analysis as potentially important volatile radionuclides. These include Ar-37, Ar-39, Ar-42, Hg-194, Hg- 203, Kr-81, Kr-85, and Xe-127.« less

Intravenous Lidocaine as an Adjuvant for Pain Associated with Sickle Cell Disease.

PubMed

Nguyen, Natalie L; Kome, Anne M; Lowe, Denise K; Coyne, Patrick; Hawks, Kelly G

2015-01-01

The objectives of this study were to evaluate the efficacy and safety of adjuvant intravenous (IV) lidocaine in adults with sickle cell disease (SCD). This was a retrospective review. Adults with SCD receiving at least one IV lidocaine infusion from 2004 to 2014 were included. Patient demographics, lidocaine treatment parameters, pain scores, pain medications, and adverse effects were recorded. Eleven patients were identified, yielding 15 IV lidocaine trials. Clinical improvement in pain scores from pre-lidocaine challenge to 24 hours post-lidocaine challenge, defined by ≥ 20% reduction in pain scores, was achieved in 53.3% (8 of 15) of IV lidocaine challenges. Of the 8 clinically successful trials, the mean reduction in morphine dose equivalents (MDE) from 24 hours pre-lidocaine challenge to 24 hours post-lidocaine challenge was 32.2%. Additionally, clinically successful trials had a mean initial and a maximum dose of 1 mg/kg/h (range: 0.5-2.7 mg/kg/h) and 1.3 mg/kg/h (range: 0.5-1.9 mg/kg/h), respectively. On average, these patients underwent 3 dose titrations (range: 1-8) and received lidocaine infusions for 4.4 days (range: 2-8 days). Two patients experienced disorientation and dizziness. The authors conclude that adjuvant IV lidocaine provided pain relief and a mean reduction in MDE during sickle cell pain crisis. These results provide preliminary insight into the use of IV lidocaine for treating pain in patients with SCD, although prospective studies are needed to determine efficacy, dosing, and tolerability of IV lidocaine in this patient population.

Exposure of infants to budesonide through breast milk of asthmatic mothers.

PubMed

Fält, Anette; Bengtsson, Thomas; Kennedy, Britt-Marie; Gyllenberg, Ann; Lindberg, Bengt; Thorsson, Lars; Stråndgarden, Kerstin

2007-10-01

Maintenance treatment with inhaled corticosteroids is often required for asthmatic nursing women. Data on the transfer of inhaled corticosteroids from plasma to breast milk and the subsequent exposure of the breast-feeding infant has been unavailable. We sought to assess budesonide concentrations in milk and plasma of asthmatic nursing women receiving maintenance treatment with the Pulmicort Turbuhaler and estimate the exposure of their breast-fed infants. Milk and plasma samples were collected up to 8 hours after dosing from 8 mothers receiving budesonide maintenance treatment (200 or 400 microg twice daily). Pharmacokinetic parameters were calculated from budesonide milk and plasma concentrations. Infant exposure was estimated based on average milk budesonide concentrations. A single blood sample was obtained from 5 infants close to expected infant maximum concentration. Budesonide concentrations in milk reflected those in maternal plasma, supporting passive diffusion of budesonide between plasma and milk, and was always lower than that in plasma. The mean milk/plasma ratio was 0.46. The estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification. Maintenance treatment with inhaled budesonide (200 or 400 microg twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants. These data support continued use of inhaled budesonide during breast-feeding.

Comparative Assessment of the Effects of Three Local Anesthetics: Lidocaine, Prilocaine, and Mepivacaine on Blood Pressure Changes in Patients with Controlled Hypertension.

PubMed

Hashemi, Seyyed Hamed Jalalian; Ladez, Shamsodin Rigi; Moghadam, Somaye Ansari

2016-10-01

Given large number of patients with hypertension attending dental clinics and the profound effects of local anesthetics containing vasoconstrictors, this study aimed to compare the effects of lidocaine 2% + epinephrine, prilocaine 3% + felypressin0.03, and mepivacaine 3% on blood pressure changes. The current study was carried out from May 2014 to February 2015.Patients with controlled hypertension (systolic blood pressure<159.94 mmHg before the injection) who attended Zahedan dental school (Zahedan , Iran) for the extraction of a mandibular tooth were selected and randomly allocated to three groups of 20. Groups 1-3 received lidocaine 2% + epinephrine, prilocaine 3% + felypressin 0.03 units, and mepivacaine3%, respectively. Patients were only included if they were injected with a maximum of two 1.8 ml cartridges (3.6 ml) for tooth extraction (maximum epinephrine dose of 0.04 mg was maintained in systemic patients).The collected data were analyzed using the analysis of variance (ANOVA) in SPSS 19.0. (SPSS Inc., Chicago, IL, USA)RESULTS: No significant differences were observed between the systolic and diastolic blood pressure of the three groups. The three evaluated local anesthetic solutions had similar effects in patients with controlled hypertension. While no significant changes in blood pressure were observed in three groups, all dental procedures on the mentioned group of patients have to be performed under careful monitoring and aspiration. Moreover, the maximum epinephrine dose (0.04mg) should never be exceeded in these patients.

Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.

PubMed

Shaw, Alice T; Felip, Enriqueta; Bauer, Todd M; Besse, Benjamin; Navarro, Alejandro; Postel-Vinay, Sophie; Gainor, Justin F; Johnson, Melissa; Dietrich, Jorg; James, Leonard P; Clancy, Jill S; Chen, Joseph; Martini, Jean-François; Abbattista, Antonello; Solomon, Benjamin J

2017-12-01

Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC. In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31-63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23-63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21-79). In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). Pfizer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effectiveness of a Third Dose of MMR Vaccine for Mumps Outbreak Control.

PubMed

Cardemil, Cristina V; Dahl, Rebecca M; James, Lisa; Wannemuehler, Kathleen; Gary, Howard E; Shah, Minesh; Marin, Mona; Riley, Jacob; Feikin, Daniel R; Patel, Manisha; Quinlisk, Patricia

2017-09-07

The effect of a third dose of the measles-mumps-rubella (MMR) vaccine in stemming a mumps outbreak is unknown. During an outbreak among vaccinated students at the University of Iowa, health officials implemented a widespread MMR vaccine campaign. We evaluated the effectiveness of a third dose for outbreak control and assessed for waning immunity. Of 20,496 university students who were enrolled during the 2015-2016 academic year, mumps was diagnosed in 259 students. We used Fisher's exact test to compare unadjusted attack rates according to dose status and years since receipt of the second MMR vaccine dose. We used multivariable time-dependent Cox regression models to evaluate vaccine effectiveness, according to dose status (three vs. two doses and two vs. no doses) after adjustment for the number of years since the second dose. Before the outbreak, 98.1% of the students had received at least two doses of MMR vaccine. During the outbreak, 4783 received a third dose. The attack rate was lower among the students who had received three doses than among those who had received two doses (6.7 vs. 14.5 cases per 1000 population, P<0.001). Students had more than nine times the risk of mumps if they had received the second MMR dose 13 years or more before the outbreak. At 28 days after vaccination, receipt of the third vaccine dose was associated with a 78.1% lower risk of mumps than receipt of a second dose (adjusted hazard ratio, 0.22; 95% confidence interval, 0.12 to 0.39). The vaccine effectiveness of two doses versus no doses was lower among students with more distant receipt of the second vaccine dose. Students who had received a third dose of MMR vaccine had a lower risk of mumps than did those who had received two doses, after adjustment for the number of years since the second dose. Students who had received a second dose of MMR vaccine 13 years or more before the outbreak had an increased risk of mumps. These findings suggest that the campaign to administer a third dose of MMR vaccine improved mumps outbreak control and that waning immunity probably contributed to propagation of the outbreak. (Funded by the Centers for Disease Control and Prevention.).

Dose calculations accounting for breathing motion in stereotactic lung radiotherapy based on 4D-CT and the internal target volume.

PubMed

Admiraal, Marjan A; Schuring, Danny; Hurkmans, Coen W

2008-01-01

The purpose of this study was to determine the 4D accumulated dose delivered to the CTV in stereotactic radiotherapy of lung tumours, for treatments planned on an average CT using an ITV derived from the Maximum Intensity Projection (MIP) CT. For 10 stage I lung cancer patients, treatment plans were generated based on 4D-CT images. From the 4D-CT scan, 10 time-sorted breathing phases were derived, along with the average CT and the MIP. The ITV with a margin of 0mm was used as a PTV to study a worst case scenario in which the differences between 3D planning and 4D dose accumulation will be largest. Dose calculations were performed on the average CT. Dose prescription was 60Gy to 95% of the PTV, and at least 54Gy should be received by 99% of the PTV. Plans were generated using the inverse planning module of the Pinnacle(3) treatment planning system. The plans consisted of nine coplanar beams with two segments each. After optimisation, the treatment plan was transferred to all breathing phases and the delivered dose per phase was calculated using an elastic body spline model available in our research version of Pinnacle (8.1r). Then, the cumulative dose to the CTV over all breathing phases was calculated and compared to the dose distribution of the original treatment plan. Although location, tumour size and breathing-induced tumour movement varied widely between patients, the PTV planning criteria could always be achieved without compromising organs at risk criteria. After 4D dose calculations, only very small differences between the initial planned PTV coverage and resulting CTV coverage were observed. For all patients, the dose delivered to 99% of the CTV exceeded 54Gy. For nine out of 10 patients also the criterion was met that the volume of the CTV receiving at least the prescribed dose was more than 95%. When the target dose is prescribed to the ITV (PTV=ITV) and dose calculations are performed on the average CT, the cumulative CTV dose compares well to the planned dose to the ITV. Thus, the concept of treatment plan optimisation and evaluation based on the average CT and the ITV is a valid approach in stereotactic lung treatment. Even with a zero ITV to PTV margin, no significantly different dose coverage of the CTV arises from the breathing motion induced dose variation over time.

MEASUREMENT OF RADIATION DOSES TO THE EYE LENS DURING ORTHOPEDIC SURGERY USING AN C-ARM X-RAY SYSTEM.

PubMed

Suzuki, Akira; Matsubara, Kosuke; Sasa, Yuko

2018-04-01

The present study aimed to determine doses delivered to the eye lenses of surgeons while using the inverted-C-arm technique and the protective effect of leaded spectacles during orthopedic surgery. The kerma in air was measured at five positions on leaded glasses positioned near the eye lens and on the neck using small optically stimulated luminescence (OSL) dosemeters. The lens equivalent dose was also measured at the neck using an OSL dosemeter. The maximum equivalent dose to the eye lens and the maximum kerma were 0.8 mSv/month and 0.66 mGy/month, respectively. The leaded glasses reduced the exposure by ~60%. Even if the surgeons are exposed to the maximum dose of X-ray radiation for 5 years, the equivalent doses to the eye lens will not exceed the present limit recommended by the ICRP.

Cancer mortality following radium treatment for uterine bleeding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inskip, P.D.; Monson, R.R.; Wagoner, J.K.

1990-09-01

Cancer mortality in relation to radiation dose was evaluated among 4153 women treated with intrauterine radium (226Ra) capsules for benign gynecologic bleeding disorders between 1925 and 1965. Average follow up was 26.5 years (maximum = 59.9 years). Overall, 2763 deaths were observed versus 2687 expected based on U.S. mortality rates (standardized mortality ratio (SMR) = 1.03). Deaths due to cancer, however, were increased (SMR = 1.30), especially cancers of organs close to the radiation source. For organs receiving greater than 5 Gy, excess mortality of 100 to 110% was noted for cancers of the uterus and bladder 10 or moremore » years following irradiation, while a deficit was seen for cancer of the cervix, one of the few malignancies not previously shown to be caused by ionizing radiation. Part of the excess of uterine cancer, however, may have been due to the underlying gynecologic disorders being treated. Among cancers of organs receiving average or local doses of 1 to 4 Gy, excesses of 30 to 100% were found for leukemia and cancers of the colon and genital organs other than uterus; no excess was seen for rectal or bone cancer. Among organs typically receiving 0.1 to 0.3 Gy, a deficit was recorded for cancers of the liver, gall bladder, and bile ducts combined, death due to stomach cancer occurred at close to the expected rate, a 30% excess was noted for kidney cancer (based on eight deaths), and there was a 60% excess of pancreatic cancer among 10-year survivors, but little evidence of dose-response. Estimates of the excess relative risk per Gray were 0.006 for uterus, 0.4 for other genital organs, 0.5 for colon, 0.2 for bladder, and 1.9 for leukemia. Contrary to findings for other populations treated by pelvic irradiation, a deficit of breast cancer was not observed (SMR = 1.0). Dose to the ovaries may have been insufficient to protect against breast cancer.« less

A retrospective analysis of chemotherapy switch suggests improved outcome in surgically removed, biologically aggressive canine haemangiosarcoma.

