"Sequential" boron neutron capture therapy (BNCT): a novel approach to BNCT for the treatment of oral cancer in the hamster cheek pouch model.

PubMed

Molinari, Ana J; Pozzi, Emiliano C C; Monti Hughes, Andrea; Heber, Elisa M; Garabalino, Marcela A; Thorp, Silvia I; Miller, Marcelo; Itoiz, Maria E; Aromando, Romina F; Nigg, David W; Quintana, Jorge; Santa Cruz, Gustavo A; Trivillin, Verónica A; Schwint, Amanda E

2011-04-01

In the present study the therapeutic effect and potential toxicity of the novel "Sequential" boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster cheek pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with "Sequential" BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the "Sequential" BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in the dose-limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47 ± 12% and 60 ± 22% of the animals, respectively. No normal tissue toxicity was associated with tumor response for any of the protocols. "Sequential" BNCT enhanced tumor response without an increase in mucositis in dose-limiting precancerous tissue. © 2011 by Radiation Research Society

Two-week, high-dose proton pump inhibitor, moxifloxacin triple Helicobacter pylori therapy after failure of standard triple or non-bismuth quadruple treatments.

PubMed

Gisbert, Javier P; Romano, Marco; Molina-Infante, Javier; Lucendo, Alfredo J; Medina, Enrique; Modolell, Inés; Rodríguez-Tellez, Manuel; Gomez, Blas; Barrio, Jesús; Perona, Monica; Ortuño, Juan; Ariño, Inés; Domínguez-Muñoz, Juan Enrique; Perez-Aisa, Ángeles; Bermejo, Fernando; Domínguez, Jose Luis; Almela, Pedro; Gomez-Camarero, Judith; Millastre, Judith; Martin-Noguerol, Elisa; Gravina, Antonietta G; Martorano, Marco; Miranda, Agnese; Federico, Alessandro; Fernandez-Bermejo, Miguel; Angueira, Teresa; Ferrer-Barcelo, Luis; Fernández, Nuria; Marín, Alicia C; McNicholl, Adrián G

2015-02-01

Aim was to evaluate the efficacy and tolerability of a moxifloxacin-containing second-line triple regimen in patients whose previous Helicobacter pylori eradication treatment failed. Prospective multicentre study including patients in whom a triple therapy or a non-bismuth-quadruple-therapy failed. Moxifloxacin (400mg qd), amoxicillin (1g bid), and esomeprazole (40 mg bid) were prescribed for 14 days. Eradication was confirmed by (13)C-urea-breath-test. Compliance was determined through questioning and recovery of empty medication envelopes. 250 patients were consecutively included (mean age 48 ± 15 years, 11% with ulcer). Previous (failed) therapy included: standard triple (n = 179), sequential (n = 27), and concomitant (n = 44); 97% of patients took all medications, 4 were lost to follow-up. Intention-to-treat and per-protocol eradication rates were 82.4% (95% CI, 77-87%) and 85.7% (95% CI, 81-90%). Cure rates were similar independently of diagnosis (ulcer, 77%; dyspepsia, 82%) and previous treatment (standard triple, 83%; sequential, 89%; concomitant, 77%). At multivariate analysis, only age was associated with eradication (OR = 0.957; 95% CI, 0.933-0.981). Adverse events were reported in 25.2% of patients: diarrhoea (9.6%), abdominal pain (9.6%), and nausea (9.2%). 14-day moxifloxacin-containing triple therapy is an effective and safe second-line strategy in patients whose previous standard triple therapy or non-bismuth quadruple (sequential or concomitant) therapy has failed, providing a simple alternative to bismuth quadruple regimen. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

[Diseases linked to Helicobacter pylori infection].

PubMed

Gisbert, Javier P

2014-09-01

Below is a summary of the main conclusions that came from reports presented at this year's Digestive Disease Week (2014) relating to Helicobacter pylori infection. Despite the undeniable decline of the infection's frequency, in the near future, developed countries--or at least some sub-populations--will continue to have a significant prevalence of the infection. Clarithromycin, metronidazole and quinolone resistance rates are considerably high in most countries and these rates are on the rise. The eradication of H. pylori improves symptoms of functional dyspepsia, although only in a minority of patients; adding antidepressants to eradication therapy could improve long-term response. In patients who were admitted with gastrointestinal bleeding from peptic ulcers, it is necessary to thoroughly study the presence of H. pylori infection and administer eradication therapy as early as possible. Eradication of H. pylori in patients undergoing endoscopic resection of early-stage gastric cancer reduces incidence of metachronous tumors. We have some diagnostic innovations, such as carrying out various techniques--a rapid urease test, culture or PCR--based on gastric samples obtained by scraping the mucosa. The effectiveness of conventional triple therapy is clearly insufficient and continues to decline. The superiority of sequential therapy over conventional triple therapies has not been definitively established. Concomitant therapy is simpler and more effective than sequential therapy. Optimized concomitant therapy (with high doses of proton-pump inhibitors [PPI] and over 14 days) is highly effective, more so than standard concomitant therapy. For patients who are allergic to penicillin, 2 treatment options were essentially described: PPI-clarithromycin-metronidazole (clarithromycin-sensitive strains) and quadruple therapy with bismuth (when the bacterial sensitivity is unknown). If conventional triple therapy fails, second-line therapy with levofloxacin is effective and is also easier and better tolerated than quadruple therapy with bismuth. Triple therapy with levofloxacin is also a promising alternative if sequential or concomitant therapy fails. New-generation quinolones, such as moxifloxacin, could be useful as part of rescue eradication therapy. Even after 3 eradication therapies have failed, a fourth empirical rescue therapy (with rifabutin) could be effective. The eradication of H. pylori can finally be obtained in the vast majority of patients by using a rescue strategy of up to 4 consecutive empirical therapies, without conducting bacterial cultures. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model.

PubMed

Perosky, Joseph E; Khoury, Basma M; Jenks, Terese N; Ward, Ferrous S; Cortright, Kai; Meyer, Bethany; Barton, David K; Sinder, Benjamin P; Marini, Joan C; Caird, Michelle S; Kozloff, Kenneth M

2016-12-01

Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in OI, or in any animal model. To determine whether cessation of sclerostin antibody therapy in a growing OI skeleton requires sequential anti-resorptive treatment to preserve anabolic gains in bone mass, we treated 3week old Brtl/+ and wild type mice for 5weeks with SclAb, and then withdrew treatment for an additional 6weeks. Trabecular bone loss was evident following cessation, but was preserved in a dose-dependent manner with single administration of pamidronate at the time of cessation. In vivo longitudinal near-infrared optical imaging of cathepsin K activation in the proximal tibia suggests an anti-resorptive effect of both SclAb and pamidronate which is reversed after three weeks of cessation. Cortical bone was considerably less susceptible to cessation effects, and showed no structural or functional deficits in the absence of pamidronate during this cessation period. In conclusion, while SclAb induces a considerable anabolic gain in the rapidly growing Brtl/+ murine model of OI, a single sequential dose of antiresorptive drug is required to maintain bone mass at trabecular sites for 6weeks following cessation. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of an antibiotic intravenous to oral sequential therapy program.

PubMed

Pablos, Ana I; Escobar, Ismael; Albiñana, Sandra; Serrano, Olga; Ferrari, José M; Herreros de Tejada, Alberto

2005-01-01

This study was designed to analyse the drug consumption difference and economic impact of an antibiotic sequential therapy focused on quinolones. We studied the consumption of quinolones (ofloxacin/levofloxacin and ciprofloxacin) 6 months before and after the implementation of a sequential therapy program in hospitalised patients. It was calculated for each antibiotic, in its oral and intravenous forms, in defined daily dose (DDD/100 stays per day) and economical terms (drug acquisition cost). At the beginning of the program ofloxacin was replaced by levofloxacin and, since their clinical uses are similar, the consumption of both drugs was compared during the period. In economic terms, the consumption of intravenous quinolones decreased 60% whereas the consumption of oral quinolones increased 66%. In DDD/100 stays per day, intravenous forms consumption decreased 53% and oral forms consumption increased 36%. Focusing on quinolones, the implementation of a sequential therapy program based on promoting an early switch from intravenous to oral regimen has proved its capacity to alter the utilisation profile of these antibiotics. The program has permitted the hospital a global saving of 41420 dollars for these drugs during the period of time considered. Copyright (c) 2004 John Wiley & Sons, Ltd.

Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study.

PubMed

Thomas, Xavier; Elhamri, Mohamed; Raffoux, Emmanuel; Renneville, Aline; Pautas, Cécile; de Botton, Stéphane; de Revel, Thierry; Reman, Oumedaly; Terré, Christine; Gardin, Claude; Chelghoum, Youcef; Boissel, Nicolas; Quesnel, Bruno; Hicheri, Yosr; Bourhis, Jean-Henri; Fenaux, Pierre; Preudhomme, Claude; Michallet, Mauricette; Castaigne, Sylvie; Dombret, Hervé

2011-08-18

To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high-dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association-9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1(+) or CEBPA(+) and FLT3-ITD(-) had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243.

Feasibility of combined modality therapy for localized high-grade soft tissue sarcomas in adults

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

Blum, R.H.; Greenberger, J.S.; Wilson, R.E.

1979-08-01

Seventeen consecutive patients with localized, high grade soft tissue sarcomas had resection of their primary tumor, radiation therapy and chemotherapy. The soft tissue sarcoma was primary in 14 patients and regionally recurrent in 3 patients. Chemotherapy consisted of cyclophosphamide 500 mg/M/sup 2/ day 1, Adriamycin (ADR) 60 mg/M/sup 2/ day 2, and DTIC 400 mg/M/sup 2/ days 1 and 2, given every 21 days to a maximum ADR dose of 450 mg/M/sup 2/. Cyclophosphamide and DTIC were then given to a total duration of 1 year. Radiation therapy consisted of 4000 to 5000 rad by megavoltage photons in 5 weeks,more » and in selected cases, an additional 1500 to 2000 rad by electron beam boost in the tumor bed delivered over 2 additional weeks. Following surgery, 12 patients were treated sequentially with an interval of chemotherapy, radiation therapy and then the completion of chemotherapy. The added morbidity of this sequential approach is minimal: one patient of 12 had delayed primary healing of her wound, 1 of 10 patients required a break in radiation therapy because of skin erythema. Four patients were treated with intensive pre-chemotherapy radiation therapy because of inadequate surgical margins. The median time on study was 18 months from onset of treatment (range, 8 to 41 months). Although there have been no local, regional or distant recurrences, the follow-up time is inadequate to assess the therapeutic benefit of this combined modality treatment.« less

Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts

PubMed Central

Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

2017-01-01

Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and recorded, and at the end of experiments, tumor xenografts were removed for Western blot and immunohistochemical analyses. Compared to control groups (negative control, regular-dose icotinib [IcoR], high-dose icotinib [IcoH], and docetaxel [DTX]) and regular icotinib dose (60 mg/kg) with docetaxel, treatment of mice with a high-dose (1200 mg/kg) of icotinib plus sequential docetaxel for 3 weeks (IcoH-DTX) had an additive effect on suppression of tumor xenograft size and volume (P < 0.05). Icotinib-containing treatments markedly reduced phosphorylation of EGFR, mitogen activated protein kinase (MAPK), and protein kinase B (Akt), but only the high-dose icotinib-containing treatments showed an additive effect on CD34 inhibition (P < 0.05), an indication of reduced microvessel density in tumor xenografts. Moreover, high-dose icotinib plus docetaxel had a similar effect on mouse weight loss (a common way to measure adverse reactions in mice), compared to the other treatment combinations. The study indicate that the high dose of icotinib plus sequential docetaxel (IcoH-DTX) have an additive effect on suppressing the growth of wild-type EGFR NSCLC cell nude mouse xenografts, possibly through microvessel density reduction. Future clinical trials are needed to confirm the findings of this study. PMID:27852073

Ten-day high-dose proton pump inhibitor triple therapy versus sequential therapy for Helicobacter pylori eradication.

PubMed

Auesomwang, Chonticha; Maneerattanaporn, Monthira; Chey, William D; Kiratisin, Pattarachai; Leelakusolwong, Somchai; Tanwandee, Tawesak

2018-05-27

Eradication rates of Helicobacter pylori following standard triple therapy are declining worldwide, but high-dose proton-pump inhibitor-based triple therapy (HD-PPI-TT) and sequential therapy (ST) have demonstrated higher cure rates. We aimed to compare the efficacy and tolerability of HD-PPI-TT and ST in H. pylori-associated functional dyspepsia (HP-FD). One hundred and twenty HP-FD patients were randomized to receive 10-day HD-PPI-TT (60 mg lansoprazole/500 mg clarithromycin/1 g amoxicillin, each administered twice daily for 10 days) or 10-day ST (30 mg lansoprazole/1 g amoxicillin, each administered twice daily for 5 days followed by 30 mg lansoprazole/500 mg clarithromycin/400 mg metronidazole, each administered twice daily for 5 days). H. pylori status was determined in post-treatment week 4 by 14 C-urea breath test. Eradication and antibiotic resistance rates, dyspeptic symptoms, drug compliance, and adverse effects were compared. Intention-to-treat (ITT) eradication rates were similar in the ST and HD-PPI-TT groups (85% vs. 80%; P=0.47). However, the eradication rate was significantly higher following ST compared with HD-PPI-TT in per protocol (PP) analysis (94.4% vs. 81.4%; P=0.035). ST achieved higher cure rates than HD-PPI-TT in clarithromycin-resistant H. pylori strains (100% vs. 33.3%; P=0.02). Treatment compliance was similar in the HD-PPI-TT and ST groups, although nausea and dizziness were more common in the ST group. ST achieved better H. pylori eradication than HD-PPI-TT in patients with FD. However, the eradication rate for ST fell from 94.4% in PP to 85% in ITT analysis. Adverse effects might result in poorer compliance and compromise actual ST efficacy. (ClinicalTrials.gov: NCT01888237). This article is protected by copyright. All rights reserved.

Comparison of Radiation Dose and Image Quality of Triple-Rule-Out Computed Tomography Angiography Between Conventional Helical Scanning and a Strategy Incorporating Sequential Scanning

PubMed Central

Manheimer, Eric D.; Peters, M. Robert; Wolff, Steven D.; Qureshi, Mehreen A.; Atluri, Prashanth; Pearson, Gregory D.N.; Einstein, Andrew J.

2011-01-01

Triple-rule-out computed tomography angiography (TRO CTA), performed to evaluate the coronary arteries, pulmonary arteries, and thoracic aorta, has been associated with high radiation exposure. Utilization of sequential scanning for coronary computed tomography angiography (CCTA) reduces radiation dose. The application of sequential scanning to TRO CTA is much less well defined. We analyzed radiation dose and image quality from TRO CTA performed in a single outpatient center, comparing scans from a period during which helical scanning with electrocardiographically controlled tube current modulation was used for all patients (n=35) and after adoption of a strategy incorporating sequential scanning whenever appropriate (n=35). Sequential scanning was able to be employed in 86% of cases. The sequential-if-appropriate strategy, compared to the helical-only strategy, was associated with a 61.6% dose decrease (mean dose-length product [DLP] of 439 mGy×cm vs 1144 mGy×cm and mean effective dose of 7.5 mSv vs 19.4 mSv, respectively, p<0.0001). Similarly, there was a 71.5% dose reduction among 30 patients scanned with the sequential protocol compared to 40 patients scanned with the helical protocol under either strategy (326 mGy×cm vs 1141 mGy×cm and 5.5 mSv vs 19.4 mSv, respectively, p<0.0001). Although image quality did not differ between strategies, there was a non-statistically significant trend towards better quality in the sequential protocol compared to the helical protocol. In conclusion, approaching TRO CTA with a diagnostic strategy of sequential scanning as appropriate offers a marked reduction in radiation dose while maintaining image quality. PMID:21306693

[Application of selection criteria in sequential double lung transplantation].

PubMed

Borro, J M; Tarazona, V; Vicente, R; Cafarena, J M; Ramos, F; Sales, G; Galán, G; Lozano, C; Morant, P; Calvo, V; Morcillo, A; París, F

1999-03-01

Since the first sequential double lung transplant was performed in 1986, such procedures have been increasing in number and the criteria used as indications for this type of surgery have broadened. Our aim was to reflect on the application of selection criteria and to describe the anesthetic and surgical techniques and postoperative follow-up of 72 patients who underwent this type of transplant surgery between March 1993 and December 1998. Actuarial survival five years after surgery was 74.4%. Among patients requiring transplantation after septic disease, actuarial survival was 90.8% for cystic fibrosis and 88.2% for bronchiectasis. Of the preoperative risk factors analyzed (prior surgery, pachypleuritis, multiresistant germs, poor nutrition, mechanical ventilation and corticoid therapy), only prior treatment with high doses of corticoids proved significant. Eleven patients have been diagnosed of bronchiolitis obliterans, four have died and only two continue to experience difficulties in daily living. The high survival rate and the restriction-free life after recovery lead us to consider sequential double lung transplantation to be the treatment of choice for all pulmonary diseases.

[Sequential course and prospective management of ifosfamide-induced multi-organ toxicity].

PubMed

Mollenkopf, A; du Bois, A; Meerpohl, H G

1996-10-01

We report on an 66-year old female in whom we diagnosed uterine carcinosarcoma and concurrent breast cancer. As first-line treatment the patient received ifosfamide 4.8 mg/m2 body surface. During her second course of chemotherapy she developed sequentially life-threatening toxicities; severe emesis followed by nephrotoxicity, neurotoxicity and myelosuppression. Early prophylactic administration of rhG-CSF (Filgrastim) helped to overcome severe, potentially fatal myelosuppression. The course of severe toxicities following high doses of ifosfamide might reflect a dependent sequence, where one organ failure causes a subsequent organ failure. Prophylactic treatment of anticipated toxicity should be considered for the management of severe ifosfamide-induced toxicity. Such treatment may consist of sufficient antiemesis, sufficient hydration, as well as a therapy with methylene blue in case of severe neurotoxicity.

TH-CD-202-04: Evaluation of Virtual Non-Contrast Images From a Novel Split-Filter Dual-Energy CT Technique

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

Huang, J; Szczykutowicz, T; Bayouth, J

Purpose: To compare the ability of two dual-energy CT techniques, a novel split-filter single-source technique of superior temporal resolution against an established sequential-scan technique, to remove iodine contrast from images with minimal impact on CT number accuracy. Methods: A phantom containing 8 tissue substitute materials and vials of varying iodine concentrations (1.7–20.1 mg I /mL) was imaged using a Siemens Edge CT scanner. Dual-energy virtual non-contrast (VNC) images were generated using the novel split-filter technique, in which a 120kVp spectrum is filtered by tin and gold to create high- and low-energy spectra with < 1 second temporal separation between themore » acquisition of low- and high-energy data. Additionally, VNC images were generated with the sequential-scan technique (80 and 140kVp) for comparison. CT number accuracy was evaluated for all materials at 15, 25, and 35mGy CTDIvol. Results: The spectral separation was greater for the sequential-scan technique than the split-filter technique with dual-energy ratios of 2.18 and 1.26, respectively. Both techniques successfully removed iodine contrast, resulting in mean CT numbers within 60HU of 0HU (split-filter) and 40HU of 0HU (sequential-scan) for all iodine concentrations. Additionally, for iodine vials of varying diameter (2–20 mm) with the same concentration (9.9 mg I /mL), the system accurately detected iodine for all sizes investigated. Both dual-energy techniques resulted in reduced CT numbers for bone materials (by >400HU for the densest bone). Increasing the imaging dose did not improve the CT number accuracy for bone in VNC images. Conclusion: VNC images from the split-filter technique successfully removed iodine contrast. These results demonstrate a potential for improving dose calculation accuracy and reducing patient imaging dose, while achieving superior temporal resolution in comparison sequential scans. For both techniques, inaccuracies in CT numbers for bone materials necessitate consideration for radiation therapy treatment planning.« less

A new approach to integrate GPU-based Monte Carlo simulation into inverse treatment plan optimization for proton therapy.

PubMed

Li, Yongbao; Tian, Zhen; Song, Ting; Wu, Zhaoxia; Liu, Yaqiang; Jiang, Steve; Jia, Xun

2017-01-07

Monte Carlo (MC)-based spot dose calculation is highly desired for inverse treatment planning in proton therapy because of its accuracy. Recent studies on biological optimization have also indicated the use of MC methods to compute relevant quantities of interest, e.g. linear energy transfer. Although GPU-based MC engines have been developed to address inverse optimization problems, their efficiency still needs to be improved. Also, the use of a large number of GPUs in MC calculation is not favorable for clinical applications. The previously proposed adaptive particle sampling (APS) method can improve the efficiency of MC-based inverse optimization by using the computationally expensive MC simulation more effectively. This method is more efficient than the conventional approach that performs spot dose calculation and optimization in two sequential steps. In this paper, we propose a computational library to perform MC-based spot dose calculation on GPU with the APS scheme. The implemented APS method performs a non-uniform sampling of the particles from pencil beam spots during the optimization process, favoring those from the high intensity spots. The library also conducts two computationally intensive matrix-vector operations frequently used when solving an optimization problem. This library design allows a streamlined integration of the MC-based spot dose calculation into an existing proton therapy inverse planning process. We tested the developed library in a typical inverse optimization system with four patient cases. The library achieved the targeted functions by supporting inverse planning in various proton therapy schemes, e.g. single field uniform dose, 3D intensity modulated proton therapy, and distal edge tracking. The efficiency was 41.6  ±  15.3% higher than the use of a GPU-based MC package in a conventional calculation scheme. The total computation time ranged between 2 and 50 min on a single GPU card depending on the problem size.

A new approach to integrate GPU-based Monte Carlo simulation into inverse treatment plan optimization for proton therapy

NASA Astrophysics Data System (ADS)

Li, Yongbao; Tian, Zhen; Song, Ting; Wu, Zhaoxia; Liu, Yaqiang; Jiang, Steve; Jia, Xun

2017-01-01

Monte Carlo (MC)-based spot dose calculation is highly desired for inverse treatment planning in proton therapy because of its accuracy. Recent studies on biological optimization have also indicated the use of MC methods to compute relevant quantities of interest, e.g. linear energy transfer. Although GPU-based MC engines have been developed to address inverse optimization problems, their efficiency still needs to be improved. Also, the use of a large number of GPUs in MC calculation is not favorable for clinical applications. The previously proposed adaptive particle sampling (APS) method can improve the efficiency of MC-based inverse optimization by using the computationally expensive MC simulation more effectively. This method is more efficient than the conventional approach that performs spot dose calculation and optimization in two sequential steps. In this paper, we propose a computational library to perform MC-based spot dose calculation on GPU with the APS scheme. The implemented APS method performs a non-uniform sampling of the particles from pencil beam spots during the optimization process, favoring those from the high intensity spots. The library also conducts two computationally intensive matrix-vector operations frequently used when solving an optimization problem. This library design allows a streamlined integration of the MC-based spot dose calculation into an existing proton therapy inverse planning process. We tested the developed library in a typical inverse optimization system with four patient cases. The library achieved the targeted functions by supporting inverse planning in various proton therapy schemes, e.g. single field uniform dose, 3D intensity modulated proton therapy, and distal edge tracking. The efficiency was 41.6  ±  15.3% higher than the use of a GPU-based MC package in a conventional calculation scheme. The total computation time ranged between 2 and 50 min on a single GPU card depending on the problem size.

A New Approach to Integrate GPU-based Monte Carlo Simulation into Inverse Treatment Plan Optimization for Proton Therapy

PubMed Central

Li, Yongbao; Tian, Zhen; Song, Ting; Wu, Zhaoxia; Liu, Yaqiang; Jiang, Steve; Jia, Xun

2016-01-01

Monte Carlo (MC)-based spot dose calculation is highly desired for inverse treatment planning in proton therapy because of its accuracy. Recent studies on biological optimization have also indicated the use of MC methods to compute relevant quantities of interest, e.g. linear energy transfer. Although GPU-based MC engines have been developed to address inverse optimization problems, their efficiency still needs to be improved. Also, the use of a large number of GPUs in MC calculation is not favorable for clinical applications. The previously proposed adaptive particle sampling (APS) method can improve the efficiency of MC-based inverse optimization by using the computationally expensive MC simulation more effectively. This method is more efficient than the conventional approach that performs spot dose calculation and optimization in two sequential steps. In this paper, we propose a computational library to perform MC-based spot dose calculation on GPU with the APS scheme. The implemented APS method performs a non-uniform sampling of the particles from pencil beam spots during the optimization process, favoring those from the high intensity spots. The library also conducts two computationally intensive matrix-vector operations frequently used when solving an optimization problem. This library design allows a streamlined integration of the MC-based spot dose calculation into an existing proton therapy inverse planning process. We tested the developed library in a typical inverse optimization system with four patient cases. The library achieved the targeted functions by supporting inverse planning in various proton therapy schemes, e.g. single field uniform dose, 3D intensity modulated proton therapy, and distal edge tracking. The efficiency was 41.6±15.3% higher than the use of a GPU-based MC package in a conventional calculation scheme. The total computation time ranged between 2 and 50 min on a single GPU card depending on the problem size. PMID:27991456

Safety of two sequential whole bladder photodynamic therapy (WBPDT) treatments in the management of resistant bladder cancer

NASA Astrophysics Data System (ADS)

Nseyo, Unyime O.; Barnes, C. R.; Martin, Jessicca I.; Lamm, Donald L.; Carpenter, Cindy

2003-06-01

While 55 - 60% of newly diagnosed bladder cancers are superficial, a significant number recur as higher grade and/or stage tumors. WBPDT has been used to treat some of these recurrent superficial tumors, although its use has been associated with dose-dependent side effects. Preclinical investigation of three sequential WBPDT treatments using lower PDT dose in normal canine bladder resulted in a lack of permanent bladder contracture. Lower dose single PDT treatment has shown less durable tumor response; however, sequential WBPDT treatments with lower dose may result in durable tumor response. Five patients (4 male, 1 female), average age 65.6 (62-72 years), with recurrent or resistant superficial TCC of the bladder received two WBPDT treatments. First treatment occurred at baseline and the second treatment at 6 months. Photofrin (1.5 mg/kg) was given intravenously 48 hours prior to each cystoscopic treatment with laser light (630 nm, Coherent Lambda-Plus laser). Total light treatment doses were 1500 - 2500 Joules at baseline and 1000- 1500 Joules at 6 months. Moderate irritative bladder symptoms occurred in all patients the first week post PDT. No cases of bladder contracture have occurred. 4 of 5 patients showed no evidence of disease during the follow-up period (12 - 18 months post second treatment). One patient had a recurrence at 18 months post second treatment. Mean disease-free interval is 16.2 months. The safety of two sequential WBPDT treatments is suggested by this preliminary data. Assessment of efficacy will be possible wit a large number of patients and a longer follow-up period.

Organometallic exposure dependence on organic–inorganic hybrid material formation in polyethylene terephthalate and polyamide 6 polymer fibers

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

Akyildiz, Halil I.; Jur, Jesse S., E-mail: jsjur@ncsu.edu

2015-03-15

The effect of exposure conditions and surface area on hybrid material formation during sequential vapor infiltrations of trimethylaluminum (TMA) into polyamide 6 (PA6) and polyethylene terephthalate (PET) fibers is investigated. Mass gain of the fabric samples after infiltration was examined to elucidate the reaction extent with increasing number of sequential TMA single exposures, defined as the times for a TMA dose and a hold period. An interdependent relationship between dosing time and holding time on the hybrid material formation is observed for TMA exposure PET, exhibited as a linear trend between the mass gain and total exposure (dose time ×more » hold time × number of sequential exposures). Deviation from this linear relationship is only observed under very long dose or hold times. In comparison, amount of hybrid material formed during sequential exposures to PA6 fibers is found to be highly dependent on amount of TMA dosed. Increasing the surface area of the fiber by altering its cross-sectional dimension is shown to have little on the reaction behavior but does allow for improved diffusion of the TMA into the fiber. This work allows for the projection of exposure parameters necessary for future high-throughput hybrid modifications to polymer materials.« less

Ultrafast treatment plan optimization for volumetric modulated arc therapy (VMAT).

PubMed

Men, Chunhua; Romeijn, H Edwin; Jia, Xun; Jiang, Steve B

2010-11-01

To develop a novel aperture-based algorithm for volumetric modulated are therapy (VMAT) treatment plan optimization with high quality and high efficiency. The VMAT optimization problem is formulated as a large-scale convex programming problem solved by a column generation approach. The authors consider a cost function consisting two terms, the first enforcing a desired dose distribution and the second guaranteeing a smooth dose rate variation between successive gantry angles. A gantry rotation is discretized into 180 beam angles and for each beam angle, only one MLC aperture is allowed. The apertures are generated one by one in a sequential way. At each iteration of the column generation method, a deliverable MLC aperture is generated for one of the unoccupied beam angles by solving a subproblem with the consideration of MLC mechanic constraints. A subsequent master problem is then solved to determine the dose rate at all currently generated apertures by minimizing the cost function. When all 180 beam angles are occupied, the optimization completes, yielding a set of deliverable apertures and associated dose rates that produce a high quality plan. The algorithm was preliminarily tested on five prostate and five head-and-neck clinical cases, each with one full gantry rotation without any couch/collimator rotations. High quality VMAT plans have been generated for all ten cases with extremely high efficiency. It takes only 5-8 min on CPU (MATLAB code on an Intel Xeon 2.27 GHz CPU) and 18-31 s on GPU (CUDA code on an NVIDIA Tesla C1060 GPU card) to generate such plans. The authors have developed an aperture-based VMAT optimization algorithm which can generate clinically deliverable high quality treatment plans at very high efficiency.

Second-line rescue triple therapy with levofloxacin after failure of non-bismuth quadruple "sequential" or "concomitant" treatment to eradicate H. pylori infection.

PubMed

Gisbert, Javier P; Molina-Infante, Javier; Marin, Alicia C; Vinagre, Gemma; Barrio, Jesus; McNicholl, Adrian Gerald

2013-06-01

Non-bismuth quadruple "sequential" and "concomitant" regimens, including a proton pump inhibitor (PPI), amoxicillin, clarithromycin and a nitroimidazole, are increasingly used as first-line treatments for Helicobacter pylori infection. Eradication with rescue regimens may be challenging after failure of key antibiotics such as clarithromycin and nitroimidazoles. To evaluate the efficacy and tolerability of a second-line levofloxacin-containing triple regimen (PPI-amoxicillin-levofloxacin) in the eradication of H. pylori after non-bismuth quadruple-containing treatment failure. prospective multicenter study. in whom a non-bismuth quadruple regimen, administered either sequentially (PPI + amoxicillin for 5 days followed by PPI + clarithromycin + metronidazole for 5 more days) or concomitantly (PPI + amoxicillin + clarithromycin + metronidazole for 10 days) had previously failed. levofloxacin (500 mg b.i.d.), amoxicillin (1 g b.i.d.) and PPI (standard dose b.i.d.) for 10 days. eradication was confirmed with (13)C-urea breath test 4-8 weeks after therapy. Compliance and tolerance: compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by means of a questionnaire. 100 consecutive patients were included (mean age 50 years, 62% females, 12% peptic ulcer and 88% dyspepsia): 37 after "sequential", and 63 after "concomitant" treatment failure. All patients took all medications correctly. Overall, per-protocol and intention-to-treat H. pylori eradication rates were 75.5% (95% CI 66-85%) and 74% (65-83%). Respective intention-to-treat cure rates for "sequential" and "concomitant" failure regimens were 74.4% and 71.4%, respectively. Adverse effects were reported in six (6%) patients; all of them were mild. Ten-day levofloxacin-containing triple therapy constitutes an encouraging second-line strategy in patients with previous non-bismuth quadruple "sequential" or "concomitant" treatment failure.

NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy.

PubMed

Jakobi, Annika; Stützer, Kristin; Bandurska-Luque, Anna; Löck, Steffen; Haase, Robert; Wack, Linda-Jacqueline; Mönnich, David; Thorwarth, Daniel; Perez, Damien; Lühr, Armin; Zips, Daniel; Krause, Mechthild; Baumann, Michael; Perrin, Rosalind; Richter, Christian

2015-01-01

To determine by treatment plan comparison differences in toxicity risk reduction for patients with head and neck squamous cell carcinoma (HNSCC) from proton therapy either used for complete treatment or sequential boost treatment only. For 45 HNSCC patients, intensity-modulated photon (IMXT) and proton (IMPT) treatment plans were created including a dose escalation via simultaneous integrated boost with a one-step adaptation strategy after 25 fractions for sequential boost treatment. Dose accumulation was performed for pure IMXT treatment, pure IMPT treatment and for a mixed modality treatment with IMXT for the elective target followed by a sequential boost with IMPT. Treatment plan evaluation was based on modern normal tissue complication probability (NTCP) models for mucositis, xerostomia, aspiration, dysphagia, larynx edema and trismus. Individual NTCP differences between IMXT and IMPT (∆NTCPIMXT-IMPT) as well as between IMXT and the mixed modality treatment (∆NTCPIMXT-Mix) were calculated. Target coverage was similar in all three scenarios. NTCP values could be reduced in all patients using IMPT treatment. However, ∆NTCPIMXT-Mix values were a factor 2-10 smaller than ∆NTCPIMXT-IMPT. Assuming a threshold of ≥ 10% NTCP reduction in xerostomia or dysphagia risk as criterion for patient assignment to IMPT, less than 15% of the patients would be selected for a proton boost, while about 50% would be assigned to pure IMPT treatment. For mucositis and trismus, ∆NTCP ≥ 10% occurred in six and four patients, respectively, with pure IMPT treatment, while no such difference was identified with the proton boost. The use of IMPT generally reduces the expected toxicity risk while maintaining good tumor coverage in the examined HNSCC patients. A mixed modality treatment using IMPT solely for a sequential boost reduces the risk by 10% only in rare cases. In contrast, pure IMPT treatment may be reasonable for about half of the examined patient cohort considering the toxicities xerostomia and dysphagia, if a feasible strategy for patient anatomy changes is implemented.

A comparison of sequential and spiral scanning techniques in brain CT.

PubMed

Pace, Ivana; Zarb, Francis

2015-01-01

To evaluate and compare image quality and radiation dose of sequential computed tomography (CT) examinations of the brain and spiral CT examinations of the brain imaged on a GE HiSpeed NX/I Dual Slice 2CT scanner. A random sample of 40 patients referred for CT examination of the brain was selected and divided into 2 groups. Half of the patients were scanned using the sequential technique; the other half were scanned using the spiral technique. Radiation dose data—both the computed tomography dose index (CTDI) and the dose length product (DLP)—were recorded on a checklist at the end of each examination. Using the European Guidelines on Quality Criteria for Computed Tomography, 4 radiologists conducted a visual grading analysis and rated the level of visibility of 6 anatomical structures considered necessary to produce images of high quality. The mean CTDI(vol) and DLP values were statistically significantly higher (P <.05) with the sequential scans (CTDI(vol): 22.06 mGy; DLP: 304.60 mGy • cm) than with the spiral scans (CTDI(vol): 14.94 mGy; DLP: 229.10 mGy • cm). The mean image quality rating scores for all criteria of the sequential scanning technique were statistically significantly higher (P <.05) in the visual grading analysis than those of the spiral scanning technique. In this local study, the sequential technique was preferred over the spiral technique for both overall image quality and differentiation between gray and white matter in brain CT scans. Other similar studies counter this finding. The radiation dose seen with the sequential CT scanning technique was significantly higher than that seen with the spiral CT scanning technique. However, image quality with the sequential technique was statistically significantly superior (P <.05).

A stepwise protocol for the treatment of refractory gastroesophageal reflux-induced chronic cough

PubMed Central

Xu, Xianghuai; Lv, Hanjing; Yu, Li; Chen, Qiang; Liang, Siwei

2016-01-01

Background Refractory gastroesophageal reflux-induced chronic cough (GERC) is difficult to manage. The purpose of the study is to evaluate the efficacy of a novel stepwise protocol for treating this condition. Methods A total of 103 consecutive patients with suspected refractory reflux-induced chronic cough failing to a standard anti-reflux therapy were treated with a stepwise therapy. Treatment commences with high-dose omeprazole and, if necessary, is escalated to subsequent sequential treatment with ranitidine and finally baclofen. The primary end-point was overall cough resolution, and the secondary end-point was cough resolution after each treatment step. Results High-dose omeprazole eliminated or improved cough in 28.1% of patients (n=29). Further stepwise of treatment with the addition of ranitide yielded a favorable response in an additional 12.6% (n=13) of patients, and subsequent escalation to baclofen provoked response in another 36.9% (n=38) of patients. Overall, this stepwise protocol was successful in 77.6% (n=80) of patients. The diurnal cough symptom score fell from 3 [1] to 1 [0] (Z=6.316, P=0.000), and the nocturnal cough symptom score decreased from 1 [1] to 0 [1] (Z=–4.511, P=0.000), with a corresponding reduction in the Gastroesophageal Reflux Diagnostic Questionnaire score from 8.6±1.7 to 6.8±0.7 (t=3.612, P=0.000). Conversely, the cough threshold C2 to capsaicin was increased from 0.49 (0.49) µmol/L to 1.95 (2.92) µmol/L (Z=–5.892, P=0.000), and the cough threshold C5 was increased from 1.95 (2.92) µmol/L to 7.8 (5.85) µmol/L (Z=–5.171, P=0.000). Conclusions Sequential stepwise anti-reflux therapy is a useful therapeutic strategy for refractory reflux-induced chronic cough. PMID:26904227

Treatment of Helicobacter pylori infection: Current status and future concepts

PubMed Central

Yang, Jyh-Chin; Lu, Chien-Wei; Lin, Chun-Jung

2014-01-01

Helicobacter pylori (H. pylori) infection is highly associated with the occurrence of gastrointestinal diseases, including gastric inflammation, peptic ulcer, gastric cancer, and gastric mucosa-associated lymphoid-tissue lymphoma. Although alternative therapies, including phytomedicines and probiotics, have been used to improve eradication, current treatment still relies on a combination of antimicrobial agents, such as amoxicillin, clarithromycin, metronidazole, and levofloxacin, and antisecretory agents, such as proton pump inhibitors (PPIs). A standard triple therapy consisting of a PPI and two antibiotics (clarithromycin and amoxicillin/metronidazole) is widely used as the first-line regimen for treatment of infection, but the increased resistance of H. pylori to clarithromycin and metronidazole has significantly reduced the eradication rate using this therapy and bismuth-containing therapy or 10-d sequential therapy has therefore been proposed to replace standard triple therapy. Alternatively, levofloxacin-based triple therapy can be used as rescue therapy for H. pylori infection after failure of first-line therapy. The increase in resistance to antibiotics, including levofloxacin, may limit the applicability of such regimens. However, since resistance of H. pylori to amoxicillin is generally low, an optimized high dose dual therapy consisting of a PPI and amoxicillin can be an effective first-line or rescue therapy. In addition, the concomitant use of alternative medicine has the potential to provide additive or synergistic effects against H. pylori infection, though its efficacy needs to be verified in clinical studies. PMID:24833858

Helicobacter pylori eradication with either seven-day or 10-day triple therapies, and with a 10-day sequential regimen

PubMed Central

Scaccianoce, Giuseppe; Hassan, Cesare; Panarese, Alba; Piglionica, Donato; Morini, Sergio; Zullo, Angelo

2006-01-01

BACKGROUND Helicobacter pylori eradication rates achieved by standard seven-day triple therapies are decreasing in several countries, while a novel 10-day sequential regimen has achieved a very high success rate. A longer 10-day triple therapy, similar to the sequential regimen, was tested to see whether it could achieve a better infection cure rate. METHODS Patients with nonulcer dyspepsia and H pylori infection were randomly assigned to one of the following three therapies: esomeprazole 20 mg, clarithromycin 500 mg and amoxycillin 1 g for seven days or 10 days, or a 10-day sequential regimen including esomeprazole 20 mg plus amoxycillin 1 g for five days and esomeprazole 20 mg, clarithromycin 500 mg and tinidazole 500 mg for the remaining five days. All drugs were given twice daily. H pylori eradication was checked four to six weeks after treatment by using a 13C-urea breath test. RESULTS Overall, 213 patients were enrolled. H pylori eradication was achieved in 75.7% and 77.9%, in 81.7% and 84.1%, and in 94.4% and 97.1% of patients following seven-day or 10-day triple therapy and the 10-day sequential regimen, at intention-to-treat and per protocol analyses, respectively. The eradication rate following the sequential regimen was higher than either seven-day (P=0.002) or 10-day triple therapy (P=0.02), while no significant difference emerged between the latter two regimens (P=0.6). CONCLUSIONS The 10-day sequential regimen was significantly more effective than both triple regimens, while 10-day triple therapy failed to significantly increase the H pylori eradication rate achieved by the standard seven-day regimen. PMID:16482238

Alternating sequential chemotherapy with high-dose ifosfamide and doxorubicin/cyclophosphamide for adult non-small round cell soft tissue sarcomas.

PubMed

Kawai, Akira; Umeda, Toru; Wada, Takuro; Ihara, Koichiro; Isu, Kazuo; Abe, Satoshi; Ishii, Takeshi; Sugiura, Hideshi; Araki, Nobuhito; Ozaki, Toshifumi; Yabe, Hiroo; Hasegawa, Tadashi; Tsugane, Shoichiro; Beppu, Yasuo

2005-05-01

Doxorubicin and ifosfamide are the two most active agents used to treat soft tissue sarcomas. However, because of their overlapping side effects, concurrent administration to achieve optimal doses of each agent is difficult. We therefore conducted a Phase II trial to investigate the efficacy and feasibility of a novel alternating sequential chemotherapy regimen consisting of high dose ifosfamide and doxorubicin/cyclophosphamide in advanced adult non-small round cell soft tissue sarcomas. Adult patients with non-small round cell soft tissue sarcomas were enrolled. The treatment consisted of four sequential courses of chemotherapy that was planned for every 3 weeks. Cycles 1 and 3 consisted of ifosfamide (14 g/m(2)), and cycles 2 and 4 consisted of doxorubicin (60 mg/m(2)) and cyclophosphamide (1200 mg/m(2)). Forty-two patients (median age 47 years) were enrolled. Of the 36 assessable patients, 1 complete response and 16 partial responses were observed, for a response rate of 47.2%. Responses were observed in 57% of patients who had received no previous chemotherapy and 13% of those who had previously undergone chemotherapy. Grade 3-4 neutropenia was observed during 70% of all cycles. Sequential administration of high-dose ifosfamide and doxorubicin/cyclophosphamide has promising activity with manageable side effects in patients with advanced adult non-small round cell soft tissue sarcomas.

Comparison of efficacy and safety of levofloxacin-containing versus standard sequential therapy in eradication of Helicobacter pylori infection in Korea.

PubMed

Lee, Hyuk; Hong, Sung Noh; Min, Byung-Hoon; Lee, Jun Haeng; Rhee, Poong-Lyul; Lee, Yong Chan; Kim, Jae J

2015-02-01

Declining of eradication rates for Helicobacter pylori in Korea may be partly from the increasing prevalence of antibiotic resistance, especially clarithromycin resistance. To compare the efficacy and the safety of using 10-day standard sequential therapy and levofloxacin-containing sequential therapy as a first-line treatment for Helicobacter pylori eradication in Korea. A total of 200 patients with proven Helicobacter pylori infection randomly received 10-day standard sequential therapy (n = 100) or levofloxacin-containing sequential therapy (n = 100). The standard sequential therapy group received rabeprazole and amoxicillin for 5 days, followed by rabeprazole, clarithromycin, and metronidazole for 5 more days. The levofloxacin-containing sequential therapy group was treated with rabeprazole and amoxicillin for 5 days, followed by rabeprazole, levofloxacin, and metronidazole for 5 more days. Intention-to-treat eradication rates were 79.0% and 78.0% for groups of standard sequential and levofloxacin-containing sequential therapy, respectively (P = 0.863). Per-protocol eradication rates were 84.9% and 81.3%, respectively, for these two therapies (P = 0.498). There were no significant differences between the groups in regard to the eradication rates and adverse events. The 10-day levofloxacin-containing sequential regimen and the standard sequential regimen showed the similar eradication rates of Helicobacter pylori in Korea. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Femoral Access and Delivery of Continuous Renal Replacement Therapy Dose.

PubMed

Bellomo, Rinaldo; Mårtensson, Johan; Lo, Serigne; Kaukonen, Kirsi-Maija; Cass, Alan; Gallagher, Martin

2016-01-01

The study aims to describe the use of dialysis catheters in critically ill patients treated with continuous renal replacement therapy (CRRT) and to study the impact of femoral versus non-femoral access on CRRT dose. Statistical analysis and predictive modelling of data from the Randomized Evaluation of Normal vs. Augmented Level renal replacement therapy trial. The femoral vein was the first access site in 937 (67%) of 1,399 patients. These patients had higher Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores (p = 0.009) and lower pH (p < 0.001) but similar mortality to patients with non-femoral access (44 vs. 45%; p = 0.63). Lower body weight was independently associated with femoral access placement (OR 0.97, 95% CI 0.96-0.98). Femoral access was associated with a 1.03% lower CRRT dose (p = 0.05), but a 4.20% higher dose was achieved with 13.5 Fr catheters (p = 0.03). Femoral access was preferred in lighter and sicker patients. Catheter gauge had greater impact than catheter site in CRRT dose delivery. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=439581. © 2015 S. Karger AG, Basel.

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

Miyawaki, Daisuke; Murakami, Masao; Demizu, Yusuke

Purpose: To assess the incidence of early delayed or late morbidity of Brain after particle therapy for skull base tumors and head-and-neck cancers. Methods and Materials: Between May 2001 and December 2005, 59 patients with cancerous invasion of the skull base were treated with proton or carbon ion therapy at the Hyogo Ion Beam Medical Center. Adverse events were assessed according to the magnetic resonance imaging findings (late effects of normal tissue-subjective, objective, management, analytic [LENT-SOMA]) and symptoms (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0). Dose-volume histograms were used to analyze the relationship between the dose and volumemore » of the irradiated brain and the occurrence of brain injury. The median follow-up time was 33 months. Results: Of the 48 patients treated with proton therapy and 11 patients treated with carbon ion radiotherapy, 8 (17%) and 7 (64%), respectively, developed radiation-induced brain changes (RIBCs) on magnetic resonance imaging (LENT-SOMA Grade 1-3). Four patients (7%) had some clinical symptoms, such as vertigo and headache (CTCAE Grade 2) or epilepsy (CTCAE Grade 3). The actuarial occurrence rate of RIBCs at 2 and 3 years was 20% and 39%, respectively, with a significant difference in the incidence between the proton and carbon ion radiotherapy groups. The dose-volume histogram analyses revealed significant differences between Brain lobes with and without RIBCs in the actuarial volume of brain lobes receiving high doses. Conclusion: Particle therapies produced minimal symptomatic brain toxicities, but sequential evaluation with magnetic resonance imaging detected a greater incidence of RIBCs. Significant differences were observed in the irradiated brain volume between Brain lobes with and without RIBCs.« less

Decongestion: Diuretics and other therapies for hospitalized heart failure

PubMed Central

Vazir, Ali; Cowie, Martin R.

2016-01-01

Acute heart failure (AHF) is a potentially life-threatening clinical syndrome, usually requiring hospital admission. Often the syndrome is characterized by congestion, and is associated with long hospital admissions and high risk of readmission and further healthcare expenditure. Despite a limited evidence-base, diuretics remain the first-line treatment for congestion. Loop diuretics are typically the first-line diuretic strategy with some evidence that initial treatment with continuous infusion or boluses of high-dose loop diuretic is superior to an initial lower dose strategy. In patients who have impaired responsiveness to diuretics, the addition of an oral thiazide or thiazide-like diuretic to induce sequential nephron blockade can be beneficial. The use of intravenous low-dose dopamine is no longer supported in heart failure patients with preserved systolic blood pressure and its use to assist diuresis in patients with low systolic blood pressures requires further study. Mechanical ultrafiltration has been used to treat patients with heart failure and fluid retention, but the evidence-base is not robust, and its place in clinical practice is yet to be established. Several novel pharmacological agents remain under investigation. PMID:27056656

Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated and sequential boosts in patients with locally advanced gynecologic malignancies.

PubMed

Boyle, John; Craciunescu, Oana; Steffey, Beverly; Cai, Jing; Chino, Junzo

2014-11-01

To evaluate the safety of dose escalated radiotherapy using a simultaneous integrated boost technique in patients with locally advanced gynecological malignancies. Thirty-nine women with locally advanced gynecological malignancies were treated with intensity modulated radiation therapy utilizing a simultaneous integrated boost (SIB) technique for gross disease in the para-aortic and/or pelvic nodal basins, sidewall extension, or residual primary disease. Women were treated to 45Gy in 1.8Gy fractions to elective nodal regions. Gross disease was simultaneously treated to 55Gy in 2.2Gy fractions (n=44 sites). An additional sequential boost of 10Gy in 2Gy fractions was delivered if deemed appropriate (n=29 sites). Acute and late toxicity, local control in the treated volumes (LC), overall survival (OS), and distant metastases (DM) were assessed. All were treated with a SIB to a dose of 55Gy. Twenty-four patients were subsequently treated with a sequential boost to a median dose of 65Gy. Median follow-up was 18months. Rates of acute>grade 2 gastrointestinal (GI), genitourinary (GU), and hematologic (heme) toxicities were 2.5%, 0%, and 30%, respectively. There were no grade 4 acute toxicities. At one year, grade 1-2 late GI toxicities were 24.5%. There were no grade 3 or 4 late GI toxicities. Rates of grade 1-2 late GU toxicities were 12.7%. There were no grade 3 or 4 late GU toxicities. Dose escalated radiotherapy using a SIB results in acceptable rates of acute toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison of Image Quality and Radiation Dose of Coronary Computed Tomography Angiography Between Conventional Helical Scanning and a Strategy Incorporating Sequential Scanning

PubMed Central

Einstein, Andrew J.; Wolff, Steven D.; Manheimer, Eric D.; Thompson, James; Terry, Sylvia; Uretsky, Seth; Pilip, Adalbert; Peters, M. Robert

2009-01-01

Radiation dose from coronary computed tomography angiography may be reduced using a sequential scanning protocol rather than a conventional helical scanning protocol. Here we compare radiation dose and image quality from coronary computed tomography angiography in a single center between an initial period during which helical scanning with electrocardiographically-controlled tube current modulation was used for all patients (n=138) and after adoption of a strategy incorporating sequential scanning whenever appropriate (n=261). Using the sequential-if-appropriate strategy, sequential scanning was employed in 86.2% of patients. Compared to the helical-only strategy, this strategy was associated with a 65.1% dose reduction (mean dose-length product of 305.2 vs. 875.1 and mean effective dose of 14.9 mSv vs. 5.2 mSv, respectively), with no significant change in overall image quality, step artifacts, motion artifacts, or perceived image noise. For the 225 patients undergoing sequential scanning, the dose-length product was 201.9 ± 90.0 mGy·cm, while for patients undergoing helical scanning under either strategy, the dose-length product was 890.9 ± 293.3 mGy·cm (p<0.0001), corresponding to mean effective doses of 3.4 mSv and 15.1 mSv, respectively, a 77.5% reduction. Image quality was significantly greater for the sequential studies, reflecting the poorer image quality in patients undergoing helical scanning in the sequential-if-appropriate strategy. In conclusion, a sequential-if-appropriate diagnostic strategy reduces dose markedly compared to a helical-only strategy, with no significant difference in image quality. PMID:19892048

A Phase 2 Open Label, Single-Arm Trial to Evaluate the Combination of Cetuximab Plus Taxotere, Cisplatin, and 5-Flurouracil as an Induction Regimen in Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck

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

Mesía, Ricard, E-mail: rmesia@iconcologia.net; Vázquez, Silvia; Grau, Juan J.

Purpose: Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN. Methods and Materials: A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 yearsmore » of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m{sup 2} day 1; cisplatin, 75 mg/m{sup 2} day 1; 5-fluorouracil [5-FU], 750 mg/m{sup 2} day 1-5) and cetuximab, 250 mg/m{sup 2} weekly (loading dose of 400 mg/m{sup 2}). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF. Results: Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%). Conclusions: C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.« less

Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized study.

PubMed

Nasa, Mukesh; Choksey, Ajay; Phadke, Aniruddha; Sawant, Prabha

2013-11-01

Antimicrobial resistance has decreased eradication rates for Helicobacter pylori infection worldwide. A sequential treatment schedule has been reported to be effective, but studies published to date were performed in Italy. We undertook this study to determine whether these results could be replicated in India. A randomized, open-labeled, prospective controlled trial comparing sequential vs. standard triple-drug therapy was carried out at Lokmanya Tilak Municipal General Hospital, Mumbai. Two hundred and thirty-one patients with dyspepsia were randomized to a 10-day sequential regimen (40 mg of pantoprazole, 1 g of amoxicillin, each administered twice daily for the first 5 days, followed by 40 mg of pantoprazole, 500 mg of clarithromycin, and 500 mg of tinidazole, each administered twice daily for the remaining 5 days) or to standard 14-day therapy (40 mg of pantoprazole, 500 mg of clarithromycin, and 1 g of amoxicillin, each administered twice daily). The eradication rate achieved with the sequential regimen was significantly greater than that obtained with the triple therapy. Per-protocol eradication rate of sequential therapy was 92.4% (95% CI 85.8-96.1%) vs. 81.8% (95% CI 73.9-87.8%) (p = 0.027) for standard drug therapy. Intention-to-treat eradication rates were 88.2% (95% CI 80.9-93.0%) vs. 79.1% (95% CI 71.1-85.4%), p = 0.029, respectively. The incidence of major and minor side effects between therapy groups was not significantly different (14.6% in the triple therapy group vs. 23.5% in sequential group, p = 0.12). Follow up was incomplete in 3.3% and 4.7% patients in standard and sequential therapy groups, respectively. Sequential therapy includes one additional antibiotic (tinidazole) that is not contained in standard therapy. Sequential therapy was significantly better than standard therapy for eradicating H. pylori infection.

Cisplatin Cross-Linked Multifunctional Nanodrugplexes for Combination Therapy.

PubMed

Zhang, Weiqi; Tung, Ching-Hsuan

2017-03-15

Combination therapy efficiently tackles cancer by hitting multiple action mechanisms. However, drugs administered, simultaneously or sequentially, may not reach the targeted sites with the desired dose and ratio. The outcomes of combination therapy could be improved with a polymeric nanoparticle, which can simultaneously transport an optimal combination of drugs. We have demonstrated a simple one-pot strategy to formulate nanomedicines based on platinum coordination and the noncovalent interactions of the drugs. A naturally occurring polymer, hyaluronan (HA), was chosen as the building scaffold to form a nanodrugplex with cisplatin and aromatic-cationic drugs. The platinum coordination between cisplatin and HA induces the formation of a nanocomplex. The aromatic-cationic drugs are tightly packed by an electrostatic interaction and π-π stacking. The nanodrugplex bears excellent flexibility in drug combination and size control. It is stable in storage and has favorable release kinetics and targeting capabilities toward CD44, a receptor for HA that is highly expressed on many types of cancer cells.

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.

Dapagliflozin and saxagliptin tablets for adults with type 2 diabetes.

PubMed

Scheen, André J

2017-12-01

Saxagliptin (a dipeptidyl peptidase-4 inhibitor, DPP-4i) and dapagliflozin (a sodium-glucose cotransporter type 2 inhibitor, SGLT2i) improve glucose control in type 2 diabetes (T2D) through different potentially complementary mechanisms, thus offering the opportunity for a combined therapy. Area covered: The characteristics of the saxagliptin/dapagliflozin combination are analysed, focusing on: 1) pharmacokinetic and pharmacodynamic properties; 2) efficacy and safety in phase III trials with concurrent and sequential add-on therapy; and 3) potential use in clinical practice, including in special populations (cardiovascular disease, heart failure, chronic kidney disease, elderly). Expert commentary: Conclusions drawn from clinical trials investigating combination with the separate drugs are considered to apply to the fixed-dose combination (FDC) that demonstrates bioequivalence. Dual saxagliptin/dapagliflozin therapy is more potent than either monotherapy and can be used as an initial combination or a stepwise sequential approach. Dual therapy is generally well tolerated and may be used in special populations, with some limitations because of the presence of dapagliflozin. However, the latter may offer some advantages because of multiple effects attributed to SGLT2i. The best place of this dual combination for the management of T2D and the profile of patients who will make the most of this combined therapy remains to be defined.

Rethinking the laryngopharyngeal reflux treatment algorithm: Evaluating an alternate empiric dosing regimen and considering up-front, pH-impedance, and manometry testing to minimize cost in treating suspect laryngopharyngeal reflux disease.

PubMed

Carroll, Thomas L; Werner, Astrid; Nahikian, Kael; Dezube, Aaron; Roth, Douglas F

2017-10-01

Empiric proton pump inhibitor (PPI) trials for laryngopharyngeal reflux (LPR) are common. A majority of the patients respond to acid suppression. This work intends to evaluate once-daily, 40 mg omeprazole and once-nightly, 300 mg ranitidine (QD/QHS) dosing as an alternative regimen, and use this study's cohort to evaluate empiric regimens prescribed for LPR as compared to up-front testing with pH impedance multichannel intraluminal impedance (MII) with dual pH probes and high-resolution manometry (HRM) for potential cost minimization. Retrospective cohort review and cost minimization study. A chart review identified patients diagnosed with LPR. All subjects were treated sequentially and outcomes recorded. Initial QD/QHS dosing increased after 3 months to BID if no improvement and ultimately prescribed MII and HRM if they failed BID dosing. Decision tree diagrams were constructed to determine costs of two empiric regimens and up-front MII and HRM. Ninety-seven subjects met the criteria. Responders and nonresponders to empiric therapy were identified. Seventy-two subjects (74%) responded. Forty-eight (67% of responders and 49% of all) improved with QD/QHS dosing. Forty-nine (51%) subjects escalated to BID dosing. Twenty-four subjects (33% of responders and 25% of all) improved on BID therapy. Twenty-five subjects (26%) did not respond to acid suppression. Average weighted cost was $1,897.00 per patient for up-front testing, $3,033.00 for initial BID, and $3,366.00 for initial QD/QHS. An alternate QD/QHS regimen improved the majority who presented with presumed LPR. Cost estimates demonstrate that the QD/QHS regimen was more expensive than the initial BID high-dose PPI for 6 months. Overall per-patient cost appears less with up-front MII and HRM. 4. Laryngoscope, 127:S1-S13, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Intensity Modulated Radiation Therapy With Dose Painting to Treat Rhabdomyosarcoma

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

Yang, Joanna C.; Dharmarajan, Kavita V.; Wexler, Leonard H.

Purpose: To examine local control and patterns of failure in rhabdomyosarcoma patients treated with intensity modulated radiation therapy (RT) with dose painting (DP-IMRT). Patients and Methods: A total of 41 patients underwent DP-IMRT with chemotherapy for definitive treatment. Nineteen also underwent surgery with or without intraoperative RT. Fifty-six percent had alveolar histologic features. The median interval from beginning chemotherapy to RT was 17 weeks (range, 4-25). Very young children who underwent second-look procedures with or without intraoperative RT received reduced doses of 24-36 Gy in 1.4-1.8-Gy fractions. Young adults received 50.4 Gy to the primary tumor and lower doses ofmore » 36 Gy in 1.8-Gy fractions to at-risk lymph node chains. Results: With 22 months of median follow-up, the actuarial local control rate was 90%. Patients aged {<=}7 years who received reduced overall and fractional doses had 100% local control, and young adults had 79% (P=.07) local control. Three local failures were identified in young adults whose primary target volumes had received 50.4 Gy in 1.8-Gy fractions. Conclusions: DP-IMRT with lower fractional and cumulative doses is feasible for very young children after second-look procedures with or without intraoperative RT. DP-IMRT is also feasible in adolescents and young adults with aggressive disease who would benefit from prophylactic RT to high-risk lymph node chains, although dose escalation might be warranted for improved local control. With limited follow-up, it appears that DP-IMRT produces local control rates comparable to those of sequential IMRT in patients with rhabdomyosarcoma.« less

AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

PubMed

Rangarajan, Savita; Walsh, Liron; Lester, Will; Perry, David; Madan, Bella; Laffan, Michael; Yu, Hua; Vettermann, Christian; Pierce, Glenn F; Wong, Wing Y; Pasi, K John

2017-12-28

Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all seven participants. In this small study, no safety events were noted, but no safety conclusions can be drawn. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .).

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

Besemer, A; Marsh, I; Bednarz, B

Purpose: The calculation of 3D internal dose calculations in targeted radionuclide therapy requires the acquisition and temporal coregistration of a serial PET/CT or SPECT/CT images. This work investigates the dosimetric impact of different temporal coregistration methods commonly used for 3D internal dosimetry. Methods: PET/CT images of four mice were acquired at 1, 24, 48, 72, 96, 144 hrs post-injection of {sup 124}I-CLR1404. The therapeutic {sup 131}I-CLR1404 absorbed dose rate (ADR) was calculated at each time point using a Geant4-based MC dosimetry platform using three temporal image coregistration Methods: (1) no coregistration (NC), whole body sequential CT-CT affine coregistration (WBAC), andmore » individual sequential ROI-ROI affine coregistration (IRAC). For NC, only the ROI mean ADR was integrated to obtain ROI mean doses. For WBAC, the CT at each time point was coregistered to a single reference CT. The CT transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the whole CT volume. For IRAC, each individual ROI was isolated and sequentially coregistered to a single reference ROI. The ROI transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the ROI volumes. Results: The percent differences in the ROI mean doses were as large as 109%, 88%, and 32%, comparing the WBAC vs. IRAC, NC vs. IRAC, and NC vs. WBAC methods, respectively. The CoV in the mean dose between the all three methods ranged from 2–36%. The pronounced curvature of the spinal cord was not adequately coregistered using WBAC which resulted in large difference between the WBAC and IRAC. Conclusion: The method used for temporal image coregistration can result in large differences in 3D internal dosimetry calculations. Care must be taken to choose the most appropriate method depending on the imaging conditions, clinical site, and specific application. This work is partially funded by NIH Grant R21 CA198392-01.« less

Treatment of mites folliculitis with an ornidazole-based sequential therapy: A randomized trial.

PubMed

Luo, Yang; Sun, Yu-Jiao; Zhang, Li; Luan, Xiu-Li

2016-07-01

Treatment of Demodex infestations is often inadequate and associated with low effective rate. We sought to evaluate the efficacy of an ornidazole-based sequential therapy for mites folliculitis treatment. Two-hundred patients with mites folliculitis were sequentially treated with either an ornidazole- or metronidazole-based regimen. Sebum cutaneum was extruded from the sebaceous glands of each patient's nose and the presence of Demodex mites were examined by light microscopy. The clinical manifestations of relapse of mites folliculitis were recorded and the subjects were followed up at 2, 4, 8, and 12 weeks post-treatment. Patients treated with the ornidazole-based regimen showed an overall effective rate of 94.0%. Additionally, at the 2, 4, 8, and 12-week follow-up, these patients had significantly lower rates of Demodex mite relapse and new lesion occurrence compared with patients treated with the metronidazole-based regimen (P < 0.05). Sequential therapy using ornidazole, betamethasone, and recombinant bovine basic fibroblast growth factor (rbFGF) gel is highly effective for treating mites folliculitis.

Decongestion: Diuretics and other therapies for hospitalized heart failure.

PubMed

Vazir, Ali; Cowie, Martin R

2016-04-01

Acute heart failure (AHF) is a potentially life-threatening clinical syndrome, usually requiring hospital admission. Often the syndrome is characterized by congestion, and is associated with long hospital admissions and high risk of readmission and further healthcare expenditure. Despite a limited evidence-base, diuretics remain the first-line treatment for congestion. Loop diuretics are typically the first-line diuretic strategy with some evidence that initial treatment with continuous infusion or boluses of high-dose loop diuretic is superior to an initial lower dose strategy. In patients who have impaired responsiveness to diuretics, the addition of an oral thiazide or thiazide-like diuretic to induce sequential nephron blockade can be beneficial. The use of intravenous low-dose dopamine is no longer supported in heart failure patients with preserved systolic blood pressure and its use to assist diuresis in patients with low systolic blood pressures requires further study. Mechanical ultrafiltration has been used to treat patients with heart failure and fluid retention, but the evidence-base is not robust, and its place in clinical practice is yet to be established. Several novel pharmacological agents remain under investigation. Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy.

PubMed

Ishihara, Hiroki; Takagi, Toshio; Kondo, Tsunenori; Tachibana, Hidekazu; Yoshida, Kazuhiko; Omae, Kenji; Iizuka, Junpei; Kobayashi, Hirohito; Tanabe, Kazunari

2018-06-01

The number of studies evaluating the efficacy and safety of third-line molecular-targeted therapy for metastatic renal cell carcinoma (mRCC) is limited. The data for 48 patients with disease progression after first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI) and second-line targeted therapy were evaluated. Patients with prior cytokine therapy were excluded. Overall survival (OS) after first- and second-line therapy initiation was compared between patients with and without third-line therapy. In addition, dose-limiting toxicities (DLTs) were evaluated. Twenty-two of 48 patients (45.8%) received third-line therapy, and TKI and mammalian target of rapamycin inhibitor were each administered in 11 patients (50%). Patients with third-line therapy had significantly longer median OS after first-line therapy (26.6 vs. 14.6 months, p = 0.0010) and second-line therapy (18.2 vs. 7.4 months, p < 0.0001) compared to those without third-line therapy. Multivariate analysis showed that the use of third-line therapy following second-line therapy was an independent prognosticator for longer OS (hazard ratio 0.29, 95% confidence interval 0.14-0.58, p = 0.0005). The median progression-free survival and OS after third-line therapy was 2.76 and 8.71 months, respectively. Although a high frequency of DLTs was observed (n = 10, 45.5%), the frequencies were similar among the sequential therapies. Third-line therapy has a beneficial therapeutic effect in patients with mRCC that is resistant to previous therapies. However, there is a need to evaluate in detail the high frequency of adverse events, including DLTs.

Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

PubMed Central

Nathwani, Amit C.; Tuddenham, Edward G.D.; Rangarajan, Savita; Rosales, Cecilia; McIntosh, Jenny; Linch, David C.; Chowdary, Pratima; Riddell, Anne; Pie, Arnulfo Jaquilmac; Harrington, Chris; O’Beirne, James; Smith, Keith; Pasi, John; Glader, Bertil; Rustagi, Pradip; Ng, Catherine Y.C.; Kay, Mark A.; Zhou, Junfang; Spence, Yunyu; Morton, Christopher L.; Allay, James; Coleman, John; Sleep, Susan; Cunningham, John M.; Srivastava, Deokumar; Basner-Tschakarjan, Etiena; Mingozzi, Federico; High, Katherine A.; Gray, John T.; Reiss, Ulrike M.; Nienhuis, Arthur W.; Davidoff, Andrew M.

2012-01-01

BACKGROUND Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. METHODS We infused a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. RESULTS AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid–specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. CONCLUSIONS Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.) PMID:22149959

Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy.

PubMed

Svensson, Elin M; Yngman, Gunnar; Denti, Paolo; McIlleron, Helen; Kjellsson, Maria C; Karlsson, Mats O

2018-05-01

Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations. In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation. The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target). The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.

Dose finding with the sequential parallel comparison design.

PubMed

Wang, Jessie J; Ivanova, Anastasia

2014-01-01

The sequential parallel comparison design (SPCD) is a two-stage design recommended for trials with possibly high placebo response. A drug-placebo comparison in the first stage is followed in the second stage by placebo nonresponders being re-randomized between drug and placebo. We describe how SPCD can be used in trials where multiple doses of a drug or multiple treatments are compared with placebo and present two adaptive approaches. We detail how to analyze data in such trials and give recommendations about the allocation proportion to placebo in the two stages of SPCD.

Phase 2 Study of Combined Sorafenib and Radiation Therapy in Patients With Advanced Hepatocellular Carcinoma

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

Chen, Shang-Wen, E-mail: sjfchiou@gmail.com; School of Medicine, Taipei Medical University, Taipei, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan

Purpose: This phase 2 study evaluated the efficacy of radiation therapy (RT) with concurrent and sequential sorafenib therapy in patients with unresectable hepatocellular carcinoma (HCC). Methods and Materials: Forty patients with unresectable HCC unfit for transarterial chemoembolization were treated with RT with concurrent and sequential sorafenib. Sorafenib was administered from the commencement of RT at a dose of 400 mg twice daily and continued to clinical or radiologic progression, unacceptable adverse events, or death. All patients had underlying Child-Pugh A cirrhosis. The maximal tumor diameter ranged from 3.0 cm to 15.5 cm. Coexisting portal vein thrombosis was found in 24 patients and wasmore » irradiated simultaneously. The cumulative RT dose ranged from 40 Gy to 60 Gy (median, 50 Gy). Image studies were done 1 month after RT and then every 3 months thereafter. Results: Thirty-three (83%) completed the allocated RT. During RT, the incidence of hand-foot skin reactions ≥ grade 2 and diarrhea were 37.5% and 25%, respectively, and 35% of patients had hepatic toxicities grade ≥2. Twenty-two (55.0%) patients achieved complete or partial remission at the initial assessment, and 18 (45%) had stable or progressive disease. The 2-year overall survival and infield progression-free survival (IFPS) were 32% and 39%, respectively. A Cancer of the Liver Italian Program (CLIP) score ≥2 was associated with an inferior outcome in overall survival. Six patients (15%) developed treatment-related hepatic toxicity grade ≥3 during the sequential phase, and 3 of them were fatal. Conclusions: When RT and sorafenib therapy were combined in patients with unresectable HCC, the initial complete or partial response rate was 55% with a 2-year IFPS of 39%. A CLIP score ≥2 was associated with an inferior outcome in overall survival. Hepatic toxicities are a major determinant of the safety; the combination should be used with caution and needs further investigation.« less

Losartan/hydrochlorothiazide combination vs. high-dose losartan in patients with morning hypertension--a prospective, randomized, open-labeled, parallel-group, multicenter trial.

PubMed

Ueda, Tamenobu; Kai, Hisashi; Imaizumi, Tsutomu

2012-07-01

The treatment of morning hypertension has not been established. We compared the efficacy and safety of a losartan/hydrochlorothiazide (HCTZ) combination and high-dose losartan in patients with morning hypertension. A prospective, randomized, open-labeled, parallel-group, multicenter trial enrolled 216 treated outpatients with morning hypertension evaluated by home blood pressure (BP) self-measurement. Patients were randomly assigned to receive a combination therapy of 50 mg losartan and 12.5 mg HCTZ (n=109) or a high-dose therapy with 100 mg losartan (n=107), each of which were administered once every morning. Primary efficacy end points were morning systolic BP (SBP) level and target BP achievement rate after 3 months of treatment. At baseline, BP levels were similar between the two therapy groups. Morning SBP was reduced from 150.3±10.1 to 131.5±11.5 mm Hg by combination therapy (P<0.001) and from 151.0±9.3 to 142.5±13.6 mm Hg by high-dose therapy (P<0.001). The morning SBP reduction was greater in the combination therapy group than in the high-dose therapy group (P<0.001). Combination therapy decreased evening SBP from 141.6±13.3 to 125.3±13.1 mm Hg (P<0.001), and high-dose therapy decreased evening SBP from 138.9±9.9 to 131.4±13.2 mm Hg (P<0.01). Although both therapies improved target BP achievement rates in the morning and evening (P<0.001 for both), combination therapy increased the achievement rates more than high-dose therapy (P<0.001 and P<0.05, respectively). In clinic measurements, combination therapy was superior to high-dose therapy in reducing SBP and improving the achievement rate (P<0.001 and P<0.01, respectively). Combination therapy decreased urine albumin excretion (P<0.05) whereas high-dose therapy reduced serum uric acid. Both therapies indicated strong adherence and few adverse effects (P<0.001). In conclusion, losartan/HCTZ combination therapy was more effective for controlling morning hypertension and reducing urine albumin than high-dose losartan.

Clinical outcomes of image guided radiation therapy (IGRT) with gold fiducial vaginal cuff markers for high-risk endometrial cancer.

PubMed

Monroe, Alan T; Pikaart, Dirk; Peddada, Anuj V

2013-06-01

To report two year clinical outcomes of image guided radiation therapy (IGRT) to the vaginal cuff and pelvic lymph nodes in a series of high-risk endometrial cancer patients. Twenty-six consecutive high-risk endometrial cancer patients requiring adjuvant radiation to the vaginal cuff and regional lymph nodes were treated with vaginal cuff fiducial-based IGRT. Seventeen (65%) received sequential chemotherapy, most commonly with a sandwich technique. Brachytherapy followed external radiation in 11 patients to a median dose of 18 Gy in 3 fractions. The median external beam dose delivered was 47.5 Gy in 25 fractions. All 656 fractions were successfully imaged and treated. The median overall translational shift required for correction was 9.1 mm (standard deviation, 5.2 mm) relative to clinical set-up with skin tattoos. Shifts of 1 cm, 1.5 cm, and 2 cm or greater were performed in 43%, 14%, and 4% of patients, respectively. Acute grade 2 gastrointestinal (GI) toxicity occurred in eight patients (30%) and grade 3 toxicity occurred in one. At two years, there have been no local or regional failures and actuarial overall survival is 95%. Daily image guidance for high-risk endometrial cancer results in a low incidence of acute GI/genitourinary (GU) toxicity with uncompromised tumor control at two years. Vaginal cuff translations can be substantial and may possibly result in underdosing if not properly considered.

Computed Tomography–Guided Interstitial High-Dose-Rate Brachytherapy in Combination With Regional Positive Lymph Node Intensity-Modulated Radiation Therapy in Locally Advanced Peripheral Non–Small Cell Lung Cancer: A Phase 1 Clinical Trial

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

Xiang, Li; Zhang, Jian-wen; Lin, Sheng

2015-08-01

Purpose: To assess the technical safety, adverse events, and efficacy of computed tomography (CT)-guided interstitial high-dose-rate (HDR) brachytherapy in combination with regional positive lymph node intensity modulated radiation therapy in patients with locally advanced peripheral non–small cell lung cancer (NSCLC). Methods and Materials: Twenty-six patients with histologically confirmed NSCLC were enrolled in a prospective, officially approved phase 1 trial. Primary tumors were treated with HDR brachytherapy. A single 30-Gy dose was delivered to the 90% isodose line of the gross lung tumor volume. A total dose of at least 70 Gy was administered to the 95% isodose line of the planningmore » target volume of malignant lymph nodes using 6-MV X-rays. The patients received concurrent or sequential chemotherapy. We assessed treatment efficacy, adverse events, and radiation toxicity. Results: The median follow-up time was 28 months (range, 7-44 months). There were 3 cases of mild pneumothorax but no cases of hemothorax, dyspnea, or pyothorax after the procedure. Grade 3 or 4 acute hematologic toxicity was observed in 5 patients. During follow-up, mild fibrosis around the puncture point was observed on the CT scans of 2 patients, but both patients were asymptomatic. The overall response rates (complete and partial) for the primary mass and positive lymph nodes were 100% and 92.3%, respectively. The 1-year and 2-year overall survival (OS) rates were 90.9% and 67%, respectively, with a median OS of 22.5 months. Conclusion: Our findings suggest that HDR brachytherapy is safe and feasible for peripheral locally advanced NSCLC, justifying a phase 2 clinical trial.« less

Sequential (as Opposed to Simultaneous) Antibiotic Therapy Improves Helicobacter pylori Eradication in the Pediatric Population: A Meta-Analysis.

PubMed

Lau, Christine S M; Ward, Amanda; Chamberlain, Ronald S

2016-06-01

Helicobacter pylori is a common infection associated with many gastrointestinal diseases. Triple or quadruple therapy is the current recommendation for H pylori eradication in children but is associated with success rates as low as 50%. Recent studies have demonstrated that a 10-day sequential therapy regimen, rather than simultaneous antibiotic administration, achieved eradication rates of nearly 95%. This meta-analysis found that sequential therapy increased eradication rates by 14.2% (relative risk [RR] = 1.142; 95% confidence interval [CI] = 1.082-1.207; P < .001). Ten-day sequential therapy significantly improved H pylori eradication rates compared to the 7-day standard therapy (RR = 1.182; 95% CI = 1.102-1.269; p < .001) and 10-day standard therapy (RR = 1.179; 95% CI = 1.074-1.295; P = .001), but had lower eradication rates compared to 14-day standard therapy (RR = 0.926; 95% CI = 0.811-1.059; P = .261). The use of sequential therapy is associated with increased H pylori eradication rates in children compared to standard therapy of equal or shorter duration. © The Author(s) 2015.

Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients

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

Penoncello, Gregory P.; Ding, George X., E-mail: george.ding@vanderbilt.edu

The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, andmore » 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2 cm{sup 3} for head and neck plans and brain plans and a contiguous volume of 5 cm{sup 3} for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens.« less

A phase I human trial of mitoguazone and gemcitabine sequential bi-weekly treatment of cancer patients.

PubMed

Ishmael, D Richard; Chen, Wei R; Hamilton, Steven A; Liu, Hong; Nordquist, Robert E

2003-01-01

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m2, gemcitabine 1500 mg/m2), three at dose level 2 (mitoguazone 500 mg/m2, gemcitabine 2000 mg/m2), and one at dose level 3 (mitoguazone 600 mg/m2, gemcitabine 2000 mg/m2). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.

A randomized phase III study between sequential versus simultaneous integrated boost intensity-modulated radiation therapy in nasopharyngeal carcinoma.

PubMed

Lertbutsayanukul, Chawalit; Prayongrat, Anussara; Kannarunimit, Danita; Chakkabat, Chakkapong; Netsawang, Buntipa; Kitpanit, Sarin

2018-05-01

This study was performed to compare the acute and late toxicities between sequential (SEQ) and simultaneous integrated boost (SIB) intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC). Stage I-IVB NPC patients were randomized to receive SEQ-IMRT or SIB-IMRT. SEQ-IMRT consisted of two plans: 2 Gy × 25 fractions to low-risk planning target volume (PTV) followed by a sequential boost (2 Gy × 10 fractions) to high-risk PTV, while SIB-IMRT treated low- and high-risk PTVs with doses of 56 and 70 Gy in 33 fractions. Toxicities and survival outcomes were analyzed. Between October 2010 and September 2015, of the 209 patients who completed treatment, 102 in the SEQ and 107 in the SIB arm were analyzed. The majority had undifferentiated squamous cell carcinoma (82%). Mucositis and dysphagia were the most common grade 3-5 acute toxicities. There were no statistically significant differences in the cumulative incidence of grade 3-4 acute toxicities between the two arms (59.8% in SEQ vs. 58.9% in SIB; P = 0.892). Common grade 3-4 late toxicities for SEQ and SIB included hearing loss (2.9 vs. 8.4%), temporal lobe injury (2.9 vs. 0.9%), cranial nerve injury (0 vs. 2.8%), and xerostomia (2 vs. 0.9%). With the median follow-up of 41 months, 3‑year progression-free and overall survival rates were 72.7 vs. 73.4% (P = 0.488) and 86.3 vs. 83.6% (P = 0.938), respectively. SEQ and SIB provide excellent survival outcomes with few late toxicities. According to our study, SIB with a satisfactory dose-volume constraint to nearby critical organs is the technique of choice for NPC treatment due to its convenience.

Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia

PubMed Central

Barta, Stefan K.; Zou, Yiyu; Schindler, John; Shenoy, Niraj; Bhagat, Tushar D.; Steidl, Ulrich; Verma, Amit

2013-01-01

The outcome for patients with refractory or relapsed acute lymphoblastic leukemia (ALL) treated with conventional therapy is poor. Immunoconjugates present a novel approach and have recently been shown to have efficacy in this setting. Combotox is a mixture of two ricin-conjugated monoclonal antibodies (RFB4 and HD37) directed against CD19 and CD22, respectively, and has shown activity in pediatric and adult ALL. We created a murine xenograft model of advanced ALL using the NALM/6 cell line to explore whether the combination of Combotox with the cytotoxic agent cytarabine (Ara-C) results in better outcomes. In our model the combination of both low- and high-dose Combotox and Ara-C resulted in significantly longer median survival. Sequential administration of Ara-C and Combotox, however, was shown to be superior to concurrent administration. These findings have led to a phase I clinical trial exploring this combination in adults with relapsed or refractory B-lineage ALL (ClinicalTrials.gov identifier NCT01408160). PMID:22448921

Efficacy of Helicobacter pylori eradication therapies in Korea: A systematic review and network meta-analysis.

PubMed

Jung, Yoon Suk; Park, Chan Hyuk; Park, Jung Ho; Nam, Eunwoo; Lee, Hang Lak

2017-08-01

The efficacy of Helicobacter pylori eradication regimens may depend on the country where the studies were performed because of the difference in antibiotic resistance. We aimed to analyze the efficacy of H. pylori eradication regimens in Korea where clarithromycin resistance rate is high. We searched for all relevant randomized controlled trials published until November 2016 that investigated the efficacy of H. pylori eradication therapies in Korea. A network meta-analysis was performed to calculate the direct and indirect estimates of efficacy among the eradication regimens. Forty-three studies were identified through a systematic review, of which 34 studies, published since 2005, were included in the meta-analysis. Among 21 included regimens, quinolone-containing sequential therapy for 14 days (ST-Q-14) showed the highest eradication rate (91.4% [95% confidence interval [CI], 86.9%-94.4%] in the intention-to-treat [ITT] analysis). The eradication rate of the conventional triple therapy for 7 days, standard sequential therapy for 10 days, hybrid therapy for 10-14 days, and concomitant therapy for 10-14 days was 71.1% (95% CI, 68.3%-73.7%), 76.2% (95% CI, 72.8%-79.3%), 79.4% (95% CI, 75.5%-82.8%), and 78.3% (95% CI, 75.3%-80.9%), respectively, in the ITT analysis. In the network meta-analysis, ST-Q-14 showed a better comparative efficacy than the conventional triple therapy, standard sequential therapy, hybrid therapy, and concomitant therapy. In addition, tolerability of ST-Q-14 was comparable to those regimens. In Korea, ST-Q-14 showed the highest efficacy in terms of eradication and a comparable tolerability, compared to the results reported for the conventional triple therapy, standard sequential therapy, hybrid therapy, and concomitant therapy. © 2017 John Wiley & Sons Ltd.

Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy.

PubMed

Akdim, Fatima; Stroes, Erik S G; Sijbrands, Eric J G; Tribble, Diane L; Trip, Mieke D; Jukema, J Wouter; Flaim, Joann D; Su, John; Yu, Rosie; Baker, Brenda F; Wedel, Mark K; Kastelein, John J P

2010-04-13

The aim of this study was to evaluate the efficacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Mipomersen is an apolipoprotein (apo) B synthesis inhibitor that has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled sequentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the first 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-specified end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema [90%]) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations >or=3x the upper limit of normal, 4 of which persisted on 2 consecutive occasions. Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569). Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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.

Treatment of mites folliculitis with an ornidazole-based sequential therapy

PubMed Central

Luo, Yang; Sun, Yu-Jiao; Zhang, Li; Luan, Xiu-Li

2016-01-01

Abstract Objective: Treatment of Demodex infestations is often inadequate and associated with low effective rate. We sought to evaluate the efficacy of an ornidazole-based sequential therapy for mites folliculitis treatment. Methods: Two-hundred patients with mites folliculitis were sequentially treated with either an ornidazole- or metronidazole-based regimen. Sebum cutaneum was extruded from the sebaceous glands of each patient's nose and the presence of Demodex mites were examined by light microscopy. The clinical manifestations of relapse of mites folliculitis were recorded and the subjects were followed up at 2, 4, 8, and 12 weeks post-treatment. Results: Patients treated with the ornidazole-based regimen showed an overall effective rate of 94.0%. Additionally, at the 2, 4, 8, and 12-week follow-up, these patients had significantly lower rates of Demodex mite relapse and new lesion occurrence compared with patients treated with the metronidazole-based regimen (P < 0.05). Conclusion: Sequential therapy using ornidazole, betamethasone, and recombinant bovine basic fibroblast growth factor (rbFGF) gel is highly effective for treating mites folliculitis. PMID:27399141

Sequential psychological and pharmacological therapies for comorbid and primary insomnia: study protocol for a randomized controlled trial.

PubMed

Morin, Charles M; Edinger, Jack D; Krystal, Andrew D; Buysse, Daniel J; Beaulieu-Bonneau, Simon; Ivers, Hans

2016-03-03

Chronic insomnia is a prevalent disorder associated with significant psychosocial, health, and economic impacts. Cognitive behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported therapeutic approaches for insomnia management. However, few investigations have directly compared their relative and combined benefits, and even fewer have tested the benefits of sequential treatment for those who do not respond to initial insomnia therapy. Moreover, insomnia treatment studies have been limited by small, highly screened study samples, fixed-dose, and fixed-agent pharmacotherapy strategies that do not represent usual clinical practices. This study will address these limitations. This is a two-site randomized controlled trial, which will enroll 224 adults who meet the criteria for a chronic insomnia disorder with or without comorbid psychiatric disorders. Prospective participants will complete clinical assessments and polysomnography and then will be randomly assigned to first-stage therapy involving either behavioral therapy (BT) or zolpidem. Treatment outcomes will be assessed after 6 weeks, and treatment remitters will be followed for the next 12 months on maintenance therapy. Those not achieving remission will be offered randomization to a second, 6-week treatment, again involving either pharmacotherapy (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy (CT)). All participants will be re-evaluated 12 weeks after the protocol initiation and at 3-, 6-, 9-, and 12-month follow-ups. Insomnia remission, defined categorically as a score < 8 on the Insomnia Severity Index, a patient-reported outcome, will serve as the primary endpoint for treatment comparisons. Secondary outcomes will include sleep parameters derived from daily sleep diaries and from polysomnography, subjective measures of fatigue, mood, quality of life, and functional impairments; and measures of adverse events; dropout rates; and treatment acceptability. Centrally trained therapists will administer therapies according to manualized, albeit flexible, treatment algorithms. This clinical trial will provide new information about optimal treatment sequencing and will have direct implication for the development of clinical guidelines for managing chronic insomnia with and without comorbid psychiatric conditions. ClinicalTrials.gov Identifier: NCT01651442 , Protocol version 4, 20 April 2011, registered 26 June 2012.

Safety and tolerability of dapagliflozin, saxagliptin and metformin in combination: Post-hoc analysis of concomitant add-on versus sequential add-on to metformin and of triple versus dual therapy with metformin.

PubMed

Del Prato, Stefano; Rosenstock, Julio; Garcia-Sanchez, Ricardo; Iqbal, Nayyar; Hansen, Lars; Johnsson, Eva; Chen, Hungta; Mathieu, Chantal

2018-06-01

The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin versus dual therapy with dapagliflozin or saxagliptin plus metformin was compared in a post-hoc analysis of 3 randomized trials of sequential or concomitant add-on of dapagliflozin and saxagliptin to metformin. In the concomitant add-on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus saxagliptin 5 mg/d. In sequential add-on trials, patients on metformin plus either saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or saxagliptin 5 mg/d, respectively, as add-on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add-on regimens. Urinary tract infections were more common with sequential than with concomitant add-on therapy; genital infections were reported only with sequential add-on of dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, saxagliptin and metformin, as either concomitant or sequential add-on, were similar to dual therapy with either agent added to metformin. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Randomised controlled trial of improvisational music therapy's effectiveness for children with autism spectrum disorders (TIME-A): study protocol.

PubMed

Geretsegger, Monika; Holck, Ulla; Gold, Christian

2012-01-05

Previous research has suggested that music therapy may facilitate skills in areas typically affected by autism spectrum disorders such as social interaction and communication. However, generalisability of previous findings has been restricted, as studies were limited in either methodological accuracy or the clinical relevance of their approach. The aim of this study is to determine effects of improvisational music therapy on social communication skills of children with autism spectrum disorders. An additional aim of the study is to examine if variation in dose of treatment (i.e., number of music therapy sessions per week) affects outcome of therapy, and to determine cost-effectiveness. Children aged between 4;0 and 6;11 years who are diagnosed with autism spectrum disorder will be randomly assigned to one of three conditions. Parents of all participants will receive three sessions of parent counselling (at 0, 2, and 5 months). In addition, children randomised to the two intervention groups will be offered individual, improvisational music therapy over a period of five months, either one session (low-intensity) or three sessions (high-intensity) per week. Generalised effects of music therapy will be measured using standardised scales completed by blinded assessors (Autism Diagnostic Observation Schedule, ADOS) and parents (Social Responsiveness Scale, SRS) before and 2, 5, and 12 months after randomisation. Cost effectiveness will be calculated as man years. A group sequential design with first interim look at N = 235 will ensure both power and efficiency. Responding to the need for more rigorously designed trials examining the effectiveness of music therapy in autism spectrum disorders, this pragmatic trial sets out to generate findings that will be well generalisable to clinical practice. Addressing the issue of dose variation, this study's results will also provide information on the relevance of session frequency for therapy outcome. Current Controlled Trials ISRCTN78923965.

Randomised controlled trial of improvisational music therapy's effectiveness for children with autism spectrum disorders (TIME-A): study protocol

PubMed Central

2012-01-01

Background Previous research has suggested that music therapy may facilitate skills in areas typically affected by autism spectrum disorders such as social interaction and communication. However, generalisability of previous findings has been restricted, as studies were limited in either methodological accuracy or the clinical relevance of their approach. The aim of this study is to determine effects of improvisational music therapy on social communication skills of children with autism spectrum disorders. An additional aim of the study is to examine if variation in dose of treatment (i.e., number of music therapy sessions per week) affects outcome of therapy, and to determine cost-effectiveness. Methods/Design Children aged between 4;0 and 6;11 years who are diagnosed with autism spectrum disorder will be randomly assigned to one of three conditions. Parents of all participants will receive three sessions of parent counselling (at 0, 2, and 5 months). In addition, children randomised to the two intervention groups will be offered individual, improvisational music therapy over a period of five months, either one session (low-intensity) or three sessions (high-intensity) per week. Generalised effects of music therapy will be measured using standardised scales completed by blinded assessors (Autism Diagnostic Observation Schedule, ADOS) and parents (Social Responsiveness Scale, SRS) before and 2, 5, and 12 months after randomisation. Cost effectiveness will be calculated as man years. A group sequential design with first interim look at N = 235 will ensure both power and efficiency. Discussion Responding to the need for more rigorously designed trials examining the effectiveness of music therapy in autism spectrum disorders, this pragmatic trial sets out to generate findings that will be well generalisable to clinical practice. Addressing the issue of dose variation, this study's results will also provide information on the relevance of session frequency for therapy outcome. Trial Registration Current Controlled Trials ISRCTN78923965. PMID:22221670

The Effect of Ezetimibe/Statin Combination and High-Dose Statin Therapy on Thyroid Autoimmunity in Women with Hashimoto's Thyroiditis and Cardiovascular Disease: A Pilot Study.

PubMed

Krysiak, R; Szkróbka, W; Okopień, B

2016-10-01

Background: Intensive statin therapy was found to reduce thyroid autoimmunity in women with Hashimoto's thyroiditis. No similar data are available for other hypolipidemic agents. Methods: The participants of the study were 16 women with Hashimoto's thyroiditis and coronary artery disease. On the basis of statin tolerance, they were divided into 2 groups. 8 patients who did not tolerate high-dose statin therapy were treated with a statin, the dose of which was reduced by half, together with ezetimibe. The remaining 8 patients tolerating the treatment continued high-dose statin therapy. Plasma lipids, serum levels of thyrotropin, free thyroxine and free triiodothyronine, as well as titers of thyroid peroxidase and thyroglobulin antibodies were measured at the beginning of the study and 6 months later. Results: Replacing high-dose statin therapy with ezetimibe/statin combination therapy increased serum titers of thyroid peroxidase as well as led to an insignificant increase in serum titers of thyroglobulin antibodies. At the end of the study, thyroid peroxidase and thyroglobulin antibody titers were higher in patients receiving the combination therapy than in those treated only with high-dose statin. Conclusions: Our study shows that high-dose statin therapy produces a stronger effect on thyroid autoimmunity than ezetimibe/statin combination therapy. © Georg Thieme Verlag KG Stuttgart · New York.

Introduction of Sequential Inactivated Polio Vaccine–Oral Polio Vaccine Schedule for Routine Infant Immunization in Brazil’s National Immunization Program

PubMed Central

Domingues, Carla Magda Allan S.; de Fátima Pereira, Sirlene; Marreiros, Ana Carolina Cunha; Menezes, Nair; Flannery, Brendan

2015-01-01

In August 2012, the Brazilian Ministry of Health introduced inactivated polio vaccine (IPV) as part of sequential polio vaccination schedule for all infants beginning their primary vaccination series. The revised childhood immunization schedule included 2 doses of IPV at 2 and 4 months of age followed by 2 doses of oral polio vaccine (OPV) at 6 and 15 months of age. One annual national polio immunization day was maintained to provide OPV to all children aged 6 to 59 months. The decision to introduce IPV was based on preventing rare cases of vaccine-associated paralytic polio, financially sustaining IPV introduction, ensuring equitable access to IPV, and preparing for future OPV cessation following global eradication. Introducing IPV during a national multivaccination campaign led to rapid uptake, despite challenges with local vaccine supply due to high wastage rates. Continuous monitoring is required to achieve high coverage with the sequential polio vaccine schedule. PMID:25316829

Dosimetric comparison of standard three-dimensional conformal radiotherapy followed by intensity-modulated radiotherapy boost schedule (sequential IMRT plan) with simultaneous integrated boost-IMRT (SIB IMRT) treatment plan in patients with localized carcinoma prostate.

PubMed

Bansal, A; Kapoor, R; Singh, S K; Kumar, N; Oinam, A S; Sharma, S C

2012-07-01

DOSIMETERIC AND RADIOBIOLOGICAL COMPARISON OF TWO RADIATION SCHEDULES IN LOCALIZED CARCINOMA PROSTATE: Standard Three-Dimensional Conformal Radiotherapy (3DCRT) followed by Intensity Modulated Radiotherapy (IMRT) boost (sequential-IMRT) with Simultaneous Integrated Boost IMRT (SIB-IMRT). Thirty patients were enrolled. In all, the target consisted of PTV P + SV (Prostate and seminal vesicles) and PTV LN (lymph nodes) where PTV refers to planning target volume and the critical structures included: bladder, rectum and small bowel. All patients were treated with sequential-IMRT plan, but for dosimetric comparison, SIB-IMRT plan was also created. The prescription dose to PTV P + SV was 74 Gy in both strategies but with different dose per fraction, however, the dose to PTV LN was 50 Gy delivered in 25 fractions over 5 weeks for sequential-IMRT and 54 Gy delivered in 27 fractions over 5.5 weeks for SIB-IMRT. The treatment plans were compared in terms of dose-volume histograms. Also, Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) obtained with the two plans were compared. The volume of rectum receiving 70 Gy or more (V > 70 Gy) was reduced to 18.23% with SIB-IMRT from 22.81% with sequential-IMRT. SIB-IMRT reduced the mean doses to both bladder and rectum by 13% and 17%, respectively, as compared to sequential-IMRT. NTCP of 0.86 ± 0.75% and 0.01 ± 0.02% for the bladder, 5.87 ± 2.58% and 4.31 ± 2.61% for the rectum and 8.83 ± 7.08% and 8.25 ± 7.98% for the bowel was seen with sequential-IMRT and SIB-IMRT plans respectively. For equal PTV coverage, SIB-IMRT markedly reduced doses to critical structures, therefore should be considered as the strategy for dose escalation. SIB-IMRT achieves lesser NTCP than sequential-IMRT.

Dosimetric rationale and early experience at UFPTI of thoracic proton therapy and chemotherapy in limited-stage small cell lung cancer.

PubMed

Colaco, Rovel J; Huh, Soon; Nichols, Romaine C; Morris, Christopher G; D'Agostino, Harry; Flampouri, Stella; Li, Zuofeng; Pham, Dat C; Bajwa, Abubakr A; Hoppe, Bradford S

2013-04-01

Concurrent chemoradiotherapy (CRT) is the standard of care in patients with limited-stage small cell lung cancer (SCLC). Treatment with conventional x-ray therapy (XRT) is associated with high toxicity rates, particularly acute grade 3+ esophagitis and pneumonitis. We present outcomes for the first known series of limited-stage SCLC patients treated with proton therapy and a dosimetric comparison of lung and esophageal doses with intensity-modulated radiation therapy (IMRT). Six patients were treated: five concurrently and one sequentially. Five patients received 60-66 CGE in 30-34 fractions once daily and one patient received 45 CGE in 30 fractions twice daily. All six patients received prophylactic cranial irradiation. Common Terminology Criteria for Adverse Events, v3.0, was used to grade toxicity. IMRT plans were also generated and compared with proton plans. The median follow-up was 12.0 months. The one-year overall and progression-free survival rates were 83% and 66%, respectively. There were no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis, and no other acute grade 3+ non-hematological toxicities were seen. One patient with a history of pulmonary fibrosis and atrial fibrillation developed worsening symptoms four months after treatment requiring oxygen. Three patients died: two of progressive disease and one after a fall; the latter patient was disease-free at 36 months after treatment. Another patient recurred and is alive, while two patients remain disease-free at 12 months of follow-up. Proton therapy proved superior to IMRT across all esophageal and lung dose volume points. In this small series of SCLC patients treated with proton therapy with radical intent, treatment was well tolerated with no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis. Dosimetric comparison showed better sparing of lung and esophagus with proton therapy. Proton therapy merits further investigation as a method of reducing the toxicity of CRT.

Use of tomotherapy in treatment of synchronous bilateral breast cancer: dosimetric comparison study

PubMed Central

Wadasadawala, T; Sarin, R; Upreti, R R; Paul, S; Phurailatpam, R

2015-01-01

Objective: Synchronous malignancy in both breasts is a rare incidence. The present study aims at dosimetric comparison of conventional bitangential radiotherapy (RT) technique with conventional [field-in-field (FIF)] and rotational [Helical TomoTherapy® and TomoDirect™ (TD); Accuray Inc., Sunnyvale, CA] intensity-modulated RT for patients with synchronous bilateral breast cancer (SBBC). Methods: CT data sets of 10 patients with SBBC were selected for the present study. RT was planned for all patients on both sides to whole breast and/or chest wall using the above-mentioned techniques. Six females with breast conservation on at least one side also had a composite plan along with tumour bed (TB) boost using sequential electrons for bitangential and FIF techniques or sequential helical tomotherapy (HT) boost (for TD) or simultaneous integrated boost (SIB) for HT. Results: All techniques produced acceptable target coverage. The hotspot was significantly lower with FIF technique and HT but higher with TD. For the organs at risk doses, HT resulted in significant reduction of the higher dose volumes. Similarly, TD resulted in significant reduction of the mean dose to the heart and total lung by reducing the lower dose volumes. All techniques of delivering boost to the TB were comparable in terms of target coverage. HT-SIB markedly reduced mean doses to the total lung and heart by specifically lowering the higher dose volumes. Conclusion: This study demonstrates the cardiac and pulmonary sparing ability of tomotherapy in the setting of SBBC. Advances in knowledge: This is the first study demonstrating feasibility of treatment of SBBC using tomotherapy. PMID:25605345

Characterization of a commercial multileaf collimator used for intensity modulated radiation therapy.

PubMed

Low, D A; Sohn, J W; Klein, E E; Markman, J; Mutic, S; Dempsey, J F

2001-05-01

The characteristics of a commercial multileaf collimator (MLC) to deliver static and dynamic multileaf collimation (SMLC and DMLC, respectively) were investigated to determine their influence on intensity modulated radiation therapy (IMRT) treatment planning and quality assurance. The influence of MLC leaf positioning accuracy on sequentially abutted SMLC fields was measured by creating abutting fields with selected gaps and overlaps. These data were also used to measure static leaf positioning precision. The characteristics of high leaf-velocity DMLC delivery were measured with constant velocity leaf sequences starting with an open field and closing a single leaf bank. A range of 1-72 monitor units (MU) was used providing a range of leaf velocities. The field abutment measurements yielded dose errors (as a percentage of the open field max dose) of 16.7+/-0.7% mm(-1) and 12.8+/-0.7% mm(-1) for 6 MV and 18 MV photon beams, respectively. The MLC leaf positioning precision was 0.080+/-0.018 mm (single standard deviation) highlighting the excellent delivery hardware tolerances for the tested beam delivery geometry. The high leaf-velocity DMLC measurements showed delivery artifacts when the leaf sequence and selected monitor units caused the linear accelerator to move the leaves at their maximum velocity while modulating the accelerator dose rate to deliver the desired leaf and MU sequence (termed leaf-velocity limited delivery). According to the vendor, a unique feature to their linear accelerator and MLC is that the dose rate is reduced to provide the correct cm MU(-1) leaf velocity when the delivery is leaf-velocity limited. However, it was found that the system delivered roughly 1 MU per pulse when the delivery was leaf-velocity limited causing dose profiles to exhibit discrete steps rather than a smooth dose gradient. The root mean square difference between the steps and desired linear gradient was less than 3% when more than 4 MU were used. The average dose per MU was greater and less than desired for closing and opening leaf patterns, respectively, when the delivery was leaf-velocity limited. The results indicated that the dose delivery artifacts should be minor for most clinical cases, but limit the assumption of dose linearity when significantly reducing the delivered dose for dosimeter characterization studies or QA measurements.

A retrospective study on sequential desensitization-rechallenge for antituberculosis drug allergy

PubMed Central

Chia, Faith Li-Ann; Tan, Sze-Chin; Tan, Teck-Choon; Leong, Khai-Pang; Tan, Justina Wei-Lyn; Tang, Chwee-Ying; Hou, Jin-Feng; Chan, Grace Yin-Lai; Chng, Hiok-Hee

2014-01-01

Background Antituberculosis (anti-TB) drug allergy often involves multiple concurrently administered drugs which subsequently need to be reinitiated as no better alternatives exist. Objective To describe the results of tailored sequential desensitization-rechallenge (D-R) for anti-TB drug allergy. Methods Consecutive patients who had undergone D-R to anti-TB drugs between 1 September 1997 and 31 January 2012 were recruited. Following resolution of the acute reaction, anti-TB drug was restarted at 1:6,000 to 1:3 of the final daily dose (FDD), with gradual single or multiple step daily dose escalation to the FDD. Subsequent drugs were sequentially added ≥3 days later when the preceding drug was tolerated. Full blood count and liver function tests were monitored prior to addition of each new drug. Results There were 11 patients of whom 10 were male, predominantly Chinese (8 patients). Regimens comprised at least 3 drugs: isoniazid (INH), rifampicin (RIF), ethambutol (EMB), pyrazinamide (PZA), or streptomycin. All patients had nonimmediate reactions, with cutaneous eruptions, where maculopapular exanthema (MPE) was the most common (8 patients). Drug-induced hypersensitivity syndrome (DIHS) occurred in 6 patients, and Stevens Johnson syndrome (SJS) in 2 patients. D-R to INH was successful in 7/9 patients (77.8%) and to RIF/EMB/PZA/streptomycin in all. Of the 2 patients who failed INH D-R, 1 developed fever and MPE on day 3, the other MPE on day 8. D-R with INH and RIF respectively was successful in 2 patients with SJS. Among DIHS patients, 1 failed D-R with INH (fever and MPE on day 3). There were 23/25 (92%) successful D-R among the 11 patients. All patients completed TB treatment of ≥5 months' duration with no cases of drug-resistant TB. Conclusion Tailored sequential TB drug D-R is successful where no better alternative therapies are available, with careful dose escalation and close monitoring, and after a careful risk-benefit assessment. PMID:25097851

The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.

PubMed

Gills, Jessie; Parker, William P; Pate, Scott; Niu, Sida; Van Veldhuizen, Peter; Mirza, Moben; Holzbeierlein, Jeffery M; Lee, Eugene K

2017-09-01

We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients.

PubMed

Penoncello, Gregory P; Ding, George X

2016-01-01

The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2cm(3) for head and neck plans and brain plans and a contiguous volume of 5cm(3) for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens. Copyright © 2016 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

High-Dose Methylprednisolone for Veno-Occlusive Disease of the Liver in Pediatric Hematopoietic Stem Cell Transplantation Recipients

PubMed Central

Myers, Kasiani C.; Lawrence, Julia; Marsh, Rebecca A.; Davies, Stella M.; Jodele, Sonata

2017-01-01

Veno-occlusive disease (VOD) of the liver is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT), with few successful treatment modalities available for severe disease. Some reports have demonstrated success in adults with the use of high-dose steroid therapy, but experience in the pediatric population is lacking. We retrospectively reviewed HSCT patients treated at our institution since 2003 and identified 15 (2.4%) who developed VOD. Of these, nine (60%) were treated with intravenous high-dose methylprednisolone (500 mg/m2 per dose every 12 hours for six doses). Steroid therapy was initiated at or before first ultrasound evidence of reversal of portal venous flow and before meeting criteria for initiation of defibrotide therapy. Four patients were also treated with defibrotide starting 2 to 5 days after initiation of steroids. Eight of nine patients (88%) with VOD were diagnosed with multiorgan failure. Response to high-dose steroid therapy as defined by decrease in bilirubin by 50% in 10 days from therapy initiation was noted in six of nine patients (67%), occurring within 3 to 6 days of steroid therapy. Two patients died from multiorgan failure due to VOD. Seven survivors of VOD recovered at the median 6 days (range, 5 to 38) from VOD diagnosis. Overall, VOD survival as a group was 78%; however, survival among responders was 100%. No serious toxicities related to high-dose steroid therapy were observed. We conclude that high-dose steroid therapy if initiated early may reverse VOD of the liver in pediatric HSCT patients, abrogating the need for defibrotide therapy with its associated toxicities and regulatory difficulties. PMID:23211838

Neoadjuvant therapy for organ preservation in head and neck cancer.

PubMed

Urba, S G; Wolf, G T; Bradford, C R; Thornton, A F; Eisbruch, A; Terrell, J E; Carpenter, V; Miller, T; Tang, G; Strawderman, M

2000-12-01

We designed two sequential trials of induction chemotherapy followed by definitive radiation in patients with potentially resectable head and neck cancer to determine whether organ preservation is feasible without apparent compromise of survival Study Design Both trials were Phase II studies. Two clinical trials were conducted sequentially at the University of Michigan. Fifty-two patients enrolled in the first study and were treated with a planned three cycles of carboplatin and 5-fluorouracil. Patients who achieved at least 50% reduction in the size of the primary tumor received definitive radiation therapy, to a dose of 6600 to 7380 cGy. Patients with minimal response or progression had immediate salvage surgery. Thirty-seven patients enrolled in the second trial, in which the chemotherapy consisted of carboplatin, 5-fluororuracil, and leukovorin. Responders were treated with accelerated radiation therapy, to a total dose of 7120 cGy delivered in 41 fractions over 5.5 weeks. Toxicity and response were similar in both trials; therefore, the results are reported first separately and then combined for all 89 patients. Tumor sites included: oropharynx, 55 patients; hypopharynx, 34 patients. Eighty-three percent of patients tolerated all three cycles of chemotherapy and toxicity was mild. Response to chemotherapy was: 48% complete response at the primary tumor site, and 34% partial response at the primary tumor site. Initial organ preservation at individual tumor sites was: oropharynx, 58%; hypopharynx, 59%. Median survival was 28 months, and survival at 3 and 5 years was 40% and 24%, respectively. These two regimens were well tolerated, and survival did not appear to be compromised by organ preservation treatment compared with historical controls. This approach warrants further investigation, particularly in those patients for whom surgery could be functionally debilitating.

ATO/ATRA/anthracycline-chemotherapy sequential consolidation achieves long-term efficacy in primary acute promyelocytic leukemia.

PubMed

Long, Zi-Jie; Hu, Yuan; Li, Xu-Dong; He, Yi; Xiao, Ruo-Zhi; Fang, Zhi-Gang; Wang, Dong-Ning; Liu, Jia-Jun; Yan, Jin-Song; Huang, Ren-Wei; Lin, Dong-Jun; Liu, Quentin

2014-01-01

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3, ATO) has been effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but the long-term efficacy and safety among newly diagnosed APL patients are unclear. In this retrospective study, total 45 newly diagnosed APL patients received ATRA/chemotherapy combination regimen to induce remission. Among them, 43 patients (95.6%) achieved complete remission (CR) after induction therapy, followed by ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment with a median follow-up of 55 months. In these patients, the estimated overall survival (OS) and the relapse-free survival (RFS) were 94.4% ± 3.9% and 94.6 ± 3.7%, respectively. The toxicity profile was mild and reversible. No secondary carcinoma was observed. These results demonstrated the high efficacy and minimal toxicity of ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for APL.

The effect of ezetimibe-statin combination on steroid hormone production in men with coronary artery disease and low cholesterol levels.

PubMed

Krysiak, Robert; Kowalska, Beata; Żmuda, Witold; Okopień, Bogusław

2015-04-01

Aggressive statin treatment was found to slightly reduce testosterone production. The aim of this study was to compare the effects of ezetimibe-statin combination and high-dose statin therapy on testicular and adrenal cortex function in men with LDL cholesterol levels below 70 mg/dL. The study included 26 adult men with coronary artery disease. Twelve of these patients did not tolerate high-dose statin therapy and were treated with lower doses of a statin plus ezetimibe. Fourteen patients tolerating high-dose simvastatin or rosuvastatin treatment continued high-dose statin therapy throughout the study period. Plasma lipids, glucose homeostasis markers and plasma levels of testosterone, cortisol, dehydroepiandrosterone sulphate, sex hormone-binding globulin, gonadotropins and ACTH, as well as urine free cortisol were assessed at baseline and after 16 weeks of treatment. Replacing high-dose statin therapy with ezetimibe/statin combination therapy reduced plasma levels of LH by 32% (p=0.043), as well as increased plasma levels of testosterone by 20% (p=0.038). Ezetimibe/statin combination did not induce any significant changes in plasma levels or urine excretion of the remaining hormones. At the end of the study, plasma LH levels were higher, while plasma testosterone levels were lower in patients receiving the combination therapy than in those treated only with high-dose statin. Our results indicate that ezetimibe combined with moderate statin dose exerts a less pronounced effect on testicular function in comparison with high-dose statin therapy. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

[LDL cholesterol lowering therapy: no target value but personalised treatment].

PubMed

Simoons, Maarten L; Deckers, Jaap W

2015-01-01

We previously recommended that LDL cholesterol lowering therapy be based on the risk for (recurrent) coronary events, rather than on arbitrary targets for serum LDL cholesterol concentration. We also recommended refraining from therapy with ezetimibe until its efficacy in preventing cardiovascular events had been documented. At the American Heart Association scientific sessions 2014 the results of the IMPROVE-IT study were reported. In this large, randomised trial, a modest benefit of the combination of simvastatin plus ezetimibe over simvastatin alone was reported after 7 years of treatment. The efficacy of such combination therapy was similar to the efficacy of high-dose statin therapy, while the combination therapy is much more expensive. Comparing the efficacy and costs of different preventive therapies, we recommend first prescribing aspirin and a moderate dose of statin, secondly an ACE inhibitor. A high-dose statin should be considered in high-risk patients. The combination of simvastatin and ezetimibe should be prescribed only in high-risk patients (e.g. diabetics after myocardial infarction) who do not tolerate high-dose statins.

Dosimetric Analysis of Radiation-induced Gastric Bleeding

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

Feng, Mary, E-mail: maryfeng@umich.edu; Normolle, Daniel; Pan, Charlie C.

2012-09-01

Purpose: Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy. Methods and Materials: The records of 139 sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of {>=}grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models. Results: Sixteen of 116 evaluable patients (14%) developed gastric bleeds at amore » median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD{sub 50} (normal) = 56 Gy and TD{sub 50} (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD{sub 50} value for the cirrhosis patients points out their greater sensitivity. Conclusions: This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.« less

Short-Course Hypofractionated Radiation Therapy With Boost in Women With Stages 0 to IIIa Breast Cancer: A Phase 2 Trial.

PubMed

Ahlawat, Stuti; Haffty, Bruce G; Goyal, Sharad; Kearney, Thomas; Kirstein, Laurie; Chen, Chunxia; Moore, Dirk F; Khan, Atif J

2016-01-01

Conventionally fractionated whole-breast irradiation (WBI) with a boost takes approximately 6 to 7 weeks. We evaluated a short course of hypofractionated (HF), accelerated WBI in which therapy was completed in 3 weeks inclusive of a sequential boost. We delivered a whole-breast dose of 36.63 Gy in 11 fractions of 3.33 Gy over 11 days, followed by a lumpectomy bed boost in 4 fractions of 3.33 Gy delivered once daily for a total of 15 treatment days. Acute toxicities were scored using Common Terminology Criteria for Adverse Events version 4. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Cosmesis was scored using the Harvard Cosmesis Scale. Our primary endpoint was freedom from locoregional failure; we incorporated early stopping criteria based on predefined toxicity thresholds. Cosmesis was examined as a secondary endpoint. We enrolled 83 women with stages 0 to IIIa breast cancer. After a median follow-up of 40 months, 2 cases of isolated ipsilateral breast tumor recurrence occurred (2 of 83; crude rate, 2.4%). Three-year estimated local recurrence-free survival was 95.9% (95% confidence interval [CI]: 87.8%-98.7%). The 3-year estimated distant recurrence-free survival was 97.3% (95% CI: 89.8%-99.3%). Three-year secondary malignancy-free survival was 94.3% (95% CI: 85.3%-97.8%). Twenty-nine patients (34%) had grade 2 acute toxicity, and 1 patient had a late grade 2 toxicity (fibrosis). One patient had acute grade 3 dermatitis, whereas 2 patients experienced grade 3 late skin toxicity. Ninety-four percent of evaluable patients had good or excellent cosmesis. Our phase 2 institutional study offers one of the shortest courses of HF therapy, delivered in 15 fractions inclusive of a sequential boost. We demonstrated expected low toxicity and high local control rates with good to excellent cosmetic outcomes. This fractionation scheme is feasible and well tolerated and offers women WBI in a highly convenient schedule. Copyright © 2016 Elsevier Inc. All rights reserved.

Administration of Concurrent Vaginal Brachytherapy During Chemotherapy for Treatment of Endometrial Cancer

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

Nagar, Himanshu; Boothe, Dustin; Parikh, Amar

2013-11-15

Purpose: To evaluate the tolerability and toxicity of administering vaginal brachytherapy (VB) concurrently during chemotherapy compared with the sequential approach for patients with endometrial cancer. Methods and Materials: A retrospective analysis of 372 surgically staged patients with endometrial cancer American Joint Committee on Cancer 2009 stages I to IV treated with adjuvant postoperative radiation therapy (RT) at our institution from 2001 to 2012 was conducted. All patients received VB + external beam RT (EBRT) + 6 cycles of adjuvant carboplatin- and paclitaxel-based chemotherapy. The VB mean dose was 15.08 Gy (range, 15-20 Gy), with 3 to 4 weekly applications, andmore » the EBRT mean dose was 45 Gy delivered with 3-dimensional or intensity modulated RT techniques. Hematologic, gastrointestinal (GI), and genitourinary (GU) toxicities were assessed by Common Toxicity Criteria (CTC) and compared between sequential and concurrent chemotherapy and VB schedules. Results: Among patients who received RT and adjuvant chemotherapy, 180 of 372 patients (48%) received RT sandwiched between cycles 3 and 4 of chemotherapy. A separate group of 192 patients (52%) were treated with VB during the first 3 cycles of chemotherapy, with a weekly application on nonchemotherapy days, and received the EBRT portion in a sandwiched fashion. Patients treated with VB during chemotherapy had a decreased overall treatment time by 4 weeks (P<.001; 95% confidence interval: 3.99-4.02) and sustained no difference in CTC-graded acute hematologic, GI, or GU toxicities in comparison with the patients treated with VB and chemotherapy in a sequential manner (P>.05). CTC grade 3 or 4 hematologic, GI, and GU toxicities were zero. Conclusions: VB during chemotherapy is well tolerated, decreases overall treatment time, and does not render more toxicity than the sequential regimen.« less

Radial to femoral arterial blood pressure differences in septic shock patients receiving high-dose norepinephrine therapy.

PubMed

Kim, Won Young; Jun, Jong Hun; Huh, Jin Won; Hong, Sang Bum; Lim, Chae-Man; Koh, Younsuck

2013-12-01

The accuracy of arterial blood pressure (ABP) monitoring is crucial in treating septic shock patients. Clinically significant differences in central to peripheral ABP could develop into sepsis during vasopressor therapy. The aim of this study was to investigate the difference between radial (peripheral) and femoral (central) ABP in septic shock patients receiving high-dose norepinephrine (NE) therapy. This prospective observational study comparing simultaneous intra-arterial measurements of radial and femoral ABP was performed at a university-affiliated, tertiary referral center between October 2008 and March 2009. Patients with septic shock who needed continuous blood pressure monitoring and high-dose NE therapy 0.1 µg/kg per minute or greater to maintain mean arterial pressure (MAP) of 65 mmHg or greater were included. Statistical analysis was conducted using the Bland-Altman method for comparison of repeated measures. In total, 250 sets of systolic, mean, and diastolic femoral and radial ABP were recorded at baseline and after NE titration. Arterial blood pressure readings from the radial artery were underestimated compared with those from the femoral artery. Overall bias (mean difference between simultaneous measurements) between radial and femoral MAP was +4.9 mmHg; however, during high-dose NE therapy, the bias increased to +6.2 mmHg (95% limits of agreement: -6.0 to +18.3 mmHg). Clinically significant radial-femoral MAP differences (MAP ≥5 mmHg) occurred in up to 62.2% of patients with high-dose NE therapy. Radial artery pressure frequently underestimates central pressure in septic shock patients receiving high-dose NE therapy. Femoral arterial pressure monitoring may be more appropriate when high-dose NE therapy is administered.

Losartan/hydrochlorothiazide combination is safe and effective for morning hypertension in Very-Elderly patients.

PubMed

Uchiwa, Hiroki; Kai, Hisashi; Iwamoto, Yoshiko; Anegawa, Takahiro; Kajimoto, Hidemi; Fukuda, Kenji; Imaizumi, Tsutomu; Fukumoto, Yoshihiro

2018-01-01

Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (<75 years). This study was a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy study, in which patients with morning hypertension (≥135/85 mmHg) received a 50-mg losartan/12.5-mg HCTZ combination tablet (combination therapy) or 100-mg losartan (high-dose therapy) for 3 months. High adherence rates and few adverse effects were observed in Very-Elderly patients receiving combination (n = 32) and high-dose (n = 34) therapies and in Young/Elderly patients receiving combination (n = 69) and high-dose (n = 66) therapies. Baseline morning systolic BP (SBP) was similar in both age groups receiving either therapy. Morning SBP was reduced by 20.2 and 18.1 mmHg with combination therapy and by 7.1 and 9.1 mmHg with high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Morning BP target (<135/85 mmHg) was achieved in 40.6% and 55.1% by combination therapy and in 14.7% and 24.2% by high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Neither therapy changed renal function and serum potassium in Very-Elderly patients. In conclusion, the losartan/HCTZ combination was safe and effective in controlling morning hypertension in Very-Elderly as well as Young/Elderly patients. In addition, combination therapy was also superior to high-dose therapy for lowering morning SBP in Very-Elderly patients.

Efficacy of Low-Dose Corticosteroid Therapy Versus High-Dose Corticosteroid Therapy in Bell's Palsy in Children.

PubMed

Arican, Pinar; Dundar, Nihal Olgac; Gencpinar, Pinar; Cavusoglu, Dilek

2017-01-01

Bell's palsy is the most common cause of acute peripheral facial nerve paralysis, but the optimal dose of corticosteroids in pediatric patients is still unclear. This retrospective study aimed to evaluate the efficacy of low-dose corticosteroid therapy compared with high-dose corticosteroid therapy in children with Bell's palsy. Patients were divided into 2 groups based on the dose of oral prednisolone regimen initiated. The severity of idiopathic facial nerve paralysis was graded according to the House-Brackmann Grading Scale. The patients were re-assessed in terms of recovery rate at the first, third, and sixth months of treatment. There was no significant difference in complete recovery between the 2 groups after 1, 3, and 6 months of treatment. In our study, we concluded that even at a dose of 1 mg/kg/d, oral prednisolone was highly effective in the treatment of Bell's palsy in children.

Nonbismuth concomitant quadruple therapy for Helicobacter pylori eradication in Chinese regions: A meta-analysis of randomized controlled trials

PubMed Central

Lin, Lien-Chieh; Hsu, Tzu-Herng; Huang, Kuang-Wei; Tam, Ka-Wai

2016-01-01

AIM: To evaluate the applicability of nonbismuth concomitant quadruple therapy for Helicobacter pylori (H. pylori) eradication in Chinese regions. METHODS: A systematic review and meta-analysis of randomized controlled trials was performed to evaluate the efficacy of nonbismuth concomitant quadruple therapy between sequential therapy or triple therapy for H. pylori eradication in Chinese regions. The defined Chinese regions include China, Hong Kong, Taiwan, and Singapore. The primary outcome was the H. pylori eradication rate; the secondary outcome was the compliance with therapy. The PubMed, Embase, Scopus, and Cochrane databases were searched for studies published in the period up to March 2016 with no language restriction. RESULTS: We reviewed six randomized controlled trials and 1616 patients. In 3 trials comparing concomitant quadruple therapy with triple therapy, the H. pylori eradication rate was significantly higher for 7-d nonbismuth concomitant quadruple therapy than for 7-d triple therapy (91.2% vs 77.9%, risk ratio = 1.17, 95%CI: 1.09-1.25). In 3 trials comparing quadruple therapy with sequential therapy, the eradication rate was not significant between groups (86.9% vs 86.0%). However, higher compliance was achieved with concomitant therapy than with sequential therapy. CONCLUSION: The H. pylori eradication rate was higher for nonbismuth concomitant quadruple therapy than for triple therapy. Moreover, higher compliance was achieved with nonbismuth concomitant quadruple therapy than with sequential therapy. Thus, nonbismuth concomitant quadruple therapy should be the first-line treatment in Chinese regions. PMID:27340362

Tandem autologous non-myeloablative allogeneic transplantation in patients with multiple myeloma relapsing after a first high dose therapy.

PubMed

Karlin, L; Arnulf, B; Chevret, S; Ades, L; Robin, M; De Latour, R P; Malphettes, M; Kabbara, N; Asli, B; Rocha, V; Fermand, J P; Socie, G

2011-02-01

We retrospectively studied a series of 23 patients (median age 50 years, range 29-59 years) with multiple myeloma (MM), treated in first relapse by a sequential autologous-allogeneic tandem approach. Tandem transplantation (TT) consisted in high dose melphalan (HDT) and auto-SCT followed by an (allo-SCT) preceded by two gray TBI non-myeloablative conditioning. All patients received a first HDT as frontline treatment. At day 100 post allo-SCT, complete donor chimerism was detected in 22 patients (95%). Acute GVHD was observed in 19 patients (15 grade I-II (65%) and 4 grade III-IV (17%)). Ten patients (43%) developed an extensive chronic GVHD. The non-relapse mortality at 1 year was 17%. After TT, the overall response rate was 91% (17% partial response, 35% very good partial remission and 39% complete remission). At 2 years, OS was 61%. Median event-free survival and OS were 36.8 and 60 months, respectively. Based on the propensity score matching method, a significant survival advantage could be seen in patients treated with TT as compared with non-allografted patients. Thus, allo-SCT, in TT approach, provides a high response rate with low toxicity and may improve survival of patients with relapsing MM.

Helicobacter pylori-related diseases.

PubMed

Gisbert, Javier P

2016-09-01

This article describes the main conclusions drawn from the presentations on Helicobacter pylori infection in Digestive Diseases Week, 2016. Despite the undeniable widespread reduction in the prevalence of this infection, infection rates continue to be high in developing countries. The prevalence of clarithromycin, metronidazole and quinolone resistance is markedly high in most countries and continues to rise. The management of H. pylori infection in patients with peptic ulcers still leaves much to be desired. Although H. pylori eradication reduces the incidence of gastric adenocarcinoma, it does not completely avoid its appearance. The new rapid stool antigen tests show promising results. The efficacy of standard triple therapy is clearly inadequate and continues to decline, and cannot therefore be recommended. Vonoprazan, when associated with 2 antibiotics, is more effective than traditional proton pump inhibitors, especially in clarithromycin-resistant patients. Non-bismuth quadruple (concomitant) therapy achieves eradication rates of around 90% and has a good safety profile. Concomitant therapy is more effective and simpler than sequential therapy. Although some probiotics can increase the efficacy and tolerability of triple therapy, the utility of its association with quadruple concomitant therapy has not been established. If a first treatment with clarithromycin fails, both bismuth-containing quadruple therapy and levofloxacin-containing triple therapy achieve good-but still suboptimal-results. The combination of bismuth and levofloxacin in the same regimen increases the efficacy of rescue therapy. The management of H. pylori infection by European gastroenterologists is widely heterogeneous and the eradication rates achieved by them are generally unacceptable. In Spain, the highest first-line eradication rate is obtained with quadruple concomitant therapy in 14-day regimens and with double doses of proton pump inhibitors; in second-line therapy, the use of levofloxacin- and bismuth-containing quadruple therapy improves the rates traditionally obtained with quinolones. On the other hand, there is a clear disconnect between the recommendations made in consensus documents and clinical practice in primary care. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

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

Yang, Y. M., E-mail: ymingy@gmail.com; Bednarz, B.; Svatos, M.

Purpose: The future of radiation therapy will require advanced inverse planning solutions to support single-arc, multiple-arc, and “4π” delivery modes, which present unique challenges in finding an optimal treatment plan over a vast search space, while still preserving dosimetric accuracy. The successful clinical implementation of such methods would benefit from Monte Carlo (MC) based dose calculation methods, which can offer improvements in dosimetric accuracy when compared to deterministic methods. The standard method for MC based treatment planning optimization leverages the accuracy of the MC dose calculation and efficiency of well-developed optimization methods, by precalculating the fluence to dose relationship withinmore » a patient with MC methods and subsequently optimizing the fluence weights. However, the sequential nature of this implementation is computationally time consuming and memory intensive. Methods to reduce the overhead of the MC precalculation have been explored in the past, demonstrating promising reductions of computational time overhead, but with limited impact on the memory overhead due to the sequential nature of the dose calculation and fluence optimization. The authors propose an entirely new form of “concurrent” Monte Carlo treat plan optimization: a platform which optimizes the fluence during the dose calculation, reduces wasted computation time being spent on beamlets that weakly contribute to the final dose distribution, and requires only a low memory footprint to function. In this initial investigation, the authors explore the key theoretical and practical considerations of optimizing fluence in such a manner. Methods: The authors present a novel derivation and implementation of a gradient descent algorithm that allows for optimization during MC particle transport, based on highly stochastic information generated through particle transport of very few histories. A gradient rescaling and renormalization algorithm, and the concept of momentum from stochastic gradient descent were used to address obstacles unique to performing gradient descent fluence optimization during MC particle transport. The authors have applied their method to two simple geometrical phantoms, and one clinical patient geometry to examine the capability of this platform to generate conformal plans as well as assess its computational scaling and efficiency, respectively. Results: The authors obtain a reduction of at least 50% in total histories transported in their investigation compared to a theoretical unweighted beamlet calculation and subsequent fluence optimization method, and observe a roughly fixed optimization time overhead consisting of ∼10% of the total computation time in all cases. Finally, the authors demonstrate a negligible increase in memory overhead of ∼7–8 MB to allow for optimization of a clinical patient geometry surrounded by 36 beams using their platform. Conclusions: This study demonstrates a fluence optimization approach, which could significantly improve the development of next generation radiation therapy solutions while incurring minimal additional computational overhead.« less

Moderate Hypofractionated Protracted Radiation Therapy and Dose Escalation for Prostate Cancer: Do Dose and Overall Treatment Time Matter?

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

Kountouri, Melpomeni; Zilli, Thomas; Rouzaud, Michel

2016-02-01

Purpose: This was a retrospective study of 2 sequential dose escalation regimens of twice-weekly 4 Gy/fractions hypofractionated intensity modulated radiation therapy (IMRT): 56 Gy and 60 Gy delivered within a protracted overall treatment time (OTT) of 6.5 and 7 weeks, respectively. Methods and Materials: 163 prostate cancer patients with cT1c-T3a disease and nodal involvement risk ≤20% (Roach index) were treated twice weekly to the prostate ± seminal vesicles with 2 sequential dose-escalated IMRT schedules: 56 Gy (14 × 4 Gy, n=81) from 2003 to 2007 and 60 Gy (15 × 4 Gy, n=82) from 2006 to 2010. Patient repositioning was made with bone matching on portal images. Gastrointestinal (GI) and genitourinary (GU) toxicities weremore » scored according to the Common Terminology Criteria for Adverse Events version 3.0 grading scale. Results: There were no significant differences regarding the acute GU and GI toxicities in the 2 dose groups. The median follow-up times were 80.2 months (range, 4.5-121 months) and 56.5 months (range, 1.4-91.2 months) for patients treated to 56 and 60 Gy, respectively. The 5-year grade ≥2 late GU toxicity-free survivals with 56 Gy and 60 Gy were 96 ± 2.3% and 78.2 ± 5.1% (P=.001), respectively. The 5-year grade ≥2 late GI toxicity-free survivals with 56 Gy and 60 Gy were 98.6 ± 1.3% and 85.1 ± 4.5% (P=.005), respectively. Patients treated with 56 Gy showed a 5-year biochemical progression-free survival (bPFS) of 80.8 ± 4.7%, worse than patients treated with 60 Gy (93.2 ± 3.9%, P=.007). A trend for a better 5-year distant metastasis-free survival was observed among patients treated in the high-dose group (95.3 ± 2.7% vs 100%, P=.073, respectively). On multivariate analysis, only the 60-Gy group predicted for a better bPFS (P=.016, hazard ratio = 4.58). Conclusions: A single 4-Gy additional fraction in patients treated with a hypofractionated protracted IMRT schedule of 14 × 4 Gy resulted in a similar and minimal acute toxicity, in worse moderate to severe urinary and GI late effects, but a significantly better biochemical control.« less

Concurrent Monte Carlo transport and fluence optimization with fluence adjusting scalable transport Monte Carlo

PubMed Central

Svatos, M.; Zankowski, C.; Bednarz, B.