PubMed

Finotello, R; Henriques, J; Sabattini, S; Stefanello, D; Felisberto, R; Pizzoni, S; Ferrari, R; Marconato, L

2017-06-01

Haemangiosarcoma (HSA) has an aggressive biological behaviour and carries a poor prognosis, with less than 10% of treated dogs surviving longer than 1 year. In this retrospective study a varied metronomic chemotherapy (MC) regimen preceded by adjuvant doxorubicin-based maximum-tolerated dose chemotherapy (MTDC) was compared with MTDC, in terms of efficacy [time to metastasis, (TTM) and survival time (ST)] and safety in dogs with biologically aggressive HSA. Dogs were eligible if they had no metastasis after MTDC and received either no further chemotherapy or MC maintenance. Twelve dogs received MTDC, and 10 received MC thereafter. Median TTM and ST were significantly longer for dogs receiving MTDC-MC (not reached versus 150 days, P = 0.028; and not reached versus 168 days, P = 0.030, respectively). Treatment was well tolerated. MTDC followed by MC is safe and suggests improved TTM and ST in dogs with surgically removed, biologically aggressive HSA that are treated in the microscopic setting. © 2016 John Wiley & Sons Ltd.

A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer.

PubMed

Alvarez, Edwin A; Wolfson, Aaron H; Pearson, J Matt; Crisp, Meredith P; Mendez, Luis E; Lambrou, Nicholas C; Lucci, Joseph A

2009-05-01

This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy (RT) for the primary treatment of locally advanced squamous cell carcinoma of the cervix. Eligible patients included those with locally advanced squamous cell cervical cancer without para-aortic lymph node involvement. Docetaxel dose levels were 20 mg/m(2), 30 mg/m(2) and 40 mg/m(2) given intravenously weekly for 6 cycles. Three patients were to be treated at each dose level and 6 to receive the MTD. Fifteen patients completed 4-6 cycles of chemotherapy. One of three patients experienced 2 delayed grade 3 severe adverse events (SAE) at the 20 mg/m(2) dose level consisting of colonic and ureteral obstruction. At the 30 mg/m(2) dose level, 1/4 patients had a probable treatment-related celiotomy due to obstipation and a necrotic tumor. Of the 8 patients treated at the 40 mg/m(2) dose level, 1 experienced grade 3 pneumonitis, likely treatment related. Overall, 10/15 (67%) experienced grade 1 or 2 diarrhea, 6 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. 10 of 16 patients (67%) had no evidence of disease with follow-up ranging from 10-33 months (average 23 months). The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for locally advanced squamous cell carcinoma of the cervix is 40 mg/m(2).

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study.

PubMed

Phuphanich, Surasak; Baker, Sharyn D; Grossman, Stuart A; Carson, Kathryn A; Gilbert, Mark R; Fisher, Joy D; Carducci, Michael A

2005-04-01

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting.

PubMed

Chiocca, E Antonio; Abbed, Khalid M; Tatter, Stephen; Louis, David N; Hochberg, Fred H; Barker, Fred; Kracher, Jean; Grossman, Stuart A; Fisher, Joy D; Carson, Kathryn; Rosenblum, Mark; Mikkelsen, Tom; Olson, Jeff; Markert, James; Rosenfeld, Steven; Nabors, L Burt; Brem, Steven; Phuphanich, Surasak; Freeman, Scott; Kaplan, Rick; Zwiebel, James

2004-11-01

ONYX-015 is an oncolytic virus untested as a treatment for malignant glioma. The NABTT CNS Consortium conducted a dose-escalation trial of intracerebral injections of ONYX-015. Cohorts of six patients at each dose level received doses of vector from 10(7) plaque-forming units (pfu) to 10(10) pfu into a total of 10 sites within the resected glioma cavity. Adverse events were identified on physical exams and testing of hematologic, renal, and liver functions. Efficacy data were obtained from serial MRI scans. None of the 24 patients experienced serious adverse events related to ONYX-015. The maximum tolerated dose was not reached at 10(10) pfu. The median time to progression after treatment with ONYX-015 was 46 days (range 13 to 452 + days). The median survival time was 6.2 months (range 1.3 to 28.0 + months). One patient has not progressed and 1 patient showed regression of interval-increased enhancement. With more than 19 months of follow-up, 1/6 recipients at a dose of 10(9) and 2/6 at a dose of 10(10) pfu remain alive. In 2 patients who underwent a second resection 3 months after ONYX-015 injection, a lymphocytic and plasmacytoid cell infiltrate was observed. Injection of ONYX-015 into glioma cavities is well tolerated at doses up to 10(10) pfu.

[Clinical pharmacist influence at hospital to prevent overdosed prescription of acetaminophen].

PubMed

Viguier, F; Roessle, C; Zerhouni, L; Rouleau, A; Benmelouka, C; Chevallier, A; Chast, F; Conort, O

2016-11-01

The recommended daily dose of acetaminophen is limited to 60mg/kg/day with a maximum of 3g daily dose in adults weighing less than 50kg or in patients undergoing certain risk factors. This study aimed at assessing the fulfillment of those recommendations and the possible impact on the liver dysfunction at supra-therapeutic doses of acetaminophen. This study was performed one day in 9 services. Patients characteristics, acetaminophen dose, daily dose administered, physiopathological aspects, markers of liver damage were collected. Among 542 prescriptions analyzed, 343 of them contained acetaminophen. The median age of patients studied was 81 years and one third weighed less than 50kg. The main risk factor of supra-therapeutic prescriptions was the lack of dose acetaminophen based on weight with 14% patients concerned and this risk raised at 17% when the pathophysiological conditions were included. The presence of pharmacists in medicals departments was more effective than the use of informatics programs limiting the dose systematically to 3g/day, or a distant pharmaceutical validation from care services to reduce the risk of acetaminophen overdose. According to the statement of administrations, only 4 of 49 patients received doses above 60mg/kg/day with a low impact on liver function tests. The continuous presence in pharmaceutical care services was the most effective measure to ensure effective implementation of acetaminophen recommendations. Copyright © 2016 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Direct measurement of a patient's entrance skin dose during pediatric cardiac catheterization

PubMed Central

Sun, Lue; Mizuno, Yusuke; Iwamoto, Mari; Goto, Takahisa; Koguchi, Yasuhiro; Miyamoto, Yuka; Tsuboi, Koji; Chida, Koichi; Moritake, Takashi

2014-01-01

Children with complex congenital heart diseases often require repeated cardiac catheterization; however, children are more radiosensitive than adults. Therefore, radiation-induced carcinogenesis is an important consideration for children who undergo those procedures. We measured entrance skin doses (ESDs) using radio-photoluminescence dosimeter (RPLD) chips during cardiac catheterization for 15 pediatric patients (median age, 1.92 years; males, n = 9; females, n = 6) with cardiac diseases. Four RPLD chips were placed on the patient's posterior and right side of the chest. Correlations between maximum ESD and dose–area products (DAP), total number of frames, total fluoroscopic time, number of cine runs, cumulative dose at the interventional reference point (IRP), body weight, chest thickness, and height were analyzed. The maximum ESD was 80 ± 59 (mean ± standard deviation) mGy. Maximum ESD closely correlated with both DAP (r = 0.78) and cumulative dose at the IRP (r = 0.82). Maximum ESD for coiling and ballooning tended to be higher than that for ablation, balloon atrial septostomy, and diagnostic procedures. In conclusion, we directly measured ESD using RPLD chips and found that maximum ESD could be estimated in real-time using angiographic parameters, such as DAP and cumulative dose at the IRP. Children requiring repeated catheterizations would be exposed to high radiation levels throughout their lives, although treatment influences radiation dose. Therefore, the radiation dose associated with individual cardiac catheterizations should be analyzed, and the effects of radiation throughout the lives of such patients should be followed. PMID:24968708

Bone fractures following external beam radiotherapy and limb-preservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume, tumor location and dose.

PubMed

Dickie, Colleen I; Parent, Amy L; Griffin, Anthony M; Fung, Sharon; Chung, Peter W M; Catton, Charles N; Ferguson, Peter C; Wunder, Jay S; Bell, Robert S; Sharpe, Michael B; O'Sullivan, Brian

2009-11-15

To examine the relationship between tumor location, bone dose, and irradiated bone length on the development of radiation-induced fractures for lower extremity soft tissue sarcoma (LE-STS) patients treated with limb-sparing surgery and radiotherapy (RT). Of 691 LE-STS patients treated from 1989 to 2005, 31 patients developed radiation-induced fractures. Analysis was limited to 21 fracture patients (24 fractures) who were matched based on tumor size and location, age, beam arrangement, and mean total cumulative RT dose to a random sample of 53 nonfracture patients and compared for fracture risk factors. Mean dose to bone, RT field size (FS), maximum dose to a 2-cc volume of bone, and volume of bone irradiated to >or=40 Gy (V40) were compared. Fracture site dose was determined by comparing radiographic images and surgical reports to fracture location on the dose distribution. For fracture patients, mean dose to bone was 45 +/- 8 Gy (mean dose at fracture site 59 +/- 7 Gy), mean FS was 37 +/- 8 cm, maximum dose was 64 +/- 7 Gy, and V40 was 76 +/- 17%, compared with 37 +/- 11 Gy, 32 +/- 9 cm, 59 +/- 8 Gy, and 64 +/- 22% for nonfracture patients. Differences in mean, maximum dose, and V40 were statistically significant (p = 0.01, p = 0.02, p = 0.01). Leg fractures were more common above the knee joint. The risk of radiation-induced fracture appears to be reduced if V40 <64%. Fracture incidence was lower when the mean dose to bone was <37 Gy or maximum dose anywhere along the length of bone was <59 Gy. There was a trend toward lower mean FS for nonfracture patients.

SU-F-T-389: Validation in 4D Dosimetry Using Dynamic Phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, C; Lin, C; Tu, P

2016-06-15

Purpose: Tumor motion due to respiration causes the uncertainties during the radiotherapy. This study aims to find the differences between planning dose by treatment planning and the received dose using dynamic phantom. Methods: Respiratory motion was simulated by the DYNAMIC THORAX PHANTOM (Model 008A). 4D-CT scans and maximum intensity projection (MIP) images for GTV were acquired for analysis. The amplitude of craniocaudal tumor motion including 2mm, 5mm, 10mm and 20mm with 3cm2 tumor size were performed in this study. The respiratory cycles of 4-seconds and 6-seconds were included as the different breathing modes. IMRT, VAMT, and Tomotherapy were utilized formore » treatment planning. Ion chamber and EBT3 were used to measure the point dose and planar dose. Dose distributions with different amplitudes, respiratory cycles, and planning techniques were all measured and compared to calculations. Results: The variations between the does measurements and calculation dose by treatment planning system were found in both point dose and dose distribution. The 0.83% and 5.46 % differences in dose average were shown on phantom with motions using 2mm amplitude in 4 second respiratory cycle, and 20mm amplitude in 4 second respiratory cycle, respectively. The most point dose overestimation as compared of the calculations was shown the plan generated by Tomotherapy. The underestimations of planar dose as compared of calculations was found in the 100% coverage doses for GTV. Conclusion: The loss of complete (100%) GTV coverage was the predominant effect of respiratory motion observed in this study. Motion amplitude and treatment planning system were the major factors leading the dose measurement variation as compared of planning calculations.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez-Nieto, Beatriz, E-mail: bsanchez@fis.puc.cl; Goset, Karen C.; Caviedes, Ivan

Purpose: To propose multivariate predictive models for changes in pulmonary function tests ({Delta}PFTs) with respect to preradiotherapy (pre-RT) values in patients undergoing RT for breast cancer and lymphoma. Methods and Materials: A prospective study was designed to measure {Delta}PFTs of patients undergoing RT. Sixty-six patients were included. Spirometry, lung capacity (measured by helium dilution), and diffusing capacity of carbon monoxide tests were used to measure lung function. Two lung definitions were considered: paired lung vs. irradiated lung (IL). Correlation analysis of dosimetric parameters (mean lung dose and the percentage of lung volume receiving more than a threshold dose) and {Delta}PFTsmore » was carried out to find the best dosimetric predictor. Chemotherapy, age, smoking, and the selected dose-volume parameter were considered as single and interaction terms in a multivariate analysis. Stability of results was checked by bootstrapping. Results: Both lung definitions proved to be similar. Modeling was carried out for IL. Acute and late damage showed the highest correlations with volumes irradiated above {approx}20 Gy (maximum R{sup 2} = 0.28) and {approx}40 Gy (maximum R{sup 2} = 0.21), respectively. RT alone induced a minor and transitory restrictive defect (p = 0.013). Doxorubicin-cyclophosphamide-paclitaxel (Taxol), when administered pre-RT, induced a late, large restrictive effect, independent of RT (p = 0.031). Bootstrap values confirmed the results. Conclusions: None of the dose-volume parameters was a perfect predictor of outcome. Thus, different predictor models for {Delta}PFTs were derived for the IL, which incorporated other nondosimetric parameters mainly through interaction terms. Late {Delta}PFTs seem to behave more serially than early ones. Large restrictive defects were demonstrated in patients pretreated with doxorubicin-cyclophosphamide-paclitaxel.« less

Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article.

PubMed

Boockvar, John A; Tsiouris, Apostolos J; Hofstetter, Christoph P; Kovanlikaya, Ilhami; Fralin, Sherese; Kesavabhotla, Kartik; Seedial, Stephen M; Pannullo, Susan C; Schwartz, Theodore H; Stieg, Philip; Zimmerman, Robert D; Knopman, Jared; Scheff, Ronald J; Christos, Paul; Vallabhajosula, Shankar; Riina, Howard A

2011-03-01

The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. A total of 30 patients with recurrent malignant glioma were included in the current study. The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

[Rivastigmine as treatment for patients with mild to moderately severe Alzheimer disease under normal clinical practice conditions. The ENTERPRISE study].

PubMed

Cruz Jentoft, A J; Hernández, B

2014-01-01

Alzheimer disease (AD) causes progressive cognitive decline leading to loss of independence for activities of daily living; rivastigmine is one of the drugs used for symptomatic management. To assess the therapeutic use of different pharmaceutical forms of rivastigmine in patients with AD in normal clinical practice. Cross-sectional, observational, multi-centre study conducted on patients with mild to moderate AD treated with rivastigmine in Spanish outpatient clinics specialising in Geriatrics, Psychiatry, and Neurology. Data regarding use of oral (OR) and transdermal (TDR) rivastigmine, compliance (degree of adherence), and caregiver satisfaction with treatment were evaluated. In total, 2252 patients with a mean age of 77.2 years were included; 60.2% were women. AD was moderate to moderately severe in 58.4%. Rivastigmine treatment was started orally in 54.4% of the patients and transdermally in 45.6%; 35.6% of those who started treatment by the OR route switched to TDR. A single dose adjustment was sufficient for 77.5% of patients on TDR treatment vs 11.8% of patients receiving OR treatment. More patients on TDR treatment (80.8% vs. 57.1% on OR treatment) reached the maximum therapeutic dose of rivastigmine and did so in a shorter period of time (51.6 vs 205.8 days). Compliance rates (60.5% vs 47.2%) and caregivers' satisfaction with treatment (89.4% vs 81.9%) were also higher for TDR. In normal clinical practice, using the TDR route of administration improves dose titration and drug compliance, allowing more patients to reach the maximum recommended dose of rivastigmine in a shorter time period. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Bioavailability of the Yuzpe and levonorgestrel regimens of emergency contraception: vaginal vs. oral administration.

PubMed

Kives, Sari; Hahn, Philip M; White, Emily; Stanczyk, Frank Z; Reid, Robert L

2005-03-01

Separate crossover studies compared the bioavailability of oral vs. vaginal routes of administration for the Yuzpe (n=5) and levonorgestrel regimens (n=4) of emergency contraception. Twice the standard dose of the Yuzpe regimen (200 microg of ethinyl estradiol, 1000 microg of levonorgestrel) or the levonorgestrel regimen (1500 microg of levonorgestrel) was self-administered vaginally. One week later, each subject received orally the standard dose of the assigned medication. Serial blood samples were collected over 24 h and assayed for levonorgestrel and ethinyl estradiol (for the Yuzpe regimen only). Paired t tests were used to compare oral vs. vaginal administration for maximum concentration (Cmax), time to maximum concentration (Tmax) and area under the curve over 24 h (AUC0-24). Relative bioavailability (vaginal/oral) was derived from AUC0-24. Vaginal administration of double the standard dose of the Yuzpe regimen resulted in a lower Cmax (vaginal=5.4 vs. oral=14.6 ng/mL, p=.038) and a later Tmax (5.9 vs. 2.0 h, p=.066) for levonorgestrel, compared to oral administration. Corresponding ethinyl estradiol concentrations were higher (786 vs. 391 pg/mL, p=.039) and peaked later (4.0 vs. 1.9 hr, p=.154) with vaginal administration. Relative bioavailabilities for levonorgestrel and ethinyl estradiol were 58% and 175%, respectively. Similarly, vaginal administration of the levonorgestrel regimen resulted in a lower Cmax (vaginal=5.4 vs. oral=15.2 ng/mL, p=.006) and a later Tmax (7.4 vs. 1.3 h, p=.037) for levonorgestel, compared to oral administration. The relative bioavailability was 62%. Our preliminary data suggest that vaginal administration of these emergency contraception regimens appears to require at least three times the standard oral dose to achieve equivalent systemic levonorgestrel concentrations.

Multivariate Normal Tissue Complication Probability Modeling of Heart Valve Dysfunction in Hodgkin Lymphoma Survivors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cella, Laura, E-mail: laura.cella@cnr.it; Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples; Liuzzi, Raffaele

Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced asymptomatic heart valvular defects (RVD). Methods and Materials: Fifty-six patients treated with sequential chemoradiation therapy for Hodgkin lymphoma (HL) were retrospectively reviewed for RVD events. Clinical information along with whole heart, cardiac chambers, and lung dose distribution parameters was collected, and the correlations to RVD were analyzed by means of Spearman's rank correlation coefficient (Rs). For the selection of the model order and parameters for NTCP modeling, a multivariate logistic regression method using resampling techniques (bootstrapping) was applied. Model performance was evaluated using the area under themore » receiver operating characteristic curve (AUC). Results: When we analyzed the whole heart, a 3-variable NTCP model including the maximum dose, whole heart volume, and lung volume was shown to be the optimal predictive model for RVD (Rs = 0.573, P<.001, AUC = 0.83). When we analyzed the cardiac chambers individually, for the left atrium and for the left ventricle, an NTCP model based on 3 variables including the percentage volume exceeding 30 Gy (V30), cardiac chamber volume, and lung volume was selected as the most predictive model (Rs = 0.539, P<.001, AUC = 0.83; and Rs = 0.557, P<.001, AUC = 0.82, respectively). The NTCP values increase as heart maximum dose or cardiac chambers V30 increase. They also increase with larger volumes of the heart or cardiac chambers and decrease when lung volume is larger. Conclusions: We propose logistic NTCP models for RVD considering not only heart irradiation dose but also the combined effects of lung and heart volumes. Our study establishes the statistical evidence of the indirect effect of lung size on radio-induced heart toxicity.« less

Design of simplified maximum-likelihood receivers for multiuser CPM systems.

PubMed

Bing, Li; Bai, Baoming

2014-01-01

A class of simplified maximum-likelihood receivers designed for continuous phase modulation based multiuser systems is proposed. The presented receiver is built upon a front end employing mismatched filters and a maximum-likelihood detector defined in a low-dimensional signal space. The performance of the proposed receivers is analyzed and compared to some existing receivers. Some schemes are designed to implement the proposed receivers and to reveal the roles of different system parameters. Analysis and numerical results show that the proposed receivers can approach the optimum multiuser receivers with significantly (even exponentially in some cases) reduced complexity and marginal performance degradation.

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

Factors determining anti-poliovirus type 3 antibodies among orally immunised Indian infants.

PubMed

Kaliappan, Saravanakumar Puthupalayam; Venugopal, Srinivasan; Giri, Sidhartha; Praharaj, Ira; Karthikeyan, Arun S; Babji, Sudhir; John, Jacob; Muliyil, Jayaprakash; Grassly, Nicholas; Kang, Gagandeep

2016-09-22

Among the three poliovirus serotypes, the lowest responses after vaccination with trivalent oral polio vaccine (tOPV) are to serotype 3. Although improvements in routine immunisation and supplementary immunisation activities have greatly increased vaccine coverage, there are limited data on antibody prevalence in Indian infants. Children aged 5-11months with a history of not having received inactivated polio vaccine were screened for serum antibodies to poliovirus serotype 3 (PV3) by a micro-neutralisation assay according to a modified World Health Organization (WHO) protocol. Limited demographic information was collected to assess risk-factors for a lack of protective antibodies. Student's t-test, logistic regression and multilevel logistic regression (MLR) model were used to estimate model parameters. Of 8454 children screened at a mean age of 8.3 (standard deviation [SD]-1.8) months, 88.1% (95% confidence interval (CI): 87.4-88.8) had protective antibodies to PV3. The number of tOPV doses received was the main determinant of seroprevalence; the maximum likelihood estimate yields a 37.7% (95% CI: 36.2-38.3) increase in seroprevalence per dose of tOPV. In multivariable logistic regression analysis increasing age, male sex, and urban residence were also independently associated with seropositivity (Odds Ratios (OR): 1.17 (95% CI: 1.12-1.23) per month of age, 1.27 (1.11-1.46) and 1.24 (1.05-1.45) respectively). Seroprevalence of antibodies to PV3 is associated with age, gender and place of residence, in addition to the number of tOPV doses received. Ensuring high coverage and monitoring of response are essential as long as oral vaccines are used in polio eradication. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer.

PubMed

Uwagawa, Tadashi; Sakamoto, Taro; Abe, Kyohei; Okui, Norimitsu; Hata, Daigo; Shiba, Hiroaki; Futagawa, Yasuro; Aiba, Keisuke; Yanaga, Katsuhiko

2015-01-01

To date, gemcitabine-based or fluoropyrimidine-based regimens are recommended for unresectable advanced biliary tract cancer. Then, we conducted a phase I study of gemcitabine/cisplatin and S-1 that is an oral fluoropyrimidine. The aim of this study was to determine the dose-limiting toxicity (DLT), maximum-tolerated dose, and a recommended phase II dose of S-1. Response was assessed as a secondary endpoint. Patients who have been diagnosed with unresectable or postoperative recurrent biliary tract cancer received cisplatin (25 mg/m² i.v. for 120 min) followed by gemcitabine (1,000 mg/m² i.v. for 30 min) on days 1 and 8, and oral S-1 on alternate days; this regimen was repeated at 21-day intervals. A standard '3 + 3' phase I dose-escalation design was adopted. This study was registered with University hospital Medical Information Network (UMIN) Center in Japan, number UMIN000008415. Twelve patients were evaluable in this study. No patients developed DLTs. Recommended dose of S-1 was 80 (<1.25 m²), 100 (1.25 ≤ 1.5 m²), and 120 mg (1.5 m²≥) per day. One patient could achieve conversion to curative surgery. This phase I study was performed safely and demonstrated encouraging response.

The anticonvulsant action of nafimidone on kindled amygdaloid seizures in rats.

PubMed

Albertson, T E; Walby, W F

1988-01-01

The anticonvulsant effectiveness of nafimidone (1-[2-naphthoylmethyl]imidazole hydrochloride) was evaluated in the kindled amygdaloid seizure model in rats. Nafimidone (3.1-120 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and supranthreshold (400 microA) paradigms. Nafimidone (25-50 mg/kg) significantly reduced supranthreshold elicited afterdischarge length and seizure severity only at doses with some prestimulation toxicity. The maximum anticonvulsant effectiveness for the 25 mg/kg i.p. dose of nafimidone was seen between 15 and 30 min utilizing a suprathreshold kindling paradigm. Nafimidone did not significantly elevate seizure thresholds at the doses tested; however, nafimidone (3.1-50 mg/kg) reduced the severity and afterdischarge duration of threshold elicited seizures in a non-dose response manner. Drug-induced electroencephalographic spikes were seen in both cortex and amygdala in most kindled rats receiving 100-120 mg/kg i.p. within 30 min of dosing before electrical stimulation. The frequency of spike and wave complexes increased in most of these animals leading to drug-induced spontaneous seizures and death in approximately 25% before electrical stimulation. This study has demonstrated that although nafimidone can modify both threshold and suprathreshold elicited kindled amygdaloid seizures, it lacks significant specificity in this model of epilepsy.

The safety of dosing dalteparin based on actual body weight for the treatment of acute venous thromboembolism in obese patients.