2016-01-01

Purpose: The future of radiation therapy will require advanced inverse planning solutions to support single-arc, multiple-arc, and “4π” delivery modes, which present unique challenges in finding an optimal treatment plan over a vast search space, while still preserving dosimetric accuracy. The successful clinical implementation of such methods would benefit from Monte Carlo (MC) based dose calculation methods, which can offer improvements in dosimetric accuracy when compared to deterministic methods. The standard method for MC based treatment planning optimization leverages the accuracy of the MC dose calculation and efficiency of well-developed optimization methods, by precalculating the fluence to dose relationship within a patient with MC methods and subsequently optimizing the fluence weights. However, the sequential nature of this implementation is computationally time consuming and memory intensive. Methods to reduce the overhead of the MC precalculation have been explored in the past, demonstrating promising reductions of computational time overhead, but with limited impact on the memory overhead due to the sequential nature of the dose calculation and fluence optimization. The authors propose an entirely new form of “concurrent” Monte Carlo treat plan optimization: a platform which optimizes the fluence during the dose calculation, reduces wasted computation time being spent on beamlets that weakly contribute to the final dose distribution, and requires only a low memory footprint to function. In this initial investigation, the authors explore the key theoretical and practical considerations of optimizing fluence in such a manner. Methods: The authors present a novel derivation and implementation of a gradient descent algorithm that allows for optimization during MC particle transport, based on highly stochastic information generated through particle transport of very few histories. A gradient rescaling and renormalization algorithm, and the concept of momentum from stochastic gradient descent were used to address obstacles unique to performing gradient descent fluence optimization during MC particle transport. The authors have applied their method to two simple geometrical phantoms, and one clinical patient geometry to examine the capability of this platform to generate conformal plans as well as assess its computational scaling and efficiency, respectively. Results: The authors obtain a reduction of at least 50% in total histories transported in their investigation compared to a theoretical unweighted beamlet calculation and subsequent fluence optimization method, and observe a roughly fixed optimization time overhead consisting of ∼10% of the total computation time in all cases. Finally, the authors demonstrate a negligible increase in memory overhead of ∼7–8 MB to allow for optimization of a clinical patient geometry surrounded by 36 beams using their platform. Conclusions: This study demonstrates a fluence optimization approach, which could significantly improve the development of next generation radiation therapy solutions while incurring minimal additional computational overhead. PMID:27277051

Moderator's view: Treatment of IgA nephropathy-getting comfortable with uncertainty.

PubMed

Glassock, Richard J

2016-11-01

A Polar Views discussion by Pozzi and Rauen et al. on the interpretation and clinical application of the recently published Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP-IgAN) trial has elucidated important points concerning potential strengths and weaknesses of this landmark randomized trial. This critical examination of the impact of steroid monotherapy or steroid plus an immunosuppressive (IS) agent compared with 'supportive' therapy with inhibitors of the renin-angiotensin system (RAS) has enhanced our appreciation of the importance of rigorous application of titrated RAS inhibition in high-risk patients with persistent proteinuria >0.75 g/day. At the same time, it brings a new level of uncertainty concerning the overall value and risk of steroid or steroid plus IS therapy in patients failing such 'supportive' therapy. Some of these uncertainties revolve on issues of study design, such as the duration of follow-up, participant stratification (particularly underlying pathology) and dosing regimens. It is hoped that additional trials, better methods of patient selection, improved surrogate end points and safer regimens will lead to less uncertainty over the best treatment practices. On balance, the STOP-IgAN trial raises some key concerns about the merits of steroid alone or steroid plus IS therapy for selected subjects with IgAN, but it does not by itself close the door on the utility of steroid monotherapy in subjects with high-risk IgAN, even as it further degrades the value of steroid plus IS, at least with sequential cyclophosphamide and azathioprine. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Split high-dose oral levothyroxine treatment as a successful therapy option in myxedema coma.

PubMed

Charoensri, Suranut; Sriphrapradang, Chutintorn; Nimitphong, Hataikarn

2017-10-01

High-dose intravenous thyroxine (T4) is the preferable treatment for myxedema coma. We describe the clinical course of a 69-year-old man who presented with myxedema coma and received oral levothyroxine (LT4) therapy (1 mg) in a split dose. This suggests split high-dose oral LT4 as a therapeutic option in myxedema coma.

SU-F-P-26: Study of Radiation Dose Evaluation for Organs at Risk Using MRI in Intensity Modulated Radiation Therapy for Nasopharyngeal Carcinoma

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

Gong, G; Guo, Y; Yin, Y

Purpose: To study the contour and dosimetric feature of organs at risk (OARs) applying magnetic resonance imaging (MRI) images in intensity modulated radiation therapy (IMRT) of nasopharyngeal carcinoma (NPC) compared to computed tomography (CT) images. Methods: 35 NPC patients was selected into this trail. CT simulation with non-contrast and contrast enhanced scan, MRI simulation with non-contrast and contrast enhanced T1, T2 and diffusion weighted imaging were achieved sequentially. And the OARs were contoured on the CT and MRI images after rigid registration respectively. 9 beams IMRT plan with equal division angle were designed for every patients, and the prescription dosemore » for tumor target was set as 72Gy (2.4Gy/ fration). The boundary display, volume and dose-volume indices of each organ were compared between on MRI and CT images. Results: Compared to CT, MRI showed clearer boundary of brainstem, spinal cord, the deep lobe of Parotid gland and the optical nerve in canal. MRI images increase the volume of lens, optical nerve, while reducing the volume of eye slightly, and the maximum dose of lens, the mean dose of eyes and optical raised in different percentage, while there was no statistical differences were found. The left and right parotid volume on MRI increased by 7.07%, 8.13%, and the mean dose raised by 14.95% (4.01Gy), 18.76% (4.95Gy) with statistical significant difference (p<0.05). The brainstem volume reduced by 9.33% (p<0.05), and the dose of 0.1cm3 volume (D0.1cm3) reduced by mean 8.46% (4.32Gy), and D0.1cm3 of spinal cord increased by 1.5Gy on MRI. Conclusion: It is credible to evaluate the radiation dose of lens, eye and the spinal cord, while it should be necessary to evaluate the dose of brainstem, parotid and the optical nerve applying MRI images sometime, it will be more meaningful for these organs with high risk of radiation injury.« less

Lung dose and the potential risk of death in postoperative radiation therapy for non-small cell lung cancer: A study using the method of stratified grouping.

PubMed

Heo, Jaesung; Noh, O Kyu; Kim, Hwan-Ik; Chun, Mison; Cho, Oyeon; Park, Rae Woong; Yoon, Dukyong; Oh, Young-Taek

2018-04-19

Postoperative radiation therapy may have a detrimental effect on survival in patients with non-small cell lung cancer. We investigated the association of the lung radiation dose with the risk of death in patients treated with postoperative radiation therapy. We analyzed 178 patients with non-small cell lung cancer who received postoperative radiation therapy. The mean lung dose was calculated from dose-volume data, and we categorized patients into the high and low lung dose groups using 2 different methods; (1) simple grouping using the median lung dose of all patients, and (2) stratified grouping using the median lung dose of each subgroup sharing the same confounders. We compared clinical variables, and survival between the high and low lung dose groups. In the simple grouping, there were no significant differences in survivals between the high and low lung dose groups. After stratification, the overall survival of low lung dose group was significantly longer than that of high lung dose group (5-year survival, 60.1% vs. 35.3%, p = 0.039). On multivariable analyses, the lung dose remained a significant prognostic factor for overall survival (hazard ratio, HR = 2.08, p = 0.019). The lung dose was associated with the risk of death in patients with non-small cell lung cancer having the same confounders. Further studies evaluating the risk of death according to the lung dose will be helpful to administer more precise and individualized postoperative radiation therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Assessments of Sequential Intensity Modulated Radiation Therapy Boost (SqIB) Treatments Using HART

NASA Astrophysics Data System (ADS)

Pyakuryal, Anil

2009-05-01

A retrospective study was pursued to evaluate the SqIB treatments performed on ten head and neck cancer patients(n=10).Average prescription doses (PDs) of 39 Gy,15Gy and 17.8Gy were delivered consecutively from larger to smaller planning target volumes(ptvs) in three different treatment plans using 6 MV X-ray photon beams from a Linear accelerator (SLA Linac, Elekta) on BID weak on-weak off schedules. These plans were statistically evaluated on basis of plan indices (PIs),dose response of targets and critical structures, and dose tolerance(DT) of various organs utilizing the DVH analysis automated software known as Histogram Analysis in Radiation Therapy-HART(S.Jang et al., 2008, Med Phys 35, p.2812). Mean SqIB PIs were found consistent with the reported values for varying radio-surgical systems.The 95.5%(n=10)of each ptvs and the gross tumor volume also received 95% (n=10)of PDs in treatments. The average volume of ten organs (N=10) affected by each PDs shrank with decreasing size of ptvs in above plans.A largest volume of Oropharynx (79%,n=10,N=10) irradiated at PD, but the largest volume of Larynx (98%, n=10, N=10) was vulnerable to DT of structure (TD50).Thus, we have demonstrated the efficiency and accuracy of HART in the assessment of Linac based plans in radiation therapy treatments of cancer.

Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy

PubMed Central

Yang, Qiang; Ma, Yanling; Zhao, Yongxue; She, Zhennan; Wang, Long; Li, Jie; Wang, Chunling; Deng, Yihui

2013-01-01

Background Sequential low-dose chemotherapy has received great attention for its unique advantages in attenuating multidrug resistance of tumor cells. Nevertheless, it runs the risk of producing new problems associated with the accelerated blood clearance phenomenon, especially with multiple injections of PEGylated liposomes. Methods Liposomes were labeled with fluorescent phospholipids of 1,2-dipalmitoyl-snglycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) and epirubicin (EPI). The pharmacokinetics profile and biodistribution of the drug and liposome carrier following multiple injections were determined. Meanwhile, the antitumor effect of sequential low-dose chemotherapy was tested. To clarify this unexpected phenomenon, the production of polyethylene glycol (PEG)-specific immunoglobulin M (IgM), drug release, and residual complement activity experiments were conducted in serum. Results The first or sequential injections of PEGylated liposomes within a certain dose range induced the rapid clearance of subsequently injected PEGylated liposomal EPI. Of note, the clearance of EPI was two- to three-fold faster than the liposome itself, and a large amount of EPI was released from liposomes in the first 30 minutes in a complement-activation, direct-dependent manner. The therapeutic efficacy of liposomal EPI following 10 days of sequential injections in S180 tumor-bearing mice of 0.75 mg EPI/kg body weight was almost completely abolished between the sixth and tenth day of the sequential injections, even although the subsequently injected doses were doubled. The level of PEG-specific IgM in the blood increased rapidly, with a larger amount of complement being activated while the concentration of EPI in blood and tumor tissue was significantly reduced. Conclusion Our investigation implied that the accelerated blood clearance phenomenon and its accompanying rapid leakage and clearance of drug following sequential low-dose injections may reverse the unique pharmacokinetic–toxicity profile of liposomes which deserved our attention. Therefore, a more reasonable treatment regime should be selected to lessen or even eliminate this phenomenon. PMID:23576868

Intra-individual diagnostic image quality and organ-specific-radiation dose comparison between spiral cCT with iterative image reconstruction and z-axis automated tube current modulation and sequential cCT.

PubMed

Wenz, Holger; Maros, Máté E; Meyer, Mathias; Gawlitza, Joshua; Förster, Alex; Haubenreisser, Holger; Kurth, Stefan; Schoenberg, Stefan O; Groden, Christoph; Henzler, Thomas

2016-01-01

To prospectively evaluate image quality and organ-specific-radiation dose of spiral cranial CT (cCT) combined with automated tube current modulation (ATCM) and iterative image reconstruction (IR) in comparison to sequential tilted cCT reconstructed with filtered back projection (FBP) without ATCM. 31 patients with a previous performed tilted non-contrast enhanced sequential cCT aquisition on a 4-slice CT system with only FBP reconstruction and no ATCM were prospectively enrolled in this study for a clinical indicated cCT scan. All spiral cCT examinations were performed on a 3rd generation dual-source CT system using ATCM in z-axis direction. Images were reconstructed using both, FBP and IR (level 1-5). A Monte-Carlo-simulation-based analysis was used to compare organ-specific-radiation dose. Subjective image quality for various anatomic structures was evaluated using a 4-point Likert-scale and objective image quality was evaluated by comparing signal-to-noise ratios (SNR). Spiral cCT led to a significantly lower (p < 0.05) organ-specific-radiation dose in all targets including eye lense. Subjective image quality of spiral cCT datasets with an IR reconstruction level 5 was rated significantly higher compared to the sequential cCT acquisitions (p < 0.0001). Consecutive mean SNR was significantly higher in all spiral datasets (FBP, IR 1-5) when compared to sequential cCT with a mean SNR improvement of 44.77% (p < 0.0001). Spiral cCT combined with ATCM and IR allows for significant-radiation dose reduction including a reduce eye lens organ-dose when compared to a tilted sequential cCT while improving subjective and objective image quality.

Myxedema coma: a new look into an old crisis.

PubMed

Mathew, Vivek; Misgar, Raiz Ahmad; Ghosh, Sujoy; Mukhopadhyay, Pradip; Roychowdhury, Pradip; Pandit, Kaushik; Mukhopadhyay, Satinath; Chowdhury, Subhankar

2011-01-01

Myxedema crisis is a severe life threatening form of decompensated hypothyroidism which is associated with a high mortality rate. Infections and discontinuation of thyroid supplements are the major precipitating factors while hypothermia may not play a major role in tropical countries. Low intracellular T3 leads to cardiogenic shock, respiratory depression, hypothermia and coma. Patients are identified on the basis of a low index of suspicion with a careful history and examination focused on features of hypothyroidism and precipitating factors. Arrythmias and coagulation disorders are increasingly being identified in myxedema crisis. Thyroid replacement should be initiated as early as possible with careful attention to hypotension, fluid replacement and steroid replacement in an intensive care facility. Studies have shown that replacement of thyroid hormone through ryles tube with a loading dose and maintenance therapy is as efficacious as intravenous therapy. In many countries T3 is not available and oral therapy with T4 can be used effectively without major significant difference in outcomes. Hypotension, bradycardia at presentation, need for mechanical ventilation, hypothermia unresponsive to treatment, sepsis, intake of sedative drugs, lower GCS and high APACHE II scores and Sequential Organ Failure Assessment (SOFA) scores more than 6 are significant predictors of mortality in myxedema crisis. Early intervention in hypothyroid patients developing sepsis and other precipitating factors and ensuring continued intake of thyroid supplements may prevent mortality and morbidity associated with myxedema crisis.

Myxedema Coma: A New Look into an Old Crisis

PubMed Central

Mathew, Vivek; Misgar, Raiz Ahmad; Ghosh, Sujoy; Mukhopadhyay, Pradip; Roychowdhury, Pradip; Pandit, Kaushik; Mukhopadhyay, Satinath; Chowdhury, Subhankar

2011-01-01

Myxedema crisis is a severe life threatening form of decompensated hypothyroidism which is associated with a high mortality rate. Infections and discontinuation of thyroid supplements are the major precipitating factors while hypothermia may not play a major role in tropical countries. Low intracellular T3 leads to cardiogenic shock, respiratory depression, hypothermia and coma. Patients are identified on the basis of a low index of suspicion with a careful history and examination focused on features of hypothyroidism and precipitating factors. Arrythmias and coagulation disorders are increasingly being identified in myxedema crisis. Thyroid replacement should be initiated as early as possible with careful attention to hypotension, fluid replacement and steroid replacement in an intensive care facility. Studies have shown that replacement of thyroid hormone through ryles tube with a loading dose and maintenance therapy is as efficacious as intravenous therapy. In many countries T3 is not available and oral therapy with T4 can be used effectively without major significant difference in outcomes. Hypotension, bradycardia at presentation, need for mechanical ventilation, hypothermia unresponsive to treatment, sepsis, intake of sedative drugs, lower GCS and high APACHE II scores and Sequential Organ Failure Assessment (SOFA) scores more than 6 are significant predictors of mortality in myxedema crisis. Early intervention in hypothyroid patients developing sepsis and other precipitating factors and ensuring continued intake of thyroid supplements may prevent mortality and morbidity associated with myxedema crisis. PMID:21941682

A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer.

PubMed

Wang, Xin-Shuai; Kong, De-Jiu; Lin, Tzu-Yin; Li, Xiao-Cen; Izumiya, Yoshihiro; Ding, Xue-Zhen; Zhang, Li; Hu, Xiao-Chen; Yang, Jun-Qiang; Gao, She-Gan; Lam, Kit S; Li, Yuan-Pei

2017-06-01

One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.

Dosimetric comparison of standard three-dimensional conformal radiotherapy followed by intensity-modulated radiotherapy boost schedule (sequential IMRT plan) with simultaneous integrated boost–IMRT (SIB IMRT) treatment plan in patients with localized carcinoma prostate

PubMed Central

Bansal, A.; Kapoor, R.; Singh, S. K.; Kumar, N.; Oinam, A. S.; Sharma, S. C.

2012-01-01

Aims: Dosimeteric and radiobiological comparison of two radiation schedules in localized carcinoma prostate: Standard Three-Dimensional Conformal Radiotherapy (3DCRT) followed by Intensity Modulated Radiotherapy (IMRT) boost (sequential-IMRT) with Simultaneous Integrated Boost IMRT (SIB-IMRT). Material and Methods: Thirty patients were enrolled. In all, the target consisted of PTV P + SV (Prostate and seminal vesicles) and PTV LN (lymph nodes) where PTV refers to planning target volume and the critical structures included: bladder, rectum and small bowel. All patients were treated with sequential-IMRT plan, but for dosimetric comparison, SIB-IMRT plan was also created. The prescription dose to PTV P + SV was 74 Gy in both strategies but with different dose per fraction, however, the dose to PTV LN was 50 Gy delivered in 25 fractions over 5 weeks for sequential-IMRT and 54 Gy delivered in 27 fractions over 5.5 weeks for SIB-IMRT. The treatment plans were compared in terms of dose–volume histograms. Also, Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) obtained with the two plans were compared. Results: The volume of rectum receiving 70 Gy or more (V > 70 Gy) was reduced to 18.23% with SIB-IMRT from 22.81% with sequential-IMRT. SIB-IMRT reduced the mean doses to both bladder and rectum by 13% and 17%, respectively, as compared to sequential-IMRT. NTCP of 0.86 ± 0.75% and 0.01 ± 0.02% for the bladder, 5.87 ± 2.58% and 4.31 ± 2.61% for the rectum and 8.83 ± 7.08% and 8.25 ± 7.98% for the bowel was seen with sequential-IMRT and SIB-IMRT plans respectively. Conclusions: For equal PTV coverage, SIB-IMRT markedly reduced doses to critical structures, therefore should be considered as the strategy for dose escalation. SIB-IMRT achieves lesser NTCP than sequential-IMRT. PMID:23204659

Assessing advantages of sequential boron neutron capture therapy (BNCT) in an oral cancer model with normalized blood vessels.

PubMed

Molinari, Ana J; Thorp, Silvia I; Portu, Agustina M; Saint Martin, Gisela; Pozzi, Emiliano C C; Heber, Elisa M; Bortolussi, Silva; Itoiz, Maria E; Aromando, Romina F; Monti Hughes, Andrea; Garabalino, Marcela A; Altieri, Saverio; Trivillin, Verónica A; Schwint, Amanda E

2015-01-01

We previously demonstrated the therapeutic success of sequential boron neutron capture therapy (Seq-BNCT) in the hamster cheek pouch oral cancer model. It consists of BPA-BNCT followed by GB-10-BNCT 24 or 48 hours later. Additionally, we proved that tumor blood vessel normalization with thalidomide prior to BPA-BNCT improves tumor control. The aim of the present study was to evaluate the therapeutic efficacy and explore potential boron microdistribution changes in Seq-BNCT preceded by tumor blood vessel normalization. Tumor bearing animals were treated with thalidomide for tumor blood vessel normalization, followed by Seq-BNCT (Th+ Seq-BNCT) or Seq-Beam Only (Th+ Seq-BO) in the window of normalization. Boron microdistribution was assessed by neutron autoradiography. Th+ Seq-BNCT induced overall tumor response of 100%, with 87 (4)% complete tumor response. No cases of severe mucositis in dose-limiting precancerous tissue were observed. Differences in boron homogeneity between tumors pre-treated and not pre-treated with thalidomide were observed. Th+ Seq-BNCT achieved, for the first time, response in all treated tumors. Increased homogeneity in tumor boron microdistribution is associated to an improvement in tumor control.

Radiotherapy and hyperthermia in the treatment of fibrosarcomas in the dog.

PubMed

Brewer, W G; Turrel, J M

1982-07-15

Ten dogs with oral or external nasal fibrosarcoma were treated sequentially with orthovoltage radiation and radiofrequency (RF)-induced hyperthermia. Total radiation doses ranged from 3,200 to 4,800 rad given in 8 to 12 fractions of 400 rad. Immediately after 2 to 4 radiation treatments, hyperthermia was given. Six oral fibrosarcomas were heated to 50 C for 30 sec, using a hand-held RF generator. Four nasomaxillary fibrosarcomas were heated to 43 C for 30 minutes, using a 500-kHz RF generator. Hyperthermia of 50 C resulted in tumor necrosis and infection in 3 dogs and fatal septicemia in 1 dog. Nine of 10 tumors responded to therapy. One year after therapy, 5 dogs were free of disease. Tumor regrowth occurred in 5 dogs. Mean time to tumor regrowth and mean survival time of all dogs were 343 and 398 days, respectively. The results suggested that sequential radiation-hyperthermia is an effective therapeutic regimen for canine fibrosarcoma. It was concluded that this modality not only may be beneficial in the treatment of canine tumors but may be useful for designing new therapeutic approaches to similar tumors in man.

Sequential therapy with "vacuum sealing drainage-artificial dermis implantation-thin partial thickness skin grafting" for deep and infected wound surfaces in children.

PubMed

Yuan, X-G; Zhang, X; Fu, Y-X; Tian, X-F; Liu, Y; Xiao, J; Li, T-W; Qiu, L

2016-05-01

To evaluate the efficacy of a "vacuum sealing drainage (VSD) - artificial dermis implantation (ADI) - thin partial thickness skin grafting (TSG)" sequential therapy for deep and infected wounds in children. Fifty-three pediatric patients with deep and infected wounds were treated with sequential VSD-ADI-TSG therapy. The efficacy of this treatment was compared with that of the surgical debridement-change dressings-thin partial thickness skin grafting previously performed on 20 patients. Survival of tissue grafts, color and flexibility, subcutaneous fullness and scar formation of the graft site were examined and compared. The sequential therapy combined the advantages of the VSD treatment, in reducing tissue necrosis and infection on the wound surfaces and promoting the growth of granulation tissue, with the enhancement of grafting by artificial dermis. Compared with the 20 controls, skin grafted on the artificial dermis was more smooth and glossy, while the textures of the region were more elastic, and the scars were significantly lighter in Vancouver scale. The sequential VSD-ADI-TSG therapy is a simple and effective treatment for children with deep and infected wounds. IV. Copyright © 2016. Published by Elsevier Masson SAS.

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

Shusharina, N; Khan, F; Sharp, G

Purpose: To determine the dose level and timing of the boost in locally advanced lung cancer patients with confirmed tumor recurrence by comparing different boosting strategies by an impact of dose escalation in improvement of the therapeutic ratio. Methods: We selected eighteen patients with advanced NSCLC and confirmed recurrence. For each patient, a base IMRT plan to 60 Gy prescribed to PTV was created. Then we compared three dose escalation strategies: a uniform escalation to the original PTV, an escalation to a PET-defined target planned sequentially and concurrently. The PET-defined targets were delineated by biologically-weighed regions on a pre-treatment 18F-FDGmore » PET. The maximal achievable dose, without violating the OAR constraints, was identified for each boosting method. The EUD for the target, spinal cord, combined lung, and esophagus was compared for each plan. Results: The average prescribed dose was 70.4±13.9 Gy for the uniform boost, 88.5±15.9 Gy for the sequential boost and 89.1±16.5 Gy for concurrent boost. The size of the boost planning volume was 12.8% (range: 1.4 – 27.9%) of the PTV. The most prescription-limiting dose constraints was the V70 of the esophagus. The EUD within the target increased by 10.6 Gy for the uniform boost, by 31.4 Gy for the sequential boost and by 38.2 for the concurrent boost. The EUD for OARs increased by the following amounts: spinal cord, 3.1 Gy for uniform boost, 2.8 Gy for sequential boost, 5.8 Gy for concurrent boost; combined lung, 1.6 Gy for uniform, 1.1 Gy for sequential, 2.8 Gy for concurrent; esophagus, 4.2 Gy for uniform, 1.3 Gy for sequential, 5.6 Gy for concurrent. Conclusion: Dose escalation to a biologically-weighed gross tumor volume defined on a pre-treatment 18F-FDG PET may provide improved therapeutic ratio without breaching predefined OAR constraints. Sequential boost provides better sparing of OARs as compared with concurrent boost.« less

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.

Tissue feature-based intra-fractional motion tracking for stereoscopic x-ray image guided radiotherapy

NASA Astrophysics Data System (ADS)

Xie, Yaoqin; Xing, Lei; Gu, Jia; Liu, Wu

2013-06-01

Real-time knowledge of tumor position during radiation therapy is essential to overcome the adverse effect of intra-fractional organ motion. The goal of this work is to develop a tumor tracking strategy by effectively utilizing the inherent image features of stereoscopic x-ray images acquired during dose delivery. In stereoscopic x-ray image guided radiation delivery, two orthogonal x-ray images are acquired either simultaneously or sequentially. The essence of markerless tumor tracking is the reliable identification of inherent points with distinct tissue features on each projection image and their association between two images. The identification of the feature points on a planar x-ray image is realized by searching for points with high intensity gradient. The feature points are associated by using the scale invariance features transform descriptor. The performance of the proposed technique is evaluated by using images of a motion phantom and four archived clinical cases acquired using either a CyberKnife equipped with a stereoscopic x-ray imaging system, or a LINAC equipped with an onboard kV imager and an electronic portal imaging device. In the phantom study, the results obtained using the proposed method agree with the measurements to within 2 mm in all three directions. In the clinical study, the mean error is 0.48 ± 0.46 mm for four patient data with 144 sequential images. In this work, a tissue feature-based tracking method for stereoscopic x-ray image guided radiation therapy is developed. The technique avoids the invasive procedure of fiducial implantation and may greatly facilitate the clinical workflow.

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.

Introduction of sequential inactivated polio vaccine-oral polio vaccine schedule for routine infant immunization in Brazil's National Immunization Program.

PubMed

Domingues, Carla Magda Allan S; de Fátima Pereira, Sirlene; Cunha Marreiros, Ana Carolina; Menezes, Nair; Flannery, Brendan

2014-11-01

In August 2012, the Brazilian Ministry of Health introduced inactivated polio vaccine (IPV) as part of sequential polio vaccination schedule for all infants beginning their primary vaccination series. The revised childhood immunization schedule included 2 doses of IPV at 2 and 4 months of age followed by 2 doses of oral polio vaccine (OPV) at 6 and 15 months of age. One annual national polio immunization day was maintained to provide OPV to all children aged 6 to 59 months. The decision to introduce IPV was based on preventing rare cases of vaccine-associated paralytic polio, financially sustaining IPV introduction, ensuring equitable access to IPV, and preparing for future OPV cessation following global eradication. Introducing IPV during a national multivaccination campaign led to rapid uptake, despite challenges with local vaccine supply due to high wastage rates. Continuous monitoring is required to achieve high coverage with the sequential polio vaccine schedule. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study

PubMed Central

Kaplovitch, Eric; Gomes, Tara; Camacho, Ximena; Dhalla, Irfan A.; Mamdani, Muhammad M.; Juurlink, David N.

2015-01-01

Background The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. Methods and Findings We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Conclusions Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated. PMID:26291716

Predicting pneumonitis risk: a dosimetric alternative to mean lung dose.

PubMed

Tucker, Susan L; Mohan, Radhe; Liengsawangwong, Raweewan; Martel, Mary K; Liao, Zhongxing

2013-02-01

To determine whether the association between mean lung dose (MLD) and risk of severe (grade ≥3) radiation pneumonitis (RP) depends on the dose distribution pattern to normal lung among patients receiving 3-dimensional conformal radiation therapy for non-small-cell lung cancer. Three cohorts treated with different beam arrangements were identified. One cohort (2-field boost [2FB]) received 2 parallel-opposed (anteroposterior-posteroanterior) fields per fraction initially, followed by a sequential boost delivered using 2 oblique beams. The other 2 cohorts received 3 or 4 straight fields (3FS and 4FS, respectively), ie, all fields were irradiated every day. The incidence of severe RP was plotted against MLD in each cohort, and data were analyzed using the Lyman-Kutcher-Burman (LKB) model. The incidence of grade ≥3 RP rose more steeply as a function of MLD in the 2FB cohort (N=120) than in the 4FS cohort (N=138), with an intermediate slope for the 3FS group (N=99). The estimated volume parameter from the LKB model was n=0.41 (95% confidence interval, 0.15-1.0) and led to a significant improvement in fit (P=.05) compared to a fit with volume parameter fixed at n=1 (the MLD model). Unlike the MLD model, the LKB model with n=0.41 provided a consistent description of the risk of severe RP in all three cohorts (2FB, 3FS, 4FS) simultaneously. When predicting risk of grade ≥3 RP, the mean lung dose does not adequately take into account the effects of high doses. Instead, the effective dose, computed from the LKB model using volume parameter n=0.41, may provide a better dosimetric parameter for predicting RP risk. If confirmed, these findings support the conclusion that for the same MLD, high doses to small lung volumes ("a lot to a little") are worse than low doses to large volumes ("a little to a lot"). Copyright © 2013 Elsevier Inc. All rights reserved.

First-line treatment of Helicobacter pylori in Lebanon: Comparison of bismuth-containing quadruple therapy versus 14-days sequential therapy.

PubMed

Tarhini, Mahdi; Fayyad-Kazan, Mohammad; Fayyad-Kazan, Hussein; Mokbel, Mahmoud; Nasreddine, Mohammad; Badran, Bassam; Kchour, Ghada

2018-04-01

Helicobacter Pylori (H. Pylori) is the most common cause of peptic ulcer disease (PUD) and represents a strong risk factor for gastric cancer. Treatment of H. Pylori is, therefore, a persistent need to avoid serious medical complications. Resistance to antibiotics remains to be the major challenge for H. Pylori eradication. In this study, we determined the prevalence of H. pylori infection and evaluated H. pylori eradication efficacy of bismuth-containing quadruple therapy (Pylera) versus 14-days sequential therapy in treatment naïve-Lebanese patients. 1030 patients, showing symptoms of peptic ulcer (PU) and gastritis, underwent 14 C-Urea Breath Test and esophagogastroduodenoscopy to examine H. Pylori infection and gastrointestinal disorders. Among the H. Pylori-positive patients 60 individuals were randomly selected, separated into two groups (each consisting of 30 patients) and treated with either bismuth-containing quadruple therapy or 14-days sequential therapy. We show that of the 1050 patients tested: 46.2% were H. pylori-positive, 55% had gastritis, 46.2% had both gastritis and H. pylori infection, 8.8% had gastritis but no H. pylori infection, 44.9% had neither gastritis nor H. pylori infection. Following the 14-days sequential therapy, the eradication rate was significantly higher than that obtained upon using bismuth-containing quadruple therapy [80% (24/30) versus 50% (15/30), χ 2  = 5.93, P = 0.015]. In conclusion, we determined H. pylori and gastritis prevalence among Lebanese PU-patients and showed that 14-days sequential therapy is more efficient than bismuth-containing quadruple therapy in terms of H. Pylori-eradication. Published by Elsevier Ltd.

Adjuvant breast cancer therapy: current status and future strategies--growth kinetics and the improved drug therapy of breast cancer.

PubMed

Norton, L

1999-02-01

It is well-established that the adjuvant treatment of breast cancer is effective in prolonging both disease-free and overall survival. The pressing questions are how to improve on existing treatment, whether new agents should be incorporated into adjuvant regimens, and, if so, how they should best be utilized. The application of log-kill principles to the sigmoid growth curve characteristic of human cancers suggests that the chances of eradicating tumor will be increased by dose-dense schedules. If the tumor is composed of several cell lines with different sensitivities, the optimum therapy is likely to consist of several drugs given in sequence at a good dose and on a dense schedule. Such sequential chemotherapy, rather than the use of drugs given in combination at longer intervals, should maximize log-kill at the same time as minimizing tumor regrowth. There is now evidence that the actions of chemotherapy may involve Ras, tyrosine kinases (epidermal growth factor receptor, HER2), TC21, or similar molecules. This concept may provide important clues for optimizing the clinical applications of drug therapy and for designing new therapeutic approaches. It might also explain the reason why dose density may be more effective than other schedules of administration. New blood vessel formation is an obligatory step in the establishment of a tumor in its sigmoid growth course and there is evidence that taxanes adversely affect this process. Major practical advances in the curative drug therapy of cancer should follow the demonstration of better ways to maximize cell kill, the development of predictive in vitro methods of selecting active agents, the discovery of techniques to minimize both drug resistance and host-cell toxicity, and the improved understanding of cancer-stromal interactions and their therapeutic perturbation.

The roles of safety and compliance in determining effectiveness of topical therapy for psoriasis.

PubMed

Stein Gold, Linda; Corvari, Linda

2007-01-01

Topical therapies are the mainstays of treatment for most patients with psoriasis because they relieve symptoms and reduce the size and severity of lesions. The effectiveness of a therapeutic intervention is a function of drug efficacy (determined by randomized clinical trial results) and patient safety and compliance. Alterations in any parameter can have a substantial influence on clinical outcomes. However, topical agents can be associated with unwanted and potentially toxic side effects that make physicians reluctant to prescribe them, and patients intentionally discontinue treatment with these topical agents. To maximize effectiveness and improve patient safety, physicians may prescribe medications in combination, sequential, or rotational therapeutic regimens. This treatment strategy has the potential to improve the overall efficacy and safety of topical therapy; however, the effectiveness of this method may be compromised because the complexity of the therapeutic regimen may decrease patient compliance. Newer topical therapies that have a convenient once-daily dosing schedule are needed and will have important implications for patient compliance.

Measurements of the neutron dose equivalent for various radiation qualities, treatment machines and delivery techniques in radiation therapy

NASA Astrophysics Data System (ADS)

Hälg, R. A.; Besserer, J.; Boschung, M.; Mayer, S.; Lomax, A. J.; Schneider, U.

2014-05-01

In radiation therapy, high energy photon and proton beams cause the production of secondary neutrons. This leads to an unwanted dose contribution, which can be considerable for tissues outside of the target volume regarding the long term health of cancer patients. Due to the high biological effectiveness of neutrons in regards to cancer induction, small neutron doses can be important. This study quantified the neutron doses for different radiation therapy modalities. Most of the reports in the literature used neutron dose measurements free in air or on the surface of phantoms to estimate the amount of neutron dose to the patient. In this study, dose measurements were performed in terms of neutron dose equivalent inside an anthropomorphic phantom. The neutron dose equivalent was determined using track etch detectors as a function of the distance to the isocenter, as well as for radiation sensitive organs. The dose distributions were compared with respect to treatment techniques (3D-conformal, volumetric modulated arc therapy and intensity-modulated radiation therapy for photons; spot scanning and passive scattering for protons), therapy machines (Varian, Elekta and Siemens linear accelerators) and radiation quality (photons and protons). The neutron dose equivalent varied between 0.002 and 3 mSv per treatment gray over all measurements. Only small differences were found when comparing treatment techniques, but substantial differences were observed between the linear accelerator models. The neutron dose equivalent for proton therapy was higher than for photons in general and in particular for double-scattered protons. The overall neutron dose equivalent measured in this study was an order of magnitude lower than the stray dose of a treatment using 6 MV photons, suggesting that the contribution of the secondary neutron dose equivalent to the integral dose of a radiotherapy patient is small.

Measurements of the neutron dose equivalent for various radiation qualities, treatment machines and delivery techniques in radiation therapy.

PubMed

Hälg, R A; Besserer, J; Boschung, M; Mayer, S; Lomax, A J; Schneider, U

2014-05-21

In radiation therapy, high energy photon and proton beams cause the production of secondary neutrons. This leads to an unwanted dose contribution, which can be considerable for tissues outside of the target volume regarding the long term health of cancer patients. Due to the high biological effectiveness of neutrons in regards to cancer induction, small neutron doses can be important. This study quantified the neutron doses for different radiation therapy modalities. Most of the reports in the literature used neutron dose measurements free in air or on the surface of phantoms to estimate the amount of neutron dose to the patient. In this study, dose measurements were performed in terms of neutron dose equivalent inside an anthropomorphic phantom. The neutron dose equivalent was determined using track etch detectors as a function of the distance to the isocenter, as well as for radiation sensitive organs. The dose distributions were compared with respect to treatment techniques (3D-conformal, volumetric modulated arc therapy and intensity-modulated radiation therapy for photons; spot scanning and passive scattering for protons), therapy machines (Varian, Elekta and Siemens linear accelerators) and radiation quality (photons and protons). The neutron dose equivalent varied between 0.002 and 3 mSv per treatment gray over all measurements. Only small differences were found when comparing treatment techniques, but substantial differences were observed between the linear accelerator models. The neutron dose equivalent for proton therapy was higher than for photons in general and in particular for double-scattered protons. The overall neutron dose equivalent measured in this study was an order of magnitude lower than the stray dose of a treatment using 6 MV photons, suggesting that the contribution of the secondary neutron dose equivalent to the integral dose of a radiotherapy patient is small.

A fast algorithm for solving a linear feasibility problem with application to Intensity-Modulated Radiation Therapy.

PubMed

Herman, Gabor T; Chen, Wei

2008-03-01

The goal of Intensity-Modulated Radiation Therapy (IMRT) is to deliver sufficient doses to tumors to kill them, but without causing irreparable damage to critical organs. This requirement can be formulated as a linear feasibility problem. The sequential (i.e., iteratively treating the constraints one after another in a cyclic fashion) algorithm ART3 is known to find a solution to such problems in a finite number of steps, provided that the feasible region is full dimensional. We present a faster algorithm called ART3+. The idea of ART3+ is to avoid unnecessary checks on constraints that are likely to be satisfied. The superior performance of the new algorithm is demonstrated by mathematical experiments inspired by the IMRT application.

Whole-Pelvic Nodal Radiation Therapy in the Context of Hypofractionation for High-Risk Prostate Cancer Patients: A Step Forward

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

Kaidar-Person, Orit; Roach, Mack; Créhange, Gilles, E-mail: gcrehange@cgfl.fr

2013-07-15

Given the low α/β ratio of prostate cancer, prostate hypofractionation has been tested through numerous clinical studies. There is a growing body of literature suggesting that with high conformal radiation therapy and even with more sophisticated radiation techniques, such as high-dose-rate brachytherapy or image-guided intensity modulated radiation therapy, morbidity associated with shortening overall treatment time with higher doses per fraction remains low when compared with protracted conventional radiation therapy to the prostate only. In high-risk prostate cancer patients, there is accumulating evidence that either dose escalation to the prostate or hypofractionation may improve outcome. Nevertheless, selected patients who have amore » high risk of lymph node involvement may benefit from whole-pelvic radiation therapy (WPRT). Although combining WPRT with hypofractionated prostate radiation therapy is feasible, it remains investigational. By combining modern advances in radiation oncology (high-dose-rate prostate brachytherapy, intensity modulated radiation therapy with an improved image guidance for soft-tissue sparing), it is hypothesized that WPRT could take advantage of recent results from hypofractionation trials. Moreover, the results from hypofractionation trials raise questions as to whether hypofractionation to pelvic lymph nodes with a high risk of occult involvement might improve the outcomes in WPRT. Although investigational, this review discusses the challenging idea of WPRT in the context of hypofractionation for patients with high-risk prostate cancer.« less

A perspective on diuretic resistance in chronic congestive heart failure.

PubMed

Shah, Niel; Madanieh, Raef; Alkan, Mehmet; Dogar, Muhammad U; Kosmas, Constantine E; Vittorio, Timothy J

2017-10-01

Chronic congestive heart failure (CHF) is a complex disorder characterized by inability of the heart to keep up the demands on it, followed by the progressive pump failure and fluid accumulation. Although the loop diuretics are widely used in heart failure (HF) patients, both pharmacodynamic and pharmacokinetic alterations are thought to be responsible for diuretic resistance in these patients. Strategies to overcome diuretic resistance include sodium intake restriction, changes in diuretic dose and route of administration and sequential nephron diuretic therapy. In this review, we discuss the definition, prevalence, mechanism of development and management strategies of diuretic resistance in HF patients.

Efficacy of sequential three-step empirical therapy for chronic cough.

PubMed

Yu, Li; Xu, Xianghuai; Hang, Jingqing; Cheng, Kewen; Jin, Xiaoyan; Chen, Qiang; Lv, Hanjing; Qiu, Zhongmin

2017-06-01

Empirical three-step therapy has been proved in just one hospital. This study aimed to demonstrate applicability of the sequential empirical three-step therapy for chronic cough in different clinical settings. Sequential empirical three-step therapy was given to patients with chronic cough in one tertiary and three secondary care respiratory clinics. Recruiters were initially treated with methoxyphenamine compound as the first-step therapy, followed by corticosteroids as the second-step therapy and the combination of a proton-pump inhibitor and a prokinetic agent as the third-step therapy. The efficacy of the therapy was verified according to the changes in cough symptom score between pre- and post-treatment, and compared among the different clinics. In total 155 patients in one tertiary clinic and 193 patients in secondary care clinics were recruited. The total dropout ratio is significantly higher in the secondary care clinics than that in the tertiary clinic (9.3% versus 3.2%, p = 0.023). The therapeutic success rate for cough was 38.7% at first-step therapy, 32.3% at second-step therapy and 20.0% at third-step therapy in the tertiary clinic, and comparable to corresponding 49.7%, 31.1% and 4.1% in secondary care clinics. Furthermore, the overall cough resolution rate was not significantly different (91.0% versus 85.0%, p = 0.091). However, the efficacy of the third-step therapy is much higher (20.0% versus 4.1%, p = 0.001) in the tertiary clinic than in the secondary care clinics. Sequential empirical three-step therapy is universally efficacious and useful for management of chronic cough in different clinical settings.

Safety of low-dose aspirin in endovascular treatment for intracranial atherosclerotic stenosis.

PubMed

Ma, Ning; Xu, Ziqi; Mo, Dapeng; Gao, Feng; Gao, Kun; Sun, Xuan; Xu, Xiaotong; Liu, Lian; Song, Ligang; Wang, Tiejun; Zhao, Xingquan; Wang, Yilong; Wang, Yongjun; Miao, Zhongrong

2014-01-01

To evaluate the safety of low-dose aspirin plus clopidogrel versus high-dose aspirin plus clopidogrel in prevention of vascular risk within 90 days of duration of dual antiplatelet therapy in patients treated with intracranial endovascular treatment. From January 2012 to December 2013, this prospective and observational study enrolled 370 patients with symptomatic intracranial atherosclerotic stenosis of ≥70% with poor collateral undergoing intracranial endovascular treatment. Antiplatelet therapy consists of aspirin, at a low-dose of 100 mg or high-dose of 300 mg daily; clopidogrel, at a dose of 75 mg daily for 5 days before endovascular treatment. The dual antiplatelet therapy continued for 90 days after intervention. The study endpoints include acute thrombosis, subacute thrombosis, stroke or death within 90 days after intervention. Two hundred and seventy three patients received low-dose aspirin plus clopidogrel and 97 patients received high-dose aspirin plus clopidogrel before intracranial endovascular treatment. Within 90 days after intervention, there were 4 patients (1.5%) with acute thrombosis, 5 patients (1.8%) with subacute thrombosis, 17 patients (6.2%) with stroke, and 2 death (0.7%) in low-dose aspirin group, compared with no patient (0%) with acute thrombosis, 2 patient (2.1%) with subacute thrombosis, 6 patients (6.2%) with stroke, and 2 death (2.1%) in high-dose aspirin group, and there were no significant difference in all study endpoints between two groups. Low-dose aspirin plus clopidogrel is comparative in safety with high-dose aspirin plus clopidogrel within 90 days of duration of dual antiplatelet therapy in patients treated with intracranial endovascular treatment.

A Novel Method for Studying the Pharmacokinetics of [14C]Umeclidinium After Application to the Axilla or Palm of Healthy Male Subjects

PubMed Central

Santos, LL; Hughes, SC; Pereira, AI; Young, GC; Hussey, E; Charlton, P; Baptiste‐Brown, S; Stuart, JS; Vincent, V; van Marle, SP; Schmith, VD

2016-01-01

Umeclidinium (UMEC), a long‐acting muscarinic antagonist approved for chronic obstructive pulmonary disease (COPD), was investigated for primary hyperhidrosis as topical therapy. This study evaluated the pharmacokinetics, safety, and tolerability of a single dose of [14C]UMEC applied to either unoccluded axilla (UA), occluded axilla (OA), or occluded palm (OP) of healthy males. After 8 h the formulation was removed. [14C]UMEC plasma concentrations (Cp) were quantified by accelerator mass spectrometry. Occlusion increased systemic exposure by 3.8‐fold. Due to UMEC absorption‐limited pharmacokinetics, Cp data from the OA were combined with intravenous data from a phase I study. The data were described by a two‐compartment population model with sequential zero and first‐order absorption and linear elimination. Simulated systemic exposure following q.d. doses to axilla was similar to the exposure from the inhaled therapy, suggesting that systemic safety following dermal administration can be bridged to the inhaled program, and offering the potential for a reduced number of studies and/or subjects. PMID:27304394

Daily subcutaneous parecoxib injection for cancer pain: an open label pilot study.

PubMed

Kenner, David J; Bhagat, Sandeep; Fullerton, Sonia L

2015-04-01

Nonsteroidal anti-inflammatory analgesics (NSAIDs) are useful in cancer pain but the specific use of subcutaneous parecoxib has not been previously reported. This pilot study aimed to establish the efficacy and side effect profile of short-term sequential single daily dose subcutaneous parecoxib sodium in patients with severe cancer bone pain. Nineteen hospitalized patients with advanced cancer and uncontrolled malignant bone pain (9 males, 10 females) received 24 courses of one, two, or three days sequential therapy with 'off-label' daily subcutaneous parecoxib. All patients were receiving opioid therapy; the median baseline daily oral equivalent dose (OED) of morphine was 180 mg. Pain was assessed at baseline, 24 hours, 48 hours, and 72 hours. Pain scores as assessed on an 11-point numeric pain rating scale (NPRS), any side effects including subcutaneous site reactions, as well as patient satisfaction rating with analgesia were recorded. A clinically significant decrease in pain scores was defined as a reduction of two or more points on the NPRS. Median pain score of all patient treatments decreased from 7 to 4.5 at 24 hours (p<0.001) and 4.0 at 48 hours. A response was seen in 17 (71%) of the 24 treatments at 24 hours. There was no difference between median negative change in pain scores in 19 (79%) treatments where pain was either strongly movement related, or in 22 (94%) treatments where local bone tenderness was more pronounced. No major side effects were observed during treatment. One patient died from pulmonary embolism after cessation of concurrent prophylactic low molecular weight heparin prior to staging liver biopsy. Subcutaneous site reactions occurred in 2 (8%) treatments and were mild and self limiting. Short-term daily subcutaneous parecoxib injection was effective for malignant bone pain when added to existing analgesic therapy and was well tolerated. Further research is warranted into the short-term use of parecoxib in hospitalized patients with intractable malignant bone pain.

Is Parenteral Levothyroxine Therapy Safe in Intractable Hypothyroidism?

PubMed

Peynirci, Hande; Taskiran, Bengur; Erturk, Erdinc; Sisman, Pınar; Ersoy, Canan

2018-06-01

A 32-year old woman was admitted to the hospital due to intractable hypothyroidism refractory to high dose of oral l-thyroxine therapy. She underwent total thyroidectomy and radioactive iodine therapy due to papillary thyroid cancer. After excluding poor adherence to therapy and malabsorption, levothyroxine absorption test was performed. No response was detected. Transient neurologic symptoms developed during the test. She developed 3 attacks consisting of neurologic symptoms during high dose administration. The patient was considered a case of isolated l-thyroxine malabsorption. She became euthyroid after intramuscular twice weekly l-thyroxine therapy. There are a few case reports regarding isolated l-thyroxine. We report successful long term results of twice weekly administered intramuscular l-thyroxine therapy. We also draw attention to neurologic side effects of high dose l-thyroxine therapy. Copyright © 2017 National Medical Association. Published by Elsevier Inc. All rights reserved.

Randomised clinical trial: the efficacy of a 10-day sequential therapy vs. a 14-day standard proton pump inhibitor-based triple therapy for Helicobacter pylori in Korea.

PubMed

Kim, Y S; Kim, S J; Yoon, J H; Suk, K T; Kim, J B; Kim, D J; Kim, D Y; Min, H J; Park, S H; Shin, W G; Kim, K H; Kim, H Y; Baik, G H

2011-11-01

The eradication rates of Helicobacter pylori (H. pylori) using a proton pump inhibitor (PPI)-based triple therapy have declined due to antibiotic resistance worldwide. To compare the eradication rate of the 10-day sequential therapy for H. pylori infection with that of the 14-day standard PPI-based triple therapy. This was a prospective, randomised, controlled study. A total of 409 patients with H. pylori infection were randomly assigned to receive either the 10-day sequential therapy regimen, which consisted of pantoprazole (40 mg) plus amoxicillin (1000 mg) twice a day for 5 days, then pantoprazole (40 mg) with clarithromycin (500 mg) and metronidazole (500 mg) twice a day for another five consecutive days or the 14-day PPI-based triple therapy regimen, which consisted of pantoprazole (40 mg) with amoxicillin (1000 mg) and clarithromycin (500 mg) twice a day for 14 days. The pre- and post-treatment H. pylori status were assessed by rapid urease test, urea breath test, or histology. Successful eradication was confirmed at least 4 weeks after finishing the treatment. In the intention-to-treat analysis, the eradication rates of the 10-day sequential therapy and of the 14-day PPI-based triple therapy were 85.9% (176/205) and 75.0% (153/205), respectively (P = 0.006). In the per-protocol analysis, the eradication rates were 92.6% (175/205) and 85% (153/204), respectively (P = 0.019). There was no statistically significant difference between the two investigated groups regarding the occurrence of adverse event rates (18.9% vs. 13.3%, P = 0.143). The 10-day sequential therapy achieved significantly higher eradication rates than the 14-day standard PPI-based triple therapy in Korea. © 2011 Blackwell Publishing Ltd.

Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial.

PubMed

Rakoczy, Elizabeth P; Lai, Chooi-May; Magno, Aaron L; Wikstrom, Matthew E; French, Martyn A; Pierce, Cora M; Schwartz, Steven D; Blumenkranz, Mark S; Chalberg, Thomas W; Degli-Esposti, Mariapia A; Constable, Ian J

2015-12-12

Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. In this single-centre, phase 1, randomised controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularisation, with best corrected visual acuity (BCVA) of 3/60-6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 10(10) vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 10(11) vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomography, and fluorescein angiography. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, number NCT01494805. From Dec 16, 2011, to April 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of rAAV.sFLT-1 was highly reproducible. No drug-related adverse events were noted; procedure-related adverse events (subconjunctival or subretinal haemorrhage and mild cell debris in the anterior vitreous) were generally mild and self-resolving. There was no evidence of chorioretinal atrophy. Clinical laboratory assessments generally remained unchanged from baseline. Four (67%) of six patients in the treatment group required zero rescue injections, and the other two (33%) required only one rescue injection each. rAAV.sFLT-1 was safe and well tolerated. These results support ocular gene therapy as a potential long-term treatment option for wet age-related macular degeneration. National Health and Medical Research Council of Australia, Richard Pearce Bequest, Lions Save Sight Foundation, Brian King Fellowship, and Avalanche Biotechnologies, Inc. Copyright © 2015 Elsevier Ltd. All rights reserved.

Development of a center for light ion therapy and accurate tumor diagnostics at karolinska institutet and hospital

NASA Astrophysics Data System (ADS)

Brahme, Anders; Lind, Bengt K.

2002-04-01

Radiation therapy is today in a state of very rapid development with new intensity modulated treatment techniques continuously being developed. This has made intensity modulated electron and photon beams almost as powerful as conventional uniform beam proton therapy. To be able to cure also the most advanced hypoxic and radiation resistant tumors of complex local spread, intensity modulated light ion beams are really the ultimate tool and only slightly more expensive than proton therapy. The aim of the new center for ion therapy and tumor diagnostics in Stockholm is to develop radiobiologically optimized 3-dimensional pencil beam scanning techniques. Beside the "classical" approaches using low ionization density hydrogen ions (protons, but also deuterons and tritium nuclei) and high ionization density carbon ions, two new approaches will be developed. In the first one lithium or beryllium ions, that induce the least detrimental biological effect to normal tissues for a given biological effect in a small volume of the tumor, will be key particles. In the second approach, referred patients will be given a high-dose high-precision "boost" treatment with carbon or oxygen ions during one week preceding the final treatment with conventional radiations in the referring hospital. The rationale behind these approaches is to reduce the high ionization density dose to the normal tissue stroma inside the tumor and to ensure a microscopically uniform dose delivery. The principal idea of the center is to closely integrate ion therapy into the clinical routine and research of a large radiotherapy department. The light ion therapy center will therefore be combined with advanced tumor diagnostics including MR and PET-CT imaging to facilitate efficient high-precision high-dose boost treatment of remitted patients. The possibility to do 3D tumor diagnostics and 3D dose delivery verification with the same PET camera will be the ultimate step in high quality adaptive radiation therapy where alterations in the delivered dose can be corrected by subsequent treatments

Survival After Shock Requiring High-Dose Vasopressor Therapy

PubMed Central

Lanspa, Michael J.; Jones, Jason P.; Kuttler, Kathryn G.; Li, Yao; Carlson, Rick; Miller, Russell R.; Hirshberg, Eliotte L.; Grissom, Colin K.; Morris, Alan H.

2013-01-01

Background: Some patients with hypotensive shock do not respond to usual doses of vasopressor therapy. Very little is known about outcomes after high-dose vasopressor therapy (HDV). We sought to characterize survival among patients with shock requiring HDV. We also evaluated the possible utility of stress-dose corticosteroid therapy in these patients. Methods: We conducted a retrospective study of patients with shock requiring HDV in the ICUs of five hospitals from 2005 through 2010. We defined HDV as receipt at any point of ≥ 1 μg/kg/min of norepinephrine equivalent (calculated by summing norepinephrine-equivalent infusion rates of all vasopressors). We report survival 90 days after hospital admission. We evaluated receipt of stress-dose corticosteroids, cause of shock, receipt of CPR, and withdrawal or withholding of life support therapy. Results: We identified 443 patients meeting inclusion criteria. Seventy-six (17%) survived. Survival was similar (20%) among the 241 patients with septic shock. Among the 367 nonsurvivors, 254 (69%) experienced withholding/withdrawal of care, and 115 (31%) underwent CPR. Stress-dose corticosteroid therapy was associated with increased survival (P = .01). Conclusions: One in six patients with shock survived to 90 days after HDV. The majority of nonsurvivors died after withdrawal or withholding of life support therapy. A minority of patients underwent CPR. Additionally, stress-dose corticosteroid therapy appears reasonable in patients with shock requiring HDV. PMID:22911566

Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants.

PubMed

Karim, Aziz; Laurent, Aziz; Munsaka, Melvin; Wann, Elisabeth; Fleck, Penny; Mekki, Qais

2009-10-01

Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.

Neutropenia during High Dose Intravenous Oxacillin Therapy

PubMed Central

Ahern, Mary Jean; Hicks, Jeanne E.; Andriole, Vincent T.

1976-01-01

Five patients who developed neutropenia following intravenous administration of high dose oxacillin for serious Staphylococcus aureus infection are described. Neutropenia was reversible with cessation of intravenous oxacillin therapy. Two patients were continued on oral oxacillin without untoward effects. PMID:997595

A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC).

PubMed

Atchison, Elizabeth; Eklund, John; Martone, Brenda; Wang, Lili; Gidron, Adi; Macvicar, Gary; Rademaker, Alfred; Goolsby, Charles; Marszalek, Laura; Kozlowski, James; Smith, Norm; Kuzel, Timothy M

2010-09-01

High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.

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

Ahlawat, Stuti; Haffty, Bruce G.; Goyal, Sharad

Purpose: Conventionally fractionated whole-breast irradiation (WBI) with a boost takes approximately 6 to 7 weeks. We evaluated a short course of hypofractionated (HF), accelerated WBI in which therapy was completed in 3 weeks inclusive of a sequential boost. Methods and Materials: We delivered a whole-breast dose of 36.63 Gy in 11 fractions of 3.33 Gy over 11 days, followed by a lumpectomy bed boost in 4 fractions of 3.33 Gy delivered once daily for a total of 15 treatment days. Acute toxicities were scored using Common Terminology Criteria for Adverse Events version 4. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Researchmore » and Treatment of Cancer scale. Cosmesis was scored using the Harvard Cosmesis Scale. Our primary endpoint was freedom from locoregional failure; we incorporated early stopping criteria based on predefined toxicity thresholds. Cosmesis was examined as a secondary endpoint. Results: We enrolled 83 women with stages 0 to IIIa breast cancer. After a median follow-up of 40 months, 2 cases of isolated ipsilateral breast tumor recurrence occurred (2 of 83; crude rate, 2.4%). Three-year estimated local recurrence-free survival was 95.9% (95% confidence interval [CI]: 87.8%-98.7%). The 3-year estimated distant recurrence-free survival was 97.3% (95% CI: 89.8%-99.3%). Three-year secondary malignancy-free survival was 94.3% (95% CI: 85.3%-97.8%). Twenty-nine patients (34%) had grade 2 acute toxicity, and 1 patient had a late grade 2 toxicity (fibrosis). One patient had acute grade 3 dermatitis, whereas 2 patients experienced grade 3 late skin toxicity. Ninety-four percent of evaluable patients had good or excellent cosmesis. Conclusions: Our phase 2 institutional study offers one of the shortest courses of HF therapy, delivered in 15 fractions inclusive of a sequential boost. We demonstrated expected low toxicity and high local control rates with good to excellent cosmetic outcomes. This fractionation scheme is feasible and well tolerated and offers women WBI in a highly convenient schedule.« less

Orphan therapies: making best use of postmarket data.

PubMed

Maro, Judith C; Brown, Jeffrey S; Dal Pan, Gerald J; Li, Lingling

2014-08-01

Postmarket surveillance of the comparative safety and efficacy of orphan therapeutics is challenging, particularly when multiple therapeutics are licensed for the same orphan indication. To make best use of product-specific registry data collected to fulfill regulatory requirements, we propose the creation of a distributed electronic health data network among registries. Such a network could support sequential statistical analyses designed to detect early warnings of excess risks. We use a simulated example to explore the circumstances under which a distributed network may prove advantageous. We perform sample size calculations for sequential and non-sequential statistical studies aimed at comparing the incidence of hepatotoxicity following initiation of two newly licensed therapies for homozygous familial hypercholesterolemia. We calculate the sample size savings ratio, or the proportion of sample size saved if one conducted a sequential study as compared to a non-sequential study. Then, using models to describe the adoption and utilization of these therapies, we simulate when these sample sizes are attainable in calendar years. We then calculate the analytic calendar time savings ratio, analogous to the sample size savings ratio. We repeat these analyses for numerous scenarios. Sequential analyses detect effect sizes earlier or at the same time as non-sequential analyses. The most substantial potential savings occur when the market share is more imbalanced (i.e., 90% for therapy A) and the effect size is closest to the null hypothesis. However, due to low exposure prevalence, these savings are difficult to realize within the 30-year time frame of this simulation for scenarios in which the outcome of interest occurs at or more frequently than one event/100 person-years. We illustrate a process to assess whether sequential statistical analyses of registry data performed via distributed networks may prove a worthwhile infrastructure investment for pharmacovigilance.

Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?

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

Harriss-Phillips, Wendy M., E-mail: wharrphil@gmail.com; School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia; Bezak, Eva

Purpose: To simulate stereotactic ablative radiation therapy on hypoxic and well-oxygenated in silico tumors, incorporating probabilistic parameter distributions and linear-quadratic versus linear-quadratic-cubic methodology and the evaluation of optimal fractionation schemes using biological effective dose (BED{sub α/β=10} {sub or} {sub 3}) comparisons. Methods and Materials: A temporal tumor growth and radiation therapy algorithm simulated high-dose external beam radiation therapy using stochastic methods. Realistic biological proliferative cellular hierarchy and pO{sub 2} histograms were incorporated into the 10{sup 8}-cell tumor model, with randomized radiation therapy applied during continual cell proliferation and volume-based gradual tumor reoxygenation. Dose fractions ranged from 6-35 Gy, with predictive outcomes presentedmore » in terms of the total doses (converted to BED) required to eliminate all cells that could potentially regenerate the tumor. Results: Well-oxygenated tumor control BED{sub 10} outcomes were not significantly different for high-dose versus conventional radiation therapy (BED{sub 10}: 79-84 Gy; Equivalent Dose in 2 Gy fractions with α/β of 10: 66-70 Gy); however, total treatment times decreased from 7 down to 1-3 weeks. For hypoxic tumors, an additional 28 Gy (51 Gy BED{sub 10}) was required, with BED{sub 10} increasing with dose per fraction due to wasted dose in the final fraction. Fractions of 9 Gy compromised well for total treatment time and BED, with BED{sub 10}:BED{sub 3} of 84:176 Gy for oxic and 132:278 Gy for non-reoxygenating hypoxic tumors. Initial doses of 12 Gy followed by 6 Gy further increased the therapeutic ratio. When delivering ≥9 Gy per fraction, applying reoxygenation and/or linear-quadratic-cubic cell survival both affected tumor control doses by a significant 1-2 fractions. Conclusions: The complex temporal dynamics of tumor oxygenation combined with probabilistic cell kinetics in the modeling of radiation therapy requires sophisticated stochastic modeling to predict tumor cell kill. For stereotactic ablative radiation therapy, high doses in the first week followed by doses that are more moderate may be beneficial because a high percentage of hypoxic cells could be eradicated early while keeping the required BED{sub 10} relatively low and BED{sub 3} toxicity to tolerable levels.« less

The sequential organ failure assessment (SOFA) score is an effective triage marker following staggered paracetamol (acetaminophen) overdose.

PubMed

Craig, D G; Zafar, S; Reid, T W D J; Martin, K G; Davidson, J S; Hayes, P C; Simpson, K J

2012-06-01

The sequential organ failure assessment (SOFA) score is an effective triage marker following single time point paracetamol (acetaminophen) overdose, but has not been evaluated following staggered (multiple supratherapeutic doses over >8 h, resulting in cumulative dose of >4 g/day) overdoses. To evaluate the prognostic accuracy of the SOFA score following staggered paracetamol overdose. Time-course analysis of 50 staggered paracetamol overdoses admitted to a tertiary liver centre. Individual timed laboratory samples were correlated with corresponding clinical parameters and the daily SOFA scores were calculated. A total of 39/50 (78%) patients developed hepatic encephalopathy. The area under the SOFA receiver operator characteristic for death/liver transplantation was 87.4 (95% CI 73.2-95.7), 94.3 (95% CI 82.5-99.1), and 98.4 (95% CI 84.3-100.0) at 0, 24 and 48 h, respectively, postadmission. A SOFA score of <6 at tertiary care admission predicted survival with a sensitivity of 100.0% (95% CI 76.8-100.0) and specificity of 58.3% (95% CI 40.8-74.5), compared with 85.7% (95% CI 60.6-97.4) and 75.0% (95% CI 65.2-79.5) , respectively, for the modified Kings College criteria. Only 2/21 patients with an admission SOFA score <6 required renal replacement therapy or intracerebral pressure monitoring. SOFA significantly outperformed the Model for End-stage Liver Disease, but not APACHE II, at 0, 24-and 48-h following admission. A SOFA score <6 at tertiary care admission following a staggered paracetamol overdose, is associated with a good prognosis. Both the SOFA and APACHE II scores could improve triage of high-risk staggered paracetamol overdose patients. © 2012 Blackwell Publishing Ltd.

Thyroid V30 Predicts Radiation-Induced Hypothyroidism in Patients Treated With Sequential Chemo-Radiotherapy for Hodgkin's Lymphoma

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

Cella, Laura; Department of Diagnostic Imaging and Radiation Oncology, Federico II University School of Medicine, Naples; Conson, Manuel

Purpose: Hypothyroidism (HT) is a frequent late side effect of Hodgkin's lymphoma (HL) therapy. The purpose of this study is to determine dose-volume constraints that correlate with functional impairment of the thyroid gland in HL patients treated with three-dimensional radiotherapy. Methods and Materials: A total of 61 consecutive patients undergoing antiblastic chemotherapy and involved field radiation treatment (median dose, 32 Gy; range, 30-36 Gy) for HL were retrospectively considered. Their median age was 28 years (range, 14-70 years). Blood levels of thyroid-stimulating hormone (TSH), free triiodo-thyronine (FT3), free thyroxine (FT4), and thyroglobulin antibody (ATG) were recorded basally and at differentmore » times after the end of therapy. For the thyroid gland, normal tissue complication probability (NTCP), dosimetric parameters, and the percentage of thyroid volume exceeding 10, 20, and 30 Gy (V10, V20, and V30) were calculated in all patients. To evaluate clinical and dosimetric factors possibly associated with HT, univariate and multivariate logistic regression analyses were performed. Results: Eight of 61 (13.1%) patients had HT before treatment and were excluded from further evaluation. At a median follow-up of 32 months (range, 6-99 months), 41.5% (22/53) of patients developed HT after treatment. Univariate analyses showed that all dosimetric factors were associated with HT (p < 0.05). On multivariate analysis, the thyroid V30 value was the single independent predictor associated with HT (p = 0.001). This parameter divided the patients into low- vs. high-risk groups: if V30 was {<=} 62.5%, the risk of developing HT was 11.5%, and if V30 was >62.5%, the risk was 70.8% (p < 0.0001). A Cox regression curve stratified by two levels of V30 value was created (odds ratio, 12.6). Conclusions: The thyroid V30 predicts the risk of developing HT after sequential chemo-radiotherapy and defines a useful constraint to consider for more accurate HL treatment planning.« less

COMPARISON OF THE PERIPHERAL DOSES FROM DIFFERENT IMRT TECHNIQUES FOR PEDIATRIC HEAD AND NECK RADIATION THERAPY.

PubMed

Toyota, Masahiko; Saigo, Yasumasa; Higuchi, Kenta; Fujimura, Takuya; Koriyama, Chihaya; Yoshiura, Takashi; Akiba, Suminori

2017-11-01

Intensity-modulated radiation therapy (IMRT) can deliver high and homogeneous doses to the target area while limiting doses to organs at risk. We used a pediatric phantom to simulate the treatment of a head and neck tumor in a child. The peripheral doses were examined for three different IMRT techniques [dynamic multileaf collimator (DMLC), segmental multileaf collimator (SMLC) and volumetric modulated arc therapy (VMAT)]. Peripheral doses were evaluated taking thyroid, breast, ovary and testis as the points of interest. Doses were determined using a radio-photoluminescence glass dosemeter, and the COMPASS system was used for three-dimensional dose evaluation. VMAT achieved the lowest peripheral doses because it had the highest monitor unit efficiency. However, doses in the vicinity of the irradiated field, i.e. the thyroid, could be relatively high, depending on the VMAT collimator angle. DMLC and SMLC had a large area of relatively high peripheral doses in the breast region. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

Serin, E.; Codel, G.; Mabhouti, H.

Purpose: In small field geometries, the electronic equilibrium can be lost, making it challenging for the dose-calculation algorithm to accurately predict the dose, especially in the presence of tissue heterogeneities. In this study, dosimetric accuracy of Monte Carlo (MC) advanced dose calculation and sequential algorithms of Multiplan treatment planning system were investigated for small radiation fields incident on homogeneous and heterogeneous geometries. Methods: Small open fields of fixed cones of Cyberknife M6 unit 100 to 500 mm2 were used for this study. The fields were incident on in house phantom containing lung, air, and bone inhomogeneities and also homogeneous phantom.more » Using the same film batch, the net OD to dose calibration curve was obtained using CK with the 60 mm fixed cone by delivering 0- 800 cGy. Films were scanned 48 hours after irradiation using an Epson 1000XL flatbed scanner. The dosimetric accuracy of MC and sequential algorithms in the presence of the inhomogeneities was compared against EBT3 film dosimetry Results: Open field tests in a homogeneous phantom showed good agreement between two algorithms and film measurement For MC algorithm, the minimum gamma analysis passing rates between measured and calculated dose distributions were 99.7% and 98.3% for homogeneous and inhomogeneous fields in the case of lung and bone respectively. For sequential algorithm, the minimum gamma analysis passing rates were 98.9% and 92.5% for for homogeneous and inhomogeneous fields respectively for used all cone sizes. In the case of the air heterogeneity, the differences were larger for both calculation algorithms. Overall, when compared to measurement, the MC had better agreement than sequential algorithm. Conclusion: The Monte Carlo calculation algorithm in the Multiplan treatment planning system is an improvement over the existing sequential algorithm. Dose discrepancies were observed for in the presence of air inhomogeneities.« less

High-dose sequential epirubicin and cyclophosphamide with peripheral blood stem cell support for advanced breast cancer: results of a phase II study

PubMed Central

Cottu, P H; Extra, J M; Espie, M; Marolleau, J P; Roquancourt, A de; Makke, J; Miclea, J M; Laurence, V; Mayeur, D; Lerebours, F; Cuvier, C; Marty, M

2001-01-01

The aim of this study was to evaluate the feasibility of a high-dose intensity and high-dose density multicycle epirubicin and cyclophosphamide regimen with peripheral blood stem cells (PBSC) and haematopoietic growth factor (G-CSF) support in advanced breast cancer patients. From August 1994 to September 1999, 56 breast cancer patients (8 stage IIIB and 48 stage IV) received 205 courses of cyclophosphamide 3 g m−2and epirubicin 100 mg m−2every 14 days. G-CSF 5 μg kg−1day−1was administered from day 3 to neutrophil recovery. 4 courses were planned. PBSC were collected after course 1, and reinfused after courses 3 and 4, with ≥ 2 × 106CD34+ PBSC kg−1required for each reinfusion. 48 patients (86%) received all 4 planned courses. Early withdrawal was consecutive to infectious complications (n= 4), severe asthenia (n= 3), haemorrhagic cystitis (n= 1). A median number of 10.8 × 106CD34+ PBSC kg−1(range, 3–80) was harvested with 1 or 2 apheresis in 48 patients (94%). Median relative dose intensity was 91.3% (range, 72–102%). Grade 4 neutrophil toxicity was observed in 100% of patients. Febrile neutropenia was observed in 40% of courses (median duration 2 days). Red blood cells and platelets had to be transfused in 54% and 27% of courses, respectively. There were no toxic deaths. Objective response rate was 69% in stage IV patients (31/45 evaluable pts), with a 16% complete response rate. Their median progression-free and overall survivals were 22.5 and 37 months, respectively. This epirubicine-containing high-dose regimen appeared feasible, albeit with high toxicity. Time-related progression parameters exceed commonly reported ones. Controlled studies of upfront sequential high-dose chemotherapy are still needed to evaluate its real benefit. © 2001 Cancer Research Campaign PMID:11720455

Basic study of less invasive high-intensity focused ultrasound (HIFU) in fetal therapy for twin reversed arterial perfusion (TRAP) sequence.

PubMed

Ichizuka, Kiyotake; Matsuoka, Ryu; Aoki, Hiroko; Hasegawa, Junichi; Okai, Takashi; Umemura, Shin-Ichiro

2016-10-01

The objective of the present study was to develop a high-intensity focused ultrasound (HIFU) transducer more suitable for clinical use in fetal therapy for twin reversed arterial perfusion (TRAP) sequence. We created a cooling and degassed water-circulating-type HIFU treatment device. HIFU was applied to renal branch vessels in three rabbits. Sequential HIFU irradiation contains a trigger wave, heating wave, and rest time. The duration of HIFU application was 10 s/course. Targeting could be achieved by setting the imaging probe in the center and placing the HIFU beam and imaging ultrasonic wave on the same axis. We confirmed under sequential HIFU irradiation with a total intensity of 1.94 kW/cm(2) (spatial average temporal average intensity) that the vein and artery were occluded in all three rabbits. Simultaneous occluding of the veins and arteries was confirmed with trigger waves and a resting phase using the HIFU transducer treatment device created for this study. Clinical application appears possible and may represent a promising option for fetal therapy involving TRAP sequence.

Impact of primary antibiotic resistance on the effectiveness of sequential therapy for Helicobacter pylori infection: lessons from a 5-year study on a large number of strains.

PubMed

Gatta, L; Scarpignato, C; Fiorini, G; Belsey, J; Saracino, I M; Ricci, C; Vaira, D

2018-05-01

The increasing prevalence of strains resistant to antimicrobial agents is a critical issue in the management of Helicobacter pylori (H. pylori) infection. (1) To evaluate the prevalence of primary resistance to clarithromycin, metronidazole and levofloxacin (2) to assess the effectiveness of sequential therapy on resistant strains (3) to identify the minimum number of subjects to enrol for evaluating the effectiveness of an eradication regimen in patients harbouring resistant strains. Consecutive 1682 treatment naïve H. pylori-positive patients referred for upper GI endoscopy between 2010 and 2015 were studied and resistances assessed by E-test. Sequential therapy was offered, effectiveness evaluated and analysed. H. pylori-primary resistance to antimicrobials tested was high, and increased between 2010 and 2015. Eradication rates were (estimates and 95% CIs): 97.3% (95.6-98.4) in strains susceptible to clarithromycin and metronidazole; 96.1% (91.7-98.2) in strains resistant to metronidazole but susceptible to clarithromycin; 93.4% (88.2-96.4) in strains resistant to clarithromycin but susceptible to metronidazole; 83.1% (77.7-87.3) in strains resistant to clarithromycin and metronidazole. For any treatment with a 75%-85% eradication rate, some 98-144 patients with resistant strains need to be studied to get reliable information on effectiveness in these patients. H. pylori-primary resistance is increasing and represents the most critical factor affecting effectiveness. Sequential therapy eradicated 83% of strains resistant to clarithromycin and metronidazole. Reliable estimates of the effectiveness of a given regimen in patients harbouring resistant strains can be obtained only by assessing a large number of strains. © 2018 John Wiley & Sons Ltd.

A threshold dose distribution approach for the study of PDT resistance development: A threshold distribution approach for the study of PDT resistance.

PubMed

de Faria, Clara Maria Gonçalves; Inada, Natalia Mayumi; Vollet-Filho, José Dirceu; Bagnato, Vanderlei Salvador

2018-05-01

Photodynamic therapy (PDT) is a technique with well-established principles that often demands repeated applications for sequential elimination of tumor cells. An important question concerns the way surviving cells from a treatment behave in the subsequent one. Threshold dose is a core concept in PDT dosimetry, as the minimum amount of energy to be delivered for cell destruction via PDT. Concepts of threshold distribution have shown to be an important tool for PDT results analysis in vitro. In this study, we used some of these concepts for demonstrating subsequent treatments with partial elimination of cells modify the distribution, which represents an increased resistance of the cells to the photodynamic action. HepG2 and HepaRG were used as models of tumor and normal liver cells and a protocol to induce resistance, consisted of repeated PDT sessions using Photogem® as a photosensitizer, was applied to the tumor ones. The response of these cells to PDT was assessed using a standard viability assay and the dose response curves were used for deriving the threshold distributions. The changes in the distribution revealed that the resistance protocol effectively eliminated the most sensitive cells. Nevertheless, HepaRG cell line was the most resistant one among the cells analyzed, which indicates a specificity in clinical applications that enables the use of high doses and drug concentrations with minimal damage to the surrounding normal tissue. Copyright © 2018 Elsevier B.V. All rights reserved.

Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.

PubMed

Niesvizky, Ruben; Badros, Ashraf Z; Costa, Luciano J; Ely, Scott A; Singhal, Seema B; Stadtmauer, Edward A; Haideri, Nisreen A; Yacoub, Abdulraheem; Hess, Georg; Lentzsch, Suzanne; Spicka, Ivan; Chanan-Khan, Asher A; Raab, Marc S; Tarantolo, Stefano; Vij, Ravi; Zonder, Jeffrey A; Huang, Xiangao; Jayabalan, David; Di Liberto, Maurizio; Huang, Xin; Jiang, Yuqiu; Kim, Sindy T; Randolph, Sophia; Chen-Kiang, Selina

2015-01-01

This phase 1/2 study was the first to evaluate the safety and efficacy of the cyclin-dependent kinase (CDK) 4/6-specific inhibitor palbociclib (PD-0332991) in sequential combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. The recommended phase 2 dose was palbociclib 100 mg orally once daily on days 1-12 of a 21-day cycle with bortezomib 1.0 mg/m2 (intravenous) and dexamethasone 20 mg (orally 30 min pre-bortezomib dosing) on days 8 and 11 (early G1 arrest) and days 15 and 18 (cell cycle resumed). Dose-limiting toxicities were primarily cytopenias; most other treatment-related adverse events were grade≤3. At a bortezomib dose lower than that in other combination therapy studies, antitumor activity was observed (phase 1). In phase 2, objective responses were achieved in 5 (20%) patients; 11 (44%) achieved stable disease. Biomarker and pharmacodynamic assessments demonstrated that palbociclib inhibited CDK4/6 and the cell cycle initially in most patients.

A system for electron therapy dosimetry surveys with thermoluminescence dosimeters.

PubMed

Soares, C G; Ehrlich, M; Padikal, T N; Gromadzki, Z C

1982-11-01

Radiation-therapy dosimetry surveys employing thermoluminescence dosimeters (TLDs) are now being considered for high-energy electron beams. Using a system of individually calibrated pressed LiF TLDs in a water and a polystyrene phantom, we established that the distortions of depth-dose distributions in non-conducting materials previously observed at high absorbed doses and high dose rates were not detectable in the present geometry at doses and dose rates as much as 40 times higher than those employed in radiation therapy. The system was then used to measure TLD response in water and in polystyrene in the nominal electron-energy range from 7 to 18 MeV. In the water phantom, the well-known trend for TLD response to decrease with increasing electron energy was observed. In the polystyrene phantom, TLD response was found to be independent of electron energy.

Microfluidic Thrombosis under Multiple Shear Rates and Antiplatelet Therapy Doses

PubMed Central

Ku, David N.; Forest, Craig R.

2014-01-01

The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non-quantitative studies. In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s−1) and therapy concentrations (0–2.4 µM for eptifibatide, 0–2 mM for acetyl-salicylic acid (ASA), 3.5–40 Units/L for heparin) using a microfluidic device. We also measured complete blood counts (CBC) and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models. Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose). Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment. PMID:24404131

Evaluation of High Ipsilateral Subventricular Zone Radiation Therapy Dose in Glioblastoma: A Pooled Analysis

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

Lee, Percy, E-mail: percylee@mednet.ucla.edu; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California; Eppinga, Wietse

Purpose: Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. Methods and Materials: 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships betweenmore » high SVZ doses and PFS and OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection. Results: Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS and OS on multivariate analysis. Conclusion: High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.« less

Role of Systemic Therapy in the Development of Lung Sequelae After Conformal Radiotherapy in Breast Cancer Patients

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

Varga, Zoltan; Cserhati, Adrienn; Kelemen, Gyoengyi

2011-07-15

Purpose: To analyze the risk of radiogenic lung damage in breast cancer patients after conformal radiotherapy and different forms of systemic treatment. Methods and Materials: In 328 patients receiving sequential taxane-based chemotherapy, concomitant hormone therapy (tamoxifen or aromatase inhibitors), or no adjuvant systemic therapy, symptomatic and asymptomatic lung sequelae were prospectively evaluated via the detection of visible CT abnormalities, 3 months or 1 year after the completion of the radiotherapy. Results: Significant positive associations were detected between the development of both pneumonitis and fibrosis of Grade 1 and patient age, ipsilateral mean lung dose, volume of the ipsilateral lung receivingmore » 20 Gy, and irradiation of the regional lymph nodes. In multivariate analysis, age and mean lung dose proved to be independent predictors of early (odds ratio [OR] = 1.035, 95% confidence interval [CI] 1.011-1.061 and OR = 1.113, 95% CI 1.049-1.181, respectively) and late (OR = 1.074, 95% CI 1.042-1.107 and OR = 1.207, 95% CI 1.124-1.295, respectively) radiogenic lung damage, whereas the role of systemic therapy was significant in the development of Grade 1 lung fibrosis (p = 0.01). Among the various forms of systemic therapy, tamoxifen increased the risk of late lung sequelae (OR = 2.442, 95% CI 1.120-5.326, p = 0.025). No interaction was demonstrated between the administration of systemic therapy and the other above-mentioned parameters as regards the risk of radiogenic lung damage. Conclusions: Our analyses demonstrate the independent role of concomitant tamoxifen therapy in the development of radiogenic lung fibrosis but do not suggest such an effect for the other modes of systemic treatment.« less

Combined model-based and patient-specific dosimetry for 18F-DCFPyL, a PSMA-targeted PET agent.

PubMed

Plyku, Donika; Mena, Esther; Rowe, Steven P; Lodge, Martin A; Szabo, Zsolt; Cho, Steve Y; Pomper, Martin G; Sgouros, George; Hobbs, Robert F

2018-06-01

Prostate-specific membrane antigen (PSMA), a type-II integral membrane protein highly expressed in prostate cancer, has been extensively used as a target for imaging and therapy. Among the available PET radiotracers, the low molecular weight agents that bind to PSMA are proving particularly effective. We present the dosimetry results for 18 F-DCFPyL in nine patients with metastatic prostate cancer. Nine patients were imaged using sequential PET/CT scans at approximately 1, 12, 35 and 70 min, and a final PET/CT scan at approximately 120 min after intravenous administration of 321 ± 8 MBq (8.7 ± 0.2 mCi) of 18 F-DCFPyL. Time-integrated-activity coefficients were calculated and used as input in OLINDA/EXM software to obtain dose estimates for the majority of the major organs. The absorbed doses (AD) to the eye lens and lacrimal glands were calculated using Monte-Carlo models based on idealized anatomy combined with patient-specific volumes and activity from the PET/CT scans. Monte-Carlo based models were also developed for calculation of the dose to two major salivary glands (parotid and submandibular) using CT-based patient-specific gland volumes. The highest calculated mean AD per unit administered activity of 18 F was found in the lacrimal glands, followed by the submandibular glands, kidneys, urinary bladder wall, and parotid glands. The S-values for the lacrimal glands to the eye lens (0.42 mGy/MBq h), the tear film to the eye lens (1.78 mGy/MBq h) and the lacrimal gland self-dose (574.10 mGy/MBq h) were calculated. Average S-values for the salivary glands were 3.58 mGy/MBq h for the parotid self-dose and 6.78 mGy/MBq h for the submandibular self-dose. The resultant mean effective dose of 18 F-DCFPyL was 0.017 ± 0.002 mSv/MBq. 18 F-DCFPyL dosimetry in nine patients was obtained using novel models for the lacrimal and salivary glands, two organs with potentially dose-limiting uptake for therapy and diagnosis which lacked pre-existing models.

Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

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

Prokic, Vesna, E-mail: vesna.prokic@uniklinik-freiburg.de; Wiedenmann, Nicole; Fels, Franziska

2013-01-01

Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individualmore » brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 {+-} 0.62 Gy and 6.29 {+-} 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 {+-} 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 {+-} 0.7 Gy and 32.7 {+-} 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 {+-} 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.« less

Randomized Controlled Trial for Helicobacter pylori Eradication in a Naive Portuguese Population: Is Sequential Treatment Superior to Triple Therapy in Real World Clinical Setting?

PubMed

Boal Carvalho, Pedro; Magalhães, Joana; Dias de Castro, Francisca; Rosa, Bruno; Cotter, José

2017-03-31

Helicobacter pylori eradication has become increasingly difficult as resistances to several antibiotics develop. We aimed to compare Helicobacter pylori eradication rates between triple therapy and sequential therapy in a naive Portuguese population. Prospective randomized trial including consecutive patients referred for first-line Helicobacter pylori eradication treatment. previous gastric surgery/neoplasia, pregnancy/lactancy, allergy to any of the drugs. The compared eradication regimens were triple therapy (pantoprazol, amoxicillin and clarithromycin 12/12 hours, 14 days) and sequential therapy (pantoprazol 12/12 hours for 10 days, amoxicillin 12/12 hours for days 1 - 5 and clarithromycin plus metronidazol 12/12 hours during days 6 - 10). Eradication success was confirmed with urea breath test. Statistical analysis was performed with SPSS v21.0 and a p-value < 0.05 was considered statistically significant. Included 60 patients, 39 (65%) female with mean age 52 years (SD ± 14.3). Treatment groups were homogeneous for gender, age, indication for treatment and smoking status. No statistical differences were encountered between sequential and triple therapy eradication rates (86.2% vs 77.4%, p = 0.379), global eradication rate was 82%. Tobacco consumption was associated with a significantly lower eradication success (54.5 vs 87.8%, p = 0.022). In this randomized controlled trial in a naive Portuguese population, we found a satisfactory global Helicobacter pylori eradication rate of 82%, with no statistical differences observed in the efficacy of the treatment between triple and sequential regimens. These results support the use of either therapy for the first-line eradication of Helicobacter pylori.

Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy.

PubMed

Vaduganathan, Muthiah; Bhatt, Deepak L; Cryer, Byron L; Liu, Yuyin; Hsieh, Wen-Hua; Doros, Gheorghe; Cohen, Marc; Lanas, Angel; Schnitzer, Thomas J; Shook, Thomas L; Lapuerta, Pablo; Goldsmith, Mark A; Laine, Loren; Cannon, Christopher P

2016-04-12

The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin. The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets. Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into "low-dose" (≤ 100 mg) and "high-dose" (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists. Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group. Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity.

PubMed

Rigual, Nestor; Shafirstein, Gal; Cooper, Michele T; Baumann, Heinz; Bellnier, David A; Sunar, Ulas; Tracy, Erin C; Rohrbach, Daniel J; Wilding, Gregory; Tan, Wei; Sullivan, Maureen; Merzianu, Mihai; Henderson, Barbara W

2013-12-01

The primary objective was to evaluate safety of 3-(1'-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction. Patients with histologically proven oral dysplasia, carcinoma in situ, or early-stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies used an HPPH dose of 4 mg/m(2) and light doses from 50 to 140 J/cm(2). Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of STAT3 were assessed as potential indicators of PDT effective reaction. Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and carcinoma in situ and 82% for squamous cell carcinomas (SCC) lesions at 140 J/cm(2). The responses in the carcinoma in situ/dysplasia cohort are not durable. The PDT-induced STAT3 cross-links is significantly higher (P = 0.0033) in SCC than in carcinoma in situ/dysplasia for all light doses. HPPH-PDT is safe for the treatment of carcinoma in situ/dysplasia and early-stage cancer of the oral cavity. Early-stage oral HNSCC seems to respond better to HPPH-PDT in comparison with premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT-mediated photoreaction. ©2013 AACR.

[Helicobacter pylori-associated diseases].

PubMed

Gisbert, Javier P

2015-09-01

This article summarizes the main conclusions of the studies presented at Digestive Disease Week this year (2015) related to Helicobacter pylori infection. Despite the undeniable widespread reduction in the prevalence of H. pylori infection, developing countries continue to have substantial infection rates. The prevalence of clarithromycin, metronidazole and quinolone resistance is markedly higher in most countries and continues to rise. Although H. pylori eradication reduces the incidence of gastric adenocarcinoma, it does not completely prevent its development; the presence of precancerous lesions--intestinal atrophy and metaplasia--is associated with a higher risk of developing this neoplasm, despite H. pylori eradication. The use of molecular diagnostic methods (polymerase chain reaction) in faecal samples could allow non-invasive evaluation of the antibiotic susceptibility of H. pylori. The effectiveness of standard triple therapy is clearly insufficient and continues to decrease. The effectiveness of sequential therapy in recent studies is lower than initially described and consequently this treatment cannot be recommended in clinical practice. Concomitant therapy is more effective and simpler than sequential therapy. In penicillin-allergic patients, quadruple therapy with bismuth is the treatment of choice in our environment. After the failure of standard triple therapy, second-line therapy with levofloxacin is effective and, moreover, is simpler and better tolerated than quadruple therapy with bismuth. Quadruple therapy with a proton pump inhibitor, bismuth, levofloxacin and amoxicillin is an effective (≥ 90% eradication), simple and safe second-line therapy if triple or quadruple therapy without bismuth (sequential or concomitant) fails to eradicate the infection. The new-generation quinolones, such as moxifloxacin or sitafloxacin, could be useful in second- or third-line rescue eradication therapy. Even after the failure of 3 eradication treatments, a fourth empirical rescue therapy (with rifabutin) can be effective. The management of H. pylori infection by European gastroenterologists is widely heterogeneous, and their eradication rates are generally unacceptable. In addition, there is a clear discrepancy between consensus document recommendations and clinical practice in primary care. The incidence of H. pylori reinfection is very low in the most developed regions, but is high in developing countries. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Long-Term Efficacy and Safety of Cyclosporine in a Cohort of Steroid-Refractory Acute Severe Ulcerative Colitis Patients from the ENEIDA Registry (1989-2013): A Nationwide Multicenter Study.

PubMed

Ordás, I; Domènech, E; Mañosa, M; García-Sánchez, V; Iglesias-Flores, E; Peñalva, M; Cañas-Ventura, A; Merino, O; Fernández-Bañares, F; Gomollón, F; Vera, M; Gutiérrez, A; Garcia-Planella, E; Chaparro, M; Aguas, M; Gento, E; Muñoz, F; Aguirresarobe, M; Muñoz, C; Fernández, L; Calvet, X; Jiménez, C E; Montoro, M A; Mir, A; De Castro, M L; García-Sepulcre, M F; Bermejo, F; Panés, J; Esteve, M

2017-11-01

To determine the efficacy and safety of cyclosporine (CyA) in a large national registry-based population of patients with steroid-refractory (SR) acute severe ulcerative colitis (ASUC) and to establish predictors of efficacy and adverse events. Multicenter study of SR-ASUC treated with CyA, based on data from the ENEIDA registry. SR-ASUC patients treated with infliximab (IFX) or sequential rescue therapy (CyA-IFX or IFX-CyA) were used as comparators. Of 740 SR-ASUC patients, 377 received CyA, 131 IFX and 63 sequential rescue therapy. The cumulative colectomy rate was higher in the CyA (24.1%) and sequential therapy (32.7%) than in the IFX group (14.5%; P=0.01) at 3 months and 5 years. There were no differences in early and late colectomy between CyA and IFX in patients treated after 2005. 62% of patients receiving CyA remained colectomy-free in the long term (median 71 months). There were no differences in mortality between CyA (2.4%), IFX (1.5%) and sequential therapy (0%; P=0.771). The proportion of patients with serious adverse events (SAEs) was lower in CyA (15.4%) than in IFX treated patients (26.5%) or sequential therapy (33.4%; P<0.001). This difference in favor of CyA was maintained when only patients treated after 2005 were analyzed. Treatment with CyA showed a lower rate of SAE and a similar efficacy to that of IFX thereby supporting the use of either CyA or IFX in SR-ASUC. In addition, the risk-benefit of sequential CyA-IFX for CyA non-responders is acceptable.

Inhibition of Interferon-beta Responses in Multiple Sclerosis Immune Cells Associated With High-Dose Statins

PubMed Central

Feng, Xuan; Han, Diana; Kilaru, Bharat K.; Franek, Beverly S.; Niewold, Timothy B.; Reder, Anthony T.

2014-01-01

Objective To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). Design Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. Patients The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. Interventions Statin effects on in vitro and in vivo interferon-beta–induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. Results In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P< .001), interferon regulatory factor 1 protein by 30% (P= .006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy–induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. Conclusions High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease. PMID:22801747

A randomized controlled trial comparing sequential with triple therapy for Helicobacter pylori in an Aboriginal community in the Canadian North

PubMed Central

Morse, Amy L; Goodman, Karen J; Munday, Rachel; Chang, Hsiu-Ju; Morse, John; Keelan, Monika; Geary, Janis; van Zanten, Sander Veldhuyzen

2013-01-01

BACKGROUND: Helicobacter pylori infection occurs more frequently in Arctic Aboriginal settings than elsewhere in North America and Europe. Research aimed at reducing health risks from H pylori infection has been conducted in the Aboriginal community of Aklavik, Northwest Territories. OBJECTIVE: To compare the effectiveness of the Canadian standard therapy with an alternative therapy for eliminating H pylori infection in Aklavik. METHODS: Treatment-naive H pylori-positive individuals were randomly assigned to a 10-day regimen (oral twice-daily doses) with rabeprazole (20 mg): standard triple therapy (proton pump inhibitor, added clarithromycin [500 mg] and amoxicillin [1 g] [PPI-CA]); sequential therapy (ST) added amoxicillin (1 g) on days 1 to 5, and metronidazole (500 mg) and clarithromycin (500 mg) on days 6 to 10. Participants with clarithromycin-resistant H pylori were randomly assigned to ST or quadruple therapy. Treatment effectiveness was estimated as per cent (95% CI) with a negative urea breath test at least 10 weeks after treatment. RESULTS: Of 104 (53 PPI-CA, 51 ST) randomized participants, 89 (49 PPI-CA, 40 ST) had post-treatment results. Per-protocol treatment effectiveness was 59% (95% CI 45% to 73%) for PPI-CA and 73% (95% CI 58% to 87%) for ST. Based on intention to treat, effectiveness was 55% (95% CI 41% to 69%) for PPI-CA and 57% (95% CI 43% to 71%) for ST. Of 77 participants (43 PPI-CA, 34 ST) with 100% adherence, effectiveness was 63% (95% CI 43% to 82%) for PPI-CA and 81% (95% CI 63% to 99%) for ST. CONCLUSIONS: While additional evidence is needed to confirm that ST is more effective for Arctic Aboriginal communities than the Canadian standard H pylori treatment, these results show standard PPI-CA treatment to be inadequate for communities such as Aklavik. PMID:24340314

Durability of Adherence to Antiretroviral Therapy on Initial and Subsequent Regimens

PubMed Central

GARDNER, EDWARD M.; BURMAN, WILLIAM J.; MARAVI, MOISES E.; DAVIDSON, ARTHUR J.

2007-01-01

There is uncertainty regarding the durability of adherence to antiretroviral therapy. This study is a retrospective review of previously antiretroviral naïve patients initiating therapy between 1997 and 2002. Antiretroviral adherence was calculated using prescription refill data and was analyzed over time on an initial regimen and on sequential antiretroviral regimens. Three hundred forty-four patients were included. The median lengths of the first, second, and third regimens were stable at 1.7 years, 1.2 years, and 1.5 years, respectively (p = 0.10). In multivariate analysis the factor most significantly associated with earlier initial regimen termination was poor adherence. On an initial regimen, adherence decreased over time and declined most rapidly in patients with the shortest regimens (4 to <16 months, −43% per year), followed by patients with intermediate regimen duration (16 to <28 months, −19% per year), and then patients with longer regimens (≥28 months, −5% per year). In patients progressing to a third regimen, there was a trend toward decreasing adherence over successive regimens. In conclusion, sequential antiretroviral regimens are of similar lengths, with adherence being highly associated with first regimen duration. Adherence decreases during an initial regimen and on sequential antiretroviral regimens. Effective and durable interventions to prevent declining adherence are needed. PMID:16987049

Comparing the dosimetric impact of interfractional anatomical changes in photon, proton and carbon ion radiotherapy for pancreatic cancer patients

NASA Astrophysics Data System (ADS)

Houweling, Antonetta C.; Crama, Koen; Visser, Jorrit; Fukata, Kyohei; Rasch, Coen R. N.; Ohno, Tatsuya; Bel, Arjan; van der Horst, Astrid

2017-04-01

Radiotherapy using charged particles is characterized by a low dose to the surrounding healthy organs, while delivering a high dose to the tumor. However, interfractional anatomical changes can greatly affect the robustness of particle therapy. Therefore, we compared the dosimetric impact of interfractional anatomical changes (i.e. body contour differences and gastrointestinal gas volume changes) in photon, proton and carbon ion therapy for pancreatic cancer patients. In this retrospective planning study, photon, proton and carbon ion treatment plans were created for 9 patients. Fraction dose calculations were performed using daily cone-beam CT (CBCT) images. To this end, the planning CT was deformably registered to each CBCT; gastrointestinal gas volumes were delineated on the CBCTs and copied to the deformed CT. Fraction doses were accumulated rigidly. To compare planned and accumulated dose, dose-volume histogram (DVH) parameters of the planned and accumulated dose of the different radiotherapy modalities were determined for the internal gross tumor volume, internal clinical target volume (iCTV) and organs-at-risk (OARs; duodenum, stomach, kidneys, liver and spinal cord). Photon plans were highly robust against interfractional anatomical changes. The difference between the planned and accumulated DVH parameters for the photon plans was less than 0.5% for the target and OARs. In both proton and carbon ion therapy, however, coverage of the iCTV was considerably reduced for the accumulated dose compared with the planned dose. The near-minimum dose ({{D}98 % } ) of the iCTV reduced with 8% for proton therapy and with 10% for carbon ion therapy. The DVH parameters of the OARs differed less than 3% for both particle modalities. Fractionated radiotherapy using photons is highly robust against interfractional anatomical changes. In proton and carbon ion therapy, such changes can severely reduce the dose coverage of the target.

A perspective on diuretic resistance in chronic congestive heart failure

PubMed Central

Shah, Niel; Madanieh, Raef; Alkan, Mehmet; Dogar, Muhammad U.; Kosmas, Constantine E.; Vittorio, Timothy J.

2017-01-01

Chronic congestive heart failure (CHF) is a complex disorder characterized by inability of the heart to keep up the demands on it, followed by the progressive pump failure and fluid accumulation. Although the loop diuretics are widely used in heart failure (HF) patients, both pharmacodynamic and pharmacokinetic alterations are thought to be responsible for diuretic resistance in these patients. Strategies to overcome diuretic resistance include sodium intake restriction, changes in diuretic dose and route of administration and sequential nephron diuretic therapy. In this review, we discuss the definition, prevalence, mechanism of development and management strategies of diuretic resistance in HF patients. PMID:28728476

128-slice Dual-source Computed Tomography Coronary Angiography in Patients with Atrial Fibrillation: Image Quality and Radiation Dose of Prospectively Electrocardiogram-triggered Sequential Scan Compared with Retrospectively Electrocardiogram-gated Spiral Scan.

PubMed

Lin, Lu; Wang, Yi-Ning; Kong, Ling-Yan; Jin, Zheng-Yu; Lu, Guang-Ming; Zhang, Zhao-Qi; Cao, Jian; Li, Shuo; Song, Lan; Wang, Zhi-Wei; Zhou, Kang; Wang, Ming

2013-01-01

Objective To evaluate the image quality (IQ) and radiation dose of 128-slice dual-source computed tomography (DSCT) coronary angiography using prospectively electrocardiogram (ECG)-triggered sequential scan mode compared with ECG-gated spiral scan mode in a population with atrial fibrillation. Methods Thirty-two patients with suspected coronary artery disease and permanent atrial fibrillation referred for a second-generation 128-slice DSCT coronary angiography were included in the prospective study. Of them, 17 patients (sequential group) were randomly selected to use a prospectively ECG-triggered sequential scan, while the other 15 patients (spiral group) used a retrospectively ECG-gated spiral scan. The IQ was assessed by two readers independently, using a four-point grading scale from excel-lent (grade 1) to non-assessable (grade 4), based on the American Heart Association 15-segment model. IQ of each segment and effective dose of each patient were compared between the two groups. Results The mean heart rate (HR) of the sequential group was 96±27 beats per minute (bpm) with a variation range of 73±25 bpm, while the mean HR of the spiral group was 86±22 bpm with a variationrange of 65±24 bpm. Both of the mean HR (t=1.91, P=0.243) and HR variation range (t=0.950, P=0.350) had no significant difference between the two groups. In per-segment analysis, IQ of the sequential group vs. spiral group was rated as excellent (grade 1) in 190/244 (78%) vs. 177/217 (82%) by reader1 and 197/245 (80%) vs. 174/214 (81%) by reader2, as non-assessable (grade 4) in 4/244 (2%) vs. 2/217 (1%) by reader1 and 6/245 (2%) vs. 4/214 (2%) by reader2. Overall averaged IQ per-patient in the sequential and spiral group showed equally good (1.27±0.19 vs. 1.25±0.22, Z=-0.834, P=0.404). The effective radiation dose of the sequential group reduced significantly compared with the spiral group (4.88±1.77 mSv vs. 10.20±3.64 mSv; t=-5.372, P=0.000). Conclusion Compared with retrospectively ECG-gated spiral scan, prospectively ECG-triggered sequential DSCT coronary angiography provides similarly diagnostically valuable images in patients with atrial fibrillation and significantly reduces radiation dose.

The effect of a dual or a triple antithrombotic therapy with apixaban on thrombus formation in vivo and in an ex vivo perfusion chamber model

PubMed Central

Weisshaar, Stefan; Litschauer, Brigitte; Bucher, Sebastian; Riesenhuber, Martin; Kapiotis, Stylianos; Kyrle, Paul Alexander; Wolzt, Michael

2016-01-01

Abstract Background: There is a need to optimize pharmacological treatment in patients with acute coronary syndrome and concomitant atrial fibrillation, in particular with newer antithrombotic medicines. We have therefore studied if dual or triple combination of antithrombotic agents exert similar effects on coagulation activation in an in vivo model in the skin microvasculature and in an ex vivo perfusion chamber. Methods and Results: Shed blood platelet activation (β-thromboglobulin [β-TG]), thrombin generation (thrombin-antithrombin complex [TAT]) and volume as well as markers of thrombus size (D-dimer) and its platelet content (P-selectin) in a perfusion chamber were studied in a sequential, open-label, parallel group trial in 40 healthy male volunteers (n = 20 per group). Subjects received ticagrelor and apixaban without or with acetylsalicylic acid (ASA). Outcome parameters were assessed at 3 hours after therapy dosing, and at steady-state trough and peak conditions. A triple or dual therapy induced a comparable decrease in shed blood β-TG at 3 hours after therapy dosing but was more pronounced at steady-state conditions with the more intense treatment combination. During both antithrombotic regimens a similarly sustained inhibition in thrombin generation was observed which was accompanied by comparable increases in shed blood volume. In contrast, no treatment effect could be observed in the perfusion chamber experiment. Conclusion: Ticagrelor and apixaban with or without ASA inhibit platelet activation and thrombin formation in vivo in healthy subjects. Platelet inhibition was greater at steady-state conditions after triple therapy administration. PMID:27399131

Effect of hyperbaric oxygen on the growth and development of medicinal maggots.

PubMed

Sherman, Ronald A; Khavari, Borna; Werner, Darryl

2013-01-01

Some wound care therapists use both maggot debridement therapy (MDT) and hyperbaric oxygen (HBO2) therapy to treat non-healing wounds. Some practitioners have reported success using both MDT and HBO2 therapy concurrently; others have not. To begin evaluating the utility of using MDT and HBO2 therapy concurrently, we assessed the effects of hyperbaric oxygen (HBO2) on maggot growth and development, as a surrogate for debridement capacity. Replicate sets of medical-grade blowfly larvae were placed on liver-agar wound models and exposed to HBO2 at 2.0 atmospheres absolute (atm abs) for 90 minutes on 0 (control), 1, 2 or 3 sequential days. The effects of HBO2 exposure were quantified by measuring the maggots' subsequent growth and development. Exposure to HBO2 was most lethal to young larvae (second instars), but not to older larvae (third instars). There was no dose-relationship between the number of HBO2 treatments and rate of larval survival. Our findings suggest that maggot therapy and HBO2 therapy may be administered concurrently, as long as the larvae are not too immature (that is, as long as they are beyond the second instar) by the time they take their first dive. A clinical trial evaluating the clinical benefits of concurrent HBO2 therapy and MDT is warranted.

[Helicobacter pylori-related diseases].

PubMed

Gisbert, Javier P

2013-10-01

This article summarizes the main conclusions drawn from the presentations on Helicobacter pylori at Digestive Disease Week 2013. Knowledge of this infection among the general population continues to be extremely limited. H. pylori is the main cause of "aging" of the human stomach. In developed countries, the prevalence of H. pylori infection has decreased but continues to be considerable. In most countries, clarithromycin and metronidazole resistance rates are markedly high. H. pylori eradication improves the symptoms of functional dyspepsia, but only in a minority of patients. The frequency of idiopathic peptic ulcers seems to be rising and their prognosis is worse. Most patients with gastric cancer have, or have had, prior H. pylori infection. The risk of developing preneoplastic lesions depends on the type (strain) of the microorganism. To prevent the development of gastric cancer, eradication therapy should be administered early (before the development of intestinal metaplasia). Among H. pylori-infected patients, those who receive long-term treatment with proton pump inhibitors more frequently develop preneoplastic lesions. In patients who undergo endoscopic resection of early gastric cancer, H. pylori eradication reduces the incidence of metachronous tumors. Eradication therapy induces regression of MALT lymphoma in most patients and tumoral recurrence in the long term is exceptional; eradication is a reasonable option even when H. pylori infection has not been identified in patients with MALT lymphoma. Several diagnostic innovations were presented, such as some polymerase chain reaction techniques for use in gastric biopsy specimens or gastric juice. The efficacy of triple standard therapy is clearly inadequate. The superiority of "sequential" therapy over standard triple therapy has not been definitively established. "Concomitant" therapy is more effective and is simpler than "sequential" therapy. After failure of standard triple therapy, second-line levofloxacin-based schemes for 10 days are effective and are also simpler and better tolerated than bismuth-based quadruple therapy. Levofloxacin-based triple therapy is also a promising alternative after failure of "sequential" and "concomitant" therapies. New-generation quinolones, such as moxifloxacin, could be useful as eradication therapy, especially as rescue therapy. After failure of clarithromycin-based triple therapy, followed by that of levofloxacin-based triple therapy, a bismuth-based quadruple scheme is an acceptable alternative. Even after the failure of 3 eradication therapies, a fourth empirical rescue therapy (with rifabutin) can be effective. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Intensification of chemotherapy for the treatment of solid tumours: feasibility of a 3-fold increase in dose intensity with peripheral blood progenitor cells and granulocyte colony-stimulating factor.

PubMed Central

Leyvraz, S.; Ketterer, N.; Perey, L.; Bauer, J.; Vuichard, P.; Grob, J. P.; Schneider, P.; von Fliedner, V.; Lejeune, F.; Bachmann, F.

1995-01-01

Dose intensity may be an important determinant of the outcome in cancer chemotherapy, but is often limited by cumulative haematological toxicity. The availability of haematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and of peripheral blood progenitor cell (PBPC) transplantation has allowed the development of a new treatment strategy in which several courses of high-dose combination chemotherapy are administered for the treatment of solid tumours. PBPCs were mobilised before chemotherapy using 12 or 30 micrograms kg-1 day-1 G-CSF (Filgrastim) for 10 days, and were collected by 2-5 leucaphereses. The yields of mononuclear cells, colony-forming units and CD34-positive cells were similar at the two dose levels of Filgrastim, and the numbers of PBPCs were sufficient for rescue following multiple cycles of chemotherapy. High-dose chemotherapy (cyclophosphamide 2.5 g m-2 for 2 days, etoposide 300 mg m-2 for 3 days and cisplatin 50 mg m-2 for 3 days) was administered sequentially for a median of three cycles (range 1-4) to ten patients. Following the 30 evaluable cycles, the median duration of leucopenia < or = 0.5 x 10(9) l-1 and < or = 1.0 x 10(9) l-1 was 7 and 8 days respectively. The median time of thrombopenia < or = 20 x 10(9) l-1 was 6 days. There was no cumulative haematological toxicity. The duration of leucopenia, but not of thrombopenia, was inversely related to the number of reinfused CFU-GM (granulocyte-macrophage colony-forming units). In the majority of patients, neurotoxicity and ototoxicity became dose limiting after three cycles of therapy. However, the average dose intensity delivered was about three times higher than in a standard regimen. The complete response rate in patients with small-cell lung cancers was 66% (95% CI 30-92%) and the median progression-free survival and overall survival were 13 months and 17 months respectively. These results are encouraging and should be compared, in a randomised fashion, with standard dose chemotherapy. PMID:7541235

Pantoprazole for the treatment of peptic ulcer bleeding and prevention of rebleeding.

PubMed

van Rensburg, Christo J; Cheer, Susan

2012-01-01

Adding proton pump inhibitors (PPIs) to endoscopic therapy has become the mainstay of treatment for peptic ulcer bleeding, with current consensus guidelines recommending high-dose intravenous (IV) PPI therapy (IV bolus followed by continuous therapy). However, whether or not high-dose PPI therapy is more effective than low-dose PPI therapy is still debated. Furthermore, maintaining pH ≥ 4 appears to prevent mucosal bleeding in patients with acute stress ulcers; thus, stress ulcer prophylaxis with acid-suppressing therapy has been increasingly recommended in intensive care units (ICUs). This review evaluates the evidence for the efficacy of IV pantoprazole, a PPI, in preventing ulcer rebleeding after endoscopic hemostasis, and in controlling gastric pH and protecting against upper gastrointestinal (GI) bleeding in high-risk ICU patients. The review concludes that IV pantoprazole provides an effective option in the treatment of upper GI bleeding, the prevention of rebleeding, and for the prophylaxis of acute bleeding stress ulcers.

Pantoprazole for the Treatment of Peptic Ulcer Bleeding and Prevention of Rebleeding

PubMed Central

van Rensburg, Christo J.; Cheer, Susan

2012-01-01

Adding proton pump inhibitors (PPIs) to endoscopic therapy has become the mainstay of treatment for peptic ulcer bleeding, with current consensus guidelines recommending high-dose intravenous (IV) PPI therapy (IV bolus followed by continuous therapy). However, whether or not high-dose PPI therapy is more effective than low-dose PPI therapy is still debated. Furthermore, maintaining pH ≥ 4 appears to prevent mucosal bleeding in patients with acute stress ulcers; thus, stress ulcer prophylaxis with acid-suppressing therapy has been increasingly recommended in intensive care units (ICUs). This review evaluates the evidence for the efficacy of IV pantoprazole, a PPI, in preventing ulcer rebleeding after endoscopic hemostasis, and in controlling gastric pH and protecting against upper gastrointestinal (GI) bleeding in high-risk ICU patients. The review concludes that IV pantoprazole provides an effective option in the treatment of upper GI bleeding, the prevention of rebleeding, and for the prophylaxis of acute bleeding stress ulcers. PMID:24833934

Outpatient management of oral vitamin K antagonist therapy: defining and measuring high-quality management.

PubMed

Phillips, Katherine W; Ansell, Jack

2008-01-01

Oral anticoagulation therapy with warfarin is the mainstay of prevention and treatment of thromboembolic disease. However, it remains one of the leading causes of harmful medication errors and medication-related adverse events. The beneficial outcomes of oral anticoagulation therapy are directly dependent upon the quality of dose and anticoagulation management, but the literature is not robust with regards to what constitutes such management. This review focuses on, and attempts to define, the parameters of high-quality anticoagulation management and identifies the appropriate outcome measures constituting high-quality management. Elements discussed include the most fundamental measure, time in therapeutic range, along with other parameters including therapy initiation, time to therapeutic range, dosing management when patients are not in therapeutic range, perioperative dosing management, patient education, and other important outcome measures. Healthcare providers who manage oral anticoagulation therapy should utilize these parameters as a measure of their performance in an effort to achieve high-quality anticoagulation management.

Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1).

PubMed

Schmitz, Norbert; Nickelsen, Maike; Ziepert, Marita; Haenel, Mathias; Borchmann, Peter; Schmidt, Christian; Viardot, Andreas; Bentz, Martin; Peter, Norma; Ehninger, Gerhard; Doelken, Gottfried; Ruebe, Christian; Truemper, Lorenz; Rosenwald, Andreas; Pfreundschuh, Michael; Loeffler, Markus; Glass, Bertram

2012-12-01

High-dose therapy (HDT) followed by transplantation of autologous haemopoietic stem cells is frequently done as part of first-line therapy in young patients with high-risk aggressive B-cell lymphoma. We investigated whether HDT with cytotoxic agents identical to those used for conventional therapy followed by autologous stem-cell transplantation (ASCT) improved survival outcome compared with conventional chemotherapy when rituximab was added to both modalities. We did an open-label, randomised trial comparing conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and rituximab (R-CHOEP-14) with dose-escalated sequential HDT and rituximab (R-MegaCHOEP) followed by repetitive ASCT in high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) patients aged 18-60 years with aggressive B-cell lymphoma. Eligible patients received radiotherapy for bulky, extranodal disease, or both. Randomisation (1:1) used the Pocock minimisation algorithm; patients were stratified by age-adjusted IPI factors, bulky disease, and centre. The primary endpoint was event-free survival. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00129090. 136 patients were randomly assigned to R-CHOEP-14 and 139 to R-MegaCHOEP. 130 patients in the R-CHOEP-14 group and 132 in the R-MegaCHOEP group were included in the intention-to-treat population. After a median of 42 months (IQR 29-59), 3-year event-free survival was 69·5% (95% CI 61·3-77·7) in the R-CHOEP-14 group and 61·4% (52·8-70·0) in the R-MegaCHOEP group (p=0·14; hazard ratio 1·3, 95% CI 0·9-2·0). All 128 evaluable patients treated with R-MegaCHOEP had grade 4 leucopenia, as did 48 (58·5%) of 82 patients with documented blood counts in the R-CHOEP-14 group. All 128 evaluable patients in the R-MegaCHOEP group had grade 3-4 thrombocytopenia, as did 26 (33·8%) of 77 patients in the R-CHOEP-14 group with documented blood counts. The most important non-haematological grade 3 or 4 adverse event was infection, which occurred in 96 (75·0%) of 128 patients treated with R-MegaCHOEP and in 40 (31·3%) of 128 patients treated with R-CHOEP-14. In young patients with high-risk aggressive B-cell lymphoma, R-MegaCHOEP was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects. R-CHOEP-14 with or without radiotherapy remains a treatment option for these patients, with encouraging efficacy. Deutsche Krebshilfe. Copyright © 2012 Elsevier Ltd. All rights reserved.

Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia.

PubMed

Sun, Bing; Xie, Yuan; Jiang, Jinfa; Wang, Yiping; Xu, Xiaolin; Zhao, Cuimei; Huang, Feifei

2015-04-14

Cardio-protective effect of fibrate therapy is controversial and current research is to evaluate the effect of fenofibrate therapy on rats with hypertriglycemia. Rats with hypertriglycemia were produced by 10% fructose administration (10 ml daily) for 4 weeks. After model has been successfully produced as reflected by increased triglyceride level, different doses of fenofibrate, namely low dose (50 mg/kg body weight) and high dose (100 mg/kg body weight), were orally prescribed for 2 weeks. At baseline, 4 weeks of fructose administration and 2 weeks of fenofibrate therapy, parameters of interest were evaluated and compared. At baseline, no significant differences of parameter were observed between groups. After 4 weeks of fructose prescription, triglyceride level increased in company with high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) decreased. C-reactive protein (CRP) and malondialdehyde (MDA) levels were also elevated. Endothelial function was impaired as reflected by reduced nitric oxide (NO) production and elevated serum asymmetric dimethylarginine (ADMA) level. All these changes were significant as compared to the control group (P<0.05), suggesting that short-term of triglyceride elevation could potently initiate atherosclerosis. With 2 weeks of fenofibrate therapy, in comparison to un-treated group, triglyceride level was significantly reduced in parallel with HDL-C and ApoA1 elevation. Inflammation and oxidation were also profoundly ameliorated as reflected by CRP and MDA reduction. Notably, NO production was enhanced in company with serum ADMA level decrease. Overall, these improvements manifested in a dose-dependent manner, which was supported by multivariate regression analysis showing that after adjusted to other variables, the dose of fenofibrate therapy remained significantly associated with NO production and serum ADMA level, with OR of 1.042 (high-dose versus low-dose, 95% CI 1.028-1.055, P<0.05). Fenofibrate therapy not only could reduce triglyceride level but also confer pleiotropic effects in terms of endothelium-protection and amelioration of inflammation and oxidation in a dose-dependent manner.

Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy.

PubMed

Singh, Anurag K; Lockett, Mary Ann; Bradley, Jeffrey D

2003-02-01

To evaluate the incidence and clinical/dosimetric predictors of acute and late Radiation Therapy Oncology Group Grade 3-5 esophageal toxicity in patients with non-small-cell lung cancer (NSCLC) treated with definitive three-dimensional conformal radiotherapy (3D-CRT). We retrospectively reviewed the charts of 207 consecutive patients with NSCLC who were treated with high-dose, definitive 3D-CRT between March 1991 and December 1998. This population consisted of 107 men and 100 women. The median age was 67 years (range 31-90). The following patient and treatment parameters were studied: age, gender, race, performance status, sequential chemotherapy, concurrent chemotherapy, presence of subcarinal nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy. All doses are reported without heterogeneity corrections. The median prescription dose to the isocenter in this population was 70 Gy (range 60-74) delivered in 2-Gy daily fractions. All patients were treated once daily. Acute and late esophageal toxicities were graded by Radiation Therapy Oncology Group criteria. Patient and clinical/dosimetric factors were coded and correlated with acute and late Grade 3-5 esophageal toxicity using univariate and multivariate regression analyses. Of 207 patients, 16 (8%) developed acute (10 patients) or late (13 patients) Grade 3-5 esophageal toxicity. Seven patients had both acute and late Grade 3-5 esophageal toxicity. One patient died (Grade 5 esophageal toxicity) of late esophageal perforation. Concurrent chemotherapy, maximal point dose to the esophagus >58 Gy, and a mean dose to the entire esophagus >34 Gy were significantly associated with a risk of Grade 3-5 esophageal toxicity on univariate analysis. Concurrent chemotherapy and maximal point dose to the esophagus >58 Gy retained significance on multivariate analysis. Of 207 patients, 53 (26%) received concurrent chemotherapy. Fourteen (88%) of the 16 patients who developed Grade 3-5 esophageal toxicity had received concurrent chemotherapy (p = 0.0001, Pearson's chi-square test). No case of Grade 3-5 esophageal toxicity occurred in patients who received a maximal point dose to the esophagus of <58 Gy (p = 0.0001, Fisher's exact test, two-tail). Only 2 patients developed Grade 3-5 esophageal toxicity in the absence of concurrent chemotherapy; both received a maximal esophageal point dose >69 Gy. All assessable patients who developed Grade 3-5 esophageal toxicity had a mean dose to the entire esophagus >34 Gy (p = 0.0351, Pearson's chi-square test). However, the mean dose was not predictive on multivariate analysis. Concurrent chemotherapy and the maximal esophageal point dose were significantly associated with a risk of Grade 3-5 esophageal toxicity in patients with NSCLC treated with high-dose 3D-CRT. In patients who received concurrent chemotherapy, the threshold maximal esophageal point dose for Grade 3-5 esophageal toxicity was 58 Gy. An insufficient number of patients developed Grade 3-5 esophageal toxicity in the absence of chemotherapy to allow a valid statistical analysis of the relationship between the maximal esophageal point dose and esophagitis.

An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma.

PubMed

von Tresckow, Bastian; Morschhauser, Franck; Ribrag, Vincent; Topp, Max S; Chien, Caly; Seetharam, Shobha; Aquino, Regina; Kotoulek, Sonja; de Boer, Carla J; Engert, Andreas

2015-04-15

This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL). Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics. Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19-75) years, median number of prior systemic therapies 6 (range, 3-14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5-8 months). Median number of cycles: 4 (range, 1-16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing). JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL. ©2015 American Association for Cancer Research.

Efficacy and safety of combination therapy of high-dose losartan and hydrochlorothiazide in patients with hypertension.

PubMed

Shiga, Yuhei; Miura, Shin-Ichiro; Norimatsu, Kenji; Hitaka, Yuka; Nagata, Itsuki; Koyoshi, Rie; Morii, Joji; Kuwano, Takashi; Uehara, Yoshinari; Inoue, Asao; Shirotani, Tetsuro; Fujisawa, Kazuaki; Matsunaga, Eiyu; Saku, Keijiro

2015-12-01

We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day). Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis. The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects. Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients. © The Author(s) 2014.

SU-E-J-42: Motion Adaptive Image Filter for Low Dose X-Ray Fluoroscopy in the Real-Time Tumor-Tracking Radiotherapy System.

PubMed

Miyamoto, N; Ishikawa, M; Sutherland, K; Suzuki, R; Matsuura, T; Takao, S; Toramatsu, C; Nihongi, H; Shimizu, S; Onimaru, R; Umegaki, K; Shirato, H

2012-06-01

In the real-time tumor-tracking radiotherapy system, fiducial markers are detected by X-ray fluoroscopy. The fluoroscopic parameters should be optimized as low as possible in order to reduce unnecessary imaging dose. However, the fiducial markers could not be recognized due to effect of statistical noise in low dose imaging. Image processing is envisioned to be a solution to improve image quality and to maintain tracking accuracy. In this study, a recursive image filter adapted to target motion is proposed. A fluoroscopy system was used for the experiment. A spherical gold marker was used as a fiducial marker. About 450 fluoroscopic images of the marker were recorded. In order to mimic respiratory motion of the marker, the images were shifted sequentially. The tube voltage, current and exposure duration were fixed at 65 kV, 50 mA and 2.5 msec as low dose imaging condition, respectively. The tube current was 100 mA as high dose imaging. A pattern recognition score (PRS) ranging from 0 to 100 and image registration error were investigated by performing template pattern matching to each sequential image. The results with and without image processing were compared. In low dose imaging, theimage registration error and the PRS without the image processing were 2.15±1.21 pixel and 46.67±6.40, respectively. Those with the image processing were 1.48±0.82 pixel and 67.80±4.51, respectively. There was nosignificant difference in the image registration error and the PRS between the results of low dose imaging with the image processing and that of high dose imaging without the image processing. The results showed that the recursive filter was effective in order to maintain marker tracking stability and accuracy in low dose fluoroscopy. © 2012 American Association of Physicists in Medicine.

Ceruletide intravenous dose-response study by a simplified scintigraphic technique

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

Krishnamurthy, G.T.; Turner, F.E.; Mangham, D.

1985-04-01

The intravenous dose response of a ceruletide diethylamine (ceruletide) was established by a simplified scintigraphic technique where multiple graded doses were given sequentially on a single occasion. The gallbladder volume was presented nongeometrically by /sup 99m/Tc-IDA counts. The mean latent period, ejection period, and ejection rate were similar for all four groups of subjects given 1-20 ng/kg of ceruletide. The ejection fractions were similar to the values when the identical dose of ceruletide was administered sequentially either before or after another dose. A dose of 5 ng/kg produced the most physiologic type of emptying. Intravenous doses of 10 ng/kg andmore » larger caused adverse reactions in 42% of the total doses in the form of abdominal pain, nausea, systolic and diastolic hypotension, or bradycardia. It is concluded that the dose response of a cholecystokininlike agent (ceruletide) can be established reliably by a scintigraphic technique where multiple graded doses are given on a single occasion.« less

Peptides and receptors in image-guided therapy: theranostics for neuroendocrine neoplasms.

PubMed

Baum, Richard P; Kulkarni, Harshad R; Carreras, Cecilia

2012-05-01

Theranostics of neuroendocrine neoplasms (NENs) based on molecular imaging using receptor positron emission tomography/computed tomography (PET/CT) with (68)Ga-labeled somatostatin (SMS) analogs and molecular radiotherapy applying peptide receptor radionuclide therapy (PRRNT) with (90)Y- and/or (177)Lu-labeled peptides has paved the way to personalized medicine. SMS receptor PET/CT enables very accurate detection of NENs and their metastases with high diagnostic sensitivity and specificity and provides quantitative, reproducible data that can be used for selecting patients for PRRNT and evaluation of therapy response. Among other advantages are the fast imaging protocol (total study time, 60-90 minutes), low radiation burden (10-12 mSv), flexibility in daily use, and lower cost than octreotide scintigraphy. As we move toward personalized medicine, the diagnostic information obtained from PET/CT must be improved, that is, by fast routine quantification of lesions. PRRNT is highly effective for the treatment of NENs, even in very advanced cases, and lends a benefit in overall survival of several years. In addition, significant improvement in clinical symptoms and excellent palliation can be achieved. In patients with progressive NENs, fractionated, personalized PRRNT with lower doses of radioactivity given over a longer period (Bad Berka Concept) results in good therapeutic responses. By this concept, severe hematologic and/or renal toxicity can be reduced or completely avoided, and the quality of life can be improved. Sequential (DUO-PRRNT) and concurrent (TANDEM-PRRNT) administrations of radiopeptides are more effective in progressive NEN than using either radionuclide alone. PRRNT should only be performed at specialized centers, as NEN patients need highly individualized interdisciplinary treatment and long-term care. Copyright © 2012 Elsevier Inc. All rights reserved.

Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release.

PubMed

Halpern, Bruno; Mancini, Marcio C

2017-01-01

Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval. Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations. Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.

Defining the "Hostile Pelvis" for Intensity Modulated Radiation Therapy: The Impact of Anatomic Variations in Pelvic Dimensions on Dose Delivered to Target Volumes and Organs at Risk in Patients With High-Risk Prostate Cancer Treated With Whole Pelvic Radiation Therapy.

PubMed

Yirmibeşoğlu Erkal, Eda; Karabey, Sinan; Karabey, Ayşegül; Hayran, Mutlu; Erkal, Haldun Şükrü

2015-07-15

The aim of this study was to evaluate the impact of variations in pelvic dimensions on the dose delivered to the target volumes and the organs at risk (OARs) in patients with high-risk prostate cancer (PCa) to be treated with whole pelvic radiation therapy (WPRT) in an attempt to define the hostile pelvis in terms of intensity modulated radiation therapy (IMRT). In 45 men with high-risk PCa to be treated with WPRT, the target volumes and the OARs were delineated, the dose constraints for the OARs were defined, and treatment plans were generated according to the Radiation Therapy Oncology Group 0924 protocol. Six dimensions to reflect the depth, width, and height of the bony pelvis were measured, and 2 indexes were calculated from the planning computed tomographic scans. The minimum dose (Dmin), maximum dose (Dmax), and mean dose (Dmean) for the target volumes and OARs and the partial volumes of each of these structures receiving a specified dose (VD) were calculated from the dose-volume histograms (DVHs). The data from the DVHs were correlated with the pelvic dimensions and indexes. According to an overall hostility score (OHS) calculation, 25 patients were grouped as having a hospitable pelvis and 20 as having a hostile pelvis. Regarding the OHS grouping, the DVHs for the bladder, bowel bag, left femoral head, and right femoral head differed in favor of the hospitable pelvis group, and the DVHs for the rectum differed for a range of lower doses in favor of the hospitable pelvis group. Pelvimetry might be used as a guide to define the challenging anatomy or the hostile pelvis in terms of treatment planning for IMRT in patients with high-risk PCa to be treated with WPRT. Copyright © 2015 Elsevier Inc. All rights reserved.

[High-dosed gestagen therapy of the metastatic mammary carcinoma (author's transl)].

PubMed

Firusian, N; Becher, R

1981-12-01

Thirty patients with histologically proven metastatic mammary carcinoma were treated, after exhaustion of hormonal and cytostatic therapeutic means, with high-dosed medroxyprogesterone acetate (MPA) during a ten-day induction phase with 1000 mg MPAi.m. per day and then with 600 mg oral MPA per day. In eleven patients a complete or partial remission was achieved. The median period of remission comprised ten months. A positive relationship was found between the response to high-dosed MPA therapy and the length of free intervals. Side effects were tolerable.

Learning style and teaching method preferences of Saudi students of physical therapy

PubMed Central

Al Maghraby, Mohamed A.; Alshami, Ali M.

2013-01-01

Context: To the researchers’ knowledge, there are no published studies that have investigated the learning styles and preferred teaching methods of physical therapy students in Saudi Arabia. Aim: The study was conducted to determine the learning styles and preferred teaching methods of Saudi physical therapy students. Settings and Design: A cross-sectional study design. Materials and Methods: Fifty-three Saudis studying physical therapy (21 males and 32 females) participated in the study. The principal researcher gave an introductory lecture to explain the different learning styles and common teaching methods. Upon completion of the lecture, questionnaires were distributed, and were collected on completion. Statistical Analysis Used: Percentages were calculated for the learning styles and teaching methods. Pearson’s correlations were performed to investigate the relationship between them. Results: More than 45 (85%) of the students rated hands-on training as the most preferred teaching method. Approximately 30 (57%) students rated the following teaching methods as the most preferred methods: “Advanced organizers,” “demonstrations,” and “multimedia activities.” Although 31 (59%) students rated the concrete-sequential learning style the most preferred, these students demonstrated mixed styles on the other style dimensions: Abstract-sequential, abstract-random, and concrete-random. Conclusions: The predominant concrete-sequential learning style is consistent with the most preferred teaching method (hands-on training). The high percentage of physical therapy students whose responses were indicative of mixed learning styles suggests that they can accommodate multiple teaching methods. It is recommended that educators consider the diverse learning styles of the students and utilize a variety of teaching methods in order to promote an optimal learning environment for the students. PMID:24672278

A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials.

PubMed

Hall, David B; Meier, Ulrich; Diener, Hans-Cristoph

2005-06-01

The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.

Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer.

PubMed

Elias, A D; Ayash, L; Anderson, K C; Hunt, M; Wheeler, C; Schwartz, G; Tepler, I; Mazanet, R; Lynch, C; Pap, S

1992-06-01

High-dose therapy with autologous marrow support results in durable complete remissions in selected patients with relapsed lymphoma and leukemia who cannot be cured with conventional dose therapy. However, substantial morbidity and mortality result from the 3- to 6-week period of marrow aplasia until the reinfused marrow recovers adequate hematopoietic function. Hematopoietic growth factors, particularly used after chemotherapy, can increase the number of peripheral blood progenitor cells (PBPCs) present in systemic circulation. The reinfusion of PBPCs with marrow has recently been reported to reduce the time to recovery of adequate marrow function. This study was designed to determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF)-mobilized PBPCs alone (without marrow) would result in rapid and reliable hematopoietic reconstitution. Sixteen patients with metastatic breast cancer were treated with four cycles of doxorubicin, 5-fluorouracil, and methotrexate (AFM induction). Patients responding after the first two cycles were administered GM-CSF after the third and fourth cycles to recruit PBPCs for collection by two leukapheresis per cycle. These PBPCs were reinfused as the sole source of hematopoietic support after high doses of cyclophosphamide, thiotepa, and carboplatin. No marrow or hematopoietic cytokines were used after progenitor cell reinfusion. Granulocytes greater than or equal to 500/microL was observed on a median of day 14 (range, 8 to 57). Transfusion independence of platelets greater than or equal to 20,000/microL occurred on a median day of 12 (range, 8 to 134). However, three patients required the use of a reserve marrow for slow platelet engraftment. In retrospect, these patients were characterized by poor baseline bone marrow cellularity and poor platelet recovery after AFM induction therapy. When compared with 29 historical control patients who had received the same high-dose intensification chemotherapy using autologous marrow support, time to engraftment, antibiotic days, transfusion requirements, and lengths of hospital stay were all significantly improved for the patients receiving PBPCs. Thus, autologous PBPCs can be efficiently collected during mobilization by chemotherapy and GM-CSF and are an attractive alternative to marrow for hematopoietic support after high-dose therapy. The enhanced speed of recovery may reduce the morbidity, mortality, and cost of high-dose treatment. Furthermore, PBPC support may enhance the effectiveness of high-dose therapy by facilitating multiple courses of therapy.

Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy

PubMed Central

Richardson, Paul; Mitsiades, Constantine; Laubach, Jacob; Schlossman, Robert; Ghobrial, Irene; Hideshima, Teru; Munshi, Nikhil; Anderson, Kenneth

2010-01-01

Introduction: Multiple myeloma (MM) is a relatively common and incurable hematological malignancy. Currently, there is no single standard therapy, with choice of treatment dependent on individual patient factors. Lenalidomide is an immunomodulatory drug with potent antitumor, antiangiogenic, immunomodulatory, and proapoptotic activity in MM. Aims: To evaluate the evidence for the use of lenalidomide in its current indication in relapsed or refractory MM, and additionally its investigational use for the treatment of newly diagnosed MM. Evidence review: In patients with relapsed and refractory MM, adding lenalidomide to high-dose dexamethasone significantly improves response rates and time-to-progression, relative to high-dose dexamethasone alone. This translates into a significant extension of overall survival (with a median extension of 9.1 months in a pivotal phase III study). Outcome is independent of patient age, number of previous therapies, type of previous therapy (including thalidomide or autologous stem cell transplantation), renal impairment, and β2-microglobulin level. Evidence suggests that combining lenalidomide with low-dose dexamethasone improves outcomes in patients with newly diagnosed disease and is superior to lenalidomide combined with high-dose dexamethasone. Myelosuppression is the predominant toxicity observed, although some studies have shown high incidences of venous thromboembolism in the absence of prophylactic antithrombotic anticoagulation therapy. There is currently only limited evidence regarding the health economics of lenalidomide. Role in therapy: The encouraging results obtained with lenalidomide alone and in combination with dexamethasone in patients with relapsed or refractory MM have led to its adoption as a recommended therapy in patients who have received at least one prior treatment. Emerging evidence supports the ongoing investigation of lenalidomide in combination with low-dose dexamethasone, and in other combinations including bortezomib, for use both in relapsed, refractory, and newly diagnosed MM. PMID:20694078

L-Phenylalanine preloading reduces the (10)B(n, α)(7)Li dose to the normal brain by inhibiting the uptake of boronophenylalanine in boron neutron capture therapy for brain tumours.

PubMed

Watanabe, Tsubasa; Tanaka, Hiroki; Fukutani, Satoshi; Suzuki, Minoru; Hiraoka, Masahiro; Ono, Koji

2016-01-01

Boron neutron capture therapy (BNCT) is a cellular-level particle radiation therapy that combines the selective delivery of boron compounds to tumour tissue with neutron irradiation. Previously, high doses of one of the boron compounds used for BNCT, L-BPA, were found to reduce the boron-derived irradiation dose to the central nervous system. However, injection with a high dose of L-BPA is not feasible in clinical settings. We aimed to find an alternative method to improve the therapeutic efficacy of this therapy. We examined the effects of oral preloading with various analogues of L-BPA in a xenograft tumour model and found that high-dose L-phenylalanine reduced the accumulation of L-BPA in the normal brain relative to tumour tissue. As a result, the maximum irradiation dose in the normal brain was 19.2% lower in the L-phenylalanine group relative to the control group. This study provides a simple strategy to improve the therapeutic efficacy of conventional boron compounds for BNCT for brain tumours and the possibility to widen the indication of BNCT to various kinds of other tumours. Copyright © 2015. Published by Elsevier Ireland Ltd.

Photodynamic Therapy with 3-(1’-hexyloxyethyl) pyropheophorbide a (HPPH) for Cancer of the Oral Cavity

PubMed Central

Rigual, Nestor; Shafirstein, Gal; Cooper, Michele T.; Baumann, Heinz; Bellnier, David A.; Sunar, Ulas; Tracy, Erin C.; Rohrbach, Daniel J.; Wilding, Gregory; Tan, Wei; Sullivan, Maureen; Merzianu, Mihai; Henderson, Barbara W.

2013-01-01

Purpose The primary objective was to evaluate safety of 3-(1’-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction. Experimental Design Patients with histologically proven oral dysplasia, carcinoma in situ (CiS ) or early stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies employed an HPPH dose of 4 mg/m2 and light doses from 50 to 140 J/cm2. Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of signal transducer and activator of transcription 3 (STAT3) were assessed as potential indicators of PDT effective reaction. Results Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and CiS, and 82% for SCCs lesions at 140 J/cm2. The responses in the CiS/dysplasia cohort are not durable. The PDT induced STAT3 cross-links is significantly higher (P=0.0033) in SCC than in CiS/dysplasia for all light-doses. Conclusion HPPH-PDT is safe for the treatment of CiS/dysplasia and early stage cancer of the oral cavity. Early stage oral HNSCC appears to respond better to HPPH-PDT in comparison to premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT mediated photoreaction. PMID:24088736

Simultaneous Integrated Boost–Intensity Modulated Radiation Therapy With Concomitant Capecitabine and Mitomycin C for Locally Advanced Anal Carcinoma: A Phase 1 Study

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

Deenen, Maarten J.; Dewit, Luc; Boot, Henk

2013-04-01

Purpose: Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost–intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses. Methods and Materials: Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.8 Gy to the primary tumor and macroscopically involved lymph nodes and 33 fractions of 1.5 Gy electively to the bilateral iliac and inguinalmore » lymph node areas. Patients received a sequential radiation boost dose of 3 × 1.8 Gy on macroscopic residual tumor if this was still present in week 5 of treatment. Mitomycin C 10 mg/m{sup 2} (maximum 15 mg) was administered intravenously on day 1, and capecitabine was given orally in a dose-escalated fashion (500-825 mg/m{sup 2} b.i.d.) on irradiation days, until dose-limiting toxicity emerged in ≥2 of maximally 6 patients. An additional 8 patients were treated at the maximum tolerated dose (MTD). Results: A total of 18 patients were included. The MTD of capecitabine was determined to be 825 mg/m{sup 2} b.i.d. The predominant acute grade ≥3 toxicities included radiation dermatitis (50%), fatigue (22%), and pain (6%). Fifteen patients (83% [95%-CI: 66%-101%]) achieved a complete response, and 3 (17%) patients a partial response. With a median follow-up of 28 months, none of the complete responders, and 2 partial responders had relapsed. Conclusions: SIB-IMRT with concomitant single dose mitomycin C and capecitabine 825 mg/m{sup 2} b.i.d. on irradiation days resulted in an acceptable safety profile, and proved to be a tolerable and effective treatment regimen for locally advanced anal cancer.« less

The effect of budesonide/formoterol maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever use: an exploratory analysis of two randomised, controlled studies with comparisons to standard therapy

PubMed Central

2012-01-01

Background Divergent strategies have emerged for the management of severe asthma. One strategy utilises high and fixed doses of maintenance treatment, usually inhaled corticosteroid/long-acting β2-agonist (ICS/LABA), supplemented by a short-acting β2-agonist (SABA) as needed. Alternatively, budesonide/formoterol is used as both maintenance and reliever therapy. The latter is superior to fixed-dose treatment in reducing severe exacerbations while achieving similar or better asthma control in other regards. Exacerbations may be reduced by the use of budesonide/formoterol as reliever medication during periods of unstable asthma. We examined the risk of a severe exacerbation in the period after a single day with high reliever use. Methods Episodes of high reliever use were quantified and exacerbations occurring post-index day with these episodes were examined post hoc in two double-blind studies comparing the efficacy and safety of budesonide/formoterol maintenance and reliever therapy (Symbicort SMART™, Turbuhaler®) 160/4.5 μg twice daily plus as needed with similar or higher maintenance doses of ICS/LABA plus SABA or formoterol. Results Budesonide/formoterol maintenance and reliever therapy significantly reduced the risk of episodes of high reliever use (>6 inhalations/day) vs. all alternative ICS/LABA regimens. With conventional fixed-dose treatment the need for exacerbation treatment within 21 days ranged from 6.0–10.1% of days post-index for all regimens compared with 2.5–3.4% of days with budesonide/formoterol maintenance and reliever therapy. Conclusions Budesonide/formoterol maintenance and reliever therapy reduces the incidence of high reliever episodes and the exacerbation burden immediately following these episodes vs. alternative ICS/LABA plus SABA regimens at up to double the maintenance dose of ICS. Trial registration These studies do not have registration numbers as they were conducted before clinical trial registration was required PMID:22816878

Relevant tumor sink effect in prostate cancer patients receiving 177Lu-PSMA-617 radioligand therapy.

PubMed

Filss, Christian; Heinzel, Alexander; Miiller, Berthold; Vogg, Andreas T J; Langen, Karl-Josef; Mottaghy, Felix M

2018-02-01

In metastatic prostate cancer patients PSMA targeting radioligands have gained significant impact as theranostic probes. In this study a correlation between total tumor volume (TTV) and measured kidney dose as well as salivary glands (SG) uptake in 177 Lu-PSMA-617 therapy was evaluated. Eleven consecutive prostate cancer patients receiving a first cylcle of 177 Lu-PSMA-617 (administered activity of approximately 6GBq) were included. The 68 Ga-PSMA-11 PET/CT scan previous to therapy was used to determine TTV and SG uptake (glandulae submandibularis) employing PMOD version 3.403 with different 68 Ga-PSMA-11 thresholds based on the standardized uptake value (SUV).The kidney dose was estimated with the software ULMDOS using planar whole-body scintigrams. Kidney dose and SG uptake was inversely correlated to TTV, indicating high kidney dose and high SG uptake in case of low tumor load and low kidney dose and low SG uptake in case of high tumor load. Our data support the hypothesis that in 177 Lu-PSMA-617 therapy an individualized treatment activity based on total tumor volume could be beneficiary. Schattauer GmbH.

Gastrointestinal Dose-Histogram Effects in the Context of Dose-Volume–Constrained Prostate Radiation Therapy: Analysis of Data From the RADAR Prostate Radiation Therapy Trial

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

Ebert, Martin A., E-mail: Martin.Ebert@health.wa.gov.au; School of Physics, University of Western Australia, Perth, Western Australia; Foo, Kerwyn

Purpose: To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint. Methods and Materials: Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with amore » comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose. Results: Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding. Conclusions: Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for informing future radiation therapy planning.« less

Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer.

PubMed

Yoda, Satoshi; Lin, Jessica J; Lawrence, Michael S; Burke, Benjamin J; Friboulet, Luc; Langenbucher, Adam; Dardaei, Leila; Prutisto-Chang, Kylie; Dagogo-Jack, Ibiayi; Timofeevski, Sergei; Hubbeling, Harper; Gainor, Justin F; Ferris, Lorin A; Riley, Amanda K; Kattermann, Krystina E; Timonina, Daria; Heist, Rebecca S; Iafrate, A John; Benes, Cyril H; Lennerz, Jochen K; Mino-Kenudson, Mari; Engelman, Jeffrey A; Johnson, Ted W; Hata, Aaron N; Shaw, Alice T

2018-06-01

The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, N -ethyl- N -nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4-ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies. Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714-29. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663 . ©2018 American Association for Cancer Research.

[Highly quality-controlled radiation therapy].

PubMed

Shirato, Hiroki

2005-04-01

Advanced radiation therapy for intracranial disease has focused on set-up accuracy for the past 15 years. However, quality control in the prescribed dose is actually as important as the tumor set-up in radiation therapy. Because of the complexity of the three-dimensional radiation treatment planning system in recent years, the highly quality-controlled prescription of the dose has now been reappraised as the mainstream to improve the treatment outcome of radiation therapy for intracranial disease. The Japanese Committee for Quality Control of Radiation Therapy has developed fundamental requirements such as a QC committee in each hospital, a medical physicist, dosimetrists (QC members), and an external audit.

[Prolonged clinical pattern of brain death in patients under barbiturate sedation: usefulness of transcranial Doppler].

PubMed

Segura, T; Jiménez, P; Jerez, P; García, F; Córcoles, V

2002-04-01

Throughout the world, is fully accepted that a person is dead when brain death exists. In most situations, neurological criteria permit the diagnosis of brain death, but in some instances, as when high-dose barbiturate therapy has been used, confirmatory testing are required by law. We report the case of a 17 year-old women who suffered high-dose barbiturate therapy due to post traumatic intracranial hypertension. During the period of the barbiturate infusion and until six days after the suppression of this therapy, neurological exploration and EEG findings seem to confirm brain death, while transcranial Doppler (TCD) study remained normal. TCD is a fast, simple and accurate confirmatory testing in the determination of brain death and its findings are not affected by high-dose barbiturate therapy. We think that TCD must be present in all hospitals where mechanical ventilation and support of patients are carried out.

Fecal hemoglobin excretion in elderly patients with atrial fibrillation: combined aspirin and low-dose warfarin vs conventional warfarin therapy.

PubMed

Blackshear, J L; Baker, V S; Holland, A; Litin, S C; Ahlquist, D A; Hart, R G; Ellefson, R; Koehler, J

1996-03-25

Antithrombotic prophylaxis using combined aspirin and low-dose warfarin is under evaluation in several clinical trials. However, therapy may result in increased gastrointestinal blood loss and clinical bleeding vs conventional single-agent antithrombotic therapy. To assess differences in gastrointestinal blood loss, we measured quantitative fecal hemoglobin equivalents (HemoQuant, Mayo Medical Laboratory, Rochester, Minn) in 117 patients, mean age 71 years, 1 month after initiation of assigned therapy in the Stroke Prevention in Atrial Fibrillation III Study. Sixty-three of these patients who had characteristics for high risk of stroke were randomly assigned to conventional adjusted-dose warfarin therapy (international normalized ratio, 2.0 to 3.0) or low-dose combined therapy (warfarin [international normalization ratio,<1.5] plus 325 mg/d of enteric-coated aspirin). The remaining 54 patients with low risk of stroke received 325 mg/d of enteric-coated aspirin. Among the 63 at high risk of stroke, abnormal values (>2mg of hemoglobin per gram of stool) were detected in 11% and values greater than 4 mg of hemoglobin per gram of stool were found in 8%. Mean ( +/- SD) values were more for those randomly assigned to receive combined therapy (1.7 +/- 3.3 mg of hemoglobin per gram of stool vs adjusted-dose warfarin therapy, 1.0 +/- 1.9 mg/g; P=.003). The 54 nonrandomized patients with low risk of stroke receiving aspirin alone had a mean (+/- SD) HemoQuant value of 0.8 +/- 0.7mg of hemoglobin per gram of stool 1 month after entry in the study. Abnormal levels of fecal hemoglobin excretion were common in elderly patients with high risk of atrial fibrillation 1 month after randomization to prophylactic antithrombotic therapy. Combined warfarin and aspirin therapy was associated with greater fecal hemoglobin excretion than standard warfarin therapy, suggesting the potential for increased gastrointestinal hemorrhage.

A pilot study: sequential gemcitabine/cisplatin and icotinib as induction therapy for stage IIB to IIIA non-small-cell lung adenocarcinoma

PubMed Central

2013-01-01

Background A phase II clinical trial previously evaluated the sequential administration of erlotinib after chemotherapy for advanced non-small-cell lung cancer (NSCLC). This current pilot study assessed the feasibility of sequential induction therapy in patients with stage IIB to IIIA NSCLC adenocarcinoma. Methods Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 on day 1, followed by oral icotinib (125 mg, three times a day) on days 15 to 28. A repeatcomputed tomography(CT) scan evaluated the response to the induction treatment after two 4-week cycles and eligible patients underwent surgical resection. The primary objective was to assess the objective response rate (ORR), while EGFR and KRAS mutations and mRNA and protein expression levels of ERCC1 and RRM1 were analyzed in tumor tissues and blood samples. Results Eleven patients, most with stage IIIA disease, completed preoperative treatment. Five patients achieved partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (ORR=45%) and six patients underwent resection. Common toxicities included neutropenia, alanine transaminase (ALT) elevation, fatigue, dry skin, rash, nausea, alopecia and anorexia. No serious complications were recorded perioperatively. Three patients had exon 19 deletions and those with EGFR mutations were more likely to achieve a clinical response (P= 0.083). Furthermore, most cases who achieved a clinical response had low levels of ERCC1 expression and high levels of RRM1. Conclusions Two cycles of sequentially administered gemcitabine/cisplatin with icotinib as an induction treatment is a feasible and efficacious approach for stage IIB to IIIA NSCLC adenocarcinoma, which provides evidence for the further investigation of these chemotherapeutic and molecularly targeted therapies. PMID:23621919

The modification of high-dose therapy shortens the duration of neutropaenia by delay of leucocyte nadir.

PubMed

Kiefer, T; Krüger, W H; Schüler, F; Lotze, C; Hirt, C; Dölken, G

2006-06-01

Infections during neutropaenia contribute still significantly to mortality and morbidity after high-dose therapy and autologous stem cell transplantation. Further acceleration of haemopoietic recovery seems impossible for biological reasons. Another approach to shorten neutropaenia could be to remove drugs from high-dose therapy protocols with strong contribution to immunosuppression and neutropaenia and unproven antineoplastic activity. In this retrospective matched-pair analysis, conventional busulphan/cyclophosphamide (Bu/Cy) high-dose therapy was compared to single-agent busulphan conditioning before autologous stem cell transplantation. This modification led to a significant shorter neutropaenic interval by protraction of cell decrease and to a significant mitigation of neutropaenia. After single-agent busulphan conditioning, leucocytes dropped below 1/nl at median 1.5 days later when compared to the patients from the busulphanBu/Cy control group (P=0.001). In a significant percentage of patients (n=6, 60%) leucocytes did not fall below 0.5 cells/nl at any time. In contrast, all patients from the Bu/Cy control group experienced deep neutropaenia (P=0.004). Thrombocytopaenia and requirement for transfusions of platelets or red cells were not influenced. Antineoplastic activity seemed to be preserved as determined by survival analysis. In conclusion, modification of high-dose regimen with the intention to shorten neutropaenia with preserved antitumour activity could be an approach to reduce infection-related morbidity and mortality and to consider economic necessities.

In vitro pharmacodynamics of human simulated exposures of ceftaroline and daptomycin against MRSA, hVISA, and VISA with and without prior vancomycin exposure.

PubMed

Bhalodi, Amira A; Hagihara, Mao; Nicolau, David P; Kuti, Joseph L

2014-01-01

The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-h in vitro pharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediate S. aureus (hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10 CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10 CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10 CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10 CFU was largest for sequential therapy with vancomycin followed by ceftaroline (-5.22 ± 1.2, P = 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (-3.60 ± 0.6, P = 0.037 versus daptomycin), compared with daptomycin (-2.24 ± 1.0), vancomycin (-1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (-1.32 ± 1.0, P > 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

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

Berrington de Gonzalez, Amy, E-mail: berringtona@mail.nih.gov; Gilbert, Ethel; Curtis, Rochelle

Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studiesmore » of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.« less

A phase I trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia

PubMed Central

How, Jonathan; Minden, Mark D.; Brian, Leber; Chen, Eric X.; Brandwein, Joseph; Schuh, Andre C.; Schimmer, Aaron D.; Gupta, Vikas; Webster, Sheila; Degelder, Tammy; Haines, Patricia; Stayner, Lee-Anne; McGill, Shauna; Wang, Lisa; Piekarz, Richard; Wong, Tracy; Siu, Lillian L.; Espinoza-Delgado, Igor; Holleran, Julianne L.; Egorin, Merrill J.; Yee, Karen W. L.

2015-01-01

This phase I trial evaluated two schedules of escalating vorinostat in combination with decitabine every 28 days: (i) sequential or (ii) concurrent. There were three dose-limiting toxicities: grade 3 fatigue and generalized muscle weakness on the sequential schedule (n = 1) and grade 3 fatigue on the concurrent schedule (n = 2). The maximum tolerated dose was not reached on both planned schedules. The overall response rate (ORR) was 23% (three complete response [CR], two CR with incomplete incomplete blood count recovery [CRi], one partial response [PR] and two morphological leukemic free state [MLFS]). The ORR for all and previously untreated patients in the sequential arm was 13% (one CRi; one MLFS) and 0% compared to 30% (three CR; one CRi; one PR; one MLFS) and 36% in the concurrent arm (p = 0.26 for both), respectively. Decitabine plus vorinostat was safe and has clinical activity in patients with previously untreated acute myeloid leukemia. Responses appear higher with the concurrent dose schedule. Cumulative toxicities may limit long-term usage on the current dose/schedules. PMID:25682963

Acute Toxicity and Efficacy of Current Medical Countermeasures against VM in Guinea Pigs: A Comparison to VX and VR

DTIC Science & Technology

2013-05-01

and diazepam with and without pretreatment with pyridostigmine bromide . The 24 hr median lethal dose (MLD) of VM was determined using a sequential... pyridostigmine bromide . The 24 hr median lethal dose (MLD) of VM was determined using a sequential stage approach. The efficacy of medical...with and without pyridostigmine bromide (PB) pretreatment against lethal intoxication with VM, VR or VX. Methods Animals: Adult male Hartley

Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials

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

Ramroth, Johanna; Cutter, David J.; Darby, Sarah C.

Purpose: The optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy. Methods and Materials: Eligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled. Results: 3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, highermore » versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2). Conclusions: In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no upper dose level was found above which there was no further benefit. These findings support the consideration of further radiation therapy dose escalation trials, making use of modern treatment methods to reduce toxicity.« less

Image Quality of 3rd Generation Spiral Cranial Dual-Source CT in Combination with an Advanced Model Iterative Reconstruction Technique: A Prospective Intra-Individual Comparison Study to Standard Sequential Cranial CT Using Identical Radiation Dose

PubMed Central

Wenz, Holger; Maros, Máté E.; Meyer, Mathias; Förster, Alex; Haubenreisser, Holger; Kurth, Stefan; Schoenberg, Stefan O.; Flohr, Thomas; Leidecker, Christianne; Groden, Christoph; Scharf, Johann; Henzler, Thomas

2015-01-01

Objectives To prospectively intra-individually compare image quality of a 3rd generation Dual-Source-CT (DSCT) spiral cranial CT (cCT) to a sequential 4-slice Multi-Slice-CT (MSCT) while maintaining identical intra-individual radiation dose levels. Methods 35 patients, who had a non-contrast enhanced sequential cCT examination on a 4-slice MDCT within the past 12 months, underwent a spiral cCT scan on a 3rd generation DSCT. CTDIvol identical to initial 4-slice MDCT was applied. Data was reconstructed using filtered backward projection (FBP) and 3rd-generation iterative reconstruction (IR) algorithm at 5 different IR strength levels. Two neuroradiologists independently evaluated subjective image quality using a 4-point Likert-scale and objective image quality was assessed in white matter and nucleus caudatus with signal-to-noise ratios (SNR) being subsequently calculated. Results Subjective image quality of all spiral cCT datasets was rated significantly higher compared to the 4-slice MDCT sequential acquisitions (p<0.05). Mean SNR was significantly higher in all spiral compared to sequential cCT datasets with mean SNR improvement of 61.65% (p*Bonferroni0.05<0.0024). Subjective image quality improved with increasing IR levels. Conclusion Combination of 3rd-generation DSCT spiral cCT with an advanced model IR technique significantly improves subjective and objective image quality compared to a standard sequential cCT acquisition acquired at identical dose levels. PMID:26288186

Image Quality of 3rd Generation Spiral Cranial Dual-Source CT in Combination with an Advanced Model Iterative Reconstruction Technique: A Prospective Intra-Individual Comparison Study to Standard Sequential Cranial CT Using Identical Radiation Dose.

PubMed

Wenz, Holger; Maros, Máté E; Meyer, Mathias; Förster, Alex; Haubenreisser, Holger; Kurth, Stefan; Schoenberg, Stefan O; Flohr, Thomas; Leidecker, Christianne; Groden, Christoph; Scharf, Johann; Henzler, Thomas

2015-01-01

To prospectively intra-individually compare image quality of a 3rd generation Dual-Source-CT (DSCT) spiral cranial CT (cCT) to a sequential 4-slice Multi-Slice-CT (MSCT) while maintaining identical intra-individual radiation dose levels. 35 patients, who had a non-contrast enhanced sequential cCT examination on a 4-slice MDCT within the past 12 months, underwent a spiral cCT scan on a 3rd generation DSCT. CTDIvol identical to initial 4-slice MDCT was applied. Data was reconstructed using filtered backward projection (FBP) and 3rd-generation iterative reconstruction (IR) algorithm at 5 different IR strength levels. Two neuroradiologists independently evaluated subjective image quality using a 4-point Likert-scale and objective image quality was assessed in white matter and nucleus caudatus with signal-to-noise ratios (SNR) being subsequently calculated. Subjective image quality of all spiral cCT datasets was rated significantly higher compared to the 4-slice MDCT sequential acquisitions (p<0.05). Mean SNR was significantly higher in all spiral compared to sequential cCT datasets with mean SNR improvement of 61.65% (p*Bonferroni0.05<0.0024). Subjective image quality improved with increasing IR levels. Combination of 3rd-generation DSCT spiral cCT with an advanced model IR technique significantly improves subjective and objective image quality compared to a standard sequential cCT acquisition acquired at identical dose levels.

Optimal medication dosing from suboptimal clinical examples: a deep reinforcement learning approach.

PubMed

Nemati, Shamim; Ghassemi, Mohammad M; Clifford, Gari D

2016-08-01

Misdosing medications with sensitive therapeutic windows, such as heparin, can place patients at unnecessary risk, increase length of hospital stay, and lead to wasted hospital resources. In this work, we present a clinician-in-the-loop sequential decision making framework, which provides an individualized dosing policy adapted to each patient's evolving clinical phenotype. We employed retrospective data from the publicly available MIMIC II intensive care unit database, and developed a deep reinforcement learning algorithm that learns an optimal heparin dosing policy from sample dosing trails and their associated outcomes in large electronic medical records. Using separate training and testing datasets, our model was observed to be effective in proposing heparin doses that resulted in better expected outcomes than the clinical guidelines. Our results demonstrate that a sequential modeling approach, learned from retrospective data, could potentially be used at the bedside to derive individualized patient dosing policies.

Low dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases.

PubMed

Sherer, Yaniv; Kuechler, Sabine; Jose Scali, Juan; Rovensky, Josef; Levy, Yair; Zandman-Goddard, Gisele; Shoenfeld, Yehuda

2008-01-01

Systemic lupus erythematosus is an autoimmune disease with diverse clinical manifestations that cannot always be regulated by steroids and immunosuppressive therapy. Intravenous immunoglobulin is an optional immunomodulatory agent for the treatment of SLE, but the appropriate indications for its use, duration of therapy and recommended dosage are yet to be established. In SLE patients, most publications report the utilization of a high dose (2 g/kg body weight) protocol. To investigate whether lower doses of IVIg are beneficial for SLE patients. We retrospectively analyzed the medical records of 62 patients who received low dose IVIg (approximately 0.5 g/kg body weight). The treatment was associated with clinical improvement in many specific disease manifestations, along with a continuous decrease in SLEDAI scores (SLE Disease Activity Index). However, thrombocytopenia, alopecia and vasculitis did not improve following IVIg therapy. Low dose IVIg is a possible therapeutic option in SLE and is associated with lower cost than the high dose regimen and possibly fewer adverse effects.

Cost-utility and budget impact analysis of drug treatments in pulmonary arterial hypertension associated with congenital heart diseases in Thailand.

PubMed

Thongsri, Watsamon; Bussabawalai, Thanaporn; Leelahavarong, Pattara; Wanitkun, Suthep; Durongpisitkul, Kritvikrom; Chaikledkaew, Usa; Teerawattananon, Yot

2016-08-01

This study aims to compare the lifetime costs and health outcomes of both first-line and sequential combination treatments with standard treatment for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) (PAH-CHD) patients. A cost-utility analysis was performed using a Markov model based on a societal perspective. One-way and probabilistic sensitivity analyses were performed to investigate the effect of parameter uncertainty. As first-line treatments, both beraprost (incremental cost-effectiveness ratio (ICER) = 192,752 and 201,308 Thai baht (THB) per quality-adjusted life year (QALY) gained) and sildenafil (ICER = 249,770 and 226,802 THB per QALY gained) seemed cost-effective for PAH-CHD patients aged ≤30 years in functional classes II and III, respectively, while no treatment was cost-effective for the sequential combination therapy. Sildenafil should be included in the National Drug List of Essential Medicines as the first-line treatment for PAH-CHD, and its price per dose should be negotiated to be reduced by 43-57%.

Differential Effects of High Dose Magnetic Seizure Therapy (MST) and Electroconvulsive Shock (ECS) on Cognitive Function

PubMed Central

Spellman, Timothy; McClintock, Shawn M.; Terrace, Herbert; Luber, Bruce; Husain, Mustafa M.; Lisanby, Sarah H.

2008-01-01

Background Magnetic seizure therapy (MST) is under investigation as an alternative form of convulsive therapy that induces more focal seizures and spares cortical regions involved in memory. Using a newly expanded version of the Columbia University Primate Cognitive Profile, we compared the cognitive effects of high-dose MST delivered at 100 Hz (6X seizure threshold) with electroconvulsive shock (ECS) delivered at 2.5X seizure threshold. Methods Daily high-dose MST, ECS, and Sham (anesthesia-only) were administered for 4 weeks each in a within-subject cross-over design. Rhesus macaques (n = 3) were trained on five cognitive tasks assessing automatic memory, anterograde learning and memory, combined anterograde and retrograde simultaneous chaining, and spatial and serial working memory. Acutely following each intervention, monkeys were tested on the cognitive battery twice daily, separated by a 3-hour retention interval. Results Subjects were slower to complete criterion tasks (p’s<0.0001) following ECS, compared to sham and high-dose MST. Moreover, time to task-completion following high-dose MST did not differ from sham. Out of 6 measures of accuracy, treatment effects were found in 4; in all of these, ECS, but not MST, fared worse than Sham. On all accuracy and time to completion measurements, subjects performed as well as following high-dose MST as did subjects from a previous study on moderate-dose MST. Conclusion These findings provide evidence that high-dose MST results in benign acute cognitive side-effect profile relative to ECS, and are in line with our previous studies. PMID:18262171

Comparison of sequential intravenous/oral ciprofloxacin plus metronidazole with intravenous ceftriaxone plus metronidazole for treatment of complicated intra-abdominal infections.

PubMed

Wacha, Hannes; Warren, Brian; Bassaris, Harry; Nikolaidis, Paul

2006-08-01

Intra-abdominal infections are a substantial clinical problem and an important cause of morbidity and death in the hospital. Optimal treatment requires both source control and antibiotic therapy. Sequential intravenous (IV) to oral therapy may improve patient convenience and reduce total health care costs. In this randomized, double-blind trial, the efficacy of sequential IV-to-oral ciprofloxacin plus metronidazole was compared with ceftriaxone plus metronidazole in adult patients with complicated intra-abdominal infections. The trial enrolled 531 patients, who began with IV therapy. Patients who improved clinically were switched to oral therapy on day three or later. The clinical and bacteriological responses four to six weeks after the end of therapy and the safety of the two regimens were assessed. To maintain blinding, the patients received placebo IV in the ciprofloxacin group or placebo orally in the ceftriaxone group. A total of 475 patients (235 ciprofloxacin plus metronidazole, 240 ceftriaxone plus metronidazole) were valid for evaluation of efficacy. All patients were included in the safety analysis. Of the patients valid for efficacy, 78% of the ciprofloxacin plus metronidazole group and 81% of the ceftriaxone plus metronidazole group were eligible for a switch to oral therapy. The clinical success rates were 98.9% and 96.9%, respectively, which were statistically equivalent. The clinical success rates for all patients, including those on continuous IV therapy, were 90.6% and 87.9%. Source control was achieved in more than 90% of the patients. The bacteriological eradication rates were similar in the two groups. Bacterial complications (e.g., surgical site infections, abscesses) were encountered more often in the ceftriaxone plus metronidazole group. Sequential ciprofloxacin plus metronidazole IV-to-oral therapy was statistically equivalent to ceftriaxone plus metronidazole. The switch to oral therapy with ciprofloxacin plus metronidazole was as effective and safe as continued IV therapy in patients able to tolerate enteral feeding.

High phenobarbital clearance during continuous renal replacement therapy: a case report and pharmacokinetic analysis.

PubMed

Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

2014-08-01

Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring.A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure.Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus.The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed.Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring.

High Phenobarbital Clearance During Continuous Renal Replacement Therapy

PubMed Central

Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

2014-01-01

Abstract Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring. A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure. Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus. The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed. Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring. PMID:25101986

Is it necessary to plan with safety margins for actively scanned proton therapy?

NASA Astrophysics Data System (ADS)

Albertini, F.; Hug, E. B.; Lomax, A. J.

2011-07-01

In radiation therapy, a plan is robust if the calculated and the delivered dose are in agreement, even in the case of different uncertainties. The current practice is to use safety margins, expanding the clinical target volume sufficiently enough to account for treatment uncertainties. This, however, might not be ideal for proton therapy and in particular when using intensity modulated proton therapy (IMPT) plans as degradation in the dose conformity could also be found in the middle of the target resulting from misalignments of highly in-field dose gradients. Single field uniform dose (SFUD) and IMPT plans have been calculated for different anatomical sites and the need for margins has been assessed by analyzing plan robustness to set-up and range uncertainties. We found that the use of safety margins is a good way to improve plan robustness for SFUD and IMPT plans with low in-field dose gradients but not necessarily for highly modulated IMPT plans for which only a marginal improvement in plan robustness could be detected through the definition of a planning target volume.

Sequential parallel comparison design with binary and time-to-event outcomes.

PubMed

Silverman, Rachel Kloss; Ivanova, Anastasia; Fine, Jason

2018-04-30

Sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials especially trials with possibly high placebo effect. Sequential parallel comparison design is conducted with 2 stages. Participants are randomized between active therapy and placebo in stage 1. Then, stage 1 placebo nonresponders are rerandomized between active therapy and placebo. Data from the 2 stages are pooled to yield a single P value. We consider SPCD with binary and with time-to-event outcomes. For time-to-event outcomes, response is defined as a favorable event prior to the end of follow-up for a given stage of SPCD. We show that for these cases, the usual test statistics from stages 1 and 2 are asymptotically normal and uncorrelated under the null hypothesis, leading to a straightforward combined testing procedure. In addition, we show that the estimators of the treatment effects from the 2 stages are asymptotically normal and uncorrelated under the null and alternative hypothesis, yielding confidence interval procedures with correct coverage. Simulations and real data analysis demonstrate the utility of the binary and time-to-event SPCD. Copyright © 2018 John Wiley & Sons, Ltd.

High-dose vitamin D in Addison's disease regulates T-cells and monocytes: A pilot trial.

PubMed

Penna-Martinez, Marissa; Filmann, Natalie; Bogdanou, Dimitra; Shoghi, Firouzeh; Huenecke, Sabine; Schubert, Ralf; Herrmann, Eva; Koehl, Ulrike; Husebye, Eystein S; Badenhoop, Klaus

2018-05-01

On the basis of the immunomodulatory actions of vitamin D (VD), we investigated the effects of high-dose VD therapy over a 3 mo period on the immune response in patients with Addison's disease (AD). This randomized, controlled, crossover trial included 13 patients with AD who received either cholecalciferol (4000 IU/d) for 3 mo followed by 3 mo placebo oil or the sequential alternative placebo followed by verum. Glucocorticoid replacement doses remained stable. The primary outcome measures were changes in 25-hydroxyvitamin D3 (25(OH)D 3 ) levels and immune cells including T helper cells (Th; CD3 + CD4 + ), late-activated Th cells (CD3 + CD4 + HLA-DR + ), regulatory T cells (CD3 + CD4 + CD25 bright CD127 dim/neg ), cytotoxic T cells (Tc; CD3 + CD8 + ), late-activated Tc cells (CD3 + CD8 + HLA-DR + ), and monocytes. The explorative analysis included the correlation of changes with VD-related gene polymorphisms and 21-hydroxylase antibody titers. Ten of 13 patients (77%) were VD deficient. Median 25(OH)D 3 concentrations increased significantly to 41.5 ng/ml (median changes: 19.95 ng/ml; P = 0.0005) after 3 mo of cholecalciferol treatment. Within the T-cells, only the late-activated Th (median changes: 1.6%; P = 0.02) and late-activated Tc cells (median changes: 4.05%; P = 0.03) decreased, whereas monocytes (median changes: 1.05%; P = 0.008) increased after VD therapy. T-cell changes were associated with two polymorphisms (CYP27B1-rs108770012 and VDR-rs10735810), but no changes in the 21-hydroxylase antibody titers were observed. Three months of treatment with cholecalciferol achieved sufficient 25(OH)D 3 levels and can regulate late-activated T-cells and monocytes in patients with AD. Explorative analysis revealed potential genetic contributions. This pilot trial provides novel insights about immunomodulation in AD. Copyright © 2017 Elsevier Inc. All rights reserved.

A dosimetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas.

PubMed

Thompson, Reid F; Mayekar, Sonal U; Zhai, Huifang; Both, Stefan; Apisarnthanarax, Smith; Metz, James M; Plastaras, John P; Ben-Josef, Edgar

2014-08-01

Uncontrolled local growth is the cause of death in ∼ 30% of patients with unresectable pancreatic cancers. The addition of standard-dose radiotherapy to gemcitabine has been shown to confer a modest survival benefit in this population. Radiation dose escalation with three-dimensional planning is not feasible, but high-dose intensity-modulated radiation therapy (IMRT) has been shown to improve local control. Still, dose-escalation remains limited by gastrointestinal toxicity. In this study, the authors investigate the potential use of double scattering (DS) and pencil beam scanning (PBS) proton therapy in limiting dose to critical organs at risk. The authors compared DS, PBS, and IMRT plans in 13 patients with unresectable cancer of the pancreatic head, paying particular attention to duodenum, small intestine, stomach, liver, kidney, and cord constraints in addition to target volume coverage. All plans were calculated to 5500 cGy in 25 fractions with equivalent constraints and normalized to prescription dose. All statistics were by two-tailed paired t-test. Both DS and PBS decreased stomach, duodenum, and small bowel dose in low-dose regions compared to IMRT (p < 0.01). However, protons yielded increased doses in the mid to high dose regions (e.g., 23.6-53.8 and 34.9-52.4 Gy for duodenum using DS and PBS, respectively; p < 0.05). Protons also increased generalized equivalent uniform dose to duodenum and stomach, however these differences were small (<5% and 10%, respectively; p < 0.01). Doses to other organs-at-risk were within institutional constraints and placed no obvious limitations on treatment planning. Proton therapy does not appear to reduce OAR volumes receiving high dose. Protons are able to reduce the treated volume receiving low-intermediate doses, however the clinical significance of this remains to be determined in future investigations.

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

High dose bystander effects in spatially fractionated radiation therapy

PubMed Central

Asur, Rajalakshmi; Butterworth, Karl T.; Penagaricano, Jose A.; Prise, Kevin M.; Griffin, Robert J.

2014-01-01

Traditional radiotherapy of bulky tumors has certain limitations. Spatially fractionated radiation therapy (GRID) and intensity modulated radiotherapy (IMRT) are examples of advanced modulated beam therapies that help in significant reductions in normal tissue damage. GRID refers to the delivery of a single high dose of radiation to a large treatment area that is divided into several smaller fields, while IMRT allows improved dose conformity to the tumor target compared to conventional three-dimensional conformal radiotherapy. In this review, we consider spatially fractionated radiotherapy approaches focusing on GRID and IMRT, and present complementary evidence from different studies which support the role of radiation induced signaling effects in the overall radiobiological rationale for these treatments. PMID:24246848

High-Dose Vitamin C (PDQ®)—Health Professional Version

Cancer.gov

High-dose vitamin C, with and without conventional cancer therapies, appeared promising in early studies and was well tolerated. However, these studies have several limitations due to lack of rigor in trial design. Get detailed information about high-dose vitamin C in cancer in this clinician summary.

Randomized Noninferiority Trial of Reduced High-Dose Volume Versus Standard Volume Radiation Therapy for Muscle-Invasive Bladder Cancer: Results of the BC2001 Trial (CRUK/01/004)

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

Huddart, Robert A., E-mail: robert.huddart@icr.ac.uk; Hall, Emma; Hussain, Syed A.

2013-10-01

Purpose: To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer. Methods and Materials: In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. Themore » primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years). Results: Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT − sRT) was 6.4% (95% confidence interval −7.3%, 16.8%) under an intention to treat analysis and 2.6% (−12.8%, 14.6%) in the “per-protocol” population. Conclusions: In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.« less

Initial Results of a Phase I Dose-Escalation Trial of Concurrent and Maintenance Erlotinib and Reirradiation for Recurrent and New Primary Head-and-Neck Cancer

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

Rusthoven, Kyle E.; Feigenberg, Steven J.; Raben, David

2010-11-15

Purpose: To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC). Methods and Materials: Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinibmore » started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days. Results: Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis. Conclusions: Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible.« less

Cognitive-Behavioral Therapy, Behavioral Weight Loss, and Sequential Treatment for Obese Patients with Binge-Eating Disorder: A Randomized Controlled Trial

ERIC Educational Resources Information Center

Grilo, Carlos M.; Masheb, Robin M.; Wilson, G. Terence; Gueorguieva, Ralitza; White, Marney A.

2011-01-01

Objective: Cognitive-behavioral therapy (CBT) is the best established treatment for binge-eating disorder (BED) but does not produce weight loss. The efficacy of behavioral weight loss (BWL) in obese patients with BED is uncertain. This study compared CBT, BWL, and a sequential approach in which CBT is delivered first, followed by BWL (CBT + BWL).…

Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression

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

Hreiche, Raymond; Megarbane, Bruno; Pirnay, Stephane

In humans, asphyxic deaths and severe poisonings have been attributed to high-dosage buprenorphine, a maintenance therapy for heroin addiction. However, in rats, intravenous buprenorphine at doses up to 90 mg kg{sup -1} was not associated with significant effects on arterial blood gases. In contrast, norbuprenorphine, the buprenorphine major cytochrome P450 (CYP) 3A-derived metabolite, is a potent respiratory depressant. Thus, our aim was to study the consequences of CYP3A induction on buprenorphine-associated effects on resting ventilation in rats. We investigated the effects on ventilation of 30 mg kg{sup -1} buprenorphine alone or following cytochrome P450 (CYP) 3A induction with dexamethasone, usingmore » whole body plethysmography (N = 24) and arterial blood gases (N = 12). Randomized animals in 4 groups received sequential intraperitoneal dosing with: (dexamethasone [days 1-3] + buprenorphine [day 4]), (dexamethasone solvent [days 1-3] + buprenorphine [day 4]), (dexamethasone [days 1-3] + buprenorphine solvent [day 4]), or (dexamethasone solvent [days 1-3] + buprenorphine solvent [day 4]). Buprenorphine alone caused a significant rapid and sustained increase in the inspiratory time (P < 0.001), without significant effects on the respiratory frequency, the tidal volume, the minute volume, or arterial blood gases. In dexamethasone-pretreated rats, there was no significant alteration in the respiratory parameters, despite CYP3A induction and significant increase of the ratio of plasma norbuprenorphine-to-buprenorphine concentrations. In conclusion, dexamethasone did not modify the effects of 30 mg kg{sup -1} buprenorphine on rat ventilation. Our results suggest a limited role of drug-mediated CYP3A induction in the occurrence of buprenorphine-attributed respiratory depression in addicts.« less

¹⁸F-choline positron emission tomography/computed tomography-driven high-dose salvage radiation therapy in patients with biochemical progression after radical prostatectomy: feasibility study in 60 patients.

PubMed

D'Angelillo, Rolando M; Sciuto, Rosa; Ramella, Sara; Papalia, Rocco; Jereczek-Fossa, Barbara A; Trodella, Luca E; Fiore, Michele; Gallucci, Michele; Maini, Carlo L; Trodella, Lucio

2014-10-01

To retrospectively review data of a cohort of patients with biochemical progression after radical prostatectomy, treated according to a uniform institutional treatment policy, to evaluate toxicity and feasibility of high-dose salvage radiation therapy (80 Gy). Data on 60 patients with biochemical progression after radical prostatectomy between January 2009 and September 2011 were reviewed. The median value of prostate-specific antigen before radiation therapy was 0.9 ng/mL. All patients at time of diagnosis of biochemical recurrence underwent dynamic (18)F-choline positron emission tomography/computed tomography (PET/CT), which revealed in all cases a local recurrence. High-dose salvage radiation therapy was delivered up to total dose of 80 Gy to 18F-choline PET/CT-positive area. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events, version 3.0, scale. Treatment was generally well tolerated: 54 patients (90%) completed salvage radiation therapy without any interruption. Gastrointestinal grade ≥2 acute toxicity was recorded in 6 patients (10%), whereas no patient experienced a grade ≥2 genitourinary toxicity. No grade 4 acute toxicity events were recorded. Only 1 patient (1.7%) experienced a grade 2 gastrointestinal late toxicity. With a mean follow-up of 31.2 months, 46 of 60 patients (76.6%) were free of recurrence. The 3-year biochemical progression-free survival rate was 72.5%. At early follow-up, (18)F-choline PET/CT-driven high-dose salvage radiation therapy seems to be feasible and well tolerated, with a low rate of toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

{sup 18}F-Choline Positron Emission Tomography/Computed Tomography–Driven High-Dose Salvage Radiation Therapy in Patients With Biochemical Progression After Radical Prostatectomy: Feasibility Study in 60 Patients

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

D'Angelillo, Rolando M., E-mail: r.dangelillo@unicampus.it; Sciuto, Rosa; Ramella, Sara

Purpose: To retrospectively review data of a cohort of patients with biochemical progression after radical prostatectomy, treated according to a uniform institutional treatment policy, to evaluate toxicity and feasibility of high-dose salvage radiation therapy (80 Gy). Methods and Materials: Data on 60 patients with biochemical progression after radical prostatectomy between January 2009 and September 2011 were reviewed. The median value of prostate-specific antigen before radiation therapy was 0.9 ng/mL. All patients at time of diagnosis of biochemical recurrence underwent dynamic {sup 18}F-choline positron emission tomography/computed tomography (PET/CT), which revealed in all cases a local recurrence. High-dose salvage radiation therapy was delivered up tomore » total dose of 80 Gy to 18F-choline PET/CT-positive area. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events, version 3.0, scale. Results: Treatment was generally well tolerated: 54 patients (90%) completed salvage radiation therapy without any interruption. Gastrointestinal grade ≥2 acute toxicity was recorded in 6 patients (10%), whereas no patient experienced a grade ≥2 genitourinary toxicity. No grade 4 acute toxicity events were recorded. Only 1 patient (1.7%) experienced a grade 2 gastrointestinal late toxicity. With a mean follow-up of 31.2 months, 46 of 60 patients (76.6%) were free of recurrence. The 3-year biochemical progression-free survival rate was 72.5%. Conclusions: At early follow-up, {sup 18}F-choline PET/CT-driven high-dose salvage radiation therapy seems to be feasible and well tolerated, with a low rate of toxicity.« less

Tumor Dosimetry and Response for 153Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

PubMed Central

Senthamizhchelvan, Srinivasan; Hobbs, Robert F.; Song, Hong; Frey, Eric C.; Zhang, Zhe; Armour, Elwood; Wahl, Richard L.; Loeb, David M.; Sgouros, George

2012-01-01

153Sm-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of 153Sm-EDTMP administered activity (AA), osteosarcoma tumor density, mass, and the shape of the tumor on absorbed dose (AD). We also studied the biologic implication of the nonuniform tumor AD distribution using radio-biologic modeling and examined the relationship between tumor AD and response. Methods Nineteen tumors in 6 patients with recurrent, refractory osteosarcoma enrolled in a phase I or II clinical trial of 153Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of 153Sm-EDTMP (37.0–51.8 MBq/kg), followed on hematologic recovery by a second, high dose (222 MBq/kg). Treatment response was evaluated using either CT or MRI after each therapy. SPECT/CT of the tumor regions were obtained at 4 and 48 h or 72 h after 153Sm-EDTMP therapy for 3D-RD analysis. Mean tumor AD was also calculated using the OLINDA/EXM unit-density sphere model and was compared with the 3D-RD estimates. Results On average, a 5-fold increase in the AA led to a 4-fold increase in the mean tumor AD over the high- versus low-dose–treated patients. The range of mean tumor AD and equivalent uniform dose (EUD) for low-dose therapy were 1.48–14.6 and 0.98–3.90 Gy, respectively. Corresponding values for high-dose therapy were 2.93–59.3 and 1.89–12.3 Gy, respectively. Mean tumor AD estimates obtained from OLINDA/EXM were within 5% of the mean AD values obtained using 3D-RD. On an individual tumor basis, both mean AD and EUD were positively related to percentage tumor volume reduction (P = 0.031 and 0.023, respectively). Conclusion The variations in tumor density, mass, and shape seen in these tumors did not affect the mean tumor AD estimation significantly. The tumor EUD was approximately 2- and 3-fold lower than the mean AD for low-and high-dose therapy, respectively. A dose–response relationship was observed for transient tumor volume shrinkage. PMID:22251554

Predictors of High-grade Esophagitis After Definitive Three-dimensional Conformal Therapy, Intensity-modulated Radiation Therapy, or Proton Beam Therapy for Non-small cell Lung Cancer

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

Gomez, Daniel R., E-mail: dgomez@mdanderson.org; Tucker, Susan L.; Martel, Mary K.

2012-11-15

Introduction: We analyzed the ability of various patient- and treatment-related factors to predict radiation-induced esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton beam therapy (PBT). Methods and Materials: Patients were treated for NSCLC with 3D-CRT, IMRT, or PBT at MD Anderson from 2000 to 2008 and had full dose-volume histogram (DVH) data available. The endpoint was severe (grade {>=}3) RE. The Lyman-Kutcher-Burman (LKB) model was used to analyze RE as a function of the fractional esophageal DVH, with clinical variables included as dose-modifying factors. Results:more » Overall, 652 patients were included: 405 patients were treated with 3D-CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade {>=}3 RE were 8%, 28%, and 6%, respectively, with a median time to onset of 42 days (range, 11-93 days). A fit of the fractional DVH LKB model demonstrated that the fractional effective dose was significantly different (P=.046) than 1 (fractional mean dose) indicating that high doses to small volumes are more predictive than mean esophageal dose. The model fit was better for 3D-CRT and PBT than for IMRT. Including receipt of concurrent chemotherapy as a dose-modifying factor significantly improved the LKB model (P=.005), and the model was further improved by including a variable representing treatment with >30 fractions. Examining individual types of chemotherapy agents revealed a trend toward receipt of concurrent taxanes and increased risk of RE (P=.105). Conclusions: Fractional dose (dose rate) and number of fractions (total dose) distinctly affect the risk of severe RE, estimated using the LKB model, and concurrent chemotherapy improves the model fit. This risk of severe RE is underestimated by this model in patients receiving IMRT.« less

Predictors of high-grade esophagitis after definitive three-dimensional conformal therapy, intensity-modulated radiation therapy, or proton beam therapy for non-small cell lung cancer.

PubMed

Gomez, Daniel R; Tucker, Susan L; Martel, Mary K; Mohan, Radhe; Balter, Peter A; Lopez Guerra, Jose Luis; Liu, Hongmei; Komaki, Ritsuko; Cox, James D; Liao, Zhongxing

2012-11-15

We analyzed the ability of various patient- and treatment-related factors to predict radiation-induced esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton beam therapy (PBT). Patients were treated for NSCLC with 3D-CRT, IMRT, or PBT at MD Anderson from 2000 to 2008 and had full dose-volume histogram (DVH) data available. The endpoint was severe (grade≥3) RE. The Lyman-Kutcher-Burman (LKB) model was used to analyze RE as a function of the fractional esophageal DVH, with clinical variables included as dose-modifying factors. Overall, 652 patients were included: 405 patients were treated with 3D-CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade≥3 RE were 8%, 28%, and 6%, respectively, with a median time to onset of 42 days (range, 11-93 days). A fit of the fractional DVH LKB model demonstrated that the fractional effective dose was significantly different (P=.046) than 1 (fractional mean dose) indicating that high doses to small volumes are more predictive than mean esophageal dose. The model fit was better for 3D-CRT and PBT than for IMRT. Including receipt of concurrent chemotherapy as a dose-modifying factor significantly improved the LKB model (P=.005), and the model was further improved by including a variable representing treatment with >30 fractions. Examining individual types of chemotherapy agents revealed a trend toward receipt of concurrent taxanes and increased risk of RE (P=.105). Fractional dose (dose rate) and number of fractions (total dose) distinctly affect the risk of severe RE, estimated using the LKB model, and concurrent chemotherapy improves the model fit. This risk of severe RE is underestimated by this model in patients receiving IMRT. Copyright © 2012 Elsevier Inc. All rights reserved.

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

Brown, J. Martin, E-mail: mbrown@stanford.edu; Carlson, David J.; Brenner, David J.

Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), are rapidly becoming accepted practice for the radiation therapy of certain tumors. Typically, SRS and SBRT involve the delivery of 1 or a few large-dose fractions of 8 to 30 Gy per fraction: a major paradigm shift from radiation therapy practice over the past 90 years, when, with relatively large amounts of normal tissues receiving high doses, the goal was to maximize tumor response for an acceptable level of normal tissue injury. The development of SRS and SBRT have come about because ofmore » technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumors with reduced margins and high gradients outside the target, thereby minimizing doses to surrounding normal tissues. Because the results obtained with SRS and SBRT have been impressive, they have raised the question whether classic radiobiological modeling, and the linear-quadratic (LQ) model, are appropriate for large doses per fraction. In addition to objections to the LQ model, the possibility of additional biological effects resulting from endothelial cell damage, enhanced tumor immunity, or both have been raised to account for the success of SRS and SBRT. In this review, we conclude that the available preclinical and clinical data do not support a need to change the LQ model or to invoke phenomena over and above the classic 5 Rs of radiobiology and radiation therapy, with the likely exception that for some tumors high doses of irradiation may produce enhanced antitumor immunity. Thus, we suggest that for most tumors, the standard radiobiology concepts of the 5 Rs are sufficient to explain the clinical data, and the excellent results obtained from clinical studies are the result of the much larger biologically effective doses that are delivered with SRS and SBRT.« less

Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients.

PubMed

Gligorov, J; Ataseven, B; Verrill, M; De Laurentiis, M; Jung, K H; Azim, H A; Al-Sakaff, N; Lauer, S; Shing, M; Pivot, X

2017-09-01

To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns.

PubMed

Dornelles, Laura Vargas; Corso, Andréa Lúcia; Silveira, Rita de Cássia; Procianoy, Renato Soibelmann

2016-01-01

To compare the efficacy of intravenous ibuprofen at high (20-10-10mg/kg/dose) and low doses (10-5-5mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns. A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p>0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p>0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p=0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p>0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p=0.86). There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

No Clinically Relevant Drug-Drug Interactions between Methadone or Buprenorphine-Naloxone and Antiviral Combination Glecaprevir and Pibrentasvir

PubMed Central

Kosloski, Matthew P.; Zhao, Weihan; Asatryan, Armen; Kort, Jens; Geoffroy, Pierre

2017-01-01

ABSTRACT The combination of glecaprevir (formerly ABT-493), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (formerly ABT-530), an NS5A protein inhibitor, is being developed as treatment for HCV genotype 1 to 6 infection. The pharmacokinetics, pharmacodynamics, safety, and tolerability of methadone or buprenorphine-naloxone when coadministered with the glecaprevir-pibrentasvir combination in HCV-negative subjects on stable opioid maintenance therapy were investigated in a phase 1, single-center, two-arm, multiple-dose, open-label sequential study. Subjects received methadone (arm 1) or buprenorphine-naloxone (arm 2) once daily (QD) per their existing individual prescriptions alone (days 1 to 9) and then in combination with glecaprevir at 300 mg QD and pibrentasvir at 120 mg QD (days 10 to 16) each morning. Dose-normalized exposures were similar with and without glecaprevir and pibrentasvir for (R)- and (S)-methadone (≤5% difference) and for buprenorphine and naloxone (≤24% difference); the norbuprenorphine area under the curve was 30% higher with glecaprevir and pibrentasvir, consistent with maximum and trough plasma concentrations that increased by 21% to 25%. No changes in pupil response, short opiate withdrawal scale score, or desire for drugs questionnaire were observed when glecaprevir and pibrentasvir were added to methadone or buprenorphine-naloxone therapy. No dose adjustment is required when glecaprevir and pibrentasvir are coadministered with methadone or buprenorphine-naloxone. PMID:28807904

High-dose nebulized budesonide is effective for mild asthma exacerbations in children under 3 years of age.

PubMed

Saito, M; Kikuchi, Y; Kawarai Lefor, A; Hoshina, M

2017-01-01

Background. High-dose inhaled steroid therapy has been shown to be effective in children and adults with asthma exacerbations. However, few reports are available regarding its efficacy for asthma exacerbations in younger children. Objective. In this study, we administered high-dose nebulized budesonide therapy for mild asthma exacerbations in children < 3 years of age and compared its efficacy and safety with systemic steroid therapy. Methods. This study included children < 3 years old with mild asthma exacerbations. Patients were randomly assigned to two groups: the BIS group was given 1 mg of nebulized budesonide twice daily, and the PSL group received prednisolone 0.5 mg/kg iv three times daily. Days to disappearance of wheezing, days of steroid use, days of oxygen use, serum cortisol level, and incidence of adverse events during treatment were compared between the groups. Result. Wheezing disappeared after an average of five days, and steroids were administered for an average of five days in both groups, with no significant difference in days of oxygen use. Serum cortisol levels at initiation and during the course of treatment remained unchanged in the BIS group, and were decreased in the PSL group; however, the decrease in the latter group was not pathologic. Conclusion. For children < 3 years old with mild asthma exacerbations, high-dose nebulized budesonide therapy is equally as effective as systemic steroid therapy.

Standard triple, bismuth pectin quadruple and sequential therapies for Helicobacter pylori eradication

PubMed Central

Gao, Xiao-Zhong; Qiao, Xiu-Li; Song, Wen-Chong; Wang, Xiao-Feng; Liu, Feng

2010-01-01

AIM: To compare the effectiveness of standard triple, bismuth pectin quadruple and sequential therapies for Helicobacter pylori (H. pylori) eradication in a randomized, double-blinded, comparative clinical trial in China. METHODS: A total of 215 H. pylori-positive patients were enrolled in the study and randomly allocated into three groups: group A (n = 72) received a 10-d bismuth pectin quadruple therapy (20 mg rabeprazole bid, 1000 mg amoxicillin bid, 100 mg bismuth pectin qid, and 500 mg levofloxacin qd); group B (n = 72) received the sequential therapy (20 mg omeprazole bid, 1000 mg amoxicillin bid, in 5 d, followed by 20 mg omeprazole bid, 500 mg tinidazole bid, 500 mg clarithromycin bid, for another 5 d); group C (n = 71) received a standard 1-wk triple therapy (20 mg omeprazole bid, 1000 mg amoxicillin bid, 500 mg clarithromycin bid). After all these treatments, 20 mg omeprazole bid was administrated for 3 wk. H. pylori status was assessed by histology, 13C-urea breath test and rapid urease test at baseline and 4-6 wk after completion of treatment. Ulcer cicatrization was assessed by gastroscopy. χ2 test (P < 0.05) was used to compare the eradication rates and ulcer cicatrisation rates among the three groups. RESULTS: The eradication rate was 83.33% (60/72) in group A, 88.89% (64/72) in group B, and 80.56% (58/71) in group C. The ulcer cicatrisation rate was 86.44% (51/59) in group A, 90.16% (55/61) in group B, and 84.91% (45/53) in group C. The sequential therapy yielded a higher eradication rate and ulcer cicatrisation rate than the standard triple and bismuth pectin quadruple therapies. Statistically, the eradication rate of group B was significantly different from groups A and C (P < 0.05), but the difference of ulcer cicatrisation rate and side effects was not statistically significant among the three groups (P > 0.05). The three protocols were generally well tolerated. CONCLUSION: The sequential therapy has achieved a significantly higher eradication rate, and is a more suitable first-line alternative protocol for anti-H. pylori infection compared with the standard triple and bismuth pectin quadruple therapies. PMID:20818821

VMAT vs. 7-Field-IMRT: Assessing the Dosimetric Parameters of Prostate Cancer Treatment with a 292-Patient Sample

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

Kopp, Robert W.; Duff, Michael, E-mail: mduff@cancercarewny.com; Catalfamo, Frank

2011-01-01

We compared normal tissue radiation dose for the treatment of prostate cancer using 2 different radiation therapy delivery methods: volumetric modulated arc therapy (VMAT) vs. fixed-field intensity-modulated radiation therapy (IMRT). Radiotherapy plans for 292 prostate cancer patients treated with VMAT to a total dose of 7740 cGy were analyzed retrospectively. Fixed-angle, 7-field IMRT plans were created using the same computed tomography datasets and contours. Radiation doses to the planning target volume (PTV) and organs at risk (bladder, rectum, penile bulb, and femoral heads) were measured, means were calculated for both treatment methods, and dose-volume comparisons were made with 2-tailed, pairedmore » t-tests. The mean dose to the bladder was lower with VMAT at all measured volumes: 5, 10, 15, 25, 35, and 50% (p < 0.05). The mean doses to 5 and 10% of the rectum, the high-dose regions, were lower with VMAT (p < 0.05). The mean dose to 15% of the rectal volume was not significantly different (p = 0.95). VMAT exposed larger rectal volumes (25, 35, and 50%) to more radiation than fixed-field IMRT (p < 0.05). Average mean dose to the penile bulb (p < 0.05) and mean dose to 10% of the femoral heads (p < 0.05) were lower with VMAT. VMAT therapy for prostate cancer has dosimetric advantages for critical structures, notably for high-dose regions compared with fixed-field IMRT, without compromising PTV coverage. This may translate into reduced acute and chronic toxicity.« less

Evaluation of Robustness to Setup and Range Uncertainties for Head and Neck Patients Treated With Pencil Beam Scanning Proton Therapy

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

Malyapa, Robert; Lowe, Matthew; Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester

Purpose: To evaluate the robustness of head and neck plans for treatment with intensity modulated proton therapy to range and setup errors, and to establish robustness parameters for the planning of future head and neck treatments. Methods and Materials: Ten patients previously treated were evaluated in terms of robustness to range and setup errors. Error bar dose distributions were generated for each plan, from which several metrics were extracted and used to define a robustness database of acceptable parameters over all analyzed plans. The patients were treated in sequentially delivered series, and plans were evaluated for both the first seriesmore » and for the combined error over the whole treatment. To demonstrate the application of such a database in the head and neck, for 1 patient, an alternative treatment plan was generated using a simultaneous integrated boost (SIB) approach and plans of differing numbers of fields. Results: The robustness database for the treatment of head and neck patients is presented. In an example case, comparison of single and multiple field plans against the database show clear improvements in robustness by using multiple fields. A comparison of sequentially delivered series and an SIB approach for this patient show both to be of comparable robustness, although the SIB approach shows a slightly greater sensitivity to uncertainties. Conclusions: A robustness database was created for the treatment of head and neck patients with intensity modulated proton therapy based on previous clinical experience. This will allow the identification of future plans that may benefit from alternative planning approaches to improve robustness.« less

Primary central nervous system lymphoma.

PubMed

Ahluwalia, Manmeet S; Peereboom, David M

2010-07-01

Management goals for patients with primary central nervous system lymphoma (PCNSL) include long-term disease control, management of neurologic complications, and preservation of neurocognitive function. Various treatment options can achieve several of these goals. Chemotherapy as monotherapy or as combination therapy has emerged as the cornerstone of therapy for patients with newly diagnosed PCNSL. Outside of a clinical trial, patients with newly diagnosed PCNSL should receive high-dose intravenous methotrexate (MTX) as a single agent or as part of a combination regimen with radiation therapy reserved for relapse. The regimen should have an adequate MTX dose (>3 g/m(2)) to reach cytotoxic concentrations in the cerebrospinal fluid (CSF) to treat occult leptomeningeal disease (LMD). Alternative modes of chemotherapy delivery for selected patients, preferably in the context of a clinical trial, include high-dose chemotherapy with autologous stem cell rescue and intra-arterial chemotherapy with blood-brain barrier disruption. Whole brain radiation therapy (WBRT) in standard doses and fractionation carries an unacceptable rate of long-term neurocognitive toxicity. However, lower doses in daily divided fractions may offer the possibility of adding this modality with preservation of cognition but should be performed only in the context of a clinical trial. The long-term efficacy and toxicity of this approach is currently under investigation. Certain presentations of PCNSL require different strategies. Patients with ocular lymphoma at diagnosis should receive high-dose MTX as this drug can reach cytotoxic intravitreal concentrations. Recurrence in the eyes is managed with intravitreal chemotherapy including MTX or rituximab or with radiation therapy. The field of treatment (eyes vs whole brain) should be individualized. Intrathecal (IT) MTX should be included in the treatment regimen for those patients with a positive CSF cytology, or in regimens in which lower doses of MTX are delivered over longer periods of time. It is probably reasonable to withhold IT chemotherapy in those patients who have no detectable subarachnoid disease and who can receive higher doses of MTX (>3 g/m(2)) over shorter infusion periods (2-4 h). Patients who develop leptomeningeal involvement despite high- dose MTX can be managed with IT chemotherapy such as liposomal cytarabine or MTX or even rituximab. Areas of bulky or symptomatic LMD should probably be treated with radiation therapy as well. Because PCNSL is an uncommon disease, entry into clinical trials must be pursued to advance the state of the art.