PubMed

Al-Yaseen, E; Wells, P S; Anderson, J; Martin, J; Kovacs, M J

2005-01-01

Data evaluating the safety of using weight-based low-molecular-weight heparin in the treatment of obese patients with acute venous thromboembolism are limited. The product monograph of dalteparin suggests the maximum dose should be limited to 18,000 U subcutaneously once daily. There are no specific data regarding the risk of recurrence or bleeding in patients given dalteparin in a weight-based dose of 200 IU kg(-1). We report a retrospective chart review of 193 obese patients who weighed more than 90 kg and who received dalteparin at or near to 200 IU kg(-1) actual body weight for 5-7 days for acute venous thromboembolism with 90 day follow-up information. Of the patients, 77% had idiopathic venous thromboembolism, 16% had an underlying malignancy, and 7% had a transient risk factor. Warfarin was initiated within 2 days with a target International Normalized Ratio range of 2.0-3.0. All patients were followed for 12 weeks post diagnosis. Only two patients had a major hemorrhage, 4 and 8 weeks from diagnosis. This study supports the safety of dosing dalteparin based on actual body weight in obese patients.

The Dosimetric Consequences of Intensity Modulated Radiotherapy for Cervix Cancer: The Impact of Organ Motion, Deformation and Tumour Regression

NASA Astrophysics Data System (ADS)

Lim, Karen Siah Huey

Hypothesis: In intensity modulated radiotherapy (IMRT) for cervix cancer, the dose received by the tumour target and surrounding normal tissues is significantly different to that indicated by a single static plan. Rationale: The optimal use of IMRT in cervix cancer requires a greater attention to clinical target volume (CTV) definition and tumour & normal organ motion to assure maximum tumour control with the fewest side effects. Research Aims: 1) Generate consensus CTV contouring guidelines for cervix cancer; 2) Evaluate intra-pelvic tumour and organ dynamics during radiotherapy; 3) Analyze the dose consequences of intra-pelvic organ dynamics on different radiotherapy strategies. Results: Consensus CTV definitions were generated using experts-in-the-field. Substantial changes in tumour volume and organ motion, resulted in significant reductions in accumulated dose to tumour targets and variability in accumulated dose to surrounding normal tissues. Significance: Formalized CTV definitions for cervix cancer is important in ensuring consistent standards of practice. Complex and unpredictable tumour and organ dynamics mandates daily soft-tissue image guidance if IMRT is used. To maximize the benefits of IMRT for cervix cancer, a strategy of adaptation is necessary.

A Pilot Safety Study of Lenalidomide and Radiotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Drappatz, Jan; Division of Cancer Neurology, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Wong, Eric T.

2009-01-01

Purpose: To define the maximum tolerated dose (MTD) of lenalidomide, an analogue of thalidomide with enhanced immunomodulatory and antiangiogenic properties and a more favorable toxicity profile, in patients with newly diagnosed glioblastoma multiforme (GBM) when given concurrently with radiotherapy. Patients and Methods: Patients with newly diagnosed GBM received radiotherapy concurrently with lenalidomide given for 3 weeks followed by a 1-week rest period and continued lenalidomide until tumor progression or unacceptable toxicity. Dose escalation occurred in groups of 6. Determination of the MTD was based on toxicities during the first 12 weeks of therapy. The primary endpoint was toxicity. Results: Twenty-threemore » patients were enrolled, of whom 20 were treated and evaluable for both toxicity and tumor response and 2 were evaluable for toxicity only. Common toxicities included venous thromboembolic disease, fatigue, and nausea. Dose-limiting toxicities were eosinophilic pneumonitis and transaminase elevations. The MTD for lenalidomide was determined to be 15 mg/m{sup 2}/d. Conclusion: The recommended dose for lenalidomide with radiotherapy is 15 mg/m{sup 2}/d for 3 weeks followed by a 1-week rest period. Venous thromboembolic complications occurred in 4 patients, and prophylactic anticoagulation should be considered.« less

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia.

PubMed

Azevedo, M C; Velloso, E D R P; Buccheri, V; Chamone, D A F; Dorlhiac-Llacer, P E

2015-02-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia

PubMed Central

Azevedo, M.C.; Velloso, E.D.R.P.; Buccheri, V.; Chamone, D.A.F.; Dorlhiac-Llacer, P.E.

2014-01-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival. PMID:25517921

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

PubMed

Iversen, Ole-Erik; Miranda, Maria Jose; Ulied, Angels; Soerdal, Terje; Lazarus, Erica; Chokephaibulkit, Kulkanya; Block, Stan L; Skrivanek, Ales; Nur Azurah, Abdul Ghani; Fong, Siew Moy; Dvorak, Vladimir; Kim, Kyung-Hyo; Cestero, Ramon M; Berkovitch, Matitiahu; Ceyhan, Mehmet; Ellison, Misoo C; Ritter, Michael A; Yuan, Shuai S; DiNubile, Mark J; Saah, Alfred J; Luxembourg, Alain

2016-12-13

Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. clinicaltrials.gov Identifier: NCT01984697.

Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing

PubMed Central

Edelman, Alison B; Cherala, Ganesh; Blue, Steven W; Erikson, David W; Jensen, Jeffrey T

2016-01-01

Objective To determine if differences exist in the pharmacokinetics (PK) of levonorgestrel-based emergency contraception (LNG-EC) in obese and normal body mass index (BMI) users and test whether doubling the dose of LNG-EC in obese women increases total and free (active) LNG serum concentrations. Study design Healthy, reproductive-age women with obese and normal BMIs received 1.5 mg LNG orally (ECx1) and then in a subsequent menstrual cycle, the obese group also received 3mg LNG (ECx2). Dosing occurred during the follicular phase. Total and free LNG PK parameters were obtained via serum samples through an indwelling catheter at 0, 0.5, 1, 1.5, 2, and 2.5 hours. The primary outcome was the difference in total and free LNG concentration maximum (Cmax) between ECx1 and ECx2 in the obese group. Results A total of 10 women enrolled and completed the study (normal BMI = 5, median 22.8 kg/m2, range 20.8–23.7; obese BMI = 5, 39.5 kg/m2, range 35.9–46.7). The total LNG Cmax for obese subjects following ECx1 (5.57±2.48 ng/mL) was significantly lower than the level observed in normal BMI women (10.30±2.47, p=0.027). Notably, ECx2 increased the Cmax significantly (10.52±2.76, p=0.002); approximating the level in normal BMI subjects receiving ECx1. Free LNG Cmax followed a similar pattern. Conclusion Obesity adversely impacts both the total and free Cmax levels of LNG EC and this likely explains its lack of efficacy in obese women. Doubling the dose appears to correct the obesity-related PK changes but additional research is needed to determine if this also improves EC effectiveness in obese women. Implications This study demonstrates that obesity interferes with the pharmacokinetics of LNG EC, and that doubling the dose may be an effective strategy to improve its efficacy in obese women. PMID:27000996

Effect of lacosamide on the steady-state pharmacokinetics of digoxin: results from a phase I, multiple-dose, double-blind, randomised, placebo-controlled, crossover trial.

PubMed

Cawello, Willi; Mueller-Voessing, Christa; Andreas, Jens-Otto

2014-05-01

Recent data suggest that P-glycoprotein may be involved in cellular transport of lacosamide. To investigate potential drug-drug interactions (DDIs) between lacosamide and digoxin, this phase I, multiple-dose, randomised, double-blind, placebo-controlled, crossover trial assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of digoxin administered in combination with lacosamide or placebo. Twenty healthy White male volunteers were randomised. After receiving digoxin 0.25 mg three times daily on day 1 (loading dose), participants received digoxin 0.25 mg once daily on days 2-22. Participants received either lacosamide (200 mg twice daily) or placebo on days 8-11 and vice versa on days 18-21, after a 6-day washout. The steady-state area under concentration-time curve over the dosing interval (AUC(24,ss)) and maximum steady-state plasma concentration (C(max,ss)) of digoxin were measured; ratios of these parameters for co-administration of digoxin + lacosamide versus digoxin alone were used to evaluate potential DDIs. Interaction was excluded if the 90 % confidence interval (CI) for the geometric mean ratio of AUC24,ss and C max,ss fell within the acceptance range for bioequivalence (0.8-1.25). The point estimates (90 % CI) of the geometric mean ratios for co-administration of digoxin with lacosamide versus digoxin alone for AUC(24,ss) [1.024 (0.979-1.071)] and C(max,ss) [1.049 (0.959-1.147)] were within the acceptance range for bioequivalence. Digoxin and lacosamide co-administration was generally well-tolerated. A small numerical increase in the mean PR interval following co-administered digoxin + lacosamide was observed versus digoxin alone and versus pre-treatment baseline values (178.5 vs. 170.4 or 166.8 ms, respectively). The RR interval increased in parallel. The change was not considered clinically relevant. Co-administration of steady-state digoxin (0.25 mg/day) with multiple-dose lacosamide (400 mg/day) versus digoxin alone revealed no differences in digoxin disposition.

Accelerated partial breast irradiation using robotic radiotherapy: a dosimetric comparison with tomotherapy and three-dimensional conformal radiotherapy.

PubMed

Rault, Erwann; Lacornerie, Thomas; Dang, Hong-Phuong; Crop, Frederik; Lartigau, Eric; Reynaert, Nick; Pasquier, David

2016-02-27

Accelerated partial breast irradiation (APBI) is a new breast treatment modality aiming to reduce treatment time using hypo fractionation. Compared to conventional whole breast irradiation that takes 5 to 6 weeks, APBI is reported to induce worse cosmetic outcomes both when using three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT). These late normal tissue effects may be attributed to the dose volume effect because a large portion of the non-target breast tissue volume (NTBTV) receives a high dose. In the context of APBI, non-coplanar beams could spare the NTBTV more efficiently. This study evaluates the dosimetric benefit of using the Cyberknife (CK) for APBI in comparison to IMRT (Tomotherapy) and three dimensional conformal radiotherapy (3D-CRT). The possibility of using surgical clips, implanted during surgery, to track target movements is investigated first. A phantom of a female thorax was designed in-house using the measurements of 20 patients. Surgical clips of different sizes were inserted inside the breast. A treatment plan was delivered to the mobile and immobile phantom. The motion compensation accuracy was evaluated using three radiochromic films inserted inside the breast. Three dimensional conformal radiotherapy (3D-CRT), Tomotherapy (TOMO) and CK treatment plans were calculated for 10 consecutive patients who received APBI in Lille. To ensure a fair comparison of the three techniques, margins applied to the CTV were set to 10 mm. However, a second CK plan was prepared using 3 mm margins to evaluate the benefits of motion compensation. Only the larger clips (VITALITEC Medium-Large) could be tracked inside the larger breast (all gamma indices below 1 for 1 % of the maximum dose and 1 mm). All techniques meet the guidelines defined in the NSABP/RTOG and SHARE protocols. As the applied dose volume constraints are very strong, insignificant dosimetric differences exist between techniques regarding the PTV coverage and the sparing of the lung and heart. However, the CK may be used to reduce high doses received by the NTBTV more efficiently. Robotic stereotactic radiotherapy may be used for APBI to more efficiently spare the NTBTV and improve cosmetic results of APBI.

Comparison of filgrastim and pegfilgrastim to prevent neutropenia and maintain dose intensity of adjuvant chemotherapy in patients with breast cancer.

PubMed

Kourlaba, Georgia; Dimopoulos, Meletios A; Pectasides, Dimitrios; Skarlos, Dimosthenis V; Gogas, Helen; Pentheroudakis, George; Koutras, Angelos; Fountzilas, George; Maniadakis, Nikos

2015-07-01

The aim of this study was to compare the effectiveness of prophylactic single fixed dose of pegfilgrastim and daily administration of filgrastim on febrile neutropenia (FN), severe neutropenia, treatment delay, and dose reduction in patients with breast cancer receiving dose-dense adjuvant chemotherapy. A retrospective cohort study with 1058 breast cancer patients matched by age and chemotherapy was conducted. The primary endpoints were FN, severe (grade 3, 4) neutropenia, dose reduction (>10 % reduction of the dose planned), and treatment delay (dose given more than 2 days later). Eighteen episodes of FN (3.4%) in the filgrastim group and 23 (4.3%) in the pegfilgrastim group (p = 0.500) were recorded. More than half of the total episodes (27/41) occurred during the first 4 cycles of treatment. Patients who received filgrastim were almost three times more likely to experience a severe neutropenia episode and were significantly more likely to experience a dose reduction (18.5%) compared to those who received pegfilgrastim (10.8%) (p < 0.001). The percentage of patients, who received their planned dose on time, was significantly lower in patients receiving filgrastim (58%) compared to those receiving pegfilgrastim (72.4%, p < 0.001). No significant difference was detected on FN rate between daily administration of filgrastim and single administration of pegfilgrastim. However, patients receiving pegfilgrastim had a significantly lower rate of severe neutropenia, as well as dose reduction and treatment delay, thus, achieving a higher dose density.

Comparing proton treatment plans of pediatric brain tumors in two pencil beam scanning nozzles with different spot sizes

PubMed Central

Kralik, John C.; Xi, Liwen; Solberg, Timothy D.; Simone, Charles B.

2015-01-01

Target coverage and organ‐at‐risk sparing were compared for 22 pediatric patients with primary brain tumors treated using two distinct nozzles in pencil beam scanning (PBS) proton therapy. Consecutive patients treated at our institution using a PBS‐dedicated nozzle (DN) were replanned using a universal nozzle (UN) beam model and the original DN plan objectives. Various cranial sites were treated among the patients to prescription doses ranging from 45 to 54 Gy. Organs at risk (OARs) evaluated were patient‐dependent; 15 unique OARs were analyzed, all of which were assessed in at least 10 patients. Clinical target volume (CTV) coverage and organ sparing were compared for the two nozzles using dose‐volume histogram data. Statistical analysis using a confidence‐interval approach demonstrates that CTV coverage is equivalent for UN and DN plans within ±5% equivalence bounds. In contrast, average mean and maximum doses are significantly higher for nearly all 15 OARs in the UN plans. The average median increase over all OARs and patients is approximately 1.7 Gy, with an increase in the 25%–75% of 1.0–2.3 Gy; the median increase to the pituitary gland, temporal lobes, eyes and cochleas are 1.8, 1.7, 0.7, and 2.7 Gy, respectively. The CTV dose distributions fall off slower for UN than for the DN plans; hence, normal tissue structures in close proximity to CTVs receive higher doses in UN plans than in DN plans. The higher OAR doses in the UN plans are likely due to the larger spot profile in plans created with UN beams. In light of the high rates of toxicities in pediatric patients receiving cranial irradiation and in light of selected brain tumor types having high cure rates, this study suggests the smaller DN beam profile is preferable for the advantage of reducing dose to OARs. PACS number: 87.55.D‐ PMID:26699553

Bioavailability, pharmacokinetics, and safety of riociguat given as an oral suspension or crushed tablet with and without food

PubMed Central

Frey, Reiner; Becker, Corina; Unger, Sigrun; Wensing, Georg; Mück, Wolfgang

2016-01-01

Abstract Riociguat is approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Some patients have difficulty swallowing tablets; therefore, 2 randomized, nonblinded, crossover studies compared the relative bioavailability of riociguat oral suspensions and immediate-release (IR) tablet and of crushed-tablet preparations versus whole IR tablet. In study 1, 30 healthy subjects received 5 single riociguat doses: 0.3 and 2.4 mg (0.15 mg/mL suspensions), 0.15 mg (0.03 mg/mL), and 1.0 mg (whole IR tablet) under fasted conditions and 2.4 mg (0.15 mg/mL) after a high-fat, high-calorie American-style breakfast. In study 2, 25 healthy men received 4 single 2.5-mg doses: whole IR tablet and crushed IR tablet suspended in applesauce and water, respectively, under fasted conditions, and whole IR tablet after a continental breakfast. In study 1, dose-normalized pharmacokinetics of riociguat oral suspensions and 1.0-mg whole IR tablet were similar in fasted conditions; 90% confidence intervals for riociguat area under the curve (AUC) to dose and mean maximum concentration (Cmax) to dose were within bioequivalence criteria. After food, dose-normalized AUC and Cmax decreased by 15% and 38%, respectively. In study 2, riociguat exposure was similar for all preparations; AUC ratios for crushed-IR-tablet preparations to whole IR tablet were within bioequivalence criteria. The Cmax increased by 17% for crushed IR tablet in water versus whole IR tablet. Food intake decreased Cmax of the whole tablet by 16%, with unaltered AUC versus fasted conditions. Riociguat bioavailability was similar between the oral suspensions and the whole IR tablet; exposure was similar between whole IR tablet and crushed-IR-tablet preparations. Minor food effects were observed. Results suggest that riociguat formulations are interchangeable. PMID:27162630

Bioavailability, pharmacokinetics, and safety of riociguat given as an oral suspension or crushed tablet with and without food.

PubMed

Saleh, Soundos; Frey, Reiner; Becker, Corina; Unger, Sigrun; Wensing, Georg; Mück, Wolfgang

2016-03-01

Riociguat is approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Some patients have difficulty swallowing tablets; therefore, 2 randomized, nonblinded, crossover studies compared the relative bioavailability of riociguat oral suspensions and immediate-release (IR) tablet and of crushed-tablet preparations versus whole IR tablet. In study 1, 30 healthy subjects received 5 single riociguat doses: 0.3 and 2.4 mg (0.15 mg/mL suspensions), 0.15 mg (0.03 mg/mL), and 1.0 mg (whole IR tablet) under fasted conditions and 2.4 mg (0.15 mg/mL) after a high-fat, high-calorie American-style breakfast. In study 2, 25 healthy men received 4 single 2.5-mg doses: whole IR tablet and crushed IR tablet suspended in applesauce and water, respectively, under fasted conditions, and whole IR tablet after a continental breakfast. In study 1, dose-normalized pharmacokinetics of riociguat oral suspensions and 1.0-mg whole IR tablet were similar in fasted conditions; 90% confidence intervals for riociguat area under the curve (AUC) to dose and mean maximum concentration (C max) to dose were within bioequivalence criteria. After food, dose-normalized AUC and C max decreased by 15% and 38%, respectively. In study 2, riociguat exposure was similar for all preparations; AUC ratios for crushed-IR-tablet preparations to whole IR tablet were within bioequivalence criteria. The C max increased by 17% for crushed IR tablet in water versus whole IR tablet. Food intake decreased C max of the whole tablet by 16%, with unaltered AUC versus fasted conditions. Riociguat bioavailability was similar between the oral suspensions and the whole IR tablet; exposure was similar between whole IR tablet and crushed-IR-tablet preparations. Minor food effects were observed. Results suggest that riociguat formulations are interchangeable.

An open treatment trial of duloxetine in elderly patients with dysthymic disorder.

PubMed

Kerner, Nancy; D'Antonio, Kristina; Pelton, Gregory H; Salcedo, Elianny; Ferrar, Jennifer; Roose, Steven P; Devanand, Dp

2014-05-08

We evaluated the efficacy and side effects of the selective serotonin and norepinephrine reuptake inhibitor antidepressant duloxetine in older adults with dysthymic disorder. Patients ≥ 60 years old with dysthymic disorder received flexible dose duloxetine 20-120 mg daily in an open-label 12-week trial. The main outcomes were change from baseline to 12 weeks in 24-item Hamilton Depression Rating Scale scores and Treatment Emergent Symptoms Scale scores. Response required ≥ 50% decline in Hamilton Depression Rating Scale scores with a Clinical Global Impression of much improved or better, and remission required final Hamilton Depression Rating Scale ≤ 6. Intent-to-treat analyses were conducted with the last observation carried forward. In 30 patients, the mean age was 70.7 (standard deviation (SD) = 7.6) years and 56.7% were female. In intent-to-treat analyses, there were 16 responders (53.3%) and 10 remitters (33.3%). Of these, 19 patients completed the trial. The mean maximum dose was 76.3 mg (SD = 38.5) in the total sample and 101 mg (SD = 17.9) in completers. In the total sample, the mean final dose was 51 mg (SD = 27.2) and correlated significantly with decline in Hamilton Depression Rating Scale ( p < .03); decline in Hamilton Depression Rating Scale correlated significantly with decline in Treatment Emergent Symptoms Scale ( p < .001). Daily doses above 60 mg were associated with greater improvement and well tolerated. This result was partly confounded by early dropouts having received low doses. Demographic and medical comorbidities, including cardiac disease and hypertension, were not related to response. Somatic side effects were common prior to duloxetine treatment and improved rather than worsened with duloxetine. There were no serious adverse events. Duloxetine at relatively high doses showed moderate efficacy in elderly patients with dysthymic disorder and was well tolerated in successful completers. Reduced somatic symptoms were associated with improvement in depressive symptoms. A systematic placebo-controlled trial of duloxetine in older patients with dysthymic disorder may be warranted.

Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers.

PubMed

Teng, Renli; Maya, Juan; Butler, Kathleen

2013-01-01

The results of two independent, randomized, two-period crossover, single-center studies, conducted to assess the pharmacokinetics of ticagrelor ± aspirin, inhibition of platelet aggregation (IPA) with ticagrelor/aspirin vs. clopidogrel/aspirin, and safety, tolerability, and bleeding times are reported here. In Study A (open-label), 16 volunteers received ticagrelor (50 mg bid Days 1-5; 200 mg bid Days 6-9; one 200 mg dose on Day 10) ± 300 mg qd aspirin (Days 1-10). In Study B (double-blind, double-dummy), 16 volunteers received aspirin (300 mg loading dose/75 mg qd Days 2-9) with either ticagrelor (200 mg bid Days 4-8, one 200 mg dose on Day 9) or clopidogrel (300 mg loading dose Day 4, 75 mg qd Days 5-9). At steady-state ticagrelor (50 mg bid, or 200 mg bid), concomitant aspirin (300 mg qd) had no effect on mean maximum plasma concentration (Cmax), median time to Cmax (tmax), or mean area under the plasma concentration-time curve for the dosing interval (AUC0-τ) for ticagrelor and its primary metabolite, AR-C124910XX. Following 200 mg bid ticagrelor, mean Cmax and AUC0-τ for both parent and metabolite were comparable with co-administration of aspirin at 75 mg and 300 mg qd. Aspirin (300 mg qd) had no effect on IPA (ADP-induced) by ticagrelor. However, aspirin and ticagrelor had an additive effect on IPA (collagen-induced). Ticagrelor/aspirin increased bleeding times vs. baseline. Ticagrelor/aspirin co-administration was well tolerated at all dose combinations evaluated. In summary, the findings of this study demonstrate that co-administration of aspirin (300 mg qd) with ticagrelor (50 mg bid, or 200 mg bid) had no effect on ticagrelor pharmacokinetics or IPA (ADP-induced) by ticagrelor.

Dexmedetomidine inhibits activation of the MAPK pathway and protects PC12 and NG108-15 cells from lidocaine-induced cytotoxicity at its maximum safe dose.

PubMed

Wang, Qiong; Tan, Yonghong; Zhang, Na; Xu, Yingyi; Wei, Wei; She, Yingjun; Bi, Xiaobao; Zhao, Baisong; Ruan, Xiangcai

2017-07-01

The developing brains of pediatric patients are highly vulnerable to anesthetic regimen (e.g., lidocaine), potentially causing neurological impairment. Recently, dexmedetomidine (DEX) has been used as an adjunct for sedation, and was shown to exert dose-dependent neuroprotective effects during brain injury. However, the maximum safe dose of DEX is unclear, and its protective effects against lidocaine-related neurotoxicity need to be confirmed. In this study, PC12 and NG108-15 cells were used to estimate safe, non-cytotoxic doses of DEX. We found that 100 and 60μM are the maximum safe dose of DEX for PC12 and NG108-15 cells, respectively, with no significant cytotoxicity. Lidocaine was found to remarkably inhibit cell vitality, but could be reversed by different doses of DEX, especially its maximum safe dose. Furthermore, the apoptosis induced by lidocaine was also assessed, and 100 and 60μM DEX showed optimal protective effects in PC12 and NG108-15 cells, respectively. Mechanistically, DEX activated the mitogen-activated protein kinase (MAPK) pathway, impaired caspase-3 expression, and enhanced anti-apoptotic factor Bcl-2 to resist lidocaine-induced apoptosis, indicating that the optimal dose of DEX alleviates lidocaine-induced cytotoxicity and should be considered in clinical application. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Comparison of codes assessing galactic cosmic radiation exposure of aircraft crew.

PubMed

Bottollier-Depois, J F; Beck, P; Bennett, B; Bennett, L; Bütikofer, R; Clairand, I; Desorgher, L; Dyer, C; Felsberger, E; Flückiger, E; Hands, A; Kindl, P; Latocha, M; Lewis, B; Leuthold, G; Maczka, T; Mares, V; McCall, M J; O'Brien, K; Rollet, S; Rühm, W; Wissmann, F

2009-10-01

The assessment of the exposure to cosmic radiation onboard aircraft is one of the preoccupations of bodies responsible for radiation protection. Cosmic particle flux is significantly higher onboard aircraft than at ground level and its intensity depends on the solar activity. The dose is usually estimated using codes validated by the experimental data. In this paper, a comparison of various codes is presented, some of them are used routinely, to assess the dose received by the aircraft crew caused by the galactic cosmic radiation. Results are provided for periods close to solar maximum and minimum and for selected flights covering major commercial routes in the world. The overall agreement between the codes, particularly for those routinely used for aircraft crew dosimetry, was better than +/-20 % from the median in all but two cases. The agreement within the codes is considered to be fully satisfactory for radiation protection purposes.