Defining the “Hostile Pelvis” for Intensity Modulated Radiation Therapy: The Impact of Anatomic Variations in Pelvic Dimensions on Dose Delivered to Target Volumes and Organs at Risk in Patients With High-Risk Prostate Cancer Treated With Whole Pelvic Radiation Therapy

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

Yirmibeşoğlu Erkal, Eda, E-mail: eyirmibesoglu@yahoo.com; Karabey, Sinan; Karabey, Ayşegül

2015-07-15

Purpose: The aim of this study was to evaluate the impact of variations in pelvic dimensions on the dose delivered to the target volumes and the organs at risk (OARs) in patients with high-risk prostate cancer (PCa) to be treated with whole pelvic radiation therapy (WPRT) in an attempt to define the hostile pelvis in terms of intensity modulated radiation therapy (IMRT). Methods and Materials: In 45 men with high-risk PCa to be treated with WPRT, the target volumes and the OARs were delineated, the dose constraints for the OARs were defined, and treatment plans were generated according to themore » Radiation Therapy Oncology Group 0924 protocol. Six dimensions to reflect the depth, width, and height of the bony pelvis were measured, and 2 indexes were calculated from the planning computed tomographic scans. The minimum dose (D{sub min}), maximum dose (D{sub max}), and mean dose (D{sub mean}) for the target volumes and OARs and the partial volumes of each of these structures receiving a specified dose (V{sub D}) were calculated from the dose-volume histograms (DVHs). The data from the DVHs were correlated with the pelvic dimensions and indexes. Results: According to an overall hostility score (OHS) calculation, 25 patients were grouped as having a hospitable pelvis and 20 as having a hostile pelvis. Regarding the OHS grouping, the DVHs for the bladder, bowel bag, left femoral head, and right femoral head differed in favor of the hospitable pelvis group, and the DVHs for the rectum differed for a range of lower doses in favor of the hospitable pelvis group. Conclusions: Pelvimetry might be used as a guide to define the challenging anatomy or the hostile pelvis in terms of treatment planning for IMRT in patients with high-risk PCa to be treated with WPRT.« less

Radiation Therapy and Hearing Loss

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

Bhandare, Niranjan; Jackson, Andrew; Eisbruch, Avraham

2010-03-01

A review of literature on the development of sensorineural hearing loss after high-dose radiation therapy for head-and-neck tumors and stereotactic radiosurgery or fractionated stereotactic radiotherapy for the treatment of vestibular schwannoma is presented. Because of the small volume of the cochlea a dose-volume analysis is not feasible. Instead, the current literature on the effect of the mean dose received by the cochlea and other treatment- and patient-related factors on outcome are evaluated. Based on the data, a specific threshold dose to cochlea for sensorineural hearing loss cannot be determined; therefore, dose-prescription limits are suggested. A standard for evaluating radiation therapy-associatedmore » ototoxicity as well as a detailed approach for scoring toxicity is presented.« less

Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis.

PubMed

Fialla, Annette D; Israelsen, Mads; Hamberg, Ole; Krag, Aleksander; Gluud, Lise Lotte

2015-09-01

Patients with cirrhosis and alcoholic hepatitis are often malnourished and have a superimposed stress metabolism, which increases nutritional demands. We performed a systematic review on the effects of nutritional therapy vs. no intervention for patients with cirrhosis or alcoholic hepatitis. We included trials on nutritional therapy designed to fulfil at least 75% of daily nutritional demand. Authors extracted data in an independent manner. Random-effects and fixed-effect meta-analyses were performed and the results expressed as risk ratios (RR) with 95% confidence intervals (CI). Sequential analyses were performed to evaluate the risk of spurious findings because of random and systematic errors. Subgroup and sensitivity analyses were performed to evaluate the risk of bias and sources of between trial heterogeneity. Thirteen randomized controlled trials with 329 allocated to enteral (nine trials) or intravenous (four trials) nutrition and 334 controls. All trials were classed as having a high risk of bias. Random-effects meta-analysis showed that nutritional therapy reduced mortality 0.80 (95% CI, 0.64 to 0.99). The result was not confirmed in sequential analysis. Fixed-effect analysis suggested that nutrition prevented overt hepatic encephalopathy (0.73; 95% CI, 0.55 to 0.96) and infection (0.66; 95% CI, 0.45 to 0.98, respectively), but the results were not confirmed in random-effects analyses. Our review suggests that nutritional therapy may have beneficial effects on clinical outcomes in cirrhosis and alcoholic hepatitis. High-quality trials are needed to verify our findings. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Empirical mono- versus combination antibiotic therapy in adult intensive care patients with severe sepsis - A systematic review with meta-analysis and trial sequential analysis.

PubMed

Sjövall, Fredrik; Perner, Anders; Hylander Møller, Morten

2017-04-01

To assess benefits and harms of empirical mono- vs. combination antibiotic therapy in adult patients with severe sepsis in the intensive care unit (ICU). We performed a systematic review according to the Cochrane Collaboration methodology, including meta-analysis, risk of bias assessment and trial sequential analysis (TSA). We included randomised clinical trials (RCT) assessing empirical mono-antibiotic therapy versus a combination of two or more antibiotics in adult ICU patients with severe sepsis. We exclusively assessed patient-important outcomes, including mortality. Two reviewers independently evaluated studies for inclusion, extracted data, and assessed risk of bias. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated and the risk of random errors was assessed by TSA. Thirteen RCTs (n = 2633) were included; all were judged as having high risk of bias. Carbapenems were the most frequently used mono-antibiotic (8 of 13 trials). There was no difference in mortality (RR 1.11, 95% CI 0.95-1.29; p = 0.19) or in any other patient-important outcomes between mono- vs. combination therapy. In TSA of mortality, the Z-curve reached the futility area, indicating that a 20% relative risk difference in mortality may be excluded between the two groups. For the other outcomes, TSA indicated lack of data and high risk of random errors. This systematic review of RCTs with meta-analysis and TSA demonstrated no differences in mortality or other patient-important outcomes between empirical mono- vs. combination antibiotic therapy in adult ICU patients with severe sepsis. The quantity and quality of data was low without firm evidence for benefit or harm of combination therapy. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Low-dose cerebral perfusion computed tomography image restoration via low-rank and total variation regularizations

PubMed Central

Niu, Shanzhou; Zhang, Shanli; Huang, Jing; Bian, Zhaoying; Chen, Wufan; Yu, Gaohang; Liang, Zhengrong; Ma, Jianhua

2016-01-01

Cerebral perfusion x-ray computed tomography (PCT) is an important functional imaging modality for evaluating cerebrovascular diseases and has been widely used in clinics over the past decades. However, due to the protocol of PCT imaging with repeated dynamic sequential scans, the associative radiation dose unavoidably increases as compared with that used in conventional CT examinations. Minimizing the radiation exposure in PCT examination is a major task in the CT field. In this paper, considering the rich similarity redundancy information among enhanced sequential PCT images, we propose a low-dose PCT image restoration model by incorporating the low-rank and sparse matrix characteristic of sequential PCT images. Specifically, the sequential PCT images were first stacked into a matrix (i.e., low-rank matrix), and then a non-convex spectral norm/regularization and a spatio-temporal total variation norm/regularization were then built on the low-rank matrix to describe the low rank and sparsity of the sequential PCT images, respectively. Subsequently, an improved split Bregman method was adopted to minimize the associative objective function with a reasonable convergence rate. Both qualitative and quantitative studies were conducted using a digital phantom and clinical cerebral PCT datasets to evaluate the present method. Experimental results show that the presented method can achieve images with several noticeable advantages over the existing methods in terms of noise reduction and universal quality index. More importantly, the present method can produce more accurate kinetic enhanced details and diagnostic hemodynamic parameter maps. PMID:27440948

Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy.

PubMed

Boissel, N; Cayuela, J M; Preudhomme, C; Thomas, X; Grardel, N; Fund, X; Tigaud, I; Raffoux, E; Rousselot, P; Sigaux, F; Degos, L; Castaigne, S; Fenaux, P; Dombret, H

2002-09-01

FLT3 internal tandem duplications (FLT3-ITDs) are present in nearly 25% of patients with AML and have been associated with poor response to conventional therapy and poor outcome. We retrospectively evaluated the effect of reinforced courses of chemotherapy on the prognostic value of FLT3-ITDs in 159 AML patients prospectively enrolled in the ALFA-9000 trial, which randomly compared three reinforced induction regimens (standard 3+7 including high-dose daunorubicin, double induction, and timed-sequential therapy). FLT3-ITD was present in 40/159 (25%) blast samples and associated with high WBC (P = 0.002) and cytogenetics (P < 0.001) with a higher incidence (35%) in patients with a normal karyotype. There was no difference in CR rate between FLT3-wt and FLT3-ITD patients (80% vs 78%). Relapse-free survival (RFS) was similar in both groups (5-year RFS, 33% vs 32%; P = 0.41), even after adjustment for age, sex, WBC, cytogenetics, and treatment arm. A trend to a worse survival was observed in the FLT3-ITD group (estimated 5-year OS, 23% vs 37%; P = 0.09), mainly in patients with a normal karyotype. This was associated with a dramatic outcome in relapsing FLT3-ITD patients (estimated 3-year post-relapse survival, 0% vs 27%; P = 0.04). These results suggest that the bad prognosis associated with FLT3-ITDs in AML might be partly overcome using reinforced chemotherapy. Early detection of FLT3 mutations might thus be useful to intensify induction as well as post-remission therapy in FLT3-ITD patients.

Outcomes of resistance-guided sequential treatment of Mycoplasma genitalium infections: a prospective evaluation.

PubMed

Read, T R H; Fairley, C K; Murray, G L; Jensen, J S; Danielewski, J; Worthington, K; Doyle, M; Mokany, E; Tan, L; Chow, E P F; Garland, S M; Bradshaw, C S

2018-06-05

Rising macrolide and quinolone resistance in Mycoplasma genitalium necessitate new treatment approaches. We evaluated outcomes of sequential antimicrobial therapy for M.genitalium guided by a macrolide-resistance assay. In mid-2016 Melbourne Sexual Health Centre switched from azithromycin to doxycycline (100mg twice daily,7 days) for non-gonococcal urethritis/cervicitis/proctitis. Cases were tested for M. genitalium and macrolide-resistance mutations (MRM) by polymerase chain reaction (PCR). Directly after doxycycline, MRM-negative infections received 2.5g azithromycin (1g then 500mg daily for 3 days), and MRM-positive infections received sitafloxacin (100mg twice daily, 7 days). Assessment of test-of-cure and reinfection risk, occurred 14-90 days after the second antibiotic. Those reporting condomless sex with incompletely treated partners were excluded. Of 244 evaluable M. genitalium infections (52 women, 68 heterosexual men, 124 men who have sex with men) diagnosed from 20 June 2016 to 15 May 2017, MRM were detected in 167 [68.4% (95%confidence interval(CI):62.2%, 74.2%)]. Treatment with doxycycline decreased bacterial load by a mean 2.60 log10 (n=56, p<0.0001). Microbiologic cure occurred in: 73/77 MRM-negative infections [94.8% (95%CI:87.2%, 98.6%)] and in 154/167 MRM-positive infections [92.2% (95%CI:87.1%, 95.8%)]. Selection of macrolide-resistance occurred in only 2 [2.6% (95%CI: 0.3%, 9.2%)] of 76 macrolide-susceptible infections. Proportions reporting no missed doses and no adverse events, respectively, were: doxycycline 89.9% and 86.6%, sitafloxacin 90.8% and 80.5%, azithromycin 100% and 91.4%. In the context of high levels of antimicrobial resistance, switching from azithromycin to doxycycline for presumptive treatment of M. genitalium, followed by resistance-guided therapy, cured ≥92% of infections, with infrequent selection of macrolide resistance.

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered.

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed Central

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Background Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. PMID:27073327

Special cases for proton beam radiotherapy: re-irradiation, lymphoma, and breast cancer.

PubMed

Plastaras, John P; Berman, Abigail T; Freedman, Gary M

2014-12-01

The dose distributions that can be achieved with protons are usually superior to those of conventional photon external-beam radiation. There are special cases where proton therapy may offer a substantial potential benefit compared to photon treatments where toxicity concerns dominate. Re-irradiation may theoretically be made safer with proton therapy due to lower cumulative lifetime doses to sensitive tissues, such as the spinal cord. Proton therapy has been used in a limited number of patients with rectal, pancreatic, esophageal, and lung cancers. Chordomas and soft tissue sarcomas require particularly high radiation doses, posing additional challenges for re-irradiation. Lymphoma is another special case where proton therapy may be advantageous. Late toxicities from even relatively low radiation doses, including cardiac complications and second cancers, are of concern in lymphoma patients with high cure rates and long life expectancies. Proton therapy has begun to be used for consolidation after chemotherapy in patients with Hodgkin and non-Hodgkin lymphoma. Breast cancer is another emerging area of proton therapy development and use. Proton therapy may offer advantages compared to other techniques in the setting of breast boosts, accelerated partial breast irradiation, and post-mastectomy radiotherapy. In these settings, proton therapy may decrease toxicity associated with breast radiotherapy. As techniques are refined in proton therapy, we may be able to improve the therapeutic ratio by maintaining the benefits of radiotherapy while better minimizing the risks. Copyright © 2014 Elsevier Inc. All rights reserved.

A Rejection Principle for Sequential Tests of Multiple Hypotheses Controlling Familywise Error Rates

PubMed Central

BARTROFF, JAY; SONG, JINLIN

2015-01-01

We present a unifying approach to multiple testing procedures for sequential (or streaming) data by giving sufficient conditions for a sequential multiple testing procedure to control the familywise error rate (FWER). Together we call these conditions a “rejection principle for sequential tests,” which we then apply to some existing sequential multiple testing procedures to give simplified understanding of their FWER control. Next the principle is applied to derive two new sequential multiple testing procedures with provable FWER control, one for testing hypotheses in order and another for closed testing. Examples of these new procedures are given by applying them to a chromosome aberration data set and to finding the maximum safe dose of a treatment. PMID:26985125

Sequential therapy with entecavir and PEG-INF in patients affected by chronic hepatitis B and high levels of HBV-DNA with non-D genotypes.

PubMed

Boglione, L; D'Avolio, A; Cariti, G; Milia, M G; Simiele, M; De Nicolò, A; Ghisetti, V; Di Perri, G

2013-04-01

Complete eradication of hepatitis B virus (HBV) is rarely achieved. Treatment options include currently available nucleos(t)ide analogues and pegylated interferon. The aim of our exploratory study was to assess the effectiveness of sequential therapy for chronic hepatitis B (CHB) vs the current standard of care. We evaluated an association with entecavir and pegylated interferon alfa-2a (PEG-IFN) in 20 patients with hepatitis B, high HBV viremia and genotypes A, B, C and E. Patients received entecavir alone for 12 weeks, then entecavir and PEG-IFN for 12 weeks, lastly PEG-IFN alone for 36 weeks. The results were compared with 20 patients (control group) treated in the past with 48 weeks of PEG-IFN monotherapy. Our results show that complete sustained virological response (SVR) and partial SVR were, respectively, 60% and 80% in the study group and 10% and 30% in the control group; anti-HBe seroconversion rate were 76.9% vs 15%, and anti-HBs seroconversion were 20% vs 0%, respectively. We found a correlation among different genotypes and virological and serological outcomes - genotype C has a better virological response, while genotype A had a better serological response, and E genotype had a poor response. These results show that a sequential approach is a promising strategy of treatment in patients with CHB and high viremia in comparison with PEG-IFN monotherapy. The E genotype seems to have the worse rate of response and requires other treatment strategies. © 2013 Blackwell Publishing Ltd.

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT.

PubMed

Regan, M M; Walley, B A; Francis, P A; Fleming, G F; Láng, I; Gómez, H L; Colleoni, M; Tondini, C; Pinotti, G; Salim, M; Spazzapan, S; Parmar, V; Ruhstaller, T; Abdi, E A; Gelber, R D; Coates, A S; Goldhirsch, A; Pagani, O

2017-09-01

Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling. Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea. Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected. NCT00066690 and NCT00066703. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Double versus single high-dose melphalan 200 mg/m2 and autologous stem cell transplantation for multiple myeloma: a region-based study in 484 patients from the Nordic area

PubMed Central

Björkstrand, Bo; Klausen, Tobias W.; Remes, Kari; Gruber, Astrid; Knudsen, Lene M.; Bergmann, Olav J.; Lenhoff, Stig; Johnsen, Hans E.

2009-01-01

Autologous stem cell transplantation is still considered the standard of care in young patients with multiple myeloma (MM). This disease is the most common indication for high-dose therapy (HDT) supported by hematopoietic stem cell transplantation and much data support the benefit of this procedure. Results of randomized studies are in favor of tandem autologous transplantation although the effect on overall survival is unclear. Based on sequential registration trials in the Nordic area, we aimed to evaluate the outcome of conventional single or double HDT. During 1994–2000 we registered a total of 484 previously untreated patients under the age of 60 years at diagnosis who on a regional basis initially were treated with single [Trial NMSG #5/94 and #7/98 (N=383)] or double [Trial Huddinge Karolinska Turku Herlev (N=101)] high-dose melphalan (200 mg/m2) therapy supported by autologous stem cell transplantation. A complete or very good partial response was achieved by 40% of patients in the single transplant group and 60% of patients in the double transplant group (p=0.0006). The probability of surviving progression free for five years after the diagnosis was 25% (95% CL 18–32%) in the singletransplant group and 46% (95% CL 33–55%) in the double transplant group (p=0.0014). The estimated overall five-year survival rate was 60% in the single transplant group and 64% in the doubletransplant (p=0.9). In a multivariate analysis of variables, including single versus double transplantation, β2 microglobulin level, age, sex and disease stage, only β2 microglobulin level was predictive for overall survival (p>0.0001) and progression free survival (p=0.001). In accordance with these results, a 1:1 case-control matched comparison between double and single transplantation did not identify significant differences in overall and progression free survival. In this retrospective analysis up front double transplantation with melphalan (200 mg/m2) as compared to single transplantation did not seem to improve the final outcome among patients in the Nordic area. These data are in accordance with recent publications from the Bologna 96 trial indicating that a second transplant should not be recommended up front as standard care.

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

Thompson, Reid F.; Zhai, Huifang; Both, Stefan

Purpose: Uncontrolled local growth is the cause of death in ∼30% of patients with unresectable pancreatic cancers. The addition of standard-dose radiotherapy to gemcitabine has been shown to confer a modest survival benefit in this population. Radiation dose escalation with three-dimensional planning is not feasible, but high-dose intensity-modulated radiation therapy (IMRT) has been shown to improve local control. Still, dose-escalation remains limited by gastrointestinal toxicity. In this study, the authors investigate the potential use of double scattering (DS) and pencil beam scanning (PBS) proton therapy in limiting dose to critical organs at risk. Methods: The authors compared DS, PBS, andmore » IMRT plans in 13 patients with unresectable cancer of the pancreatic head, paying particular attention to duodenum, small intestine, stomach, liver, kidney, and cord constraints in addition to target volume coverage. All plans were calculated to 5500 cGy in 25 fractions with equivalent constraints and normalized to prescription dose. All statistics were by two-tailed paired t-test. Results: Both DS and PBS decreased stomach, duodenum, and small bowel dose in low-dose regions compared to IMRT (p < 0.01). However, protons yielded increased doses in the mid to high dose regions (e.g., 23.6–53.8 and 34.9–52.4 Gy for duodenum using DS and PBS, respectively; p < 0.05). Protons also increased generalized equivalent uniform dose to duodenum and stomach, however these differences were small (<5% and 10%, respectively; p < 0.01). Doses to other organs-at-risk were within institutional constraints and placed no obvious limitations on treatment planning. Conclusions: Proton therapy does not appear to reduce OAR volumes receiving high dose. Protons are able to reduce the treated volume receiving low-intermediate doses, however the clinical significance of this remains to be determined in future investigations.« less

Deep Inspiration Breath Hold—Based Radiation Therapy: A Clinical Review

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

Boda-Heggemann, Judit, E-mail: judit.boda-heggemann@umm.de; Knopf, Antje-Christin; Simeonova-Chergou, Anna

Several recent developments in linear accelerator–based radiation therapy (RT) such as fast multileaf collimators, accelerated intensity modulation paradigms like volumeric modulated arc therapy and flattening filter-free (FFF) high-dose-rate therapy have dramatically shortened the duration of treatment fractions. Deliverable photon dose distributions have approached physical complexity limits as a consequence of precise dose calculation algorithms and online 3-dimensional image guided patient positioning (image guided RT). Simultaneously, beam quality and treatment speed have continuously been improved in particle beam therapy, especially for scanned particle beams. Applying complex treatment plans with steep dose gradients requires strategies to mitigate and compensate for motion effectsmore » in general, particularly breathing motion. Intrafractional breathing-related motion results in uncertainties in dose delivery and thus in target coverage. As a consequence, generous margins have been used, which, in turn, increases exposure to organs at risk. Particle therapy, particularly with scanned beams, poses additional problems such as interplay effects and range uncertainties. Among advanced strategies to compensate breathing motion such as beam gating and tracking, deep inspiration breath hold (DIBH) gating is particularly advantageous in several respects, not only for hypofractionated, high single-dose stereotactic body RT of lung, liver, and upper abdominal lesions but also for normofractionated treatment of thoracic tumors such as lung cancer, mediastinal lymphomas, and breast cancer. This review provides an in-depth discussion of the rationale and technical implementation of DIBH gating for hypofractionated and normofractionated RT of intrathoracic and upper abdominal tumors in photon and proton RT.« less

Removal of ion-implanted photoresists on GaAs using two organic solvents in sequence

NASA Astrophysics Data System (ADS)

Oh, Eunseok; Na, Jihoon; Lee, Seunghyo; Lim, Sangwoo

2016-07-01

Organic solvents can effectively remove photoresists on III-V channels without damage or etching of the channel material during the process. In this study, a two-step sequential photoresist removal process using two different organic solvents was developed to remove implanted ArF and KrF photoresists at room temperature. The effects of organic solvents with either low molar volumes or high affinities for photoresists were evaluated to find a proper combination that can effectively remove high-dose implanted photoresists without damaging GaAs surfaces. The performance of formamide, acetonitrile, nitromethane, and monoethanolamine for the removal of ion-implanted ArF and KrF photoresists were compared using a two-step sequential photoresist removal process followed by treatment in dimethyl sulfoxide (DMSO). Among the various combinations, the acetonitrile + DMSO two-step sequence exhibited the best removal of photoresists that underwent ion implantation at doses of 5 × 1013-5 × 1015 atoms/cm2 on both flat and trench-structured GaAs surfaces. The ability of the two-step process using organic solvents to remove the photoresists can be explained by considering the affinities of solvents for a polymer and its permeability through the photoresist.

Feasibility of radiotherapy after high-dose dense chemotherapy with epirubicin, preceded by dexrazoxane, and paclitaxel for patients with high-risk Stage II-III breast cancer

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

De Giorgi, Ugo; Giannini, Massimo; Department of Radiotherapy, Pierantoni Hospital, Forli

Purpose: To verify the feasibility of, and quantify the risk of, pneumonitis from locoregional radiotherapy (RT) after high-dose dense chemotherapy with epirubicin and paclitaxel with peripheral blood progenitor cell support in patients with high-risk Stage II-III breast cancer. Methods and Materials: Treatment consisted of a mobilizing course of epirubicin 150 mg/m{sup 2}, preceded by dexrazoxane (Day 1), paclitaxel 175 mg/m{sup 2} (Day 2), and filgrastim; followed by three courses of epirubicin 150 mg/m{sup 2}, preceded by dexrazoxane (Day 1), paclitaxel 400 mg/m{sup 2} (Day 2), and peripheral blood progenitor cell support and filgrastim, every 16-19 days. After chemotherapy, patients weremore » treated with locoregional RT, which included the whole breast or the chest wall, axilla, and supraclavicular area. Results: Overall, 64 of 69 patients were evaluable. The interval between the end of chemotherapy and the initiation of RT was at least 1.5-2 months (mean 2). No treatment-related death was reported. After a median follow-up of 27 months from RT (range 5-77 months), neither clinically relevant radiation pneumonitis nor congestive heart failure had been reported. Minor and transitory lung and cardiac toxicities were observed. Conclusion: Sequential high doses of epirubicin, preceded by dexrazoxane, and paclitaxel did not adversely affect the tolerability of locoregional RT in breast cancer patients. The risk of pneumonitis was not affected by the use of sequential paclitaxel with an interval of at least 1.5-2 months between the end of chemotherapy and the initiation of RT. Long-term follow-up is needed to define the risk of cardiotoxicity in these patients.« less

Proton therapy for locally advanced breast cancer: A systematic review of the literature.

PubMed

Kammerer, Emmanuel; Guevelou, Jennifer Le; Chaikh, Abdulhamid; Danhier, Serge; Geffrelot, Julien; Levy, Christelle; Saloux, Eric; Habrand, Jean-Louis; Thariat, Juliette

2018-02-01

Radiation therapy plays a major role in the management of adjuvant breast cancer with nodal involvement, with an iatrogenic increase of cardio-vascular risk. Photon therapy, even with intensity modulation, has the downsides of high mean heart dose and heterogeneous target coverage, particularly in the case of internal mammary irradiation. This systematic review of the literature aims to evaluate proton therapy in locally advanced breast cancer. PubMed was searched for original full-text articles with the following search terms: «Proton Therapy» and «Breast Cancer». On-going trials were collected using the words "Breast Cancer" and "Protons". 13 articles met the criteria: 6 with passive proton therapy (Double Scattering), 5 with Pencil Beam Scanning (PBS) and 2 with a combination of both. Proton therapy offered a better target coverage than photons, even compared with intensity modulation radiation therapy (including static or rotational IMRT or tomotherapy). With proton therapy, volumes receiving 95% of the dose were around 98%, with low volumes receiving 105% of the dose. Proton therapy often decreased mean heart dose by a factor of 2 or 3, i.e. 1 Gy with proton therapy versus 3 Gy with conventional 3D, and 6 Gy for IMRT. Lungs were better spared with proton therapy than with photon therapy. Cutaneous toxicity observed with double scattering is improved with PBS. Proton therapy reduces mean heart dose in breast cancer irradiation, probably reducing late cardio-vascular toxicity. Large clinical studies will likely confirm a clinical benefit of proton therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

High-dose buprenorphine: perioperative precautions and management strategies.

PubMed

Roberts, D M; Meyer-Witting, M

2005-02-01

Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.

Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines.

PubMed

Kim, Dae Sik; Kang, Ka-Won; Lee, Se Ryeon; Park, Yong; Sung, Hwa Jung; Kim, Seok Jin; Choi, Chul Won; Kim, Byung Soo

2015-09-01

We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3 + 7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m(2)) or combination of intermediate-dose cytarabine (1 g/m(2)) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p = 0.045; RFS, 38.6 months vs. 11.0 months, p = 0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p = 0.001). This study suggests that high-dose cytarabine consolidation may produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification.

Dosimetric comparison of photon and proton treatment techniques for chondrosarcoma of thoracic spine

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

Yadav, Poonam, E-mail: yadav@humonc.wisc.edu; Department of Medical Physics, University of Wisconsin, Madison, WI; University of Wisconsin Riverview Cancer Center, Wisconsin Rapids, WI

2013-10-01

Chondrosarcomas are relatively radiotherapy resistant, and also delivering high radiation doses is not feasible owing to anatomic constraints. In this study, the feasibility of helical tomotherapy for treatment of chondrosarcoma of thoracic spine is explored and compared with other available photon and proton radiotherapy techniques in the clinical setting. A patient was treated for high-grade chondrosarcoma of the thoracic spine using tomotherapy. Retrospectively, the tomotherapy plan was compared with intensity-modulated radiation therapy, dynamic arc photon therapy, and proton therapy. Two primary comparisons were made: (1) comparison of normal tissue sparing with comparable target volume coverage (plan-1), and (2) comparison ofmore » target volume coverage with a constrained maximum dose to the cord center (plan-2). With constrained target volume coverage, proton plans were found to yield lower mean doses for all organs at risk (spinal cord, esophagus, heart, and both lungs). Tomotherapy planning resulted in the lowest mean dose to all organs at risk amongst photon-based methods. For cord dose constrained plans, the static-field intensity-modulated radiation therapy and dynamic arc plans resulted target underdosing in 20% and 12% of planning target volume2 volumes, respectively, whereas both proton and tomotherapy plans provided clinically acceptable target volume coverage with no portion of planning target volume2 receiving less than 90% of the prescribed dose. Tomotherapy plans are comparable to proton plans and produce superior results compared with other photon modalities. This feasibility study suggests that tomotherapy is an attractive alternative to proton radiotherapy for delivering high doses to lesions in the thoracic spine.« less

Time-Dependent Recovery of Human Synovial Membrane Mesenchymal Stem Cell Function After High-Dose Steroid Therapy: Case Report and Laboratory Study.

PubMed

Yasui, Yukihiko; Hart, David A; Sugita, Norihiko; Chijimatsu, Ryota; Koizumi, Kota; Ando, Wataru; Moriguchi, Yu; Shimomura, Kazunori; Myoui, Akira; Yoshikawa, Hideki; Nakamura, Norimasa

2018-03-01

The use of mesenchymal stem cells from various tissue sources to repair injured tissues has been explored over the past decade in large preclinical models and is now moving into the clinic. To report the case of a patient who exhibited compromised mesenchymal stem cell (MSC) function shortly after use of high-dose steroid to treat Bell's palsy, who recovered 7 weeks after therapy. Case report and controlled laboratory study. A patient enrolled in a first-in-human clinical trial for autologous implantation of a scaffold-free tissue engineered construct (TEC) derived from synovial MSCs for chondral lesion repair had a week of high-dose steroid therapy for Bell's palsy. Synovial tissue was harvested for MSC preparation after a 3-week recovery period and again at 7 weeks after therapy. The MSC proliferation rates and cell surface marker expression profiles from the 3-week sample met conditions for further processing. However, the cells failed to generate a functional TEC. In contrast, MSCs harvested at 7 weeks after steroid therapy were functional in this regard. Further in vitro studies with MSCs and steroids indicated that the effect of in vivo steroids was likely a direct effect of the drug on the MSCs. This case suggests that MSCs are transiently compromised after high-dose steroid therapy and that careful consideration regarding timing of MSC harvest is critical. The drug profiles of MSC donors and recipients must be carefully monitored to optimize opportunities to successfully repair damaged tissues.

Diuretic downsides--but in low doses they still seem among the best authenticated antihypertensives.

PubMed

Opie, L H

2000-08-01

Diuretics in low doses have the greatest support among current available antihypertensives in that they have been shown to reduce total mortality, coronary mortality, stroke, and congestive heart failure in an important meta-analysis by Psaty. Recently, Messerli has linked longterm diuretic use to renal cell carcinoma in women. In some patients, diuretic use leads to increasing blood cholesterol and blood sugar levels. Impotence is a recognized side effect, with rates rising about twofold with low-dose chlorthalidone and fourfold with a higher dose. Certain population groups such as younger (<60 years) white males often do not respond to low-dose diuretic therapy with an adequate blood pressure fall. In females of a similar age group, Messerli calculates that prolonged diuretic therapy will prevent only one stroke and no coronary events nor any deaths for every renal cell carcinoma that is provoked. Despite these evident problems, the outcome data on hard endpoints in trials with initial low-dose diuretic therapy remain valid and convincing. Thus, it is argued, low- but not high-dose diuretics retain their primacy in the ranking of antihypertensive therapy.

Effect of sequential pneumatic compression therapy on venous blood velocity, refilling time, pain and quality of life in women with varicose veins: a randomized control study

PubMed Central

Yamany, Abeer; Hamdy, Bassant

2016-01-01

[Purpose] The aim of this study was to investigate the effects of sequential pneumatic compression therapy on venous blood flow, refilling time, pain level, and quality of life in women with varicose veins. [Subjects and Methods] Twenty-eight females with varicose veins were selected and randomly allocated to a control group, and experimental group. Maximum and mean venous blood velocities, the refilling time, pain by visual analog scale and quality of life by Aberdeen Varicose Veins Questionnaire were measured in all patients before and after six weeks of treatment. Both groups received lower extremity exercises; in addition, patients in the experimental group received sequential pneumatic compression therapy for 30 minutes daily, five days a week for six weeks. [Results] All measured parameters improved significantly in both groups, comparison of post treatment measurements between groups showed that the maximum and mean blood flow velocity, the pain level, and quality of life were significantly higher in the experimental group compared with the control group. On the other hand there was no significant difference between groups for refilling time. [Conclusion] Sequential pneumatic compression therapy with the applied parameters was an effective modality for increasing venous blood flow, reducing pain, and improving quality of women life with varicose veins. PMID:27512247

Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

PubMed

Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

2009-06-01

The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P < 0.05) the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05) after exposing the animals to the open field test.

Dosimetric investigation of proton therapy on CT-based patient data using Monte Carlo simulation

NASA Astrophysics Data System (ADS)

Chongsan, T.; Liamsuwan, T.; Tangboonduangjit, P.

2016-03-01

The aim of radiotherapy is to deliver high radiation dose to the tumor with low radiation dose to healthy tissues. Protons have Bragg peaks that give high radiation dose to the tumor but low exit dose or dose tail. Therefore, proton therapy is promising for treating deep- seated tumors and tumors locating close to organs at risk. Moreover, the physical characteristic of protons is suitable for treating cancer in pediatric patients. This work developed a computational platform for calculating proton dose distribution using the Monte Carlo (MC) technique and patient's anatomical data. The studied case is a pediatric patient with a primary brain tumor. PHITS will be used for MC simulation. Therefore, patient-specific CT-DICOM files were converted to the PHITS input. A MATLAB optimization program was developed to create a beam delivery control file for this study. The optimization program requires the proton beam data. All these data were calculated in this work using analytical formulas and the calculation accuracy was tested, before the beam delivery control file is used for MC simulation. This study will be useful for researchers aiming to investigate proton dose distribution in patients but do not have access to proton therapy machines.

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer.

PubMed

Blok, Erik J; Kroep, Judith R; Meershoek-Klein Kranenbarg, Elma; Duijm-de Carpentier, Marjolijn; Putter, Hein; Liefers, Gerrit-Jan; Nortier, Johan W R; Rutgers, Emiel J Th; Seynaeve, Caroline M; van de Velde, Cornelis J H

2018-04-01

For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47-0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38-0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13-1.06), although this additional analysis was underpowered for definite conclusions. This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

Stable disease and improved health-related quality of life (HRQoL) following fractionated low dose 131I-metaiodobenzylguanidine (MIBG) therapy in metastatic paediatric paraganglioma: observation on false "reverse" discordance during pre-therapy work up and its implication for patient selection for high dose targeted therapy.

PubMed

Basu, S; Nair, N

2006-08-01

The incidence of paraganglioma in the paediatric population is exceedingly rare, accounting for < 0.1% of childhood cancers. We report here the response and toxicity profile in a case of malignant paraganglioma which was treated with what is currently perceived as an unconventional and non-standard approach, using three consecutive low doses of 131I-MIBG (a cumulative dose of 11 647.6 MBq). The patient had a stable disease at the end of 42 months follow-up following the first treatment with 131I-MIBG. Excellent symptomatic and hormonal responses were observed. The only adverse effect was mild nausea in the first 24 h after therapy. In addition to the potentially primary end point of radiological and biochemical response measurement, we, in this paper, endeavoured to look for a quality of life evaluation for this form of treatment. Given the rarity of this condition, the experience gained by this therapeutic approach is intriguing from response and toxicity standpoints and may be extrapolated to malignant pheochromocytoma as well. An apparent "reverse discordance" between 131I-MIBG scintigraphy and 99Tc(m)-MDP bone scan encountered during pre-therapy work up is also described with possible explanations. This draws attention to an important clinical issue in selecting patients for high dose targeted therapy.

Sequential combination therapy of ovarian cancer with cisplatin and γ-secretase inhibitor MK-0752.

PubMed

Chen, XiuXiu; Gong, LiHua; Ou, RongYing; Zheng, ZhenZhen; Chen, JinYan; Xie, FengFeng; Huang, XiaoXiu; Qiu, JianGe; Zhang, WenJi; Jiang, QiWei; Yang, Yang; Zhu, Hua; Shi, Zhi; Yan, XiaoJian

2016-03-01

Ovarian cancer is one of the most lethal of women cancers and lack potent therapeutic options. There have many evidences demonstrate the Notch signaling has deregulation in variety of human malignancies.MK-0752 is a novel potent γ-secretase inhibitor and now assessed in clinical trial for treatment of several types of cancer, our objective was to investigate the anticancer effects and mechanisms of MK-0752 alone or combined with cisplatin in ovarian cancer. Cell lines used: A2780, OVCAR3, SKOV3, HO8910PM, the effects of MK-0752 and cisplatin on cell proliferation were measured by MTT assay. The effect of combination treatment was examined by isobologram analysis. The distribution of cell cycle and cell apoptosis were analyzed using PI and Annexin V-FITC/PI staining by flow cytometric analysis. The mechanism in biochemistry was analyzed by using Western blot. Mouse xenograft model of A2780 was established to observe the anti-ovarian cancer effects in vivo setting, nude mice were randomized into four groups (n=6 per group) and treated every 4 days with control (solvent) group, MK-0752(25mg/kg) group, cisplatin (2mg/kg)group, combination group (both of MK-0752 and cisplatin). MK-0752 alone actively induced cell growth inhibition, G2/M phase cell cycle arrest and apoptosis with down-regulation of Notch1 and its downstream effectors including Hes1, XIAP, c-Myc and MDM2 in a dose- and time-dependent manner. Moreover, sequential combination of cisplatin prior to MK-0752 significantly promoted cell apoptosis and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice. Our data supports the sequential combination of cisplatin prior to MK-0752 is a highly promising novel experimental therapeutic strategy against ovarian cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways.

PubMed

Rasul, Azhar; Yu, Bo; Khan, Muhammad; Zhang, Kun; Iqbal, Furhan; Ma, Tonghui; Yang, Hong

2012-04-01

Gastric cancer is the fourth most commonly diagnosed cancer with the second highest mortality rate worldwide. Surgery, chemotherapy and radiation therapy are generally used for the treatment of stomach cancer but only limited clinical response is shown by these therapies and still no effectual therapy for advanced gastric adenocarcinoma patients is available. Therefore, there is a need to identify other therapeutic agents against this life-threatening disease. Plants are considered as one of the most important sources for the development of anticancer drugs. Magnolol, a natural compound possesses anticancer properties. However, effects of Magnolol on human gastric cancer remain unexplored. The effects of Magnolol on the viability of SGC-7901 cells were determined by the MTT assay. Apoptosis, mitochondrial membrane potential and cell cycle were evaluated by flow cytometry. Protein expression of Bcl-2, Bax, caspase-3 and PI3K/Akt was analysed by Western blotting. Magnolol induced morphological changes in SGC-7901 cells and its cytotoxic effects were linked with DNA damage, apoptosis and S-phase arrest in a dose-dependent manner. Magnolol triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, dissipation of mitochondrial membrane potential (ΔΨm), and sequential activation of caspase-3 and inhibition of PI3K/Akt. Additionally, Magnolol induced autophagy in SGC-7901 cells at high concentration but was not involved in cell death. Magnolol-induced apoptosis of SGC-7901 cells involves mitochondria and PI3K/Akt-dependent pathways. These findings provide evidence that Magnolol is a promising natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combination antitumor therapies.

Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways

PubMed Central

RASUL, AZHAR; YU, BO; KHAN, MUHAMMAD; ZHANG, KUN; IQBAL, FURHAN; MA, TONGHUI; YANG, HONG

2012-01-01

Gastric cancer is the fourth most commonly diagnosed cancer with the second highest mortality rate worldwide. Surgery, chemotherapy and radiation therapy are generally used for the treatment of stomach cancer but only limited clinical response is shown by these therapies and still no effectual therapy for advanced gastric adenocarcinoma patients is available. Therefore, there is a need to identify other therapeutic agents against this life-threatening disease. Plants are considered as one of the most important sources for the development of anticancer drugs. Magnolol, a natural compound possesses anticancer properties. However, effects of Magnolol on human gastric cancer remain unexplored. The effects of Magnolol on the viability of SGC-7901 cells were determined by the MTT assay. Apoptosis, mitochondrial membrane potential and cell cycle were evaluated by flow cytometry. Protein expression of Bcl-2, Bax, caspase-3 and PI3K/Akt was analysed by Western blotting. Magnolol induced morphological changes in SGC-7901 cells and its cytotoxic effects were linked with DNA damage, apoptosis and S-phase arrest in a dose-dependent manner. Magnolol triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, dissipation of mitochondrial membrane potential (ΔΨm), and sequential activation of caspase-3 and inhibition of PI3K/Akt. Additionally, Magnolol induced autophagy in SGC-7901 cells at high concentration but was not involved in cell death. Magnolol-induced apoptosis of SGC-7901 cells involves mitochondria and PI3K/Akt-dependent pathways. These findings provide evidence that Magnolol is a promising natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combination antitumor therapies. PMID:22139054

Beyond Gaussians: a study of single spot modeling for scanning proton dose calculation

PubMed Central

Li, Yupeng; Zhu, Ronald X.; Sahoo, Narayan; Anand, Aman; Zhang, Xiaodong

2013-01-01

Active spot scanning proton therapy is becoming increasingly adopted by proton therapy centers worldwide. Unlike passive-scattering proton therapy, active spot scanning proton therapy, especially intensity-modulated proton therapy, requires proper modeling of each scanning spot to ensure accurate computation of the total dose distribution contributed from a large number of spots. During commissioning of the spot scanning gantry at the Proton Therapy Center in Houston, it was observed that the long-range scattering protons in a medium may have been inadequately modeled for high-energy beams by a commercial treatment planning system, which could lead to incorrect prediction of field-size effects on dose output. In the present study, we developed a pencil-beam algorithm for scanning-proton dose calculation by focusing on properly modeling individual scanning spots. All modeling parameters required by the pencil-beam algorithm can be generated based solely on a few sets of measured data. We demonstrated that low-dose halos in single-spot profiles in the medium could be adequately modeled with the addition of a modified Cauchy-Lorentz distribution function to a double-Gaussian function. The field-size effects were accurately computed at all depths and field sizes for all energies, and good dose accuracy was also achieved for patient dose verification. The implementation of the proposed pencil beam algorithm also enabled us to study the importance of different modeling components and parameters at various beam energies. The results of this study may be helpful in improving dose calculation accuracy and simplifying beam commissioning and treatment planning processes for spot scanning proton therapy. PMID:22297324

Anthrax

DTIC Science & Technology

2009-01-01

antimicrobials listed below) Initial therapye (intravenous dosing) Oral dosing Initial therapy (intravenous) IV treatment initially Switch to oral...high index of suspicion for anthrax, initiation of therapy should not be delayed for results of these confirmatory tests. 1. MICROBIOLOGICAL TESTS...Sputum specimens from inhalational anthrax patients should be plated on chocolate agar, SBA, and MAC. Cultures will show isolated B. anthracis

[Clinical effect of Saccharomyces boulardii powder combined with azithromycin sequential therapy in treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia].

PubMed

Chen, Qi-Fen; Zhang, Yi-Wei

2018-02-01

To investigate the clinical effect of Saccharomyces boulardii powder combined with azithromycin sequential therapy in the treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia. A total of 88 children with diarrhea secondary to Mycoplasma pneumoniae pneumonia between June 2015 and March 2017 were divided into control group and study group using a random number table, with 44 children in each group. The children in the control group were given routine treatment combined with azithromycin sequential therapy, and those in the study group were given oral Saccharomyces boulardii powder in addition to the treatment in the control group until the end of azithromycin sequential therapy. After the treatment ended, the two groups were compared in terms of time to improvement of clinical symptoms, length of hospital stay, clinical outcome, defecation frequency before and after treatment, condition of intestinal dysbacteriosis, and incidence of adverse events. Compared with the control group, the study group had significantly shorter time to improvement of clinical symptoms and length of hospital stay (P<0.05). The study group had a significantly higher response rate than the control group (P<0.05). On days 3 and 5 of treatment, the study group had a significant reduction in defecation frequency compared with the control group (P<0.05). The study group had a significantly lower rate of intestinal dysbacteriosis than the control group (P<0.05). There was no significant difference in the incidence of adverse events between the two groups (P>0.05). In the treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia, Saccharomyces boulardii powder combined with azithromycin sequential therapy can improve clinical symptoms, shorten the length of hospital stay, reduce defecation frequency and the incidence of intestinal dysbacteriosis, and improve clinical outcomes, and does not increase the risk of adverse events.

Predictors of High-Grade Esophagitis after Definitive 3D Conformal Therapy, Intensity Modulated Radiation Therapy, or Proton Beam Therapy for Non-Small Cell Lung Cancer

PubMed Central

Gomez, Daniel R.; Tucker, Susan L.; Martel, Mary K.; Mohan, Radhe; Balter, Peter A.; Guerra, Jose Luis Lopez; Liu, Hongmei; Komaki, Ritsuko; Cox, James D.; Liao, Zhongxing

2014-01-01

Introduction We analyzed the ability of various patient- and treatment-related factors to predict radiation-induced esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with three-dimensional (3D) conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton beam therapy (PBT). Methods and Materials Patients were treated for NSCLC with 3D-CRT, IMRT, or PBT at MD Anderson from 2000 to 2008 and had full dose-volume histogram (DVH) data available. The endpoint was severe (grade ≥3) RE. The Lyman-Kutcher-Burman (LKB) model was used to analyze RE as a function of the fractional esophageal DVH, with clinical variables included as dose-modifying factors. Results Overall, 652 patients were included: 405 treated with 3D-CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade ≥3 RE were 8%, 28%, and 6%, with a median time to onset of 42 days (range 11–93 days). A fit of the fractional-DVH LKB model demonstrated that the volume parameter n was significantly different (p=0.046) than 1, indicating that high doses to small volumes are more predictive than mean esophageal dose. The model fit was better for 3D-CRT and PBT than for IMRT. Including receipt of concurrent chemotherapy as a dose-modifying factor significantly improved the LKB model (p=0.005), and the model was further improved by including a variable representing treatment with >30 fractions. Examining individual types of chemotherapy agents revealed a trend toward receipt of concurrent taxanes and increased risk of RE (p=0.105). Conclusions The fractional dose (dose rate) and number of fractions (total dose) distinctly affect the risk of severe RE estimated using the LKB model, and concurrent chemotherapy improves the model fit. This risk of severe RE is underestimated by this model in patients receiving IMRT. PMID:22920974

Terminate Lung Cancer (TLC) Study - A mixed-methods population approach to increase lung cancer screening awareness and low-dose computed tomography in Eastern Kentucky

PubMed Central

Cardarelli, Roberto; Reese, David; Roper, Karen L.; Cardarelli, Kathryn; Feltner, Frances J.; Studts, Jamie L.; Knight, Jennifer R.; Armstrong, Debra; Weaver, Anthony; Shaffer, Dana

2017-01-01

For low dose CT lung cancer screening to be effective in curbing disease mortality, efforts are needed to overcome barriers to awareness and facilitate uptake of the current evidence-based screening guidelines. A sequential mixed-methods approach was employed to design a screening campaign utilizing messages developed from community focus groups, followed by implementation of the outreach campaign intervention in two high-risk Kentucky regions. This study reports on rates of awareness and screening in intervention regions, as compared to a control region. PMID:27866066

Delivery confirmation of bolus electron conformal therapy combined with intensity modulated x-ray therapy

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

Kavanaugh, James A.; Hogstrom, Kenneth R.; Fontenot, Jonas P.

2013-02-15

Purpose: The purpose of this study was to demonstrate that a bolus electron conformal therapy (ECT) dose plan and a mixed beam plan, composed of an intensity modulated x-ray therapy (IMXT) dose plan optimized on top of the bolus ECT plan, can be accurately delivered. Methods: Calculated dose distributions were compared with measured dose distributions for parotid and chest wall (CW) bolus ECT and mixed beam plans, each simulated in a cylindrical polystyrene phantom that allowed film dose measurements. Bolus ECT plans were created for both parotid and CW PTVs (planning target volumes) using 20 and 16 MeV beams, respectively,more » whose 90% dose surface conformed to the PTV. Mixed beam plans consisted of an IMXT dose plan optimized on top of the bolus ECT dose plan. The bolus ECT, IMXT, and mixed beam dose distributions were measured using radiographic films in five transverse and one sagittal planes for a total of 36 measurement conditions. Corrections for film dose response, effects of edge-on photon irradiation, and effects of irregular phantom optical properties on the Cerenkov component of the film signal resulted in high precision measurements. Data set consistency was verified by agreement of depth dose at the intersections of the sagittal plane with the five measured transverse planes. For these same depth doses, results for the mixed beam plan agreed with the sum of the individual depth doses for the bolus ECT and IMXT plans. The six mean measured planar dose distributions were compared with those calculated by the treatment planning system for all modalities. Dose agreement was assessed using the 4% dose difference and 0.2 cm distance to agreement. Results: For the combined high-dose region and low-dose region, pass rates for the parotid and CW plans were 98.7% and 96.2%, respectively, for the bolus ECT plans and 97.9% and 97.4%, respectively, for the mixed beam plans. For the high-dose gradient region, pass rates for the parotid and CW plans were 93.1% and 94.62%, respectively, for the bolus ECT plans and 89.2% and 95.1%, respectively, for the mixed beam plans. For all regions, pass rates for the parotid and CW plans were 98.8% and 97.3%, respectively, for the bolus ECT plans and 97.5% and 95.9%, respectively, for the mixed beam plans. For the IMXT component of the mixed beam plans, pass rates for the parotid and CW plans were 93.7% and 95.8%. Conclusions: Bolus ECT and mixed beam therapy dose delivery to the phantom were more accurate than IMXT delivery, adding confidence to the use of planning, fabrication, and delivery for bolus ECT tools either alone or as part of mixed beam therapy. The methodology reported in this work could serve as a basis for future standardization of the commissioning of bolus ECT or mixed beam therapy. When applying this technology to patients, it is recommended that an electron dose algorithm more accurate than the pencil beam algorithm, e.g., a Monte Carlo algorithm or analytical transport such as the pencil beam redefinition algorithm, be used for planning to ensure the desired accuracy.« less

Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction

PubMed Central

Keller, Frieder; Schröppel, Bernd; Ludwig, Ulla

2015-01-01

Patients with cancer have a high inherent risk of infectious complications. In addition, the incidence of acute and chronic kidney dysfunction rises in this population. Anti-infective drugs often require dosing modifications based on an estimate of kidney function, usually the glomerular filtration rate (GFR). However, there is still no preferential GFR formula to be used, and in acute kidney injury there is always a considerable time delay between true kidney function and estimated GFR. In most cases, the anti-infective therapy should start with an immediate and high loading dose. Pharmacokinetic as well as pharmacodynamic principles must be applied for further dose adjustment. Anti-infective drugs with time-dependent action should be given with the target of high trough concentrations (e.g., beta lactam antibiotics, penems, vancomycin, antiviral drugs). Anti-infective drugs with concentration-dependent action should be given with the target of high peak concentrations (e.g., aminoglycosides, daptomycin, colistin, quinolones). Our group created a pharmacokinetic database, called NEPharm, hat serves as a reference to obtain reliable dosing regimens of anti-infective drugs in kidney dysfunction as well as renal replacement therapy. To avoid the risk of either too low or too infrequent peak concentrations, we prefer the eliminated fraction rule for dose adjustment calculations. PMID:26167456

Pentobarbital quantitation using EMIT serum barbiturate assay reagents: application to monitoring of high-dose pentobarbital therapy.

PubMed

Pape, B E; Cary, P L; Clay, L C; Godolphin, W

1983-01-01

Pentobarbital serum concentrations associated with a high-dose therapeutic regimen were determined using EMIT immunoassay reagents. Replicate analyses of serum controls resulted in a within-assay coefficient of variation of 5.0% and a between-assay coefficient of variation of 10%. Regression analysis of 44 serum samples analyzed by this technique (y) and a reference procedure (x) were y = 0.98x + 3.6 (r = 0.98; x = ultraviolet spectroscopy) and y = 1.04x + 2.4 (r = 0.96; x = high-performance liquid chromatography). Clinical evaluation of the results indicates the immunoassay is sufficiently sensitive and selective for pentobarbital to allow accurate quantitation within the therapeutic range associated with high-dose therapy.

Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

PubMed Central

Zhou, Kejin; Nguyen, Liem H.; Miller, Jason B.; Yan, Yunfeng; Kos, Petra; Xiong, Hu; Li, Lin; Hao, Jing; Minnig, Jonathan T.; Siegwart, Daniel J.

2016-01-01

RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC50 < 0.02 mg/kg siRNA against FVII (siFVII)] in dose–response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer’s own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs. PMID:26729861

Variability of serial same-day left ventricular ejection fraction using quantitative gated SPECT.

PubMed

Vallejo, Enrique; Chaya, Hugo; Plancarte, Gerardo; Victoria, Diana; Bialostozky, David

2002-01-01

The accuracy of quantitative gated single photon emission computed tomography (SPECT) (QGS) and the potential limitations for estimation of left ventricular ejection fraction (LVEF) have been extensively evaluated. However, few studies have focused on the serial variability of QGS. This study was conducted to assess the serial variability of QGS for determination of LVEF between 2 sequential technetium 99m sestamibi-gated SPECT acquisitions at rest in both healthy and unhealthy subjects. The study population consisted of 2 groups: group I included 21 volunteers with a low likelihood of CAD, and group II included 22 consecutive patients with documented CAD. Both groups underwent serial SPECT imaging. The overall correlation between sequential images was high (r = 0.94, SEE = 5.3%), and the mean serial variability of LVEF was 5.15% +/- 3.51%. Serial variability was lower for images with high counts (3.45% +/- 3.23%) than for images with low counts (6.85% +/- 3.77%). The mean serial variability was not different between normal and abnormal high-dose images (3.0% +/- 1.56% vs 3.9% +/- 2.77%). However, mean serial variability for images derived from abnormal low-dose images was significantly greater than that derived from normal low-dose images (9.6% +/- 2.22% vs 3.1% +/- 2.12%, P <.05). Although QGS is an efficacious method to approximate LVEF values and is extremely valuable for incremental risk stratification of patients with coronary artery disease, it has significant variability in the estimation of LVEF on serial images. This should be taken into account when used for serial evaluation of LVEF.

The NUKDOS software for treatment planning in molecular radiotherapy.

PubMed

Kletting, Peter; Schimmel, Sebastian; Hänscheid, Heribert; Luster, Markus; Fernández, Maria; Nosske, Dietmar; Lassmann, Michael; Glatting, Gerhard

2015-09-01

The aim of this work was the development of a software tool for treatment planning prior to molecular radiotherapy, which comprises all functionality to objectively determine the activity to administer and the pertaining absorbed doses (including the corresponding error) based on a series of gamma camera images and one SPECT/CT or probe data. NUKDOS was developed in MATLAB. The workflow is based on the MIRD formalism For determination of the tissue or organ pharmacokinetics, gamma camera images as well as probe, urine, serum and blood activity data can be processed. To estimate the time-integrated activity coefficients (TIAC), sums of exponentials are fitted to the time activity data and integrated analytically. To obtain the TIAC on the voxel level, the voxel activity distribution from the quantitative 3D SPECT/CT (or PET/CT) is used for scaling and weighting the TIAC derived from the 2D organ data. The voxel S-values are automatically calculated based on the voxel-size of the image and the therapeutic nuclide ((90)Y, (131)I or (177)Lu). The absorbed dose coefficients are computed by convolution of the voxel TIAC and the voxel S-values. The activity to administer and the pertaining absorbed doses are determined by entering the absorbed dose for the organ at risk. The overall error of the calculated absorbed doses is determined by Gaussian error propagation. NUKDOS was tested for the operation systems Windows(®) 7 (64 Bit) and 8 (64 Bit). The results of each working step were compared to commercially available (SAAMII, OLINDA/EXM) and in-house (UlmDOS) software. The application of the software is demonstrated using examples form peptide receptor radionuclide therapy (PRRT) and from radioiodine therapy of benign thyroid diseases. For the example from PRRT, the calculated activity to administer differed by 4% comparing NUKDOS and the final result using UlmDos, SAAMII and OLINDA/EXM sequentially. The absorbed dose for the spleen and tumour differed by 7% and 8%, respectively. The results from the example from radioiodine therapy of benign thyroid diseases and the example given in the latest corresponding SOP were identical. The implemented, objective methods facilitate accurate and reproducible results. The software is freely available. Copyright © 2015. Published by Elsevier GmbH.

Randomized, Multicenter Trial on the Effect of Radiation Therapy on Plantar Fasciitis (Painful Heel Spur) Comparing a Standard Dose With a Very Low Dose: Mature Results After 12 Months' Follow-Up

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

Niewald, Marcus, E-mail: marcus.niewald@uks.eu; Seegenschmiedt, M. Heinrich; Micke, Oliver

2012-11-15

Purpose: To conduct a randomized trial of radiation therapy for painful heel spur, comparing a standard dose with a very low dose. Methods and Materials: Sixty-six patients were randomized to receive radiation therapy either with a total dose of 6.0 Gy applied in 6 fractions of 1.0 Gy twice weekly (standard dose) or with a total dose of 0.6 Gy applied in 6 fractions of 0.1 Gy twice weekly (low dose). In all patients lateral opposing 4- to 6-MV photon beams were used. The results were measured using a visual analogue scale, the Calcaneodynia score, and the SF12 health survey.more » The fundamental phase of the study ended after 3 months, and the follow-up was continued up to 1 year. Patients with insufficient pain relief after 3 months were offered reirradiation with the standard dosage at any time afterward. Results: Of 66 patients, 4 were excluded because of withdrawal of consent or screening failures. After 3 months the results in the standard arm were highly significantly superior compared with those in the low-dose arm (visual analogue scale, P=.001; Calcaneodynia score, P=.027; SF12, P=.045). The accrual of patients was stopped at this point. Further evaluation after 12 months' follow-up showed the following results: (1) highly significant fewer patients were reirradiated in the standard arm compared with the low-dose arm (P<.001); (2) the results of patients in the low-dose arm who were reirradiated were identical to those in the standard arm not reirradiated (reirradiation as a salvage therapy if the lower dose was ineffective); (3) patients experiencing a favorable result after 3 months showed this even after 12 months, and some results even improved further between 3 and 12 months. Conclusions: This study confirms the superior analgesic effect of radiation therapy with 6-Gy doses on painful heel spur even for a longer time period of at least 1 year.« less

Hybrid dose calculation: a dose calculation algorithm for microbeam radiation therapy

NASA Astrophysics Data System (ADS)

Donzelli, Mattia; Bräuer-Krisch, Elke; Oelfke, Uwe; Wilkens, Jan J.; Bartzsch, Stefan

2018-02-01

Microbeam radiation therapy (MRT) is still a preclinical approach in radiation oncology that uses planar micrometre wide beamlets with extremely high peak doses, separated by a few hundred micrometre wide low dose regions. Abundant preclinical evidence demonstrates that MRT spares normal tissue more effectively than conventional radiation therapy, at equivalent tumour control. In order to launch first clinical trials, accurate and efficient dose calculation methods are an inevitable prerequisite. In this work a hybrid dose calculation approach is presented that is based on a combination of Monte Carlo and kernel based dose calculation. In various examples the performance of the algorithm is compared to purely Monte Carlo and purely kernel based dose calculations. The accuracy of the developed algorithm is comparable to conventional pure Monte Carlo calculations. In particular for inhomogeneous materials the hybrid dose calculation algorithm out-performs purely convolution based dose calculation approaches. It is demonstrated that the hybrid algorithm can efficiently calculate even complicated pencil beam and cross firing beam geometries. The required calculation times are substantially lower than for pure Monte Carlo calculations.

Preoperative steroid administration: effect on morbidity among patients undergoing intestinal bowel resection for Crohńs disease.

PubMed

Bruewer, Matthias; Utech, Markus; Rijcken, Emile J M; Anthoni, Christoph; Laukoetter, Mike G; Kersting, Sabine; Senninger, Norbert; Krieglstein, Christian F

2003-12-01

Long-term steroid therapy may predispose to increased perioperative morbidity in patients undergoing surgery with bowel anastomoses. The aim of our study was to review our data to determine if the steroid dosage is associated with the incidence of early complications after bowel resection in patients with prolonged steroid therapy for Crohńs disease (CD). Altogether, 397 patients underwent bowel resection with primary intestinal anastomoses for CD between 1982 and 2000 in our institution. The mortality and morbidity rates, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and length of postoperative hospitalization in patients who were having high-dose (>/= 20 mg of prednisolone per day, n = 73) and low-dose (< 20 mg prednisolone per day, n = 146) steroid therapy for more than 1 month before surgery were compared with those of patients ( n = 177) who were not receiving steroids. Statistical analysis was performed using Fisher's exact test and Student's t-test, with p < 0.05 considered significant. The three groups were similar in terms of gender, duration since first diagnosis, American Society of Anesthesiologists classification, and obesity. Mortality, morbidity, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and average postoperative stay were not statistically different in patients with high-dose, low-dose, or no steroid therapy. The only factor associated with increased morbidity was a low preoperative hemoglobin level. Our results demonstrate that, in patients who are undergoing bowel resection for CD, even high-dose prolonged preoperative systemic steroid therapy is not associated with increased postoperative complications.

Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention.

PubMed

Battes, Linda C; Pedersen, Susanne S; Oemrawsingh, Rohit M; van Geuns, Robert J; Al Amri, Ibtihal; Regar, Evelyn; de Jaegere, Peter P T; Serruys, Patrick; van Domburg, Ron T

2012-02-01

Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose-response relationship between beta blocker dose and depressive symptoms. Patients treated with PCI (N=685) completed the depression scale of the Hospital Anxiety and Depression Scale 1 and 12 months post PCI. Information about type and dose of beta blocker use was extracted from medical records. Of all patients, 68% (466/685) were on beta blocker therapy at baseline. In adjusted analysis, beta blocker use at 1 month post PCI (OR: 0.82; 95% CI: 0.53-1.26) was not significantly associated with depressive symptoms. At 12 months post PCI, there was a significant relationship between beta blocker use and depressive symptoms (OR: 0.51; 95% CI: 0.31-0.84), with beta blocker therapy associated with a 49% risk reduction in depressive symptoms. There was a dose-response relationship between beta blocker dose and depressive symptoms 12 months post PCI, with the risk reduction in depressive symptoms in relation to a low dose being 36% (OR: 0.64; 95% CI: 0.37-1.10) and 58% (OR: 0.42; 95% CI: 0.24-0.76) in relation to a high dose. Patients treated with beta blocker therapy were less likely to experience depressive symptoms 12 months post PCI, with there being a dose-response relationship with a higher dose providing a more pronounced protective effect. Copyright © 2011 Elsevier B.V. All rights reserved.

SU-F-T-635: Lung SBRT: Dosimetric and Treatment Time Comparison of Volumetric-Modulated Arc Therapy and Three-Dimensional Conformal Radiotherapy in Clinically Treated Cases

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

Han, J; Xu, Z; Baker, J

Purpose: To compare three-dimensional conformal radiotherapy (3D CRT) and volumetric-modulated arc therapy (VMAT) in lung stereotactic body radiation therapy (SBRT) Methods: A retrospective study of clinically treated lung SBRT cases treated between 2010 and 2015 at our hospital was performed. All treatment modalities were included in this evaluation (VMAT, 3D CRT, static IMRT, and dynamic conformal arc therapy). However, the majority of treatment modalities were either VMAT or 3D CRT. Treatment times of patients and dosimetric plan quality metrics were compared. Treatment times were calculated based on the time the therapist opened and closed the patient’s treatment plan. This treatmentmore » time closely approximates the utilization time of the treatment room. The dosimetric plan quality metrics evaluated include ICRU conformity index, the volume of 105% prescribed dose outside PTV, the ratio of volume of 50% prescribed dose to the volume of PTV, the percentage of maximum dose at 2 cm away from PTV to the prescribed dose, and the V20 (percentage of lung volume receiving 20 Gy or more). Results: Treatment time comparisons show that on average VMAT has shorter treatment times than 3D CRT. Dose conformity, defined by the ICRU conformity index, and high dose spillage, defined by the volume of 105% dose outside the PTV, is reduced when using VMAT compared to 3D CRT. V20 and intermediate dose spillage/fall-off metrics of VMAT and 3D are not significantly different. Conclusion: Clinically treated lung SBRT cases indicate VMAT is superior to 3D with regard to shorter treatment times, plan dose conformity, and plan high dose spillage.« less

Two-dimensional silicon-based detectors for ion beam therapy

NASA Astrophysics Data System (ADS)

Martišíková, M.; Granja, C.; Jakůbek, J.; Hartmann, B.; Telsemeyer, J.; Huber, L.; Brons, S.; Pospíšil, S.; Jäkel, O.

2012-02-01

Radiation therapy with ion beams is a highly precise kind of cancer treatment. As ion beams traverse material, the highest ionization density occurs at the end of their path. Due to this Bragg-peak, ion beams enable higher dose conformation to the tumor and increased sparing of the surrounding tissue, in comparison to standard radiation therapy using high energy photons. Ions heavier than protons offer in addition increased biological effectiveness and lower scattering. The Heidelberg Ion Beam Therapy Center (HIT) is a state-of-the-art ion beam therapy facility and the first hospital-based facility in Europe. It provides proton and carbon ion treatments. A synchrotron is used for ion acceleration. For dose delivery to the patient, narrow pencil-like beams are scanned over the target volume.

Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.

PubMed

1996-09-07

Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, this treatment carries a risk of bleeding and the need for frequent medical monitoring. We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism. 1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening < or = 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrollment, or being a woman aged over 75 years) were randomly assigned either a combination of low-intensity, fixed-dose warfarin (international normalised ratio [INR] 1.2-1.5 for initial dose adjustment) and aspirin (325 mg/day) or adjusted-dose warfarin (INR 2.0-3.0). Drugs were given open-labelled. The mean INR during follow-up of patients taking combination therapy (n = 521) was 1.3, compared with 2.4 for those taking adjusted-dose warfarin (n = 523). During follow-up, 54% of INRs in patients taking combination therapy were 1.2-1.5 and 34% were less than 1.2. The trial was stopped after a mean, follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7.9% per year) was significantly higher than in those given adjusted-dose warfarin (1.9% per year) at an interim analysis (p < 0.0001), an absolute reduction of 6.0% per year (95% Cl 3.4, 8.6) by adjusted-dose warfarin. The annual rates of disabling stroke (5.6% vs 1.7%, p = 0.0007) and of primary event or vascular death (11.8% vs 6.4%, p = 0.002), were also higher with combination therapy. The rates of major bleeding were similar in both treatment groups. Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2.0-3.0) importantly reduces stroke for high-risk patients.

Vitamin D: Daily vs. Monthly Use in Children and Elderly-What Is Going On?

PubMed

Dalle Carbonare, Luca; Valenti, Maria Teresa; Del Forno, Francesco; Caneva, Elena; Pietrobelli, Angelo

2017-06-24

Vitamin D deficiency is highly prevalent among children and adults worldwide. Agreement exists that vitamin D deficiency should be corrected. However, the definitions of vitamin deficiency and effective vitamin D replacement therapy are inconsistent in the literature. Not only is the dosing regimen still under debate, but also the time and period of administration (i.e., daily vs. monthly dose). In pediatric as well as elderly subjects, dosing regimens with high vitamin D doses at less frequent intervals were proposed to help increase compliance to treatment: these became widespread in clinical practice, despite mounting evidence that such therapies are not only ineffective but potentially harmful, particularly in elderly subjects. Moreover, in the elderly, high doses of vitamin D seem to increase the risk of functional decline and are associated with a higher risk of falls and fractures. Achieving good adherence to recommended prophylactic regimens is definitely one of the obstacles currently being faced in view of the wide segment of the population liable to the treatment and the very long duration of prophylaxis. The daily intake for extended periods is in fact one of the frequent causes of therapeutic drop-outs, while monthly doses of vitamin D may effectively and safely improve patient compliance to the therapy. The aim of our paper is a quasi-literature review on dosing regimens among children and elderly. These two populations showed a particularly significant beneficial effect on bone metabolism, and there could be different outcomes with different dosing regimens.

Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

PubMed Central

Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

2014-01-01

Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity. PMID:24963332

Clinical study on prospective efficacy of all-trans Acid, realgar-indigo naturalis formula combined with chemotherapy as maintenance treatment of acute promyelocytic leukemia.

PubMed

Xiang-Xin, Li; Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

2014-01-01

Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity.

Treatment of Bowen Disease With Photodynamic Therapy and the Advantages of Sequential Topical Imiquimod.

PubMed

Victoria-Martínez, A M; Martínez-Leborans, L; Ortiz-Salvador, J M; Pérez-Ferriols, A

2017-03-01

Photodynamic therapy (PDT) has been shown to be useful and effective in the treatment of actinic keratosis, Bowen disease, and basal cell carcinoma. We present a series of 13 Bowen disease lesions treated using PDT. Complete responses were achieved in 11 (84%) of the lesions after 3 months of treatment; at 18 months, complete responses were seen in 9 (70%) of the lesions. Patients who presented a partial response or recurrence were treated with topical 5% imiquimod and achieved complete responses. The lesions that presented partial response or recurrence were the largest lesions, between 3 and 5cm in diameter. PDT in monotherapy or combined sequentially with imiquimod is an excellent and well-tolerated therapeutic option for Bowen disease. The treatment has few adverse effects and shows satisfactory results, particularly in multiple large lesions in areas of difficult surgical reconstruction or in elderly patients with a high surgical risk. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Dosimetric feasibility of 4DCT-ventilation imaging guided proton therapy for locally advanced non-small-cell lung cancer.

PubMed

Huang, Qijie; Jabbour, Salma K; Xiao, Zhiyan; Yue, Ning; Wang, Xiao; Cao, Hongbin; Kuang, Yu; Zhang, Yin; Nie, Ke

2018-04-25

The principle aim of this study is to incorporate 4DCT ventilation imaging into functional treatment planning that preserves high-functioning lung with both double scattering and scanning beam techniques in proton therapy. Eight patients with locally advanced non-small-cell lung cancer were included in this study. Deformable image registration was performed for each patient on their planning 4DCTs and the resultant displacement vector field with Jacobian analysis was used to identify the high-, medium- and low-functional lung regions. Five plans were designed for each patient: a regular photon IMRT vs. anatomic proton plans without consideration of functional ventilation information using double scattering proton therapy (DSPT) and intensity modulated proton therapy (IMPT) vs. functional proton plans with avoidance of high-functional lung using both DSPT and IMPT. Dosimetric parameters were compared in terms of tumor coverage, plan heterogeneity, and avoidance of normal tissues. Our results showed that both DSPT and IMPT plans gave superior dose advantage to photon IMRTs in sparing low dose regions of the total lung in terms of V5 (volume receiving 5Gy). The functional DSPT only showed marginal benefit in sparing high-functioning lung in terms of V5 or V20 (volume receiving 20Gy) compared to anatomical plans. Yet, the functional planning in IMPT delivery, can further reduce the low dose in high-functioning lung without degrading the PTV dosimetric coverages, compared to anatomical proton planning. Although the doses to some critical organs might increase during functional planning, the necessary constraints were all met. Incorporating 4DCT ventilation imaging into functional proton therapy is feasible. The functional proton plans, in intensity modulated proton delivery, are effective to further preserve high-functioning lung regions without degrading the PTV coverage.

Standard and Nonstandard Craniospinal Radiotherapy Using Helical TomoTherapy

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

Parker, William, E-mail: william@medphys.mcgill.c; Brodeur, Marylene; Roberge, David

2010-07-01

Purpose: To show the advantages of planning and delivering craniospinal radiotherapy with helical TomoTherapy (TomoTherapy Inc., Madison, WI) by presenting 4 cases treated at our institution. Methods and Materials: We first present a standard case of craniospinal irradiation in a patient with recurrent myxopapillary ependymoma (MPE) and follow this with 2 cases requiring differential dosing to multiple target volumes. One of these, a patient with recurrent medulloblastoma, required a lower dose to be delivered to the posterior fossa because the patient had been previously irradiated to the full dose, and the other required concurrent boosts to leptomeningeal metastases as partmore » of his treatment for newly diagnosed MPE. The final case presented is a patient with pronounced scoliosis who required spinal irradiation for recurrent MPE. Results: The four cases presented were planned and treated successfully with Helical Tomotherapy. Conclusions: Helical TomoTherapy delivers continuous arc-based intensity-modulated radiotherapy that gives high conformality and excellent dose homogeneity for the target volumes. Increased healthy tissue sparing is achieved at higher doses albeit at the expense of larger volumes of tissue receiving lower doses. Helical TomoTherapy allows for differential dosing of multiple targets, resulting in very elegant dose distributions. Daily megavoltage computed tomography imaging allows for precision of patient positioning, permitting a reduction in planning margins and increased healthy tissue sparing in comparison with standard techniques.« less

SU-D-16A-02: A Novel Methodology for Accurate, Semi-Automated Delineation of Oral Mucosa for Radiation Therapy Dose-Response Studies

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

Dean, J; Welsh, L; Gulliford, S

Purpose: The significant morbidity caused by radiation-induced acute oral mucositis means that studies aiming to elucidate dose-response relationships in this tissue are a high priority. However, there is currently no standardized method for delineating the mucosal structures within the oral cavity. This report describes the development of a methodology to delineate the oral mucosa accurately on CT scans in a semi-automated manner. Methods: An oral mucosa atlas for automated segmentation was constructed using the RayStation Atlas-Based Segmentation (ABS) module. A radiation oncologist manually delineated the full surface of the oral mucosa on a planning CT scan of a patient receivingmore » radiotherapy (RT) to the head and neck region. A 3mm fixed annulus was added to incorporate the mucosal wall thickness. This structure was saved as an atlas template. ABS followed by model-based segmentation was performed on four further patients sequentially, adding each patient to the atlas. Manual editing of the automatically segmented structure was performed. A dose comparison between these contours and previously used oral cavity volume contours was performed. Results: The new approach was successful in delineating the mucosa, as assessed by an experienced radiation oncologist, when applied to a new series of patients receiving head and neck RT. Reductions in the mean doses obtained when using the new delineation approach, compared with the previously used technique, were demonstrated for all patients (median: 36.0%, range: 25.6% – 39.6%) and were of a magnitude that might be expected to be clinically significant. Differences in the maximum dose that might reasonably be expected to be clinically significant were observed for two patients. Conclusion: The method developed provides a means of obtaining the dose distribution delivered to the oral mucosa more accurately than has previously been achieved. This will enable the acquisition of high quality dosimetric data for use in dose-response studies. We would like to thank the Engineering and Physical Sciences Research Council for funding. We acknowledge support from the NIHR RM/ICR Biomedical Research Centre. RayStatation was used under an evaluation agreement with RaySearch Laboratories AB.« less

Sequential Therapy with Crizotinib and Alectinib in ALK-Rearranged Non-Small Cell Lung Cancer-A Multicenter Retrospective Study.

PubMed

Ito, Kentaro; Hataji, Osamu; Kobayashi, Hiroyasu; Fujiwara, Atsushi; Yoshida, Masamichi; D'Alessandro-Gabazza, Corina N; Itani, Hidetoshi; Tanigawa, Motoaki; Ikeda, Takuya; Fujiwara, Kentaro; Fujimoto, Hajime; Kobayashi, Tetsu; Gabazza, Esteban C; Taguchi, Osamu; Yamamoto, Nobuyuki

2017-02-01

Alectinib and crizotinib have been approved for the therapy of NSCLC caused by anaplastic lymphoma kinase gene (ALK) rearrangement. The effect of alectinib or crizotinib on overall survival (OS) in patients with ALK-rearranged NSCLC remains unknown. A multicenter retrospective study was conducted to compare OS between patients receiving alectinib and crizotinib and between patients treated with alectinib and those treated sequentially with crizotinib and then alectinib after crizotinib failure. The time to treatment failure (TTF), progression-free survival (PFS), and OS were compared. Sixty-one patients with ALK-rearranged NSCLC were enrolled. Forty-six patients were treated with anaplastic lymphoma kinase (ALK) inhibitors (31 with crizotinib, 28 with alectinib, and 13 with both ALK inhibitors). The response rate was 66.7% for the crizotinib-treated group and 80.8% for the alectinib-treated group. Among all patients, TTF and PFS were significantly prolonged in the alectinib-treated group compared with in the crizotinib-treated group. Subgroup analyses revealed significantly prolonged TTF for alectinib compared with crizotinib therapy in the ALK inhibitor-naive population. OS was significantly longer in the alectinib-treated group than in the crizotinib-treated group. The TTF and OS of patients treated sequentially with crizotinib and then with alectinib after crizotinib failure tended to be longer than those of patients treated with alectinib alone. Therapy with alectinib alone was significantly superior to therapy with crizotinib alone in terms of TTF, PFS, and OS, and sequential therapy with crizotinib and alectinib after crizotinib failure tended to provide a better OS benefit than did therapy with alectinib alone in patients with ALK-positive NSCLC. However, large-scale prospective studies are needed to confirm these observations. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

PubMed Central

Meng, Fanfei; Han, Ning; Yeo, Yoon

2017-01-01

Introduction Chemotherapeutic drugs are used in combination to target multiple mechanisms involved in cancer cell survival and proliferation. Carriers are developed to deliver drug combinations to common target tissues in optimal ratios and desirable sequences. Nanoparticles (NP) have been a popular choice for this purpose due to their ability to increase the circulation half-life and tumor accumulation of a drug. Areas covered We review organic NP carriers based on polymers, proteins, peptides, and lipids for simultaneous delivery of multiple anticancer drugs, drug/sensitizer combinations, drug/photodynamic- or photothermal therapy combinations, and drug/gene therapeutics with examples in the past three years. Sequential delivery of drug combinations, based on either sequential administration or built-in release control, is introduced with an emphasis on the mechanistic understanding of such control. Expert opinion Recent studies demonstrate how a drug carrier can contribute to co-localizing drug combinations in optimal ratios and dosing sequences to maximize the synergistic effects. We identify several areas for improvement in future research, including the choice of drug combinations, circulation stability of carriers, spatiotemporal control of drug release, and the evaluation and clinical translation of combination delivery. PMID:27476442

Behavioral and stimulant treatment of hyperactive children: a therapy study with methylphenidate probes in a within-subject design.

PubMed

Pelham, W E; Schnedler, R W; Bologna, N C; Contreras, J A

1980-01-01

Eight hyperactive children were treated with a behavioral intervention focusing on teacher and parent training over a period of 5 months. Three times, before therapy and after 3 weeks and 13 weeks of intervention, children received methylphenidate during 3-week probe periods. Each week in a probe they received either a placebo, .25 mg/kg, or .75 mg/kg methylphenidate. Classroom observation of on-task behavior suggested that effectiveness of the behavioral intervention was between that of the two dosages of medication before therapy. Both dosages resulted in higher levels of on-task behavior when administered after 13 weeks of behavioral intervention than when administered before therapy. Teacher rating data showed equivalent effects of therapy and the low dosage of methylphenidate alone but a stronger effect of the high dose alone; only the high dose resulted in improved behavior after 13 weeks of behavioral intervention. As a group, only when they received the high dose of methylphenidate after 13 weeks of behavioral intervention did children reach the level of appropriate behavior shown by nonhyperactive controls. However, this level was also reached by two children with the low dose and by one child without medication, and it was not reached by one child. The results suggest that the combination of psychostimulant medication and behavior therapy may be more effective in the short-term than either treatment alone for hyperactive children in school settings. In addition, parent ratings and clinic observation of parent-child interactions suggested that children had improved in the home setting, high-lighting the importance of behavioral parent training in the treatment of hyperactivity.

A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes.

PubMed

Serra-Guillén, Carlos; Nagore, Eduardo; Hueso, Luis; Traves, Victor; Messeguer, Francesc; Sanmartín, Onofre; Llombart, Beatriz; Requena, Celia; Botella-Estrada, Rafael; Guillén, Carlos

2012-04-01

Photodynamic therapy (PDT) and imiquimod are the treatments of choice for actinic keratosis (AK). As they have different mechanisms of action, it seems reasonable to assume that applying both treatments sequentially would be efficacious. We sought to determine which of these therapeutic modalities provides a better clinical and histologic response in patients with AK and whether sequential use of both was more efficacious than each separately. Patients were randomly assigned to one treatment group: group 1, PDT only; group 2, imiquimod only; or group 3, sequential use of PDT and imiquimod. The primary outcome measure was complete clinical response. Partial clinical response was defined as a reduction of more than 75% in the initial number of lesions. A complete clinicopathologic response was defined as lack of evidence of AK in the biopsy specimen. In all, 105 patients completed the study (group 1, 40 patients; group 2, 33 patients; group 3, 32 patients). Sequential application of PDT and imiquimod was more efficacious in all the outcome measures. More patients were satisfied with PDT than with the other two modalities (P = .003). No significant differences were observed among the 3 modalities and tolerance to treatment. Only one cycle of imiquimod was administered. The follow-up period was brief. Sequential application of PDT and imiquimod provides a significantly better clinical and histologic response in the treatment of AK than PDT or imiquimod monotherapy. It also produces less intense local reactions and better tolerance and satisfaction than imiquimod monotherapy. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Long-term sequelae of autologous bone marrow or peripheral stem cell transplantation for lymphoid malignancies.

PubMed

Vose, J M; Kennedy, B C; Bierman, P J; Kessinger, A; Armitage, J O

1992-02-01

The study was made to evaluate the long-term physical and psychosocial changes after high-dose therapy and autologous bone marrow or peripheral stem transplantation for recurrent lymphoid malignancies. Patients who had undergone high dose therapy and autologous bone marrow or peripheral stem cell transplantation for recurrent lymphoid malignancies at least 1 year previously were contacted by phone interview regarding their status after the transplant. The patients' comments were confirmed by checking medical records when possible. Fifty patients who had undergone transplantation at the University of Nebraska Medical Center at least 1 year before the interview were available for interview and willing to answer questions. After transplant, many patients noticed temporary changes in their appearance, which usually returned to normal within 1 year. Few patients reported remarkable cardiovascular, gastrointestinal, or pulmonary changes after transplantation. However, up to one-third of the patients reported changes in sexual function or desire. The most common infectious problem after transplant was Herpes zoster, which occurred in 25% of the patients. Overall, the patients had a positive outlook after high-dose therapy and transplantation, with most being able to return to work and enjoy a normal life style. Ninety-six percent of the patients stated that they would be willing to undergo high-dose therapy and transplantation again under the same circumstances.

Emergence of a daptomycin-non-susceptible Enterococcus faecium strain that encodes mutations in DNA repair genes after high-dose daptomycin therapy.

PubMed

Matono, Takashi; Hayakawa, Kayoko; Hirai, Risen; Tanimura, Akira; Yamamoto, Kei; Fujiya, Yoshihiro; Mawatari, Momoko; Kutsuna, Satoshi; Takeshita, Nozomi; Mezaki, Kazuhisa; Ohmagari, Norio; Miyoshi-Akiyama, Tohru

2016-04-01

An increasing number of reports have documented the emergence of daptomycin-nonsusceptible Enterococcus in patients during daptomycin therapy. Even though several mechanisms for daptomycin-nonsusceptibility have been suggested, the potential genetic mutations which might contribute to the daptomycin-nonsusceptibility are not fully understood. We isolated a vancomycin-susceptible, daptomycin nonsusceptible Enterococcus faecium strain from a patient with acute lymphocytic leukemia who received high-dose daptomycin therapy for E. faecium endocarditis. Whole-genome sequencing analysis revealed mutations within genes encoding DNA repair proteins MutL and RecJ of the daptomycin-nonsusceptible Enterococcus strain which might have facilitated its emergence. We identified the mutations of DNA mismatch repair genes in a clinical isolate of daptomycin nonsusceptible E. faecium which emerged in spite of high-dose daptomycin therapy. The finding implicates the possible association of DNA repair mechanism and daptomycin resistance. Careful monitoring is necessary to avoid the emergence of daptomycin non-susceptible isolates of E. faecium and particularly in cases of long-term daptomycin use or in immunocompromised patients.

Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

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

Brade, Anthony M., E-mail: anthony.brade@rmp.uhn.on.ca; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario; Ng, Sylvia

Purpose: To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). Methods and Materials: Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated.more » Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. Results: Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level −1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. Conclusions: Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.« less

SU-F-J-203: Retrospective Assessment of Delivered Proton Dose in Prostate Cancer Patients Based On Daily In-Room CT Imaging

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

Stuetzer, K; Paessler, T; Valentini, C

Purpose: Retrospective calculation of the delivered proton dose in prostate cancer patients based on a unique dataset of daily CT images. Methods: Inter-fractional motion in prostate cancer patients treated at our proton facility is counteracted by water-filled endorectal ballon and bladder filling protocol. Typical plans (XiO, Elekta Instruments AB, Stockholm) for 74 Gy(RBE) sequential boost treatment in 37 fractions include two series of opposing lateral double-scattered proton beams covering the respective iCTV. Stability of fiducial markers and anatomy were checked in 12 patients by daily scheduled in-room control CT (cCT) after immobilization and positioning according to bony anatomy utilizing orthogonalmore » X-ray. In RayStation 4.6 (RaySearch Laboritories AB, Stockholm), all cCTs are delineated retrospectively and the treatment plans were recalculated on the planning CT and the registered cCTs. All fraction doses were accumulated on the planning CT after deformable registration. Parameters of delivered dose to iCTV (D98%>95%, D2%<107%), bladder (V75Gy<15%, V70Gy<25%, V65Gy<30%), rectum (V70Gy<10%, V50Gy<40%) and femoral heads (V50Gy<5%) are compared to those in the treatment plan. Intra-therapy variation is represented in DVH bands. Results: No alarming differences were observed between planned and retrospectively accumulated dose: iCTV constraints were met, except for one patient (D98%=94.6% in non-boosted iCTV). Considered bladder and femoral head values were below the limits. Rectum V70Gy was slightly exceeded (<11.3%) in two patients. First intra-therapy variability analysis in 4 patients showed no timedependent parameter drift, revealed strongest variability for bladder dose. In some fractions, iCTV coverage (D98%) and rectum V70Gy was missed. Conclusion: Double scattered proton plans are accurately delivered to prostate cancer patients due to fractionation effects and the applied precise positioning and immobilization protocols. As a result of rare interventions after daily 3D imaging of the first 12 patients, in-room CT frequency for prostate cancer patients was reduced. The presented study supports this decision. The authors acknowledge the German Federal Ministry for Education and Research for funding the High Precision Radiotherapy Group at the OncoRay - National Center for Radiation Research in Oncology (BMBF- 03Z1N51).« less

Double-modulation of 5-Fluorouracil by methotrexate and leucovorin in advanced colorectal-carcinoma.

PubMed

Leone, B; Romero, A; Rabinovich, M; Vallejo, C; Bianco, A; Perez, J; Rodriguez, R; Cuevas, M; Machiavelli, M; Paris, A; Lacava, J

1993-11-01

A phase II trial was performed to evaluate the efficacy and toxicity of a double modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and leucovorin (LV) as first line chemotherapy in advanced colorectal carcinoma. Between January 1990, and April 1992, 42 patients with metastatic or advanced recurrent (inoperable) colorectal cancer were entered into the study. Therapy consisted of a sequential combination of MTX, LV and 5-FU. MTX was administered at a dose of 150 mg/m2 over 20 minutes I.V. infusion at hour (h) 0, followed 19 h later by LV 50 mg/m2 over 2 h infusion. 5-FU 900 mg/m2 was given by I.V. push injection at h 20. Starting 24 h after MTX administration all patients received LV 15 mg/m2 intramuscularly every 6 h for six doses. Treatment was repeated every 15 days until progressive disease, severe toxicity, or death. Four patients were considered not evaluable for response. Objective regression (OR) was observed in 14 of 38 patients (37%, 95% confidence interval 23-53%). Two patients (5%) obtained complete response (CR) and 12 (32%) partial response (PR). Median time to treatment failure was 6 months (range 1-21). Median survival for the whole group of patients was 13 months (range 1-27). Toxicity was within acceptable limits but one therapy-related death due to severe leukopenia and sepsis was observed. Double modulation of 5-FU with MTX and low dose of LV is an active regimen against advanced colorectal carcinoma and represents a promising strategy that should be further explored.

Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas.

PubMed

Cortelazzo, Sergio; Tarella, Corrado; Gianni, Alessandro Massimo; Ladetto, Marco; Barbui, Anna Maria; Rossi, Andrea; Gritti, Giuseppe; Corradini, Paolo; Di Nicola, Massimo; Patti, Caterina; Mulé, Antonino; Zanni, Manuela; Zoli, Valerio; Billio, Atto; Piccin, Andrea; Negri, Giovanni; Castellino, Claudia; Di Raimondo, Francesco; Ferreri, Andrés J M; Benedetti, Fabio; La Nasa, Giorgio; Gini, Guido; Trentin, Livio; Frezzato, Maurizio; Flenghi, Leonardo; Falorio, Simona; Chilosi, Marco; Bruna, Riccardo; Tabanelli, Valentina; Pileri, Stefano; Masciulli, Arianna; Delaini, Federica; Boschini, Cristina; Rambaldi, Alessandro

2016-11-20

Purpose The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%) International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. Results Clinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% ( P = .83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = .034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = .12), or overall survival (74% v 77%, respectively; P = .64). Significantly higher hematologic toxicity ( P < .001) and more infectious complications ( P < .001) were observed in the R-HDS arm. Conclusion In this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas.

SU-E-T-295: Simultaneous Beam Sampling and Aperture Shape Optimization for Station Parameter Optimized Radiation Therapy (SPORT)

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

Zarepisheh, M; Li, R; Xing, L

Purpose: Station Parameter Optimized Radiation Therapy (SPORT) was recently proposed to fully utilize the technical capability of emerging digital LINACs, in which the station parameters of a delivery system, (such as aperture shape and weight, couch position/angle, gantry/collimator angle) are optimized altogether. SPORT promises to deliver unprecedented radiation dose distributions efficiently, yet there does not exist any optimization algorithm to implement it. The purpose of this work is to propose an optimization algorithm to simultaneously optimize the beam sampling and aperture shapes. Methods: We build a mathematical model whose variables are beam angles (including non-coplanar and/or even nonisocentric beams) andmore » aperture shapes. To solve the resulting large scale optimization problem, we devise an exact, convergent and fast optimization algorithm by integrating three advanced optimization techniques named column generation, gradient method, and pattern search. Column generation is used to find a good set of aperture shapes as an initial solution by adding apertures sequentially. Then we apply the gradient method to iteratively improve the current solution by reshaping the aperture shapes and updating the beam angles toward the gradient. Algorithm continues by pattern search method to explore the part of the search space that cannot be reached by the gradient method. Results: The proposed technique is applied to a series of patient cases and significantly improves the plan quality. In a head-and-neck case, for example, the left parotid gland mean-dose, brainstem max-dose, spinal cord max-dose, and mandible mean-dose are reduced by 10%, 7%, 24% and 12% respectively, compared to the conventional VMAT plan while maintaining the same PTV coverage. Conclusion: Combined use of column generation, gradient search and pattern search algorithms provide an effective way to optimize simultaneously the large collection of station parameters and significantly improves quality of resultant treatment plans as compared with conventional VMAT or IMRT treatments.« less

Better Efficacy of Synchrotron Spatially Microfractionated Radiation Therapy Than Uniform Radiation Therapy on Glioma.

PubMed

Bouchet, Audrey; Bräuer-Krisch, Elke; Prezado, Yolanda; El Atifi, Michèle; Rogalev, Léonid; Le Clec'h, Céline; Laissue, Jean Albert; Pelletier, Laurent; Le Duc, Géraldine

2016-08-01

Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly focused synchrotron beam into arrays of parallel microbeams, typically a few tens of microns wide and depositing several hundred grays. This irradiation modality was shown to have a high therapeutic impact on tumors, especially in intracranial locations. However, mechanisms responsible for such a property are not fully understood. Thanks to recent progress in dosimetry, we compared the effect of MRT and synchrotron broad beam (BB) radiation therapy delivered at comparable doses (equivalent to MRT valley dose) on tumor growth control and on classical radiobiological functions by histologic evaluation and/or transcriptomic analysis. MRT significantly improved survival of rats bearing 9L intracranial glioma compared with BB radiation therapy delivered at a comparable dose (P<.001); the efficacy of MRT and BB radiation therapy was similar when the MRT dose was half that of BB. The greater efficacy of MRT was not correlated with a difference in cell proliferation (Mki67 and proliferating cell nuclear antigen) or in transcriptomic stimulation of angiogenesis (vascular endothelial growth factor A or tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2) but was correlated with a higher cell death rate (factor for apoptosis signals) and higher recruitment of macrophages (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and CD68 transcripts) a few days after MRT. These results show the superiority of MRT over BB radiation therapy when applied at comparable doses, suggesting that spatial fractionation is responsible for a specific and particularly efficient tissue response. The higher induction of cell death and immune cell activation in brain tumors treated by MRT may be involved in such responses. Copyright © 2016 Elsevier Inc. All rights reserved.

Better Efficacy of Synchrotron Spatially Microfractionated Radiation Therapy Than Uniform Radiation Therapy on Glioma

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

Bouchet, Audrey, E-mail: audrey.m.bouchet@gmail.com; Biomedical Beamline, European Synchrotron Radiation Facility, Grenoble; Bräuer-Krisch, Elke

Purpose: Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly focused synchrotron beam into arrays of parallel microbeams, typically a few tens of microns wide and depositing several hundred grays. This irradiation modality was shown to have a high therapeutic impact on tumors, especially in intracranial locations. However, mechanisms responsible for such a property are not fully understood. Methods and Materials: Thanks to recent progress in dosimetry, we compared the effect of MRT and synchrotron broad beam (BB) radiation therapy delivered at comparable doses (equivalent to MRT valley dose) on tumor growth control andmore » on classical radiobiological functions by histologic evaluation and/or transcriptomic analysis. Results: MRT significantly improved survival of rats bearing 9L intracranial glioma compared with BB radiation therapy delivered at a comparable dose (P<.001); the efficacy of MRT and BB radiation therapy was similar when the MRT dose was half that of BB. The greater efficacy of MRT was not correlated with a difference in cell proliferation (Mki67 and proliferating cell nuclear antigen) or in transcriptomic stimulation of angiogenesis (vascular endothelial growth factor A or tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2) but was correlated with a higher cell death rate (factor for apoptosis signals) and higher recruitment of macrophages (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and CD68 transcripts) a few days after MRT. Conclusions: These results show the superiority of MRT over BB radiation therapy when applied at comparable doses, suggesting that spatial fractionation is responsible for a specific and particularly efficient tissue response. The higher induction of cell death and immune cell activation in brain tumors treated by MRT may be involved in such responses.« less

Cost-effectiveness analysis of intensity-modulated radiation therapy with normal and hypofractionated schemes for the treatment of localised prostate cancer.

PubMed

Zemplényi, A T; Kaló, Z; Kovács, G; Farkas, R; Beöthe, T; Bányai, D; Sebestyén, Z; Endrei, D; Boncz, I; Mangel, L

2018-01-01

The aim of our analysis was to compare the cost-effectiveness of high-dose intensity-modulated radiation therapy (IMRT) and hypofractionated intensity-modulated radiation therapy (HF-IMRT) versus conventional dose three-dimensional radiation therapy (3DCRT) for the treatment of localised prostate cancer. A Markov model was constructed to calculate the incremental quality-adjusted life years and costs. Transition probabilities, adverse events and utilities were derived from relevant systematic reviews. Microcosting in a large university hospital was applied to calculate cost vectors. The expected mean lifetime cost of patients undergoing 3DCRT, IMRT and HF-IMRT were 7,160 euros, 6,831 euros and 6,019 euros respectively. The expected quality-adjusted life years (QALYs) were 5.753 for 3DCRT, 5.956 for IMRT and 5.957 for HF-IMRT. Compared to 3DCRT, both IMRT and HF-IMRT resulted in more health gains at a lower cost. It can be concluded that high-dose IMRT is not only cost-effective compared to the conventional dose 3DCRT but, when used with a hypofractionation scheme, it has great cost-saving potential for the public payer and may improve access to radiation therapy for patients. © 2016 John Wiley & Sons Ltd.

Low-Dose Radiation Potentiates the Therapeutic Efficacy of Folate Receptor-Targeted Hapten Therapy

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

Sega, Emanuela I.; Lu Yingjuan; Ringor, Michael

2008-06-01

Purpose: Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm{sup 3} before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapymore » with low-dose radiotherapy. Methods and Materials: Mice bearing 300-mm{sup 3} subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon {alpha}) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume. Results: Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm{sup 3}. More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy. Conclusions: These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.« less

Low-dose radiation potentiates the therapeutic efficacy of folate receptor-targeted hapten therapy.

PubMed

Sega, Emanuela I; Lu, Yingjuan; Ringor, Michael; Leamon, Christopher P; Low, Philip S

2008-06-01

Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm(3) before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapy with low-dose radiotherapy. Mice bearing 300-mm(3) subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon alpha) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume. Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm(3). More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy. These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.

5-Azacitidine Monotherapy Followed by Related Haploidentical Hematopoietic Stem Cell Transplantation Achieves Durable Remission in a Pediatric Patient With Acute Undifferentiated Leukemia Refractory to High-Dose Chemotherapy.

PubMed

Polishchuk, Veronika; Khazal, Sajad; Berulava, Giorgi; Roth, Michael; Mahadeo, Kris M

2016-06-01

Patients with acute leukemias of undifferentiated lineage (AUL) generally have guarded prognosis. Here, we describe the first reported pediatric patient with AUL refractory to high-dose chemotherapy who achieved clinical remission with ALL maintenance therapy and 5-azacitidine. His induction remission was followed by consolidation with reduced toxicity haploidentical hematopoietic stem cell transplant (HSCT). At 9 months post-HSCT, the patient is alive and in remission. This combination therapy of remission induction with ALL maintenance therapy and 5-azacitidine and consolidation with reduced toxicity haploidentical HSCT is novel and promising for patients who lack conventional donors and are not candidates for myeloablative therapy. © 2016 Wiley Periodicals, Inc.

The role of intraoperative radiation therapy in patients with pancreatic cancer.

PubMed

Palta, Manisha; Willett, Christopher; Czito, Brian

2014-04-01

Intraoperative radiation therapy (IORT) techniques allow for the delivery of high doses of radiation therapy while excluding part or all of the nearby dose-limiting sensitive structures. Therefore, the effective radiation dose is increased and local tumor control potentially improved. This is pertinent in the case of pancreatic cancer because local failure rates are as high as 50%-80% in patients with resected and locally advanced disease. Available data in patients receiving IORT after pancreaticoduodenectomy reveal an improvement in local control, though overall survival benefit is unclear. Series of patients with locally advanced pancreatic cancer also suggest pain relief, and in select studies, improved survival associated with the inclusion of IORT. At present, no phase III data clearly supports the use of IORT in the management of pancreatic cancer. © 2013 Published by Elsevier Inc.

Imaging doses in radiation therapy from kilovoltage cone-beam computed tomography

NASA Astrophysics Data System (ADS)

Hyer, Daniel Ellis

Advances in radiation treatment delivery, such as intensity modulated radiation therapy (IMRT), have made it possible to deliver large doses of radiation with a high degree of conformity. While highly conformal treatments offers the advantage of sparing surrounding normal tissue, this benefit can only be realized if the patient is accurately positioned during each treatment fraction. The need to accurately position the patient has led to the development and use of gantry mounted kilovoltage cone-beam computed tomography (kV-CBCT) systems. These systems are used to acquire high resolution volumetric images of the patient which are then digitally registered with the planning CT dataset to confirm alignment of the patient on the treatment table. While kV-CBCT is a very useful tool for aligning the patient prior to treatment, daily use in a high fraction therapy regimen results in a substantial radiation dose. In order to quantify the radiation dose associated with CBCT imaging, an anthropomorphic phantom representing a 50th percentile adult male and a fiber-optic coupled (FOC) dosimetry system were both constructed as part of this dissertation. These tools were then used to directly measure organ doses incurred during clinical protocols for the head, chest, and pelvis. For completeness, the dose delivered from both the X-ray Volumetric Imager (XVI, Elekta Oncology Systems, Crawley, UK) and the On-Board Imager (OBI, Varian Medical Systems, Palo Alto, CA) were investigated. While this study provided a direct measure of organ doses for estimating risk to the patient, a practical method for estimating organ doses that could be performed with phantoms and dosimeters currently available at most clinics was also desired. To accomplish this goal, a 100 mm pencil ion chamber was used to measure the "cone beam dose index" (CBDI) inside standard CT dose index (CTDI) acrylic phantoms. A weighted CBDI (CBDIw), similar to the weighted CT dose index (CTDIw), was then calculated to represent the average dose in the acrylic phantom. By comparing this value to the measured organ doses, organ dose conversion coefficients were developed. These conversion coefficients allow specific organ doses to be estimated quickly and easily using readily available clinical equipment.

A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion.

PubMed

Shimada, Shigeki; Takeda, Masamitsu; Nishihira, Jun; Kaneuchi, Masanori; Sakuragi, Noriaki; Minakami, Hisanori; Yamada, Hideto

2009-11-01

A high dose of intravenous immunoglobulin (HIVIg) therapy is effective in various diseases such as autoimmune diseases, and also is expected to have efficacy in recurrent spontaneous abortion (RSA). The aim of this study was to understand immunological mechanisms of this therapy. By flowcytometric analyses, we examined phenotypic changes of a variety of immunological cells including natural killer (NK) cells, cytotoxic T cells, regulatory T cells and macrophages in peripheral blood of RSA women with HIVIg therapy (n = 8). Expression percentages of inhibitory CD94 on NK cells significantly (P = 0.01) increased after the therapy (58.8 +/- 21.4% versus 71.0 +/- 17.6%). Mechanisms of possible efficacy of HIVIg therapy for RSA may include enhancement of CD94 expression and subsequent suppression of NK cell cytotoxicity.

Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma.

PubMed

Jethava, Y; Mitchell, A; Zangari, M; Waheed, S; Schinke, C; Thanendrarajan, S; Sawyer, J; Alapat, D; Tian, E; Stein, C; Khan, R; Heuck, C J; Petty, N; Avery, D; Steward, D; Smith, R; Bailey, C; Epstein, J; Yaccoby, S; Hoering, A; Crowley, J; Morgan, G; Barlogie, B; van Rhee, F

2016-07-29

Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance.

High-dose methylprednisolone pulse therapy for treatment of refractory intestinal involvement caused by Henoch-Schönlein purpura: a case report.

PubMed

Kang, Hyun Sik; Chung, Hee Sup; Kang, Ki-Soo; Han, Kyoung Hee

2015-03-24

Henoch-Schönlein purpura is an immunoglobulin A-mediated, small vascular inflammatory disease that can be associated with palpable purpura, arthralgia, abdominal pain, or nephritis. The presence of purpura facilitates the diagnosis of Henoch-Schönlein purpura at the onset of associated symptoms, whereas the absence of purpura makes the diagnosis challenging. It is important to diagnose Henoch-Schönlein purpura with delayed-onset skin purpura to avoid unnecessary surgery for acute abdomen. Most cases of Henoch-Schönlein purpura with severe abdominal pain are treated with low-dose steroids and intravenous immunoglobulin. A 15-year-old Korean girl complained of severe abdominal pain and delayed-onset purpura on admission. Henoch-Schönlein purpura was diagnosed based on endoscopic findings of hemorrhagic duodenitis and duodenal vasculitis and abdominal computed tomography findings of edematous bowels. Two common initial treatments, a low-dose steroid and intravenous immunoglobulin, were administered, but there was no improvement for 1 month. Subsequently, we used high-dose intravenous methylprednisolone pulse therapy (30 mg/kg/day, with a maximum of 1g/day), which dramatically alleviated her abdominal symptoms. High-dose intravenous methylprednisolone pulse therapy can be used as the ultimate treatment for delayed-onset Henoch-Schönlein purpura with severe abdominal pain when symptoms do not improve after low-dose steroid and intravenous immunoglobulin treatments.

A small-scale anatomical dosimetry model of the liver

NASA Astrophysics Data System (ADS)

Stenvall, Anna; Larsson, Erik; Strand, Sven-Erik; Jönsson, Bo-Anders

2014-07-01

Radionuclide therapy is a growing and promising approach for treating and prolonging the lives of patients with cancer. For therapies where high activities are administered, the liver can become a dose-limiting organ; often with a complex, non-uniform activity distribution and resulting non-uniform absorbed-dose distribution. This paper therefore presents a small-scale dosimetry model for various source-target combinations within the human liver microarchitecture. Using Monte Carlo simulations, Medical Internal Radiation Dose formalism-compatible specific absorbed fractions were calculated for monoenergetic electrons; photons; alpha particles; and 125I, 90Y, 211At, 99mTc, 111In, 177Lu, 131I and 18F. S values and the ratio of local absorbed dose to the whole-organ average absorbed dose was calculated, enabling a transformation of dosimetry calculations from macro- to microstructure level. For heterogeneous activity distributions, for example uptake in Kupffer cells of radionuclides emitting low-energy electrons (125I) or high-LET alpha particles (211At) the target absorbed dose for the part of the space of Disse, closest to the source, was more than eight- and five-fold the average absorbed dose to the liver, respectively. With the increasing interest in radionuclide therapy of the liver, the presented model is an applicable tool for small-scale liver dosimetry in order to study detailed dose-effect relationships in the liver.

Prostate brachytherapy

MedlinePlus

Implant therapy - prostate cancer; Radioactive seed placement; Internal radiation therapy - prostate; High dose radiation (HDR) ... CT scan to plan and then place the seeds that deliver radiation into your prostate. The seeds ...

Dose-intensified epirubicin versus standard-dose epirubicin/cyclophosphamide followed by CMF in breast cancer patients with 10 or more positive lymph nodes: results of a randomised trial (GABG-IV E-93) - the German Adjuvant Breast Cancer Group.

PubMed

Eiermann, Wolfgang; Graf, Erika; Ataseven, Beyhan; Conrad, Bettina; Hilfrich, Jörn; Massinger-Biebl, Heidi; Vescia, Sabine; Loibl, Sibylle; von Minckwitz, Gunter; Schumacher, Martin; Kaufmann, Manfred

2010-01-01

To compare dose-intensified epirubicin monotherapy with a standard sequential regimen, patients with primary breast cancer and > or =10 involved axillary nodes were randomised to either four 21-day cycles of epirubicin 120 mg/m(2) (E120; n=202) or four 21-day cycles of epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) (EC) followed by three 28-day cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF; n=209). Simultaneous hormonal treatment was applied in both arms. At 5 years' median follow-up, the 5-year event-free survival (EFS) rates were 47.7% (95% confidence interval [CI], 40.2-55.2%) for E120 and 45.9% (38.5-53.3%) for EC-CMF. E120 was as effective as EC-CMF with regard to EFS (hazard ratio [HR] for E120 versus EC-CMF 1.04; 95% CI, 0.79-1.36; p=0.79) and overall survival (HR 1.06; 95% CI 0.77-1.46; p=0.72). The data demonstrate that 4 cycles of dose-intensified epirubicin monotherapy can be as effective as 7 cycles of standard sequential polychemotherapy in high-risk breast cancer patients with > or =10 positive lymph nodes, despite treatment with a single agent and a shorter treatment duration.

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

PubMed Central

Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

2013-01-01

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely 131I-hypericin (131I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications. PMID:23412554

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications.

PubMed

Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

2013-01-01

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely (131)I-hypericin ((131)I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.

Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks

NASA Technical Reports Server (NTRS)

Shuryak, Igor; Sachs, Rainer K.; Hlatky, Lynn; Mark P. Little; Hahnfeldt, Philip; Brenner, David J.

2006-01-01

Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. Methods: To extend the model to radiation-induced leukemias, we analyzed in addition to cellular initiation, inactivation, and proliferation a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors v^ ho were subjected to much lower radiation doses. Results: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% Cl =-0.2 to 1.9). Conclusions: An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, %Kith reasonable accuracy, risks for radiationinduced leukemia associated with exposure to therapeutic doses of radiation.

[High-dose chemotherapy as a strategy to overcome drug resistance in solid tumors].

PubMed

Selle, Frédéric; Gligorov, Joseph; Soares, Daniele G; Lotz, Jean-Pierre

2016-10-01

The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

American Brachytherapy Society Task Group Report: Combination of brachytherapy and external beam radiation for high-risk prostate cancer.

PubMed

Spratt, Daniel E; Soni, Payal D; McLaughlin, Patrick W; Merrick, Gregory S; Stock, Richard G; Blasko, John C; Zelefsky, Michael J

To review outcomes for high-risk prostate cancer treated with combined modality radiation therapy (CMRT) utilizing external beam radiation therapy (EBRT) with a brachytherapy boost. The available literature for high-risk prostate cancer treated with combined modality radiation therapy was reviewed and summarized. At this time, the literature suggests that the majority of high-risk cancers are curable with multimodal treatment. Several large retrospective studies and three prospective randomized trials comparing CMRT to dose-escalated EBRT have demonstrated superior biochemical control with CMRT. Longer followup of the randomized trials will be required to determine if this will translate to a benefit in metastasis-free survival, disease-specific survival, and overall survival. Although greater toxicity has been associated with CMRT compared to EBRT, recent studies suggest that technological advances that allow better definition and sparing of critical adjacent structures as well as increasing experience with brachytherapy have improved implant quality and the toxicity profile of brachytherapy. The role of androgen deprivation therapy is well established in the external beam literature for high-risk disease, but there is controversy regarding the applicability of these data in the setting of dose escalation. At this time, there is not sufficient evidence for the omission of androgen deprivation therapy with dose escalation in this population. Comparisons with surgery remain limited by differences in patient selection, but the evidence would suggest better disease control with CMRT compared to surgery alone. Due to a series of technological advances, modern combination series have demonstrated unparalleled rates of disease control in the high-risk population. Given the evidence from recent randomized trials, combination therapy may become the standard of care for high-risk cancers. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses.

PubMed

Wach, Achim; Dembowsky, Klaus; Dale, Glenn E

2018-04-01

Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified. Copyright © 2018 American Society for Microbiology.

Late Effects in Pediatric High-risk Neuroblastoma Survivors After Intensive Induction Chemotherapy Followed by Myeloablative Consolidation Chemotherapy and Triple Autologous Stem Cell Transplants.

PubMed

Armstrong, Amy E; Danner-Koptik, Karina; Golden, Shannon; Schneiderman, Jennifer; Kletzel, Morris; Reichek, Jennifer; Gosiengfiao, Yasmin

2018-01-01

Multimodal treatment in high-risk neuroblastoma has modestly improved survival; limited data exist on the late effects from these regimens. We report the sequelae of treatment incorporating 3 consecutive cycles of high-dose therapy and autologous stem cell transplants (ASCTs) without the use of total body irradiation (TBI). We reviewed the medical records of 61 patients treated on or following the Chicago Pilot 2 protocol between 1991 and 2008. Of the 25 patients who are alive (41%), 19 had near complete data to report. Specific treatment modalities and therapy-related side effects were collected. Fourteen of these 19 patients (74%) received 3 cycles of high-dose therapy with ASCT; follow-up occurred over a median of 13.9 years (range, 5.8 to 18.8 y). The majority of late effects were endocrine-related, including growth failure, hypothyroidism, and hypogonadism. Patients also developed secondary neoplasms and skeletal deformities. The most frequent sequela was hearing loss, seen in 17/19 patients. We found a high prevalence of various late effects in survivors of high-risk neuroblastoma using a non-TBI-based regimen including 3 cycles of high-dose therapy with ASCTs. As current treatment regimens recommend tandem ASCT without TBI, it is imperative that we understand and monitor for the sequelae from these modalities.

Improvements in dose calculation accuracy for small off-axis targets in high dose per fraction tomotherapy

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

Hardcastle, Nicholas; Bayliss, Adam; Wong, Jeannie Hsiu Ding

2012-08-15

Purpose: A recent field safety notice from TomoTherapy detailed the underdosing of small, off-axis targets when receiving high doses per fraction. This is due to angular undersampling in the dose calculation gantry angles. This study evaluates a correction method to reduce the underdosing, to be implemented in the current version (v4.1) of the TomoTherapy treatment planning software. Methods: The correction method, termed 'Super Sampling' involved the tripling of the number of gantry angles from which the dose is calculated during optimization and dose calculation. Radiochromic film was used to measure the dose to small targets at various off-axis distances receivingmore » a minimum of 21 Gy in one fraction. Measurements were also performed for single small targets at the center of the Lucy phantom, using radiochromic film and the dose magnifying glass (DMG). Results: Without super sampling, the peak dose deficit increased from 0% to 18% for a 10 mm target and 0% to 30% for a 5 mm target as off-axis target distances increased from 0 to 16.5 cm. When super sampling was turned on, the dose deficit trend was removed and all peak doses were within 5% of the planned dose. For measurements in the Lucy phantom at 9.7 cm off-axis, the positional and dose magnitude accuracy using super sampling was verified using radiochromic film and the DMG. Conclusions: A correction method implemented in the TomoTherapy treatment planning system which triples the angular sampling of the gantry angles used during optimization and dose calculation removes the underdosing for targets as small as 5 mm diameter, up to 16.5 cm off-axis receiving up to 21 Gy.« less

Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer.

PubMed

Freytag, Svend O; Stricker, Hans; Pegg, Jan; Paielli, Dell; Pradhan, Deepak G; Peabody, James; DePeralta-Venturina, Mariza; Xia, Xueqing; Brown, Steve; Lu, Mei; Kim, Jae Ho

2003-11-01

The primary study objective was to determine the safety of intraprostatic administration of a replication-competent, oncolytic adenovirus containing a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (HSV-1 TK) fusion gene concomitant with increasing durations of 5-fluorocytosine and valganciclovir prodrug therapy and conventional-dose three-dimensional conformal radiation therapy (3D-CRT) in patients with newly diagnosed, intermediate- to high-risk prostate cancer. Secondary objectives were to determine the persistence of therapeutic transgene expression in the prostate and to examine early posttreatment response. Fifteen patients in five cohorts received a single intraprostatic injection of 10(12) viral particles of the replication-competent Ad5-CD/TKrep adenovirus on day 1. Two days later, patients were administered 5-fluorocytosine and valganciclovir prodrug therapy for 1 (cohorts 1-3), 2 (cohort 4), or 3 (cohort 5) weeks along with 70-74 Gy 3D-CRT. Sextant needle biopsy of the prostate was obtained at 2 (cohort 1), 3 (cohort 2), and 4 (cohort 3) weeks for determination of the persistence of transgene expression. There were no dose-limiting toxicities and no significant treatment-related adverse events. Ninety-four percent of the adverse events observed were mild to moderate and self-limiting. Acute urinary and gastrointestinal toxicities were similar to those expected for conventional-dose 3D-CRT. Therapeutic transgene expression was found to persist in the prostate for up to 3 weeks after the adenovirus injection. As expected for patients receiving definitive radiation therapy, all patients experienced significant declines in prostate-specific antigen (PSA). The mean PSA half-life in patients administered more than 1 week of prodrug therapy was significantly shorter than that of patients receiving prodrugs for only 1 week (0.6 versus 2.0 months; P < 0.02) and markedly shorter than that reported previously for patients treated with conventional-dose 3D-CRT alone (2.4 months). With a median follow-up of only 9 months, 5 of 10 (50%) patients not treated with androgen-deprivation therapy achieved a serum PSA < or = 0.5 ng/ml. The results demonstrate that replication-competent adenovirus-mediated double-suicide gene therapy can be combined safely with conventional-dose 3D-CRT in patients with intermediate- to high-risk prostate cancer. The shorter than expected PSA half-life in patients receiving more than 1 week of prodrug therapy may suggest a possible interaction between the oncolytic adenovirus and/or double-suicide gene therapies and radiation therapy.

Practical use of a plastic scintillator for quality assurance of electron beam therapy.

PubMed

Yogo, Katsunori; Tatsuno, Yuya; Tsuneda, Masato; Aono, Yuki; Mochizuki, Daiki; Fujisawa, Yoshiki; Matsushita, Akihiro; Ishigami, Minoru; Ishiyama, Hiromichi; Hayakawa, Kazushige

2017-06-07

Quality assurance (QA) of clinical electron beams is essential for performing accurate and safe radiation therapy. However, with advances in radiation therapy, QA has become increasingly labor-intensive and time-consuming. In this paper, we propose a tissue-equivalent plastic scintillator for quick and easy QA of clinical electron beams. The proposed tool comprises a plastic scintillator plate and a charge-coupled device camera that enable the scintillation light by electron beams to be recorded with high sensitivity and high spatial resolution. Further, the Cerenkov image is directly subtracted from the scintillation image to discriminate Cerenkov emissions and accurately measure the dose profiles of electron beams with high spatial resolution. Compared with conventional methods, discrepancies in the depth profile improved from 7% to 2% in the buildup region via subtractive corrections. Further, the output brightness showed good linearity with dose, good reproducibility (deviations below 1%), and dose rate independence (within 0.5%). The depth of 50% dose measured with the tool, an index of electron beam quality, was within  ±0.5 mm of that obtained with an ionization chamber. Lateral brightness profiles agreed with the lateral dose profiles to within 4% and no significant improvement was obtained using Cerenkov corrections. Field size agreed to within 0.5 mm with those obtained with ionization chamber. For clinical QA of electron boost treatment, a disk scintillator that mimics the shape of a patient's breast is applied. The brightness distribution and dose, calculated using a treatment planning system, was generally acceptable for clinical use, except in limited zones. Overall, the proposed plastic scintillator plate tool efficiently performs QA for electron beam therapy and enables simultaneous verification of output constancy, beam quality, depth, and lateral dose profiles during monthly QAs at lower doses of irradiation (small monitor units, MUs).

TH-EF-BRB-01: BEST IN PHYSICS (THERAPY): Dosimetric Comparison of 4π and Clinical IMRT for Cortex-Sparing High-Grade Glioma Treatment

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

Woods, K; Tran, A; Yu, V

Purpose: Thinning of the cerebral cortex has been observed in patients treated with fractionated partial brain radiation therapy and may contribute to cognitive decline following treatment. The extent of this thinning is dose-dependent, and was shown comparable to that of neurodegenerative diseases such as Alzheimer’s disease at one year post-therapy. This study investigates whether 4π radiotherapy can enable better sparing of the cortex and other critical structures when compared to conventional clinical IMRT plans. Methods: Clinical cortex-sparing IMRT plans for 15 high-grade glioma patients were included in this study. 4π radiotherapy plans were created for each patient with 20 intensity-modulatedmore » non-coplanar fields selected with a greedy column-generation optimization. All plans were normalized to deliver 100% of the prescribed dose to 95% of the planning target volume (PTV). The mean and maximum dose to the cerebral cortex and other organs at risk (OARs) were compared for the two plan types, as well as the conformity index (CI), homogeneity index (HI), and 50% dose spillage volume (R50). Results: The 4π plans significantly reduced the mean cortex dose by an average of 16% (range 6% to 27%) compared to the clinical plans. The mean dose to every other OAR compared was also reduced by 15% to 43%, with statistically significant reductions to the brainstem, chiasm, eyes, optic nerves, subcortical whit, and hippocampus. The average maximum doses were also reduced for 10/12 OARs. The R50 was significantly reduced with the 4π plans (>14%) and the homogeneity index was significantly improved. Conclusion: 4π enables significant sparing of the cerebral cortex when treating high-grade gliomas with fractionated partial brain radiation therapy, potentially reducing the risk of harmful dose-dependent cortical thinning. NIH R43CA183390, NIH R01CA188300, Varian Medical Systems.« less

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

Coenzyme Q10 and vitamin E deficiency in Friedreich's ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy.

PubMed

Cooper, J M; Korlipara, L V P; Hart, P E; Bradley, J L; Schapira, A H V

2008-12-01

A pilot study of high dose coenzyme Q(10) (CoQ(10))/vitamin E therapy in Friedreich's ataxia (FRDA) patients resulted in significant clinical improvements in most patients. This study investigated the potential for this treatment to modify clinical progression in FRDA in a randomized double blind trial. Fifty FRDA patients were randomly divided into high or low dose CoQ(10)/ vitamin E groups. The change in International Co-operative Ataxia Ratings Scale (ICARS) was assessed over 2 years as the primary end-point. A post hoc analysis was made using cross-sectional data. At baseline serum CoQ(10) and vitamin E levels were significantly decreased in the FRDA patients (P < 0.001). During the trial CoQ(10) and vitamin E levels significantly increased in both groups (P < 0.01). The primary and secondary end-points were not significantly different between the therapy groups. When compared to cross-sectional data 49% of all patients demonstrated improved ICARS scores. This responder group had significantly lower baseline serum CoQ(10) levels. A high proportion of FRDA patients have a decreased serum CoQ(10) level which was the best predictor of a positive clinical response to CoQ(10)/vitamin E therapy. Low and high dose CoQ(10)/vitamin E therapies were equally effective in improving ICARS scores.

The FLUKA Monte Carlo code coupled with the NIRS approach for clinical dose calculations in carbon ion therapy

NASA Astrophysics Data System (ADS)

Magro, G.; Dahle, T. J.; Molinelli, S.; Ciocca, M.; Fossati, P.; Ferrari, A.; Inaniwa, T.; Matsufuji, N.; Ytre-Hauge, K. S.; Mairani, A.

2017-05-01

Particle therapy facilities often require Monte Carlo (MC) simulations to overcome intrinsic limitations of analytical treatment planning systems (TPS) related to the description of the mixed radiation field and beam interaction with tissue inhomogeneities. Some of these uncertainties may affect the computation of effective dose distributions; therefore, particle therapy dedicated MC codes should provide both absorbed and biological doses. Two biophysical models are currently applied clinically in particle therapy: the local effect model (LEM) and the microdosimetric kinetic model (MKM). In this paper, we describe the coupling of the NIRS (National Institute for Radiological Sciences, Japan) clinical dose to the FLUKA MC code. We moved from the implementation of the model itself to its application in clinical cases, according to the NIRS approach, where a scaling factor is introduced to rescale the (carbon-equivalent) biological dose to a clinical dose level. A high level of agreement was found with published data by exploring a range of values for the MKM input parameters, while some differences were registered in forward recalculations of NIRS patient plans, mainly attributable to differences with the analytical TPS dose engine (taken as reference) in describing the mixed radiation field (lateral spread and fragmentation). We presented a tool which is being used at the Italian National Center for Oncological Hadrontherapy to support the comparison study between the NIRS clinical dose level and the LEM dose specification.

WE-AB-209-10: Optimizing the Delivery of Sequential Fluence Maps for Efficient VMAT Delivery

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

Craft, D; Balvert, M

2016-06-15

Purpose: To develop an optimization model and solution approach for computing MLC leaf trajectories and dose rates for high quality matching of a set of optimized fluence maps to be delivered sequentially around a patient in a VMAT treatment. Methods: We formulate the fluence map matching problem as a nonlinear optimization problem where time is discretized but dose rates and leaf positions are continuous variables. For a given allotted time, which is allocated across the fluence maps based on the complexity of each fluence map, the optimization problem searches for the best leaf trajectories and dose rates such that themore » original fluence maps are closely recreated. Constraints include maximum leaf speed, maximum dose rate, and leaf collision avoidance, as well as the constraint that the ending leaf positions for one map are the starting leaf positions for the next map. The resulting model is non-convex but smooth, and therefore we solve it by local searches from a variety of starting positions. We improve solution time by a custom decomposition approach which allows us to decouple the rows of the fluence maps and solve each leaf pair individually. This decomposition also makes the problem easily parallelized. Results: We demonstrate method on a prostate case and a head-and-neck case and show that one can recreate fluence maps to high degree of fidelity in modest total delivery time (minutes). Conclusion: We present a VMAT sequencing method that reproduces optimal fluence maps by searching over a vast number of possible leaf trajectories. By varying the total allotted time given, this approach is the first of its kind to allow users to produce VMAT solutions that span the range of wide-field coarse VMAT deliveries to narrow-field high-MU sliding window-like approaches.« less

Quantifying the Combined Effect of Radiation Therapy and Hyperthermia in Terms of Equivalent Dose Distributions

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

Kok, H. Petra, E-mail: H.P.Kok@amc.uva.nl; Crezee, Johannes; Franken, Nicolaas A.P.

2014-03-01

Purpose: To develop a method to quantify the therapeutic effect of radiosensitization by hyperthermia; to this end, a numerical method was proposed to convert radiation therapy dose distributions with hyperthermia to equivalent dose distributions without hyperthermia. Methods and Materials: Clinical intensity modulated radiation therapy plans were created for 15 prostate cancer cases. To simulate a clinically relevant heterogeneous temperature distribution, hyperthermia treatment planning was performed for heating with the AMC-8 system. The temperature-dependent parameters α (Gy{sup −1}) and β (Gy{sup −2}) of the linear–quadratic model for prostate cancer were estimated from the literature. No thermal enhancement was assumed for normalmore » tissue. The intensity modulated radiation therapy plans and temperature distributions were exported to our in-house-developed radiation therapy treatment planning system, APlan, and equivalent dose distributions without hyperthermia were calculated voxel by voxel using the linear–quadratic model. Results: The planned average tumor temperatures T90, T50, and T10 in the planning target volume were 40.5°C, 41.6°C, and 42.4°C, respectively. The planned minimum, mean, and maximum radiation therapy doses were 62.9 Gy, 76.0 Gy, and 81.0 Gy, respectively. Adding hyperthermia yielded an equivalent dose distribution with an extended 95% isodose level. The equivalent minimum, mean, and maximum doses reflecting the radiosensitization by hyperthermia were 70.3 Gy, 86.3 Gy, and 93.6 Gy, respectively, for a linear increase of α with temperature. This can be considered similar to a dose escalation with a substantial increase in tumor control probability for high-risk prostate carcinoma. Conclusion: A model to quantify the effect of combined radiation therapy and hyperthermia in terms of equivalent dose distributions was presented. This model is particularly instructive to estimate the potential effects of interaction from different treatment modalities.« less

Differences in Normal Tissue Response in the Esophagus Between Proton and Photon Radiation Therapy for Non-Small Cell Lung Cancer Using In Vivo Imaging Biomarkers.

PubMed

Niedzielski, Joshua S; Yang, Jinzhong; Mohan, Radhe; Titt, Uwe; Mirkovic, Dragan; Stingo, Francesco; Liao, Zhongxing; Gomez, Daniel R; Martel, Mary K; Briere, Tina M; Court, Laurence E

2017-11-15

To determine whether there exists any significant difference in normal tissue toxicity between intensity modulated radiation therapy (IMRT) or proton therapy for the treatment of non-small cell lung cancer. A total of 134 study patients (n=49 treated with proton therapy, n=85 with IMRT) treated in a randomized trial had a previously validated esophageal toxicity imaging biomarker, esophageal expansion, quantified during radiation therapy, as well as esophagitis grade (Common Terminology Criteria for Adverse Events version 3.0), on a weekly basis during treatment. Differences between the 2 modalities were statically analyzed using the imaging biomarker metric value (Kruskal-Wallis analysis of variance), as well as the incidence and severity of esophagitis grade (χ 2 and Fisher exact tests, respectively). The dose-response of the imaging biomarker was also compared between modalities using esophageal equivalent uniform dose, as well as delivered dose to an isotropic esophageal subvolume. No statistically significant difference in the distribution of esophagitis grade, the incidence of grade ≥3 esophagitis (15 and 11 patients treated with IMRT and proton therapy, respectively), or the esophageal expansion imaging biomarker between cohorts (P>.05) was found. The distribution of imaging biomarker metric values had similar distributions between treatment arms, despite a slightly higher dose volume in the proton arm (P>.05). Imaging biomarker dose-response was similar between modalities for dose quantified as esophageal equivalent uniform dose and delivered esophageal subvolume dose. Regardless of treatment modality, there was high variability in imaging biomarker response, as well as esophagitis grade, for similar esophageal doses between patients. There was no significant difference in esophageal toxicity from either proton- or photon-based radiation therapy as quantified by esophagitis grade or the esophageal expansion imaging biomarker. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of FDG-PET on radiation therapy volume delineation in non-small-cell lung cancer.

PubMed

Bradley, Jeffrey; Thorstad, Wade L; Mutic, Sasa; Miller, Tom R; Dehdashti, Farrokh; Siegel, Barry A; Bosch, Walter; Bertrand, Rudi J

2004-05-01

Locoregional failure remains a significant problem for patients receiving definitive radiation therapy alone or combined with chemotherapy for non-small-cell lung cancer (NSCLC). Positron emission tomography (PET) with [(18)F]fluoro-2-deoxy-d-glucose (FDG) has proven to be a valuable diagnostic and staging tool for NSCLC. This prospective study was performed to determine the impact of treatment simulation with FDG-PET and CT on radiation therapy target volume definition and toxicity profiles by comparison to simulation with computed tomography (CT) scanning alone. Twenty-six patients with Stages I-III NSCLC were studied. Each patient underwent sequential CT and FDG-PET simulation on the same day. Immobilization devices used for both simulations included an alpha cradle, a flat tabletop, 6 external fiducial markers, and a laser positioning system. A radiation therapist participated in both simulations to reproduce the treatment setup. Both the CT and fused PET/CT image data sets were transferred to the radiation treatment planning workstation for contouring. Each FDG-PET study was reviewed with the interpreting nuclear radiologist before tumor volumes were contoured. The fused PET/CT images were used to develop the three-dimensional conformal radiation therapy (3DCRT) plan. A second physician, blinded to the results of PET, contoured the gross tumor volumes (GTV) and planning target volumes (PTV) from the CT data sets, and these volumes were used to generate mock 3DCRT plans. The PTV was defined by a 10-mm margin around the GTV. The two 3DCRT plans for each patient were compared with respect to the GTV, PTV, mean lung dose, volume of normal lung receiving > or =20 Gy (V20), and mean esophageal dose. The FDG-PET findings altered the AJCC TNM stage in 8 of 26 (31%) patients; 2 patients were diagnosed with metastatic disease based on FDG-PET and received palliative radiation therapy. Of the 24 patients who were planned with 3DCRT, PET clearly altered the radiation therapy volume in 14 (58%), as follows. PET helped to distinguish tumor from atelectasis in all 3 patients with atelectasis. Unsuspected nodal disease was detected by PET in 10 patients, and 1 patient had a separate tumor focus detected within the same lobe of the lung. Increases in the target volumes led to increases in the mean lung dose, V20, and mean esophageal dose. Decreases in the target volumes in the patients with atelectasis led to decreases in these normal-tissue toxicity parameters. Radiation targeting with fused FDG-PET and CT images resulted in alterations in radiation therapy planning in over 50% of patients by comparison with CT targeting. The increasing availability of integrated PET/CT units will facilitate the use of this technology for radiation treatment planning. A confirmatory multicenter, cooperative group trial is planned within the Radiation Therapy Oncology Group.

[Sequential prescriptions: Arguments for a change of therapeutic patterns in treatment resistant depressions].