Kara Sea radioactivity assessment.

PubMed

Osvath, I; Povinec, P P; Baxter, M S

1999-09-30

Investigations following five international expeditions to the Kara Sea have shown that no radiologically significant contamination has occurred outside of the dumping sites in Novaya Zemlya bays. Increased levels of radionuclides in sediment have only been observed in Abrosimov and Stepovoy Bays very close to dumped containers. Evaluations of radionuclide inventories in water and sediment of the open Kara Sea and Novaya Zemlya bays as well as soil from the shore of Abrosimov bay have shown that radionuclide contamination of the open Kara Sea is mainly due to global fallout, with smaller contributions from the Sellafield reprocessing plant, the Chernobyl accident run-off from the Ob and Yenisey rivers and local fallout. Computer modelling results have shown that maximum annual doses of approximately 1 mSv are expected for a hypothetical critical group subsisting on fish caught in the Novaya Zemlya bays whereas populations living on the mainland can be expected to receive doses at least three orders of magnitude lower.

Cyproterone acetate in treatment of precocious puberty.

PubMed Central

Kauli, R; Pertzelan, A; Prager-Lewin, R; Grünebaum, M; Laron, Z

1976-01-01

Twenty-nine children (23 girls, 6 boys) with precocious puberty were treated with cyproterone acetate for various periods of time ranging from 6 months to 3 years 4 months. They received an oral dose ranging from 70-150 mg/m2 per day, or an intramuscular depot injection once a fortnight or once a month at a dose ranging from 107-230 mg/m2. Both forms of therapy were found to suppress the signs of sexual maturation, but the oral form proved to be superior. Only the younger patients with a bone age under 11 years showed a beneficial effect upon linear growth and bone maturation. No side effects were noted, but additional advantageous effects upon behaviour and sociability were. It is concluded that at present cyproterone acetate by mouth is the drug of choice in the treatment of precocious puberty. The treatment should be initiated as early as possible to attain maximum benefit. PMID:952553

What and how can affect the exploration of Mars

NASA Astrophysics Data System (ADS)

Vidmachenko, A. P.; Morozhenko, A. V.

2017-05-01

Going to Mars, astronauts are deprived of the protection of the magnetic field. And for 15 months of flight to Mars and back astronaut will receive maximum permissible for his entire career, a dose of radiation of 1 sievert. And when powerful flash can occur on the sun, the dose of radiation will grow by an order of magnitude and can even kill the crew. The radiation background in the orbit of Mars is more than 2.2 times higher than the radiation background at the Earth's orbital station. The smallest toxic dust on Mars is also can interfere with the colonization of Mars. This dust contains a large number of toxic compounds such as perchlorates, minerals of gypsum, compounds of chromium, fine-grained salts of silicic acid, etc. The listed above factors make forced to think seriously about the possibility of organizing a Mars mission, even in the distant future.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loupot, S; Han, T; Salehpour, M

Purpose: To quantify the difference in dose to PTV-EVAL and OARs (skin and rib) as calculated by (TG43) and heterogeneous calculations (CCC). Methods: 25 patient plans (5 Contura and 20 SAVI) were selected for analysis. Clinical dose distributions were computed with a commercially available treatment planning algorithm (TG43-D-(w,w)) and then recomputed with a pre-clinical collapsed cone convolution algorithm (CCCD-( m,m)). PTV-EVAL coverage (V90%, V95%), and rib and skin maximum dose were compared via percent difference. Differences in dose to normal tissue (V150cc, V200cc of PTV-EVAL) were also compared. Changes in coverage and maximum dose to organs at risk are reportedmore » in percent change, (100*(TG43 − CCC) / TG43)), and changes in maximum dose to normal tissue are absolute change in cc (TG43 − CCC). Results: Mean differences in V90, V95, V150, and V200 for the SAVI cases were −0.2%, −0.4%, −0.03cc, and −0.14cc, respectively, with maximum differences of −0.78%, −1.7%, 1.28cc, and 1.01cc, respectively. Mean differences in the 0.1cc dose to the rib and skin were −1.4% and −0.22%, respectively, with maximum differences of −4.5% and 16%, respectively. Mean differences in V90, V95, V150, and V200 for the Contura cases were −1.2%, −2.1%, −1.8cc, and −0.59cc, respectively, with maximum differences of −2.0%, −3.16%, −2.9cc, and −0.76cc, respectively. Mean differences in the 0.1cc dose to the rib and skin were −2.6% and −3.9%, respectively, with maximum differences of −3.2% and −5.7%, respectively. Conclusion: The effects of translating clinical knowledge based on D-(w,w) to plans reported in D-(m,m) are minimal (2% or less) on average, but vary based on the type and placement of the device, source, and heterogeneity information.« less

External effective radiation dose to workers in the restricted area of the Fukushima Daiichi Nuclear Power Plant during the third year after the Great East Japan Earthquake.

PubMed

Sakumi, Akira; Miyagawa, Ryu; Tamari, Yuki; Nawa, Kanabu; Sakura, Osamu; Nakagawa, Keiichi

2016-03-01

Since the Great East Japan Earthquake on 11 March 2011, Iitate Village has continued to be classified as a deliberate evacuation area, in which residents are estimated to receive an annual additional effective radiation dose of >20 mSv. Some companies still operate in Iitate Village, with a special permit from the Cabinet Office Team in Charge of Assisting the Lives of Disaster Victims. In this study, we measured the annual effective radiation dose to workers in Iitate Village from 15 January to 13 December 2013. The workers stayed in Iitate for 10 h and left the village for the remaining 14 h each working day. They worked for 5 days each week in Iitate Village, but stayed outside of the village for the remaining 2 days each week. We found that the effective radiation dose of 70% of the workers was <2 mSv, including natural radiation; the maximum dose was 3.6 mSv. We estimated the potential annual additional effective radiation dose if people returned full-time to Iitate. Our analysis supports the plan for people to return to their home village at the end of 2017. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry.

PubMed

Kromann, Sofie; Kudirkiene, Egle; Li, Lili; Thoefner, Ida; Daldorph, Elisabeth; Christensen, Jens Peter; Meng, Hecheng; Olsen, Rikke Heidemann

2017-01-01

There is an urgent need for novel antibiotics as the current antibiotics are losing their value due to increased resistance among clinically important bacteria. Sertraline, an on-marked anti-depressive drug, has been shown to modify bacterial activity in vitro, including increasing the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline, tetracycline, a combination hereof or received no treatment. Seven days post challenge all birds were submitted to necropsy and scored pathologically for lesions. The average lesion scores were significantly higher (P<0.05) in the groups that were treated with high-dose sertraline or high-dose sertraline combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens.

Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry

PubMed Central

Kromann, Sofie; Kudirkiene, Egle; Li, Lili; Thoefner, Ida; Daldorph, Elisabeth; Christensen, Jens Peter; Meng, Hecheng

2017-01-01

There is an urgent need for novel antibiotics as the current antibiotics are losing their value due to increased resistance among clinically important bacteria. Sertraline, an on-marked anti-depressive drug, has been shown to modify bacterial activity in vitro, including increasing the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline, tetracycline, a combination hereof or received no treatment. Seven days post challenge all birds were submitted to necropsy and scored pathologically for lesions. The average lesion scores were significantly higher (P<0.05) in the groups that were treated with high-dose sertraline or high-dose sertraline combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens. PMID:29020098

Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents--dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study.

PubMed

Postel-Vinay, Sophie; Collette, Laurence; Paoletti, Xavier; Rizzo, Elisa; Massard, Christophe; Olmos, David; Fowst, Camilla; Levy, Bernard; Mancini, Pierre; Lacombe, Denis; Ivy, Percy; Seymour, Lesley; Le Tourneau, Christophe; Siu, Lillian L; Kaye, Stan B; Verweij, Jaap; Soria, Jean-Charles

2014-08-01

Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention. In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded. The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G ⩾ 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G⩾3 toxicity occurring after C1 in 18.6% of patients. Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI. Copyright © 2014 Elsevier Ltd. All rights reserved.

Estimates of the pharmacokinetics of famciclovir and its active metabolite penciclovir in young Asian elephants (Elephas maximus).

PubMed

Brock, A Paige; Isaza, Ramiro; Hunter, Robert P; Richman, Laura K; Montali, Richard J; Schmitt, Dennis L; Koch, David E; Lindsay, William A

2012-12-01

To determine plasma pharmacokinetics of penciclovir following oral and rectal administration of famciclovir to young Asian elephants (Elephas maximus). 6 healthy Asian elephants (5 females and 1 male), 4.5 to 9 years old and weighing 1,646 to 2,438 kg. Famciclovir was administered orally or rectally in accordance with an incomplete crossover design. Three treatment groups, each comprising 4 elephants, received single doses of famciclovir (5 mg/kg, PO, or 5 or 15 mg/kg, rectally); there was a minimum 12-week washout period between subsequent famciclovir administrations. Serial blood samples were collected after each administration. Samples were analyzed for famciclovir and penciclovir with a validated liquid chromatography-mass spectroscopy assay. Famciclovir was tolerated well for both routes of administration and underwent complete biotransformation to the active metabolite, penciclovir. Mean maximum plasma concentration of penciclovir was 1.3 μg/mL at 1.1 hours after oral administration of 5 mg/kg. Similar results were detected after rectal administration of 5 mg/kg. Mean maximum plasma concentration was 3.6 μg/mL at 0.66 hours after rectal administration of 15 mg/kg; this concentration was similar to results reported for humans receiving 7 mg/kg orally. Juvenile Asian elephants are susceptible to elephant endotheliotropic herpesvirus. Although most infections are fatal, case reports indicate administration of famciclovir has been associated with survival of 3 elephants. In Asian elephants, a dose of 8 to 15 mg of famciclovir/kg given orally or rectally at least every 8 hours may result in penciclovir concentrations that are considered therapeutic in humans.

Reduced radiation dose for elective nodal irradiation in node-negative anal cancer: back to the roots?

PubMed

Henkenberens, Christoph; Meinecke, Daniela; Michael, Stoll; Bremer, Michael; Christiansen, Hans

2015-11-01

Chemoradiation (CRT) is the standard of care in patients with node-positive (cN+) and node-negative (cN0) anal cancer. Depending on the tumor size (T-stage), total doses of 50-60 Gray (Gy) in daily fractions of 1.8-2.0 Gy are usually applied to the tumor site. Inguinal and iliac lymph nodes usually receive a dose of ≥ 45 Gy. Since 2010, our policy has been to apply a reduced total dose of 39.6 Gy to uninvolved nodal regions. This paper provides preliminary results of the efficacy and safety of this protocol. Overall, 30 patients with histologically confirmed and node-negative anal cancer were treated in our department from 2009-2014 with definitive CRT. Histology all cases showed squamous cell carcinoma. A total dose of 39.6 Gy [single dose (SD) 1.8 Gy] was delivered to the iliac/inguinal lymph nodes. The area of the primary tumor received 50-59.4 Gy, depending on the T-stage. In parallel with the irradiation, 5-fluorouracil (5-FU) at a dose of 1000 mg/m(2) was administered by continuous intravenous infusion over 24 h on days 1-4 and 29-32, and mitomycin C (MMC) at a dose of 10 mg/m(2) (maximum absolute dose 14 mg) was administered on days 1 and 29. The distribution of the tumor stages was as follows: T1, n = 8; T2, n = 17; T3 n = 3. Overall survival (OS), local control (LC) of the lymph nodes, colostomy-free survival (CFS), and acute and chronic toxicities were assessed. The median follow-up was 27.3 months (range 2.7-57.4 months). Three patients (10.0 %) died, 2 of cardiopulmonary diseases and one of liver failure, yielding a 3-year OS of 90.0 %. Two patients (6.7 %) relapsed early and received salvage colostomies, yielding a 3-year CFS of 93.3 %. No lymph node relapses were observed, giving a lymph node LC of 100 %. According to the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V. 4.0), there were no grade IV gastrointestinal or genitourinary acute toxicities. Seven patients showed acute grade III perineal skin toxicity. Acute grade III groin skin toxicity was not observed. Reducing the total irradiation dose to uninvolved nodal regions to 39.6 Gy in chemoradiation protocols for anal carcinoma was safe and effective, and a prospective evaluation in future clinical trials is warranted.

A comprehensive dosimetric study of pancreatic cancer treatment using three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric-modulated radiation therapy (VMAT), and passive-scattering and modulated-scanning proton therapy (PT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Xuanfeng; Dionisi, Francesco; Tang, Shikui

With traditional photon therapy to treat large postoperative pancreatic target volume, it often leads to poor tolerance of the therapy delivered and may contribute to interrupted treatment course. This study was performed to evaluate the potential advantage of using passive-scattering (PS) and modulated-scanning (MS) proton therapy (PT) to reduce normal tissue exposure in postoperative pancreatic cancer treatment. A total of 11 patients with postoperative pancreatic cancer who had been previously treated with PS PT in University of Pennsylvania Roberts Proton Therapy Center from 2010 to 2013 were identified. The clinical target volume (CTV) includes the pancreatic tumor bed as wellmore » as the adjacent high-risk nodal areas. Internal (iCTV) was generated from 4-dimensional (4D) computed tomography (CT), taking into account target motion from breathing cycle. Three-field and 4-field 3D conformal radiation therapy (3DCRT), 5-field intensity-modulated radiation therapy, 2-arc volumetric-modulated radiation therapy, and 2-field PS and MS PT were created on the patients’ average CT. All the plans delivered 50.4 Gy to the planning target volume (PTV). Overall, 98% of PTV was covered by 95% of the prescription dose and 99% of iCTV received 98% prescription dose. The results show that all the proton plans offer significant lower doses to the left kidney (mean and V{sub 18} {sub Gy}), stomach (mean and V{sub 20} {sub Gy}), and cord (maximum dose) compared with all the photon plans, except 3-field 3DCRT in cord maximum dose. In addition, MS PT also provides lower doses to the right kidney (mean and V{sub 18} {sub Gy}), liver (mean dose), total bowel (V{sub 20} {sub Gy} and mean dose), and small bowel (V{sub 15} {sub Gy} absolute volume ratio) compared with all the photon plans and PS PT. The dosimetric advantage of PT points to the possibility of treating tumor bed and comprehensive nodal areas while providing a more tolerable treatment course that could be used for dose escalation and combining with radiosensitizing chemotherapy.« less

TH-EF-BRB-03: Significant Cord and Esophagus Dose Reduction by 4π Non-Coplanar Spine Stereotactic Body Radiation Therapy and Stereotactic Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, V; Tran, A; Nguyen, D

Purpose: To demonstrate significant organ-at-risk (OAR) sparing achievable with 4π non-coplanar radiotherapy on spine SBRT and SRS patients. Methods: Twenty-five stereotactic spine cases previously treated with VMAT (n = 23) or IMRT (n = 2) were included in this study. A computer-aided-design model of a Linac with a 3D-scanned human surface was utilized to determine the feasible beam space throughout the 4π steradian and beam specific source-to-target-distances (STD) required for collision avoidance. 4π radiotherapy plans integrating beam orientation and fluence map optimization were then created using a column-generation algorithm. Twenty optimal beams were selected for each case. To evaluate themore » tradeoff between dosimetric benefit and treatment complexity, 4π plans including only isocentrically deliverable beams were also created. Beam angles of all standard and isocentric 4π plans were imported into Eclipse to recalculate the dose using the same calculation engine as the clinical plans for unbiased comparison. OAR and PTV dose statistics for the clinical, standard-4π, and isocentric-4π plans were compared. Results: Comparing standard-4π to clinical plans, particularly significant average percent reduction in the [mean, maximum] dose of the cord and esophagus of [41%, 21.7%], and [38.7%, 36.4%] was observed, along with global decrease in all other OAR dose statistics. The average cord volume receiving more than 50% prescription dose was substantially decreased by 76%. In addition, improved PTV coverage was demonstrated with a maximum dose reduction of 0.93% and 1.66% increase in homogeneity index (D95/D5). All isocentric-4π plans achieved dosimetric performance equivalent to that of the standard-4π plans with higher delivery complexity. Conclusion: 4π radiotherapy significantly improves stereotactic spine treatment dosimetry. With the substantial OAR dose sparing, PTV dose escalation is considerably safer. Isocentric-4π is sufficient to achieve the dosimetric gain. The successful implementation of 4π using an FDA approved planning system paves the way for a prospective clinical trial. Varian Medical Systems, NIH R43CA183390 and R01CA188300, NSF graduate research fellowship DGE-1144087.« less

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh).

PubMed

Flammer, Keven; Nettifee Osborne, Julie A; Webb, Donna J; Foster, Laura E; Dillard, Stacy L; Davis, Jennifer L

2008-01-01

To determine the pharmacokinetics and safety of orally administered voriconazole in African grey parrots. 20 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). In single-dose trials, 12 parrots were each administered 6, 12, and 18 mg of voriconazole/kg orally and plasma concentrations of voriconazole were determined via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) was administered orally to 6 birds every 12 hours for 9 days; a control group (2 birds) received tap water. Treatment effects were assessed via observation, clinicopathologic analyses (3 assessments), and measurement of trough plasma voriconazole concentrations (2 assessments). Voriconazole's elimination half-life was short (1.1 to 1.6 hours). Higher doses resulted in disproportional increases in the maximum plasma voriconazole concentration and area under the curve. Trough plasma voriconazole concentrations achieved in the multiple-dose trial were lower than those achieved after administration of single doses. Polyuria (the only adverse treatment effect) developed in treated and control birds but was more severe in the treatment group. In African grey parrots, voriconazole has dose-dependent pharmacokinetics and may induce its own metabolism. Oral administration of 12 to 18 mg of voriconazole/kg twice daily is a rational starting dose for treatment of African grey parrots infected with Aspergillus or other fungal organisms that have a minimal inhibitory concentration for voriconazole < or = 0.4 microg/mL. Higher doses may be needed to maintain plasma voriconazole concentrations during long-term treatment. Safety and efficacy of various voriconazole treatment regimens in this species require investigation.

A Multidisciplinary Orbit-Sparing Treatment Approach That Includes Proton Therapy for Epithelial Tumors of the Orbit and Ocular Adnexa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holliday, Emma B.; Esmaeli, Bita; Pinckard, Jamie

Purpose: Postoperative radiation is often indicated in the treatment of malignant epithelial tumors of the orbit and ocular adnexa. We present details of radiation technique and toxicity data after orbit-sparing surgery followed by adjuvant proton radiation therapy. Methods and Materials: Twenty patients underwent orbit-sparing surgery followed by proton therapy for newly diagnosed malignant epithelial tumors of the lacrimal gland (n=7), lacrimal sac/nasolacrimal duct (n=10), or eyelid (n=3). Tumor characteristics, treatment details, and visual outcomes were obtained from medical records. Acute and chronic toxicity were prospectively scored using Common Terminology Criteria for Adverse Events version 4.0. Results: The median radiation dosemore » was 60 Gy(RBE) (relative biological effectiveness; [range 50-70 Gy]); 11 patients received concurrent chemotherapy. Dose to ipsilateral anterior optic structures was reduced in 13 patients by having them gaze away from the target during treatment. At a median follow-up time of 27.1 months (range 2.6-77.2 months), no patient had experienced local recurrence; 1 had regional and 1 had distant recurrence. Three patients developed chronic grade 3 epiphora, and 3 developed grade 3 exposure keratopathy. Four patients experienced a decrease in visual acuity from baseline but maintained vision sufficient to perform all activities of daily living without difficulty. Patients with grade ≥3 chronic ocular toxicity had higher maximum dose to the ipsilateral cornea (median 46.3 Gy[RBE], range 36.6-52.7 Gy[RBE] vs median 37.4 Gy[RBE], range 9.0-47.3 Gy(RBE); P=.017). Conclusions: Orbit-sparing surgery for epithelial tumors of the orbit and ocular adnexa followed by proton therapy successfully achieved disease control and was well tolerated. No patient required orbital exenteration or enucleation. Chronic grade 3 toxicity was associated with high maximum dose to the cornea. An eye-deviation technique can be used to limit the maximum corneal dose to <35 Gy(RBE).« less

Assessment of extended-release opioid analgesics for the treatment of chronic pain.

PubMed

Gudin, Jeffrey A

2013-03-01

Approximately 3.8 million patients annually receive extended-release (ER) or long-acting opioid prescriptions in the outpatient setting, around half of which are written by primary care physicians. Compared with short-acting, immediate-release (IR) formulations, ER and oral long-acting opioid analgesics are associated with clinical advantages, such as extended periods of time during which drug plasma levels are within the therapeutic range, decreased peak-to-trough fluctuations, and prolonged analgesia over the dosing period. Additionally, ER opioids offer a more convenient, less frequent dosing regimen to chronic pain patients who are often taking several concomitant medications. The increased utilization of ER opioids has been accompanied by a rise in the misuse and abuse of these formulations. Certain pharmacokinetic parameters (e.g., longer time to maximum drug plasma concentration, lower maximum drug plasma concentration) may decrease the abuse potential of intact ER opioids by limiting the positive subjective and reinforcing effects relative to IR formulations. Putative abuse-deterrent formulations have also recently been introduced to impede physical manipulation of these formulations, or reduce the harm resulting from such behavior. Such formulations may represent an incremental advance to reduce non-oral forms of abuse. This article reviews the pharmacokinetic profiles and abuse-deterrent features of newer ER opioid analgesics for the treatment of moderate to severe chronic pain.

Update on emergency contraception.

PubMed

Fok, Wing Kay; Blumenthal, Paul D

2016-12-01

Emergency contraception provides a critical and time-sensitive opportunity for women to prevent undesired pregnancy after intercourse. Both access and available options for emergency contraception have changed over the last several years. Emergency contraceptive pills can be less effective in obese women. The maximum achieved serum concentration of levonorgestrel (LNG) is lower in obese women than women of normal BMI, and doubling the dose of LNG (3 mg) increases its concentration maximum, approximating the level in normal BMI women receiving one dose of LNG. Repeated use of both LNG and ulipristal acetate (UPA) is well tolerated. Hormonal contraception can be immediately started following LNG use, but should be delayed for 5 days after UPA use to avoid dampening the efficacy of UPA. The copper intrauterine device (IUD) is the only IUD approved for emergency contraception (and the most effective method of emergency contraception), but use of LNG IUD as emergency contraception is currently being investigated. Accurate knowledge about emergency contraception remains low both for patients and healthcare providers. Emergency contraception is an important yet underutilized tool available to women to prevent pregnancy. Current options including copper IUD and emergency contraceptive pills are safe and well tolerated. Significant gaps in knowledge of emergency contraception on both the provider and user level exist, as do barriers to expedient access of emergency contraception.

On the use of volumetric-modulated arc therapy for single-fraction thoracic vertebral metastases stereotactic body radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, Damodar, E-mail: damodar.pokhrel@uky.edu; Sood, Sumit; McClinton, Christopher

To retrospectively evaluate quality, efficiency, and delivery accuracy of volumetric-modulated arc therapy (VMAT) plans for single-fraction treatment of thoracic vertebral metastases using image-guided stereotactic body radiosurgery (SBRS) after RTOG 0631 dosimetric compliance criteria. After obtaining credentialing for MD Anderson spine phantom irradiation validation, 10 previously treated patients with thoracic vertebral metastases with noncoplanar hybrid arcs using 1 to 2 3D-conformal partial arcs plus 7 to 9 intensity-modulated radiation therapy beams were retrospectively re-optimized with VMAT using 3 full coplanar arcs. Tumors were located between T2 and T12. Contrast-enhanced T1/T2-weighted magnetic resonance images were coregistered with planning computed tomography and planningmore » target volumes (PTV) were between 14.4 and 230.1 cc (median = 38.0 cc). Prescription dose was 16 Gy in 1 fraction with 6 MV beams at Novalis-TX linear accelerator consisting of micro multileaf collimators. Each plan was assessed for target coverage using conformality index, the conformation number, the ratio of the volume receiving 50% of the prescription dose over PTV, R50%, homogeneity index (HI), and PTV-1600 coverage per RTOG 0631 requirements. Organs-at-risk doses were evaluated for maximum doses to spinal cord (D{sub 0.03} {sub cc}, D{sub 0.35} {sub cc}), partial spinal cord (D{sub 10%}), esophagus (D{sub 0.03} {sub cc} and D{sub 5} {sub cc}), heart (D{sub 0.03} {sub cc} and D{sub 15} {sub cc}), and lung (V{sub 5}, V{sub 10}, and maximum dose to 1000 cc of lung). Dose delivery efficiency and accuracy of each VMAT-SBRS plan were assessed using quality assurance (QA) plan on MapCHECK device. Total beam-on time was recorded during QA procedure, and a clinical gamma index (2%/2 mm and 3%/3 mm) was used to compare agreement between planned and measured doses. All 10 VMAT-SBRS plans met RTOG 0631 dosimetric requirements for PTV coverage. The plans demonstrated highly conformal and homogenous coverage of the vertebral PTV with mean HI, conformality index, conformation number, and R{sub 50%} values of 0.13 ± 0.03 (range: 0.09 to 0.18), 1.03 ± 0.04 (range: 0.98 to 1.09), 0.81 ± 0.06 (range: 0.72 to 0.89), and 4.2 ± 0.94 (range: 2.7 to 5.4), respectively. All 10 patients met protocol guidelines with maximum dose to spinal cord (average: 8.83 ± 1.9 Gy, range: 5.9 to 10.9 Gy); dose to 0.35 cc of spinal cord (average: 7.62 ± 1.7 Gy, range: 5.4 to 9.6 Gy); and dose to 10% of partial spinal cord (average 6.31 ± 1.5 Gy, range: 3.5 to 8.5 Gy) less than 14, 10, and 10 Gy, respectively. For all 10 patients, the maximum dose to esophagus (average: 9.41 ± 4.3 Gy, range: 1.5 to 14.9 Gy) and dose to 5 cc of esophagus (average: 7.43 ± 3.8 Gy, range: 1.1 to 11.8 Gy) were kept less than protocol requirements 16 Gy and 11.9 Gy, respectively. In a similar manner, all 10 patients met protocol compliance criteria with maximum dose to heart (average: 4.62 ± 3.5 Gy, range: 1.3 to 10.2 Gy) and dose to 15 cc of heart (average: 2.23 ± 1.8 Gy, range: 0.3 to 5.6 Gy) less than 22 and 16 Gy, respectively. The dose to the lung was retained much lower than protocol guidelines for all 10 patients. The total number of monitor units was, on average, 6919 ± 1187. The average beam-on time was 11.5 ± 2.0 minutes. The VMAT plans demonstrated dose delivery accuracy of 95.8 ± 0.7%, on average, for clinical gamma passing rate with 2%/2 mm criteria and 98.3 ± 0.8%, on average, with 3%/3 mm criteria. All VMAT-SBRS plans were considered clinically acceptable per RTOG 0631 dosimetric compliance criteria. VMAT planning provided highly conformal and homogenous dose distributions for the lower-dose vertebral PTV and the spinal cord as well as organs-at-risk such as esophagus, heart, and lung. Higher QA pass rates and shorter beam-on time suggest that VMAT-SBRS is a clinically feasible, fast, and effective treatment option for patients with thoracic vertebral metastases.« less

Dose-dependent immunogenicity of a soluble Neospora caninum tachyzoite-extract vaccine formulated with a soy lecithin/β-glucan adjuvant in cattle.

PubMed

Mansilla, F C; Czepluch, W; Malacari, D A; Hecker, Y P; Bucafusco, D; Franco-Mahecha, O L; Moore, D P; Capozzo, A V

2013-10-18

Mice immunized with a soluble extract of Neospora caninum tachyzoites (sNcAg) formulated with Providean-AVEC, an aqueous soy-based adjuvant, are fully protected from N. caninum multiplication. Here we evaluated the dose-dependent immunogenicity of this vaccine formulation in cattle. Cattle (N=3 per group) were immunized with two applications (30 days apart) of formulations containing Providean-AVEC and different payloads of sNcAg (100, 50 and 10 μg), that were five to fifty times lower than the only reported study using this same antigen in cattle. Kinetics and magnitude of the vaccine-induced immune responses were dose-dependent. Cattle immunized with 100 μg-sNcAg elicited high-avidity specific antibodies 3 weeks after the primary vaccination while those that received 50 μg of antigen had maximum levels of specific high-avidity antibodies 5 days after the day 30 boost. Vaccination with 10 μg of sNcAg induced comparable antibody responses after 2 weeks post re-vaccination. IgG1 was the predominant isotype in all vaccinated animals. Maximum systemic IFN-γ levels were measured in cattle immunized with 50 and 100 μg-sNcAg (14 ± 2.8 ng/ml). CD4(+)-T cells from vaccinated animals proliferated after sNcAg stimulation in vitro, producing IFN-γ. Recall IFN-γ responses mediated by CD4(+)-T cells were detected up to 140 days post vaccination. Formulations containing Providean-AVEC and 50 μg of sNcAg stimulated broad cellular and humoral immune responses against N. caninum in cattle. The profile and magnitude of the immune response elicited by this vaccine can be modified by the antigen-dose and vaccination schedule. This is the first dose-response study performed in cattle using sNcAg as antigen. Copyright © 2013 Elsevier B.V. All rights reserved.

WE-AB-202-04: Statistical Evaluation of Lung Function Using 4DCT Ventilation Imaging: Proton Therapy VS IMRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Q; Zhang, M; Chen, T

Purpose: Variation in function of different lung regions has been ignored so far for conventional lung cancer treatment planning, which may lead to higher risk of radiation induced lung disease. 4DCT based lung ventilation imaging provides a novel yet convenient approach for lung functional imaging as 4DCT is taken as routine for lung cancer treatment. Our work aims to evaluate the impact of accounting for spatial heterogeneity in lung function using 4DCT based lung ventilation imaging for proton and IMRT plans. Methods: Six patients with advanced stage lung cancer of various tumor locations were retrospectively evaluated for the study. Protonmore » and IMRT plans were designed following identical planning objective and constrains for each patient. Ventilation images were calculated from patients’ 4DCT using deformable image registration implemented by Velocity AI software based on Jacobian-metrics. Lung was delineated into two function level regions based on ventilation (low and high functional area). High functional region was defined as lung ventilation greater than 30%. Dose distribution and statistics in different lung function area was calculated for patients. Results: Variation in dosimetric statistics of different function lung region was observed between proton and IMRT plans. In all proton plans, high function lung regions receive lower maximum dose (100.2%–108.9%), compared with IMRT plans (106.4%–119.7%). Interestingly, three out of six proton plans gave higher mean dose by up to 2.2% than IMRT to high function lung region. Lower mean dose (lower by up to 14.1%) and maximum dose (lower by up to 9%) were observed in low function lung for proton plans. Conclusion: A systematic approach was developed to generate function lung ventilation imaging and use it to evaluate plans. This method hold great promise in function analysis of lung during planning. We are currently studying more subjects to evaluate this tool.« less

Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer

PubMed Central

Conlon, Kevin C.; Lugli, Enrico; Welles, Hugh C.; Rosenberg, Steven A.; Fojo, Antonio Tito; Morris, John C.; Fleisher, Thomas A.; Dubois, Sigrid P.; Perera, Liyanage P.; Stewart, Donn M.; Goldman, Carolyn K.; Bryant, Bonita R.; Decker, Jean M.; Chen, Jing; Worthy, Tat'Yana A.; Figg, William D.; Peer, Cody J.; Sneller, Michael C.; Lane, H. Clifford; Yovandich, Jason L.; Creekmore, Stephen P.; Roederer, Mario; Waldmann, Thomas A.

2015-01-01

Purpose Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. Conclusion IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration. PMID:25403209

A retrospective analysis of rectal and bladder dose for gynecological brachytherapy treatments with GZP6 HDR afterloading system.

PubMed

Bahreyni Toossi, Mohammad Taghi; Ghorbani, Mahdi; Makhdoumi, Yasha; Taheri, Mojtaba; Homaee Shandiz, Fatemeh; Zahed Anaraki, Siavash; Soleimani Meigooni, Ali

2012-01-01

The aim of this work is to evaluate rectal and bladder dose for the patients treated for gynecological cancers. The GZP6 high dose rate brachytherapy system has been recently introduced to a number of radiation therapy departments in Iran, for treatment of various tumor sites such as cervix and vagina. Our analysis was based on dose measurements for 40 insertions in 28 patients, treated by a GZP6 unit between June 2009 and November 2010. Treatments consisted of combined teletherapy and intracavitary brachytherapy. In vivo dosimetry was performed with TLD-400 chips and TLD-100 microcubes in the rectum and bladder. The average of maximum rectal and bladder dose values were found to be 7.62 Gy (range 1.72-18.55 Gy) and 5.17 Gy (range 0.72-15.85 Gy), respectively. It has been recommended by the ICRU that the maximum dose to the rectum and bladder in intracavitary treatment of vaginal or cervical cancer should be lower than 80% of the prescribed dose to point A in the Manchester system. In this study, of the total number of 40 insertions, maximum rectal dose in 29 insertions (72.5% of treatment sessions) and maximum bladder dose in 18 insertions (45% of treatments sessions) were higher than 80% of the prescribed dose to the point of dose prescription. In vivo dosimetry for patients undergoing treatment by GZP6 brachytherapy system can be used for evaluation of the quality of brachytherapy treatments by this system. This information could be used as a base for developing the strategy for treatment of patients treated with GZP6 system.

A retrospective analysis of rectal and bladder dose for gynecological brachytherapy treatments with GZP6 HDR afterloading system

PubMed Central

Bahreyni Toossi, Mohammad Taghi; Ghorbani, Mahdi; Makhdoumi, Yasha; Taheri, Mojtaba; Homaee Shandiz, Fatemeh; Zahed Anaraki, Siavash; Soleimani Meigooni, Ali

2012-01-01

Aim The aim of this work is to evaluate rectal and bladder dose for the patients treated for gynecological cancers. Background The GZP6 high dose rate brachytherapy system has been recently introduced to a number of radiation therapy departments in Iran, for treatment of various tumor sites such as cervix and vagina. Materials and methods Our analysis was based on dose measurements for 40 insertions in 28 patients, treated by a GZP6 unit between June 2009 and November 2010. Treatments consisted of combined teletherapy and intracavitary brachytherapy. In vivo dosimetry was performed with TLD-400 chips and TLD-100 microcubes in the rectum and bladder. Results The average of maximum rectal and bladder dose values were found to be 7.62 Gy (range 1.72–18.55 Gy) and 5.17 Gy (range 0.72–15.85 Gy), respectively. It has been recommended by the ICRU that the maximum dose to the rectum and bladder in intracavitary treatment of vaginal or cervical cancer should be lower than 80% of the prescribed dose to point A in the Manchester system. In this study, of the total number of 40 insertions, maximum rectal dose in 29 insertions (72.5% of treatment sessions) and maximum bladder dose in 18 insertions (45% of treatments sessions) were higher than 80% of the prescribed dose to the point of dose prescription. Conclusion In vivo dosimetry for patients undergoing treatment by GZP6 brachytherapy system can be used for evaluation of the quality of brachytherapy treatments by this system. This information could be used as a base for developing the strategy for treatment of patients treated with GZP6 system. PMID:24377037

Cosmic radiation exposure of biological test systems during the EXPOSE-E mission.

PubMed

Berger, Thomas; Hajek, Michael; Bilski, Pawel; Körner, Christine; Vanhavere, Filip; Reitz, Günther

2012-05-01

In the frame of the EXPOSE-E mission on the Columbus external payload facility EuTEF on board the International Space Station, passive thermoluminescence dosimeters were applied to measure the radiation exposure of biological samples. The detectors were located either as stacks next to biological specimens to determine the depth dose distribution or beneath the sample carriers to determine the dose levels for maximum shielding. The maximum mission dose measured in the upper layer of the depth dose part of the experiment amounted to 238±10 mGy, which relates to an average dose rate of 408±16 μGy/d. In these stacks of about 8 mm height, the dose decreased by 5-12% with depth. The maximum dose measured beneath the sample carriers was 215±16 mGy, which amounts to an average dose rate of 368±27 μGy/d. These values are close to those assessed for the interior of the Columbus module and demonstrate the high shielding of the biological experiments within the EXPOSE-E facility. Besides the shielding by the EXPOSE-E hardware itself, additional shielding was experienced by the external structures adjacent to EXPOSE-E, such as EuTEF and Columbus. This led to a dose gradient over the entire exposure area, from 215±16 mGy for the lowest to 121±6 mGy for maximum shielding. Hence, the doses perceived by the biological samples inside EXPOSE-E varied by 70% (from lowest to highest dose). As a consequence of the high shielding, the biological samples were predominantly exposed to galactic cosmic heavy ions, while electrons and a significant fraction of protons of the radiation belts and solar wind did not reach the samples.