PubMed

Allouche, G

2016-02-01

Among the therapeutic strategies in treatment of resistant depression, the use of sequential prescriptions is discussed here. A number of observations, initially quite isolated and few controlled studies, some large-scale, have been reported, which showed a definite therapeutic effect of certain requirements in sequential treatment of depression. The Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D) is up to now the largest clinical trial exploring treatment strategies in non psychotic resistant depression in real-life conditions with an algorithm of sequential decision. The main conclusions of this study are the following: after two unsuccessful attempts, the chance of remission decreases considerably. A 12-months follow-up showed that the higher the use of the processing steps were high, the more common the relapses were during this period. The pharmacological differences between psychotropic did not cause clinically significant difference. The positive effect of lithium in combination with antidepressants has been known since the work of De Montigny. Antidepressants allow readjustment of physiological sequence involving different monoaminergic systems together. Studies with tricyclic antidepressant-thyroid hormone T3: in depression, decreased norepinephrine at the synaptic receptors believed to cause hypersensitivity of these receptors. Thyroid hormones modulate the activity of adrenergic receptors. There would be a balance of activity between alpha and beta-adrenergic receptors, depending on the bioavailability of thyroid hormones. ECT may in some cases promote pharmacological response in case of previous resistance, or be effective in preventing relapse. Cognitive therapy and antidepressant medications likely have an effect on different types of depression. We can consider the interest of cognitive therapy in a sequential pattern after effective treatment with an antidepressant effect for treatment of residual symptoms, preventing relapses and recurrences, in antidepressant maintenance. These data support the interest of therapeutic strategies based on evolutionary criteria. Sequential models inspired by statistical methods may incorporate the effects of a future treatment by measuring the current one. Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

PubMed

Miyauchi, Katsumi; Kimura, Takeshi; Shimokawa, Hiroaki; Daida, Hiroyuki; Iimuro, Satoshi; Iwata, Hiroshi; Ozaki, Yukio; Sakuma, Ichiro; Nakagawa, Yoshihisa; Hibi, Kiyoshi; Hiro, Takafumi; Fukumoto, Yoshihiro; Hokimoto, Seiji; Ohashi, Yasuo; Ohtsu, Hiroshi; Saito, Yasushi; Matsuzaki, Masunori; Nagai, Ryozo

2018-03-30

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival

PubMed Central

Ratanarat, Ranistha; Brendolan, Alessandra; Piccinni, Pasquale; Dan, Maurizio; Salvatori, Gabriella; Ricci, Zaccaria; Ronco, Claudio

2005-01-01

Introduction Severe sepsis is the leading cause of mortality in critically ill patients. Abnormal concentrations of inflammatory mediators appear to be involved in the pathogenesis of sepsis. Based on the humoral theory of sepsis, a potential therapeutic approach involves high-volume haemofiltration (HVHF), which has exhibited beneficial effects in severe sepsis, improving haemodynamics and unselectively removing proinflammatory and anti-inflammatory mediators. However, concerns have been expressed about the feasibility and costs of continuous HVHF. Here we evaluate a new modality, namely pulse HVHF (PHVHF; 24-hour schedule: HVHF 85 ml/kg per hour for 6–8 hours followed by continuous venovenous haemofiltration 35 ml/kg per hour for 16–18 hours). Method Fifteen critically ill patients (seven male; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score 31.2, mean Simplified Acute Physiology Score [SAPS] II 62, and mean Sequential Organ Failure Assessment 14.2) with severe sepsis underwent daily PHVHF. We measured changes in haemodynamic variables and evaluated the dose of noradrenaline required to maintain mean arterial pressure above 70 mmHg during and after pulse therapy at 6 and 12 hours. PHVHF was performed with 250 ml/min blood flow rate. The bicarbonate-based replacement fluid was used at a 1:1 ratio in simultaneous pre-dilution and post-dilution. Results No treatment was prematurely discontinued. Haemodynamics were improved by PHVHF, allowing a significant reduction in noradrenaline dose during and at the end of the PHVHF session; this reduction was maintained at 6 and 12 hours after pulse treatment (P = 0.001). There was also an improvement in systolic blood pressure (P = 0.04). There were no changes in temperature, cardiac index, oxygenation, arterial pH or urine output during the period of observation. The mean daily Kt/V was 1.92. Predicted mortality rates were 72% (based on APACHE II score) and 68% (based on SAPS II score), and the observed 28-day mortality was 47%. Conclusion PHVHF is a feasible modality and improves haemodynamics both during and after therapy. It may be a beneficial adjuvant treatment for severe sepsis/septic shock in terms of patient survival, and it represents a compromise between continuous renal replacement therapy and HVHF. PMID:16137340

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)—Patient Version

Cancer.gov

Childhood non-Hodgkin lymphoma treatment can include chemotherapy, radiation therapy, targeted therapy, and high-dose chemotherapy with stem cell transplant. Learn more in this expert-reviewed summary.

Safety aspects of incobotulinumtoxinA high-dose therapy.

PubMed

Dressler, Dirk; Saberi, Fereshte Adib; Kollewe, Katja; Schrader, Christoph

2015-02-01

Botulinum toxin (BT) used for dystonia and spasticity is dosed according to the number of target muscles and the severity of their muscle hyperactivities. With this no other drug is used in a broader dose range than BT. The upper end of this range, however, still needs to be explored. We wanted to do this by a prospective non-interventional study comparing a randomly selected group of dystonia and spasticity patients receiving incobotulinumtoxinA (Xeomin(®)) high-dose therapy (HD group, n = 100, single dose ≥400 MU) to a control group receiving incobotulinumtoxinA regular-dose therapy (RD group, n = 30, single dose ≤200 MU). At the measurement point all patients were evaluated for systemic BT toxicity, i.e. systemic motor impairment or systemic autonomic dysfunction. HD group patients (56.1 ± 13.8 years, 46 dystonia, 54 spasticity) were treated with Xeomin(®) 570.1 ± 158.9 (min 400, max 1,200) MU during 10.2 ± 7.0 (min 4, max 37) injection series. In dystonia patients the number of target muscles was 46 and the dose per target muscle 56.4 ± 19.1 MU, in spasticity patients 35 and 114.9 ± 67.1 MU. HD and RD group patients reported 58 occurrences of items on the systemic toxicity questionnaire. Generalised weakness, being bedridden, feeling of residual urine and constipation were caused by the underlying tetra- or paraparesis, blurred vision by presbyopia. Dysphagia and dryness of eye were local BT adverse effects. Neurologic examination, serum chemistry and full blood count did not indicate any systemic adverse effects. Elevated serum levels for creatine kinase/MB, creatine kinase and lactate dehydrogenase were most likely iatrogenic artefacts. None of the patients developed antibody-induced therapy failure. Xeomin(®) can be used safely in doses ≥400 MU and up to 1,200 MU without detectable systemic toxicity. This allows expanding the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies-carefully designed and rigorously monitored-are necessary to explore the threshold dose for clinically detectable systemic toxicity.

SU-E-J-124: 18F-FDG PET Imaging to Improve RT Treatment Outcome for Locally Advanced Lung Cancer

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

Shusharina, N; Khan, F; Sharp, G

2015-06-15

Purpose: To investigate spatial correlation between high uptake regions of pre- and 10-days-post therapy{sup 1} {sup 8}F-FDG PET in recurrent lung cancer and to evaluate the feasibility of dose escalation boosting only regions with high FDG uptake identified on baseline PET. Methods: Nineteen patients with stages II– IV inoperable lung cancer were selected. Volumes of interest (VOI) on pre-therapy FDG-PET were defined using an isocontour at ≥50% of SUVmax. VOI of pre- and post-therapy PET images were correlated for the extent of overlap. A highly optimized IMRT plan to 60 Gy prescribed to PTV defined on the planning CT wasmore » designed using clinical dose constraints for the organs at risk. A boost of 18 Gy was prescribed to the VOI defined on baseline PET. A composite plan of the total 78 Gy was compared with the base 60 Gy plan. Increases in dose to the lungs, spinal cord and heart were evaluated. IMRT boost plan was compared with proton RT and SBRT boost plans. Results: Overlap fraction of baseline PET VOI with the VOI on 10 days-post therapy PET was 0.8 (95% CI: 0.7 – 0.9). Using baseline VOI as a boosting volume, dose could be escalated to 78 Gy for 15 patients without compromising the dose constraints. For 4 patients, the dose limiting factors were V20Gy and Dmean for the total lung, and Dmax for the spinal cord. An increase of the dose to OARs correlated significantly with the relative size of the boost volume. Conclusion: VOI defined on baseline 18F-FDG PET by the SUVmax-≥50% isocontour may be a biological target volume for escalated radiation dose. Dose escalation to this volume may provide improved tumor control without breaching predefined dose constraints for OARs. The best treatment outcome may be achieved with proton RT for large targets and with SBRT for small targets.« less

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

Yang, Y M; Bush, K; Han, B

Purpose: Accurate and fast dose calculation is a prerequisite of precision radiation therapy in modern photon and particle therapy. While Monte Carlo (MC) dose calculation provides high dosimetric accuracy, the drastically increased computational time hinders its routine use. Deterministic dose calculation methods are fast, but problematic in the presence of tissue density inhomogeneity. We leverage the useful features of deterministic methods and MC to develop a hybrid dose calculation platform with autonomous utilization of MC and deterministic calculation depending on the local geometry, for optimal accuracy and speed. Methods: Our platform utilizes a Geant4 based “localized Monte Carlo” (LMC) methodmore » that isolates MC dose calculations only to volumes that have potential for dosimetric inaccuracy. In our approach, additional structures are created encompassing heterogeneous volumes. Deterministic methods calculate dose and energy fluence up to the volume surfaces, where the energy fluence distribution is sampled into discrete histories and transported using MC. Histories exiting the volume are converted back into energy fluence, and transported deterministically. By matching boundary conditions at both interfaces, deterministic dose calculation account for dose perturbations “downstream” of localized heterogeneities. Hybrid dose calculation was performed for water and anthropomorphic phantoms. Results: We achieved <1% agreement between deterministic and MC calculations in the water benchmark for photon and proton beams, and dose differences of 2%–15% could be observed in heterogeneous phantoms. The saving in computational time (a factor ∼4–7 compared to a full Monte Carlo dose calculation) was found to be approximately proportional to the volume of the heterogeneous region. Conclusion: Our hybrid dose calculation approach takes advantage of the computational efficiency of deterministic method and accuracy of MC, providing a practical tool for high performance dose calculation in modern RT. The approach is generalizable to all modalities where heterogeneities play a large role, notably particle therapy.« less

American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer

PubMed Central

Burstein, Harold J.; Prestrud, Ann Alexis; Seidenfeld, Jerome; Anderson, Holly; Buchholz, Thomas A.; Davidson, Nancy E.; Gelmon, Karen E.; Giordano, Sharon H.; Hudis, Clifford A.; Malin, Jennifer; Mamounas, Eleftherios P.; Rowden, Diana; Solky, Alexander J.; Sowers, MaryFran R.; Stearns, Vered; Winer, Eric P.; Somerfield, Mark R.; Griggs, Jennifer J.

2010-01-01

Purpose To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for postmenopausal women with hormone receptor–positive breast cancer. Methods A literature search identified relevant randomized trials. Databases searched included MEDLINE, PREMEDLINE, the Cochrane Collaboration Library, and those for the Annual Meetings of the American Society of Clinical Oncology (ASCO) and the San Antonio Breast Cancer Symposium (SABCS). The primary outcomes of interest were disease-free survival, overall survival, and time to contralateral breast cancer. Secondary outcomes included adverse events and quality of life. An expert panel reviewed the literature, especially 12 major trials, and developed updated recommendations. Results An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5 years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIs differ in their adverse effect profiles, and these differences may inform treatment preferences. Conclusion The Update Committee recommends that postmenopausal women with hormone receptor–positive breast cancer consider incorporating AI therapy at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen. The optimal timing and duration of endocrine treatment remain unresolved. The Update Committee supports careful consideration of adverse effect profiles and patient preferences in deciding whether and when to incorporate AI therapy. PMID:20625130

[Concurrent chemoradiation in lung cancer].

PubMed

Girard, Nicolas; Mornex, Françoise

2005-12-01

Concurrent chemoradiation has become for the 15 last years the standard treatment for locally advanced non-small cell lung cancer, either as a definite therapy in non resectable tumors, or in a neoadjuvant setting in potentially resectable tumors. Associating sequential and concurrent schedules, by administering chemotherapy before or after concurrent chemoradiation, has been recently investigated, but the best sequence remains a matter of controversy. Increasing local control and survival after definite chemoradiation seems possible not only by using optimized radiation fractionation schedules and escalated total doses, but also by associating more convenient and less toxic chemotherapy agents at the right cytotoxic or radio-sensitizing dose. Moreover, recent data have suggested that surgery following induction chemoradiation is feasible and effective in selected patients without mediastinal nodes involvement, if a complete resection can be performed. In patients with localized small cell lung cancer, early concurrent chemoradiation with platinium and etoposide has been recognized as the state-of-the-art treatment. The increasing number of ongoing trials including modern radiation schedules combined with newer chemotherapy agents shows that chemoradiation is one of the most promising therapeutic strategies in thoracic oncology.

Angiotensin II receptor blocker-based therapy in Japanese elderly, high-risk, hypertensive patients.

PubMed

Ogawa, Hisao; Kim-Mitsuyama, Shokei; Matsui, Kunihiko; Jinnouchi, Tomio; Jinnouchi, Hideaki; Arakawa, Kikuo

2012-10-01

It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients. The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death. During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89-1.92; P=.17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P=.03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P=.14). This treatment-by-subgroup interaction was significant (P=.02). The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent. Copyright © 2012 Elsevier Inc. All rights reserved.

High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma.

PubMed

Chamberlain, Marc C; Johnston, Sandra K

2010-07-01

We conducted a prospective Phase II study of high-dose methotrexate (HD-MTX) and rituximab with deferred whole brain radiotherapy in patients with newly diagnosed B-cell primary central nervous system lymphoma with a primary objective of evaluating progression-free survival (PFS). Forty patients (25 men; 15 women), ages 18-93 years (median 61.5), were treated. All patients received biweekly HD-MTX/rituximab (8 g/m(2)/dose; 375 mg/m(2)/dose) for 4-6 cycles (induction) and following best radiographic response, with every 4 weeks HD-MTX (8 g/m(2)/dose) for 4 cycles (maintenance). Neurological and neuroradiographic evaluation were performed every 4 weeks during induction therapy and every 8 weeks during maintenance therapy. All patients were evaluable. A total of 303 cycles of HD-MTX (median 8 cycles; range 4-10) was administered. HD-MTX/rituximab-related toxicity included 16 grade 3 adverse events in 13 patients (32.5%). Following induction, 8 patients (20%) demonstrated progressive disease and discontinued therapy; 32 patients (80%) demonstrated a partial (8/40; 20%) or complete (24/40; 60%) radiographic response. At the conclusion of maintenance therapy (6-10 months of total therapy), 28 patients (70%) demonstrated either a partial (1/28) or complete (27/28) response. Overall, survival of these 28 patients ranged from 11 to 80 months (median 33.5). Survival in the entire cohort ranged from 6 to 80 months with an estimated median of 29 months. Overall, PFS ranged from 2 to 80 months (median 21.0). HD-MTX/rituximab and deferred radiotherapy demonstrated similar or better efficacy similar to other HD-MTX-only regimens and reduced time on therapy on average to 6 months.

High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma

PubMed Central

Chamberlain, Marc C.; Johnston, Sandra K.

2010-01-01

We conducted a prospective Phase II study of high-dose methotrexate (HD-MTX) and rituximab with deferred whole brain radiotherapy in patients with newly diagnosed B-cell primary central nervous system lymphoma with a primary objective of evaluating progression-free survival (PFS). Forty patients (25 men; 15 women), ages 18–93 years (median 61.5), were treated. All patients received biweekly HD-MTX/rituximab (8 g/m2/dose; 375 mg/m2/dose) for 4–6 cycles (induction) and following best radiographic response, with every 4 weeks HD-MTX (8 g/m2/dose) for 4 cycles (maintenance). Neurological and neuroradiographic evaluation were performed every 4 weeks during induction therapy and every 8 weeks during maintenance therapy. All patients were evaluable. A total of 303 cycles of HD-MTX (median 8 cycles; range 4–10) was administered. HD-MTX/rituximab-related toxicity included 16 grade 3 adverse events in 13 patients (32.5%). Following induction, 8 patients (20%) demonstrated progressive disease and discontinued therapy; 32 patients (80%) demonstrated a partial (8/40; 20%) or complete (24/40; 60%) radiographic response. At the conclusion of maintenance therapy (6–10 months of total therapy), 28 patients (70%) demonstrated either a partial (1/28) or complete (27/28) response. Overall, survival of these 28 patients ranged from 11 to 80 months (median 33.5). Survival in the entire cohort ranged from 6 to 80 months with an estimated median of 29 months. Overall, PFS ranged from 2 to 80 months (median 21.0). HD-MTX/rituximab and deferred radiotherapy demonstrated similar or better efficacy similar to other HD-MTX-only regimens and reduced time on therapy on average to 6 months. PMID:20511181

Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer.

PubMed

Chang, Joe Y; Komaki, Ritsuko; Lu, Charles; Wen, Hong Y; Allen, Pamela K; Tsao, Anne; Gillin, Michael; Mohan, Radhe; Cox, James D

2011-10-15

The authors sought to improve the toxicity of conventional concurrent chemoradiation therapy for stage III nonsmall cell lung cancer (NSCLC) by using proton-beam therapy to escalate the radiation dose to the tumor. They report early results of a phase 2 study of high-dose proton therapy and concurrent chemotherapy in terms of toxicity, failure patterns, and survival. Forty-four patients with stage III NSCLC were treated with 74 grays (radiobiologic equivalent) proton therapy with weekly carboplatin (area under the curve, 2 U) and paclitaxel (50 mg/m(2)). Disease was staged with positron emission tomography/computed tomography (CT), and treatments were simulated with 4-dimensional (4D) CT to account for tumor motion. Protons were delivered as passively scattered beams, and treatment simulation was repeated during the treatment process to determine the need for adaptive replanning. Median follow-up time was 19.7 months (range, 6.1-44.4 months), and median overall survival time was 29.4 months. No patient experienced grade 4 or 5 proton-related adverse events. The most common nonhematologic grade 3 toxicities were dermatitis (n = 5), esophagitis (n = 5), and pneumonitis (n = 1). Nine (20.5%) patients experienced local disease recurrence, but only 4 (9.1%) had isolated local failure. Four (9.1%) patients had regional lymph node recurrence, but only 1 (2.3%) had isolated regional recurrence. Nineteen (43.2%) patients developed distant metastasis. The overall survival and progression-free survival rates were 86% and 63% at 1 year. Concurrent high-dose proton therapy and chemotherapy are well tolerated, and the median survival time of 29.4 months is encouraging for unresectable stage III NSCLC. Copyright © 2011 American Cancer Society.

Dosimetric assessment of static and helical TomoTherapy in the clinical implementation of breast cancer treatments.

PubMed

Reynders, Truus; Tournel, Koen; De Coninck, Peter; Heymann, Steve; Vinh-Hung, Vincent; Van Parijs, Hilde; Duchateau, Michaël; Linthout, Nadine; Gevaert, Thierry; Verellen, Dirk; Storme, Guy

2009-10-01

Investigation of the use of TomoTherapy and TomoDirect versus conventional radiotherapy for the treatment of post-operative breast carcinoma. This study concentrates on the evaluation of the planning protocol for the TomoTherapy and TomoDirect TPS, dose verification and the implementation of in vivo dosimetry. Eight patients with different breast cancer indications (left/right tumor, axillary nodes involvement (N+)/no nodes (N0), tumorectomy/mastectomy) were enrolled. TomoTherapy, TomoDirect and conventional plans were generated for prone and supine positions leading to six or seven plans per patient. Dose prescription was 42Gy in 15 fractions over 3weeks. Dose verification of a TomoTherapy plan is performed using TLDs and EDR2 film inside a home-made wax breast phantom fixed on a rando-alderson phantom. In vivo dosimetry was performed with TLDs. It is possible to create clinically acceptable plans with TomoTherapy and TomoDirect. TLD calibration protocol with a water equivalent phantom is accurate. TLD verification with the phantom shows measured over calculated ratios within 2.2% (PTV). An overresponse of the TLDs was observed in the low dose regions (<0.1Gy). The film measurements show good agreement for high and low dose regions inside the phantom. A sharp gradient can be created to the thoracic wall. In vivo dosimetry with TLDs was clinically feasible. The TomoTherapy and TomoDirect modalities can deliver dose distributions which the radiotherapist judges to be equal to or better than conventional treatment of breast carcinoma according to the organ to be protected.

Successful use of full-dose dexamethasone, high-dose cytarabine, and cisplatin as part of initial therapy in non-hodgkin and hodgkin lymphoma with severe hepatic dysfunction.

PubMed

McCarthy, Jeanne; Gopal, Ajay K

2009-04-01

Anthracycline-based chemotherapy is the cornerstone of modern curative regimens for aggressive lymphomas; however, these drugs cannot be safely administered in the setting of severe hepatic dysfunction. Alternative regimens for this setting are required. We describe 2 patients with newly diagnosed advanced aggressive lymphoma (diffuse large B-cell lymphoma [DLBCL] and classic Hodgkin lymphoma [HL]) presenting with severe hepatic dysfunction with hyperbilirubinemia (4.3-13.2 mg/dL). Because of the inability to safely administer unattenuated doses of anthracycline-based regimens, dexamethasone, high-dose cytarabine, and cisplatin (DHAP) was used at full doses (along with rituximab for the DLBCL patient) until hepatic function normalized (1-5 cycles). The treatment was then converted to R-CHOP (rituximab/cyclophosphamide/ doxorubicin/vincristine/prednisone) and ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) for the DLBCL and HL patient, respectively, to complete therapy. The patients had a partial remission and complete remission, respectively. These data suggest that DHAP is a safe and effective regimen that can be used without dose modification as part of initial therapy in the setting of aggressive lymphoma and hepatic failure. The literature on the use of treatment regimens for aggressive lymphoma in the setting of hepatic dysfunction is reviewed.

[Pay attention to the application of the international intraocular retinoblastoma classification and sequential multiple modality treatment].

PubMed

Fan, X Q

2017-08-11

Retinoblastoma (RB) is the most common intraocular malignancy in childhood. It may seriously affect vision, and even threaten the life. The early diagnosis rate of RB in China remains low, and the majority of patients are at late phase with high rates of enucleation and mortality. The International Intraocular Retinoblastoma Classification and TNM staging system are guidances for therapeutic choices and bases for prognosis evaluation. Based on the sequential multi-method treatment modality, chemotherapy combined with local therapy is the mainstream in dealing with RB, which may maximize the results of eye saving and even vision retaining. New therapeutic techniques including supra-selective ophthalmic artery interventional chemotherapy and intravitreal chemotherapy can further improve the efficacy of treatment, especially the eye salvage rate. The overall level of RB treatment should be improved by promoting the international staging, new therapeutic techniques, and the sequential multiple modality treatment. (Chin J Ophthalmol, 2017, 53: 561 - 565) .

A Practical Bayesian Design to Identify the Maximum Tolerated Dose Contour for Drug Combination Trials

PubMed Central

Zhang, Liangcai; Yuan, Ying

2016-01-01

Drug combination therapy has become the mainstream approach to cancer treatment. One fundamental feature that makes combination trials different from single-agent trials is the existence of the maximum tolerated dose (MTD) contour, i.e., multiple MTDs. As a result, unlike single-agent phase I trials, which aim to find a single MTD, it is often of interest to find the MTD contour for combination trials. We propose a new dose-finding design, the waterfall design, to find the MTD contour for drug combination trials. Taking the divide-and-conquer strategy, the waterfall design divides the task of finding the MTD contour into a sequence of one-dimensional dose-finding processes, known as subtrials. The subtrials are conducted sequentially in a certain order, such that the results of each subtrial will be used to inform the design of subsequent subtrials. Such information borrowing allows the waterfall design to explore the two-dimensional dose space efficiently using a limited sample size, and decreases the chance of overdosing and underdosing patients. To accommodate the consideration that doses on the MTD contour may have very different efficacy or synergistic effects due to drug-drug interaction, we further extend our approach to a phase I/II design with the goal of finding the MTD with the highest efficacy. Simulation studies show that the waterfall design is safer and has higher probability of identifying the true MTD contour than some existing designs. The R package “BOIN” to implement the waterfall design is freely available from CRAN. PMID:27580928

Successful treatment of a primary gastric plasmacytoma mimicking intractable gastric ulcer by using high-dose dexamethasone therapy: a case report.

PubMed

Kang, Da-yeong; Kim, Gee-Bum; Choi, Byung-Seok; Seo, Jun-won; Lim, Hyun-Jong; Hong, Ran; Park, Sang-Gon

2016-03-31

Extramedullary plasmacytoma is a plasma cell neoplasm that presents as a solitary lesion in soft tissue. Most extramedullary plasmacytomas involve the nasopharynx or upper respiratory tract. Primary plasmacytoma of the stomach is extremely rare. A 78-year-old Korean woman presented with epigastric pain for 3 months. She had a history of an intractable gastric ulcer despite repeated endoscopic biopsies and appropriate medical therapy for the ulcer. She underwent another endoscopy and a biopsy was performed for multiple large and deep specimens. Ultimately, primary gastric plasmacytoma was confirmed. However, she and her attendant refused standard local radiotherapy or surgical resection. She came to our emergency room 3 months later with hematemesis due to a large gastric ulcer, despite management with medication for over 3 months at a local clinic. We again recommended local radiation or surgical resection. However, as she was willing to undergo only medical therapy, she was prescribed high-dose dexamethasone. Surprisingly, her ulcer completely regressed and remission was maintained for over 1 year. We report successful treatment of a rare primary gastric plasmacytoma mimicking intractable ulcer by using high-dose dexamethasone. To the best of our knowledge, this is the first reported case successfully treated with only high-dose dexamethasone.

A collaborative sequential meta-analysis of individual patient data from randomized trials of endovascular therapy and tPA vs. tPA alone for acute ischemic stroke: ThRombEctomy And tPA (TREAT) analysis: statistical analysis plan for a sequential meta-analysis performed within the VISTA-Endovascular collaboration.

PubMed

MacIsaac, Rachael L; Khatri, Pooja; Bendszus, Martin; Bracard, Serge; Broderick, Joseph; Campbell, Bruce; Ciccone, Alfonso; Dávalos, Antoni; Davis, Stephen M; Demchuk, Andrew; Diener, Hans-Christoph; Dippel, Diederik; Donnan, Geoffrey A; Fiehler, Jens; Fiorella, David; Goyal, Mayank; Hacke, Werner; Hill, Michael D; Jahan, Reza; Jauch, Edward; Jovin, Tudor; Kidwell, Chelsea S; Liebeskind, David; Majoie, Charles B; Martins, Sheila Cristina Ouriques; Mitchell, Peter; Mocco, J; Muir, Keith W; Nogueira, Raul; Saver, Jeffrey L; Schonewille, Wouter J; Siddiqui, Adnan H; Thomalla, Götz; Tomsick, Thomas A; Turk, Aquilla S; White, Philip; Zaidat, Osama; Lees, Kennedy R

2015-10-01

Endovascular treatment has been shown to restore blood flow effectively. Second-generation medical devices such as stent retrievers are now showing overwhelming efficacy in clinical trials, particularly in conjunction with intravenous recombinant tissue plasminogen activator. This statistical analysis plan utilizing a novel, sequential approach describes a prospective, individual patient data analysis of endovascular therapy in conjunction with intravenous recombinant tissue plasminogen activator agreed upon by the Thrombectomy and Tissue Plasminogen Activator Collaborative Group. This protocol will specify the primary outcome for efficacy, as 'favorable' outcome defined by the ordinal distribution of the modified Rankin Scale measured at three-months poststroke, but with modified Rankin Scales 5 and 6 collapsed into a single category. The primary analysis will aim to answer the questions: 'what is the treatment effect of endovascular therapy with intravenous recombinant tissue plasminogen activator compared to intravenous tissue plasminogen activator alone on full scale modified Rankin Scale at 3 months?' and 'to what extent do key patient characteristics influence the treatment effect of endovascular therapy?'. Key secondary outcomes include effect of endovascular therapy on death within 90 days; analyses of modified Rankin Scale using dichotomized methods; and effects of endovascular therapy on symptomatic intracranial hemorrhage. Several secondary analyses will be considered as well as expanding patient cohorts to intravenous recombinant tissue plasminogen activator-ineligible patients, should data allow. This collaborative meta-analysis of individual participant data from randomized trials of endovascular therapy vs. control in conjunction with intravenous thrombolysis will demonstrate the efficacy and generalizability of endovascular therapy with intravenous thrombolysis as a concomitant medication. © 2015 World Stroke Organization.

Evaluation of the Therapeutic Efficacy of Sequential Therapy Involving Percutaneous Microwave Ablation in Combination with 131I-Hypericin Using the VX2 Rabbit Breast Solid Tumor Model

PubMed Central

Zhu, Miao; Lin, Xiao-An; Zha, Xiao-Ming; Zhou, Wen-Bin; Xia, Tian-Song; Wang, Shui

2015-01-01

Purpose Combination of percutaneous microwave ablation (PMWA) and intravenous injection of 131I-hypericin(IIIH) may bear potential as a mini-invasive treatment for tumor. The objective of this study was to assess the effect of PMWA and IIIH in breast tumor growth. Methods Ten New Zealand White rabbits bearing VX2 breast carcinomas were randomly divided into two groups (each 5 examples) and processed using PMWA followed by IIIH and IIIH alone. The IIIH activity was evaluated using planar scintigraphy, autoradiography and biodistribution analysis. The maximum effective safe dose of IIIH was found through 48 rabbits with VX2 breast tumor, which were randomized into six groups (n=8 per group). Subsequently, a further 75 rabbits bearing VX2 breast solid tumors were randomly divided into five groups (each 15 examples) and treated as follows: A, no treatment group; B, PMWA alone; C, IIIH alone; D, PMWA+IIIH×1 (at 8 h post-PMWA); and E, PMWA+IIIH×2 (at 8 h and at 8 days post-PMWA). The therapeutic effect was assessed by measurement of tumor size and performation of positron emission tomography/computed tomograph (PET/CT) scans, liver and renal function tests and Kaplan-Meier survival analysis. Results The planar scintigraphy findings suggested a significant uptake of 131I in necrotic tumor tissue. The autoradiography gray scales indicated higher selective uptake of IIIH by necrotic tissue, with significant differences between the groups with and those without necrotic tumor tissue (P<0.05). The maximum effective safe dose of IIIH was 1mCi/kg. The PET/CT scans and tumor size measurement suggested improvements in treatment groups at all time points (P<0.01). Significant differences were detected among Groups A, B, D and E (P<0.05). Lower levels of lung metastasis were detected in Groups D and E (P<0.05). There were no abnormalities in liver and renal functions tests or other reported side effects. Conclusion IIIH exhibited selective uptake by necrotic tumor tissue. Sequential therapy involving PMWA+IIIH was successfully inhibiting tumor growth and prolonging survival. PMID:25799220

CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer.

PubMed

Zhang, Xiaofei; Shimodaira, Hideki; Soeda, Hiroshi; Komine, Keigo; Takahashi, Hidekazu; Ouchi, Kota; Inoue, Masahiro; Takahashi, Masanobu; Takahashi, Shin; Ishioka, Chikashi

2016-12-01

The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been observed in a subset of human colorectal cancer (CRC) cases. CIMP status, which is closely associated with specific clinicopathological and molecular characteristics, is considered a potential predictive biomarker for efficacy of cancer treatment. However, the relationship between the effect of standard chemotherapy, including cytotoxic drugs and anti-epidermal growth factor receptor (EGFR) antibodies, and CIMP status has not been elucidated. In 125 metastatic colorectal cancer (mCRC) patients, we investigated how clinical outcome of chemotherapy was related to CIMP status as detected by methylation-specific PCR (MSP) and to genetic status in five EGFR-related genes (KRAS, BRAF, PIK3CA, NRAS, and AKT1) as detected by direct sequencing. CIMP-positive status was significantly associated with proximal tumor location and peritoneum metastasis (all P values <0.05). The progression-free survival of patients with CIMP-positive tumors receiving sequential therapy with FOLFOX as the first-line treatment followed by irinotecan-based therapy as the second-line treatment (median = 6.6 months) was inferior to that of such patients receiving the reverse sequence (median = 15.2 months; P = 0.043). Furthermore, CIMP-positive tumors showed higher mutation frequencies for the five EGFR-related genes (74.1 %) than the CIMP-negative tumors did (50.0 %). Among the KRAS wild-type tumors, CIMP-positive tumors were associated with a worse clinical outcome than CIMP-negative tumors following anti-EGFR antibody therapy. Sequential FOLFOX followed by an irinotecan-based regimen is unfavorable in patients with CIMP-positive tumors. High frequencies of mutation in EGFR-related genes in CIMP-positive tumors may cause the lower response to anti-EGFR antibody therapy seen in patients with wild-type KRAS and CIMP-positive tumors.

Is It All about the Higher Dose? Why Psychoanalytic Therapy Is an Effective Treatment for Major Depression.

PubMed

Zimmermann, Johannes; Löffler-Stastka, Henriette; Huber, Dorothea; Klug, Günther; Alhabbo, Sarah; Bock, Astrid; Benecke, Cord

2015-01-01

Empirical evidence for the effectiveness of long-term psychodynamic psychotherapy (LTPP) in patients with mood disorders is growing. However, it is unclear whether the effectiveness of LTPP is due to distinctive features of psychodynamic/psychoanalytic techniques or to a higher number of sessions. We tested these rival hypotheses in a quasi-experimental study comparing psychoanalytic therapy (i.e., high-dose LTPP) with psychodynamic therapy (i.e., low-dose LTPP) and cognitive-behavioural therapy (CBT) for depression. Analyses were based on a subsample of 77 subjects, with 27 receiving psychoanalytic therapy, 26 receiving psychodynamic therapy and 24 receiving CBT. Depressive symptoms, interpersonal problems and introject affiliation were assessed prior to treatment, after treatment and at the 1-, 2- and 3-year follow-ups. Psychoanalytic techniques were assessed from three audiotaped middle sessions per treatment using the Psychotherapy Process Q-Set. Subjects receiving psychoanalytic therapy reported having fewer interpersonal problems, treated themselves in a more affiliative way directly after treatment and tended to improve in depressive symptoms and interpersonal problems during follow-up as compared with patients receiving psychodynamic therapy and/or CBT. Multilevel mediation analyses suggested that post-treatment differences in interpersonal problems and introject affiliation were mediated by the higher number of sessions, and follow-up differences in depressive symptoms were mediated by the more pronounced application of psychoanalytic techniques. We also found some evidence for indirect treatment effects via psychoanalytic techniques on changes in introject affiliation during follow-up. These results provide support for the prediction that both a high dose and the application of psychoanalytic techniques facilitate therapeutic change in patients with major depression. Psychoanalytic therapy is an effective treatment for major depression, especially in the long run. The differential effectiveness of psychoanalytic therapy cannot be fully explained by its higher dose. Distinctive features of psychoanalytic technique (e.g., focusing on patients' dreams, fantasies, sexual experiences or childhood memories) may play an important role in establishing sustained therapeutic change. Copyright © 2014 John Wiley & Sons, Ltd.

RADIATION THERAPY COMMUNICATION-REIRRADIATION OF A NASAL TUMOR IN A BRACHYCEPHALIC DOG USING INTENSITY MODULATED RADIATION THERAPY.

PubMed

Rancilio, Nicholas J; Custead, Michelle R; Poulson, Jean M

2016-09-01

A 5-year-old spayed female Shih Tzu was referred for evaluation of a nasal transitional carcinoma. A total lifetime dose of 117 Gy was delivered to the intranasal mass in three courses over nearly 2 years using fractionated intensity modulated radiation therapy (IMRT) to spare normal tissues. Clinically significant late normal tissue side effects were limited to bilaterally diminished tear production. The patient died of metastatic disease progression 694 days after completion of radiation therapy course 1. This case demonstrates that retreatment with radiation therapy to high lifetime doses for recurrent local disease may be well tolerated with IMRT. © 2016 American College of Veterinary Radiology.

The implication of non-cyclic intrafractional longitudinal motion in SBRT by TomoTherapy

NASA Astrophysics Data System (ADS)

Yang, Wensha; Van Ausdal, Ray; Read, Paul; Larner, James; Benedict, Stan; Sheng, Ke

2009-05-01

To determine the dosimetric impact of non-cyclic longitudinal intrafractional motion, TomoTherapy plans with different field sizes were interrupted during a phantom delivery, and a displacement between -5 mm and 5 mm was induced prior to the delivery of the completion procedure. The planar dose was measured by film and a cylindrical phantom, and under-dosed or over-dosed volume was observed for either positive or negative displacement. For a 2.5 cm field, there was a 4% deviation for every mm of motion and for a 1 cm field, the deviation was 8% per mm. The dimension of the under/over-dosed area was independent of the motion but dependent on the field size. The results have significant implication in small-field high-dose treatments (i.e. stereotactic body radiation therapy (SBRT)) that deliver doses in only a few fractions. Our studies demonstrate that a small longitudinal motion may cause a dose error that is difficult to compensate; however, dividing a SBRT fraction into smaller passes is helpful to reduce such adverse effects.

Proton therapy versus intensity modulated x-ray therapy in the treatment of prostate cancer: Estimating secondary cancer risks

NASA Astrophysics Data System (ADS)

Fontenot, Jonas David

External beam radiation therapy is used to treat nearly half of the more than 200,000 new cases of prostate cancer diagnosed in the United States each year. During a radiation therapy treatment, healthy tissues in the path of the therapeutic beam are exposed to high doses. In addition, the whole body is exposed to a low-dose bath of unwanted scatter radiation from the pelvis and leakage radiation from the treatment unit. As a result, survivors of radiation therapy for prostate cancer face an elevated risk of developing a radiogenic second cancer. Recently, proton therapy has been shown to reduce the dose delivered by the therapeutic beam to normal tissues during treatment compared to intensity modulated x-ray therapy (IMXT, the current standard of care). However, the magnitude of stray radiation doses from proton therapy, and their impact on this incidence of radiogenic second cancers, was not known. The risk of a radiogenic second cancer following proton therapy for prostate cancer relative to IMXT was determined for 3 patients of large, median, and small anatomical stature. Doses delivered to healthy tissues from the therapeutic beam were obtained from treatment planning system calculations. Stray doses from IMXT were taken from the literature, while stray doses from proton therapy were simulated using a Monte Carlo model of a passive scattering treatment unit and an anthropomorphic phantom. Baseline risk models were taken from the Biological Effects of Ionizing Radiation VII report. A sensitivity analysis was conducted to characterize the uncertainty of risk calculations to uncertainties in the risk model, the relative biological effectiveness (RBE) of neutrons for carcinogenesis, and inter-patient anatomical variations. The risk projections revealed that proton therapy carries a lower risk for radiogenic second cancer incidence following prostate irradiation compared to IMXT. The sensitivity analysis revealed that the results of the risk analysis depended only weakly on uncertainties in the risk model and inter-patient variations. Second cancer risks were sensitive to changes in the RBE of neutrons. However, the findings of the study were qualitatively consistent for all patient sizes and risk models considered, and for all neutron RBE values less than 100.

Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma.

PubMed

Chiron, David; Dousset, Christelle; Brosseau, Carole; Touzeau, Cyrille; Maïga, Sophie; Moreau, Philippe; Pellat-Deceunynck, Catherine; Le Gouill, Steven; Amiot, Martine

2015-04-20

The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD50 < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD50 < 10 nM). Mcl-1 and Bcl-xL both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x(L) up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.

Bridging the clinician/researcher gap with systemic research: the case for process research, dyadic, and sequential analysis.

PubMed

Oka, Megan; Whiting, Jason

2013-01-01

In Marriage and Family Therapy (MFT), as in many clinical disciplines, concern surfaces about the clinician/researcher gap. This gap includes a lack of accessible, practical research for clinicians. MFT clinical research often borrows from the medical tradition of randomized control trials, which typically use linear methods, or follow procedures distanced from "real-world" therapy. We review traditional research methods and their use in MFT and propose increased use of methods that are more systemic in nature and more applicable to MFTs: process research, dyadic data analysis, and sequential analysis. We will review current research employing these methods, as well as suggestions and directions for further research. © 2013 American Association for Marriage and Family Therapy.

The Irish Helicobacter pylori Working Group consensus for the diagnosis and treatment of H. pylori infection in adult patients in Ireland.

PubMed

Smith, Sinead; Boyle, Breida; Brennan, Denise; Buckley, Martin; Crotty, Paul; Doyle, Maeve; Farrell, Richard; Hussey, Mary; Kevans, David; Malfertheiner, Peter; Megraud, Francis; Nugent, Sean; O'Connor, Anthony; O'Morain, Colm; Weston, Shiobhan; McNamara, Deirdre

2017-05-01

Irish eradication rates for Helicobacter pylori are decreasing and there is an increase in the prevalence of antibiotic-resistant bacteria. These trends call into question current management strategies. To establish an Irish Helicobacter pylori Working Group (IHPWG) to assess, revise and tailor current available recommendations. Experts in the areas of gastroenterology and microbiology were invited to join the IHPWG. Questions of relevance to diagnosis, first-line and rescue therapy were developed using the PICO system. A literature search was performed. The 'Grading of Recommendations Assessment, Development and Evaluation' approach was then used to rate the quality of available evidence and grade the resulting recommendations. Key resultant IHPWG statements (S), the strength of recommendation and quality of evidence include S8: standard triple therapy for 7 days' duration can no longer be recommended (strong and moderate). S9: 14 days of clarithromycin-based triple therapy with a high-dose proton pump inhibitor (PPI) is recommended as first-line therapy. Bismuth quadruple therapy for 14 days is an alternative if available (strong and moderate). S12: second-line therapy depends on the first-line treatment and should not be the same treatment. The options are (a) 14 days of levofloxacin-based therapy with high-dose PPI, (b) 14 days of clarithromycin-based triple therapy with high-dose PPI or (c) bismuth quadruple therapy for 14 days (strong and moderate). S13: culture and antimicrobial susceptibility testing should be performed following two treatment failures (weak and low/very low). These recommendations are intended to provide the most relevant current best-practice guidelines for the management of H. pylori infection in adults in Ireland.

Clinical experience in treating hypertension with fixed-dose combination therapy: angiotensin II receptor blocker losartan plus hydrochlorothiazide.

PubMed

Abe, Masanori; Okada, Kazuyoshi; Matsumoto, Koichi

2009-10-01

The goal of antihypertensive treatment is to reduce cardiovascular and cerebrovascular events associated with high blood pressure. A combination therapy with different antihypertensive agents is more successful than monotherapy in most hypertensive patients, with the added advantage of a better safety profile. Therefore, treatment of hypertensive patients with fixed-dose combination therapy consisting of the angiotensin II receptor blocker losartan along with hydrochlorothiazide (HCTZ) has several potential benefits over monotherapy with each individual component. It provides more effective blood pressure control, a reduction in the likelihood of adverse effects and facilitation of patient compliance due to a simple once-daily regimen. One of the advantages of the combination of losartan with HCTZ is the potential reduction in HCTZ-induced metabolic disorders; in particular, this combination can have attractive benefits for patients of hyperuricemia. Losartan plus HCTZ fixed-dose combination therapy is frequently recommended for the treatment of hypertension and lowers blood pressure in mild-to-moderate and even severe hypertensive patients to a level comparable with other classes of antihypertensive agents in combination with HCTZ. Fixed-dose combination therapy with losartan plus HCTZ is a logical choice as antihypertensive therapy for patients in whom combination therapy is necessary to achieve additional blood pressure reduction.

Optimization of 64-MDCT urography: effect of dual-phase imaging with furosemide on collecting system opacification and radiation dose.

PubMed

Portnoy, Orith; Guranda, Larisa; Apter, Sara; Eiss, David; Amitai, Marianne Michal; Konen, Eli

2011-11-01

The purpose of this study was to compare opacification of the urinary collecting system and radiation dose associated with three-phase 64-MDCT urographic protocols and those associated with a split-bolus dual-phase protocol including furosemide. Images from 150 CT urographic examinations performed with three scanning protocols were retrospectively evaluated. Group A consisted of 50 sequentially registered patients who underwent a three-phase protocol with saline infusion. Group B consisted of 50 sequentially registered patients who underwent a reduced-radiation three-phase protocol with saline. Group C consisted of 50 sequentially registered patients who underwent a dual-phase split-bolus protocol that included a low-dose furosemide injection. Opacification of the urinary collecting system was evaluated with segmental binary scoring. Contrast artifacts were evaluated, and radiation doses were recorded. Results were compared by analysis of variance. A significant reduction in mean effective radiation dose was found between groups A and B (p < 0.001) and between groups B and C (p < 0.001), resulting in 65% reduction between groups A and C (p < 0.001). This reduction did not significantly affect opacification score in any of the 12 urinary segments (p = 0.079). In addition, dense contrast artifacts overlying the renal parenchyma observed with the three-phase protocols (groups A and B) were avoided with the dual-phase protocol (group C) (p < 0.001). A dual-phase protocol with furosemide injection is the preferable technique for CT urography. In comparison with commonly used three-phase protocols, the dual-phase protocol significantly reduces radiation exposure dose without reduction in image quality.

Cancer nanomedicine: gold nanoparticle mediated combined cancer therapy

NASA Astrophysics Data System (ADS)

Yang, C.; Bromma, Kyle; Chithrani, B. D.

2018-02-01

Recent developments in nanotechnology has provided new tools for cancer therapy and diagnosis. Among other nanomaterial systems, gold nanoparticles are being used as radiation dose enhancers and anticancer drug carriers in cancer therapy. Fate of gold nanoparticles within biological tissues can be probed using techniques such as TEM (transmission electron microscopy) and SEM (Scanning Electron Microscopy) due to their high electron density. We have shown for the first time that cancer drug loaded gold nanoparticles can reach the nucleus (or the brain) of cancer cells enhancing the therapeutic effect dramatically. Nucleus of the cancer cells are the most desirable target in cancer therapy. In chemotherapy, smart delivery of highly toxic anticancer drugs through packaging using nanoparticles will reduce the side effects and improve the quality and care of cancer patients. In radiation therapy, use of gold nanoparticles as radiation dose enhancer is very promising due to enhanced localized dose within the cancer tissue. Recent advancement in nanomaterial characterization techniques will facilitate mapping of nanomaterial distribution within biological specimens to correlate the radiobiological effects due to treatment. Hence, gold nanoparticle mediated combined chemoradiation would provide promising tools to achieve personalized and tailored cancer treatments in the near future.

Fluid Therapy and Outcome: Balance Is Best

PubMed Central

Allen, Sara J.

2014-01-01

Abstract: The use of intravenous fluids is routine in patients undergoing surgery or critical illness; however, controversy still exists regarding optimum fluid therapy. Recent literature has examined the effects of different types, doses, and timing of intravenous fluid therapy. Each of these factors may influence patient outcomes. Crystalloids consist of isotonic saline or balanced electrolyte solutions and widely distribute across extracellular fluid compartments, whereas colloids contain high-molecular-weight molecules suspended in crystalloid carrier solution and do not freely distribute across the extracellular fluid compartments. Colloids vary in composition and associated potential adverse effects. Recent evidence has highlighted safety and ethical concerns regarding the use of colloid solutions in critically ill patients, particularly the use of synthetic starch solutions. which have been associated with increased morbidity and mortality. Crystalloid solutions with a chloride-rich composition (e.g., isotonic saline) have been associated with metabolic acidosis, hyperchloremia, increased incidence of acute kidney injury, and increased requirement for renal replacement therapy. An optimum dose of intravenous fluids remains controversial with no definitive evidence to support restrictive versus liberal approaches. Further high-quality trials are needed to elucidate the optimum fluid therapy for patients, but currently a balanced approach to type, dose, and timing of fluids is recommended. PMID:24779116

Fluid therapy and outcome: balance is best.

PubMed

Allen, Sara J

2014-03-01

The use of intravenous fluids is routine in patients undergoing surgery or critical illness; however, controversy still exists regarding optimum fluid therapy. Recent literature has examined the effects of different types, doses, and timing of intravenous fluid therapy. Each of these factors may influence patient outcomes. Crystalloids consist of isotonic saline or balanced electrolyte solutions and widely distribute across extracellular fluid compartments, whereas colloids contain high-molecular-weight molecules suspended in crystalloid carrier solution and do not freely distribute across the extracellular fluid compartments. Colloids vary in composition and associated potential adverse effects. Recent evidence has highlighted safety and ethical concerns regarding the use of colloid solutions in critically ill patients, particularly the use of synthetic starch solutions, which have been associated with increased morbidity and mortality. Crystalloid solutions with a chloride-rich composition (e.g., isotonic saline) have been associated with metabolic acidosis, hyperchloremia, increased incidence of acute kidney injury, and increased requirement for renal replacement therapy. An optimum dose of intravenous fluids remains controversial with no definitive evidence to support restrictive versus liberal approaches. Further high-quality trials are needed to elucidate the optimum fluid therapy for patients, but currently a balanced approach to type, dose, and timing of fluids is recommended.

Effect of one time high dose "stoss therapy" of vitamin D on glucose homeostasis in high risk obese adolescents.

PubMed

Brar, Preneet Cheema; Contreras, Maria; Fan, Xiaozhou; Visavachaipan, Nipapat

2018-04-05

To study the effect of using a one time high dose "stoss therapy" of vitamin D2 (ergocalciferol: VD2) on indices of insulin sensitivity {whole body sensitivity index: WBISI} and secretion {insulinogenic index: IGI} measured during an oral glucose tolerance test (OGTT) in obese adolescents with VDD (25 OHD; serum metabolite of vit D: < 30 ng/dL). In a randomized placebo controlled cross over design 20 obese adolescents with vitamin D deficiency (VDD) had baseline OGTT. Arm A received one time high dose 300,000 IU of ergocalciferol and Arm B received placebo. After 6 weeks the adolescents were reassigned to Arm A if they were in Arm B and vice versa. 25OHD, calcium, parathyroid hormone, comprehensive metabolic panel, urine calcium creatinine ratio were measured at each study visit. OGTTs to assess indices of sensitivity and secretion were done at baseline, 6 weeks and 12 weeks respectively. Adolescents were obese and insulin resistant (mean ± SD: mean age = 15.1 ± 1.9 years; BMI: 32.7 ± 9.8; homeostatic model of insulin resistance: HOMA-IR: 4.2 ± 2.8). Stoss therapy with VD2 increased 25OHD from baseline (16.7 ± 2.9 to 19.5 ± 4.5; p = 0.0029) when compared to the placebo. WBISI (2.8 ± 1.9) showed a trend towards improvement in Rx group (p = 0.0577) after adjustment for covariates. IGI (3 ± 2.2) showed an improvement in both Rx and placebo groups. Our study demonstrated that using a high dose of VD2 (300,000 IU) did not have any beneficial effect on insulin sensitivity (whole body sensitivity index {WBISI}) and secretory indices (insulinogenic index {IGI}) in obese adolescents. High dose "stoss therapy" of VD2 did not appear to have any beneficial effect on glucose homeostasis on obese adolescents.

The Influence of Prostate Volume on Outcome After High-Dose-Rate Brachytherapy Alone for Localized Prostate Cancer

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

Le, Hien, E-mail: hien.le@health.sa.gov.au; Rojas, Ana; Alonzi, Roberto

2013-10-01

Objective: To determine whether late genitourinary toxicity, biochemical control of prostate cancer, and dosimetric parameters in patients with large prostate glands is different from those variables in men with smaller glands after treatment with high-dose-rate brachytherapy alone (HDR-BT). Methods: From November 2003 to July 2009, 164 patients with locally advanced prostate carcinoma were sequentially enrolled and treated with 34 or 36 Gy in 4 fractions and 31.5 Gy in 3 fractions of {sup 192}Ir HDR-BT alone. The median follow-up time was 71 months. Gland size was not considered in the selection criteria for this study. Estimates of freedom from biochemicalmore » relapse (FFbR) and late morbidity, stratified by median clinical target volume (CTV), were obtained, and differences were compared. Results: The median CTV volume was 60 cc (range, 15-208 cc). Dose–volume parameters D90 and V100 (ie, minimum dose to 90% of the prostate volume and volume receiving 100% of the prescribed isodose) achieved in patients with glands ≥60 cc were not significantly different from those with glands <60 cc (P≥.2). Nonetheless, biochemical control in patients with larger CTV was significantly higher (91% vs 78% at 6 years; P=.004). In univariate and multivariate analysis, CTV was a significant predictor for risk of biochemical relapse. This was not at the expense of an increase in either moderate (P=.6) or severe (P=.3) late genitourinary toxicity. The use of hormonal therapy was 17% lower in the large gland group (P=.01). Conclusions: Prostate gland size does not affect dosimetric parameters in HDR-BT assessed by D90 and V100. In patients with larger glands, a significantly higher biochemical control of disease was observed, with no difference in late toxicity. This improvement cannot be attributed to differences in dosimetry. Gland size should not be considered in the selection of patients for HDR-BT.« less

Systematic reviews of randomised clinical trials examining the effects of psychotherapeutic interventions versus "no intervention" for acute major depressive disorder and a randomised trial examining the effects of "third wave" cognitive therapy versus mentalization-based treatment for acute major depressive disorder.

PubMed

Jakobsen, Janus Christian

2014-10-01

Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Cognitive therapy and psychodynamic therapy may be effective treatment options for major depressive disorder, but the effects have only had limited assessment in systematic reviews. The two modern forms of psychotherapy, "third wave" cognitive therapy and mentalization-based treatment, have both gained some ground as treatments of psychiatric disorders. No randomised trial has compared the effects of these two interventions for major depressive disorder. We performed two systematic reviews with meta-analyses and trial sequential analyses using The Cochrane Collaboration methodology examining the effects of cognitive therapy and psycho-dynamic therapy for major depressive disorder. We developed a thorough treatment protocol for a randomised trial with low risks of bias (systematic error) and low risks of random errors ("play of chance") examining the effects of third wave' cognitive therapy versus mentalization-based treatment for major depressive disorder. We conducted a randomised trial according to good clinical practice examining the effects of "third wave" cognitive therapy versus mentalisation-based treatment for major depressive disorder. The first systematic review included five randomised trials examining the effects of psychodynamic therapy versus "no intervention' for major depressive disorder. Altogether the five trials randomised 365 participants who in each trial received similar antidepressants as co-interventions. All trials had high risk of bias. Four trials assessed "interpersonal psychotherapy" and one trial "short psychodynamic supportive psychotherapy". Both of these interventions are different forms of psychodynamic therapy. Meta-analysis showed that psychodynamic therapy significantly reduced depressive symptoms on the Hamilton Depression Rating Scale (HDRS) compared with "no intervention" (mean difference -3.01 (95% confidence interval -3.98 to -2.03; p = 0.00001), no significant heterogeneity between trials). Trial sequential analysis confirmed this result. The second systematic review included 12 randomised trials examining the effects of cognitive therapy versus "no intervention" for major depressive disorder. Altogether a total of 669 participants were randomised. All trials had high risk of bias. Meta-analysis showed that cognitive therapy significantly reduced depressive symptoms on the HDRS compared with "no intervention" (four trials; mean difference -3.05 (95% confidence interval, -5.23 to -0.87; p = 0.006)). Trial sequential analysis could not confirm this result. The trial protocol showed that it seemed feasible to conduct a randomised trial with low risks of bias and low risks of random errors examining the effects of "third wave" cognitive therapy versus mentalization-based therapy in a setting in the Danish healthcare system. It turned out to be much more difficult to recruit participants in the randomised trial than expected. We only included about half of the planned participants. The results from the randomised trial showed that participants randomised to "third wave" therapy compared with participants randomised to mentalization-based treatment had borderline significantly lower HDRS scores at 18 weeks in an unadjusted analysis (mean difference -4.14 score; 95% CI -8.30 to 0.03; p = 0.051). In the adjusted analysis, the difference was significant (p = 0.039). Five (22.7%) of the participants randomised to "third wave" cognitive therapy had remission at 18 weeks versus none of the participants randomised to mentalization-based treatment (p = 0.049). Sequential analysis showed that these findings could be due to random errors. No significant differences between the two groups was found regarding Beck's Depression Inventory (BDI II), Symptom Checklist 90 Revised (SCL 90-R), and The World Health Organization-Five Well-being Index 1999 (WHO 5). We concluded that cognitive therapy and psychodynamic therapy might be effective interventions for depression measured on HDRS and BDI, but the review results might be erroneous due to risks of bias and random errors. Furthermore, the effects seem relatively small. The trial protocol showed that it was possible to develop a protocol for a randomised trial examining the effects of "third wave" cognitive therapy versus mentalization-based treatment with low risks of bias and low risks of random errors. Our trial results showed that "third wave" cognitive therapy might be a more effective intervention for depressive symptoms measured on the HDRS compared with mentalization-based treatment. The two interventions did not seem to differ significantly regarding BDI II, SCL 90-R, and WHO 5. More randomised trials with low risks of bias and low risks of random errors are needed to assess the effects of cognitive therapy, psychodynamic therapy, "third wave" cognitive therapy, and mentalization-based treatment.

Preliminary results of antiscarring therapy in the prevention of postendoscopic esophageal mucosectomy strictures

PubMed Central

Wu, Yuhsin; Schomisch, Steve J.; Cipriano, Cassandra; Chak, Amitabh; Lash, Richard H.; Ponsky, Jeffrey L.

2015-01-01

Background Esophageal endoscopic submucosal dissection (ESD) is an effective minimally invasive therapy for early esophageal cancer and high-grade Barrett dysplasia. However, esophageal stricture formation after circumferential or large ESD has limited its wide adoption. Mitomycin C (MMC), halofuginone (Hal), and transforming growth factor β3 (TGF-β3) exhibits antiscarring effects that may prevent post-ESD stricture formation. Methods Using endoscopic mucosectomy (EEM) technique, an 8- to 10-cm-long circumferential esophageal mucosal segment was excised in a porcine model. The site was either untreated (control, n = 6) or received 40 evenly distributed injections of antiscarring agent immediately and at weeks 1 and 2. High and low doses were used: MMC 5 mg (n = 2), 0.5 mg (n = 2); Hal 5 mg (n = 2), 1.5 mg (n = 2), 0.5 mg (n = 2); TGF-β3 2 μg (n = 2), 0.5 μg (n = 2). The degree of stricture formation was determined by the percentage reduction of the esophageal lumen on weekly fluoroscopic examination. Animals were euthanized when strictures exceeded 80 % or the animals were unable to maintain weight. Results The control group had a luminal diameter reduction of 78.2 ± 10.9 % by 2 weeks and were euthanized by week 3. Compared at 2 weeks, the Hal group showed a decrease in mean stricture formation (68.4 % low dose, 57.7 % high dose), while both TGF-β3 dosage groups showed no significant change (65.3 % low dose, 76.2 % high dose). MMC was most effective in stricture prevention (53.6 % low dose, 35 % high dose). Of concern, the esophageal wall treated with high-dose MMC appeared to be necrotic and eventually led to perforation. In contrast, low dose MMC, TGF-β3 and Hal treated areas appeared re-epithelialized and healthy. Conclusions Preliminary data on MMC and Hal demonstrated promise in reducing esophageal stricture formation after EEM. More animal data are needed to perform adequate statistical analysis in order to determine overall efficacy of antiscarring therapy. PMID:24100858

Bisphosphonate associated osteonecrosis of the jaw.

PubMed

Khan, Aliya A; Sándor, George K B; Dore, Edward; Morrison, Archibald D; Alsahli, Mazen; Amin, Faizan; Peters, Edmund; Hanley, David A; Chaudry, Sultan R; Lentle, Brian; Dempster, David W; Glorieux, Francis H; Neville, Alan J; Talwar, Reena M; Clokie, Cameron M; Mardini, Majd Al; Paul, Terri; Khosla, Sundeep; Josse, Robert G; Sutherland, Susan; Lam, David K; Carmichael, Robert P; Blanas, Nick; Kendler, David; Petak, Steven; Ste-Marie, Louis Georges; Brown, Jacques; Evans, A Wayne; Rios, Lorena; Compston, Juliet E

2009-03-01

In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BP) were published. These cases occurred in patients with cancer receiving high-dose intravenous BP; however, 5% of the cases were in patients with osteoporosis receiving low-dose bisphosphonate therapy. We present the results of a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BP associated ONJ. We conducted a comprehensive literature search for relevant studies on BP associated ONJ in oncology and osteoporosis patients published before February 2008.All selected relevant articles were sorted by area of focus. Data for each area were abstracted by 2 independent reviewers. The results showed that the diagnosis is made clinically. Prospective data evaluating the incidence and etiologic factors are very limited. In oncology patients receiving high-dose intravenous BP, ONJ appears to be dependent on the dose and duration of therapy, with an estimated incidence of 1%-12% at 36 months of exposure. In osteoporosis patients, it is rare, with an estimated incidence < 1 case per 100,000 person-years of exposure. The incidence of ONJ in the general population is not known. Currently, there is insufficient evidence to confirm a causal link between low-dose BP use in the osteoporosis patient population and ONJ. We concluded BP associated ONJ is associated with high-dose BP therapy primarily in the oncology patient population. Prevention and treatment strategies are currently based on expert opinion and focus on maintaining good oral hygiene and conservative surgical intervention.

Serial betamethasone administration: effect on maternal salivary estriol levels.

PubMed

Hendershott, C M; Dullien, V; Goodwin, T M

1999-01-01

Maternal salivary estriol levels are an indirect measure of fetal adrenal activity, which may be affected by administration of betamethasone. The objective was to compare sequential salivary estriol levels in patients receiving serial betamethasone therapy with those of healthy pregnant patients. Ten patients at high risk for preterm delivery were asked to obtain salivary specimens before and 1 to 2 days after each administration of weekly betamethasone treatments between 24 and 32 weeks' gestation. These values were compared with those of specimens obtained throughout gestation in healthy women who were not delivered preterm. Unconjugated salivary estriol was measured with a sensitive and specific enzyme-linked immunoassay (Biex, Inc, Dublin, Calif). The effect of betamethasone on salivary estriol levels did not change with time, showing an average of 23.1% drop from pretreatment to posttreatment levels but rebounding to the same starting level before the next dose. When weekly pretreatment values were looked at across time, the geometric mean of the individual patients' slopes did not differ significantly from no change. The same was true of the posttreatment values. The rate of change with advancing gestation was compared between 182 control subjects and the 10 study subjects. The average change was +8.8% per week in the control subjects and -1.3% per week in the study patients (P =.003). Maternal administration of betamethasone significantly suppressed salivary estriol levels. These levels returned to pretreatment values each week before the next dose; however, the rise normally associated with advancing gestational age was not observed.

Ultrasound Evaluation of Thyroid Gland Pathologies After Radiation Therapy and Chemotherapy to Treat Malignancy During Childhood

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

Lollert, André, E-mail: andre.lollert@unimedizin-mainz.de; Gies, Christina; Laudemann, Katharina

Purpose: The purpose of this study was to evaluate correlations between treatment of malignancy by radiation therapy during childhood and the occurrence of thyroid gland pathologies detected by ultrasonography in follow-up examinations. Methods and Materials: Reductions of thyroid gland volume below 2 standard deviations of the weight-specific mean value, occurrence of ultrasonographically detectable thyroid gland pathologies, and hypothyroidism were retrospectively assessed in 103 children and adolescents 7 months to 20 years of age (median: 7 years of age) at baseline (1997-2013) treated with chemoradiation therapy (with the thyroid gland dose assessable) or with chemotherapy alone and followed by ultrasonography and laboratory examinations throughmore » 2014 (median follow-up time: 48 months). Results: A relevant reduction of thyroid gland volume was significantly correlated with thyroid gland dose in univariate (P<.001) and multivariate analyses for doses above 2 Gy. Odds ratios were 3.1 (95% confidence interval: 1.02-9.2; P=.046) for medium doses (2-25 Gy) and 14.8 (95% confidence interval: 1.4-160; P=.027) for high doses (>25 Gy). Thyroid gland dose was significantly higher in patients with thyroid gland pathologies during follow-up (P=.03). Univariate analysis revealed significant correlations between hypothyroidism and thyroid gland dose (P<.001). Conclusions: Ultrasonographically detectable changes, that is, volume reductions, pathologies, and hypothyroidism, after malignancy treatment during childhood are associated with thyroid gland dose. Both ultrasonography and laboratory follow-up examinations should be performed regularly after tumor therapy during childhood, especially if the treatment included radiation therapy.« less

Ultrasound Evaluation of Thyroid Gland Pathologies After Radiation Therapy and Chemotherapy to Treat Malignancy During Childhood.

PubMed

Lollert, André; Gies, Christina; Laudemann, Katharina; Faber, Jörg; Jacob-Heutmann, Dorothee; König, Jochem; Düber, Christoph; Staatz, Gundula

2016-01-01

The purpose of this study was to evaluate correlations between treatment of malignancy by radiation therapy during childhood and the occurrence of thyroid gland pathologies detected by ultrasonography in follow-up examinations. Reductions of thyroid gland volume below 2 standard deviations of the weight-specific mean value, occurrence of ultrasonographically detectable thyroid gland pathologies, and hypothyroidism were retrospectively assessed in 103 children and adolescents 7 months to 20 years of age (median: 7 years of age) at baseline (1997-2013) treated with chemoradiation therapy (with the thyroid gland dose assessable) or with chemotherapy alone and followed by ultrasonography and laboratory examinations through 2014 (median follow-up time: 48 months). A relevant reduction of thyroid gland volume was significantly correlated with thyroid gland dose in univariate (P<.001) and multivariate analyses for doses above 2 Gy. Odds ratios were 3.1 (95% confidence interval: 1.02-9.2; P=.046) for medium doses (2-25 Gy) and 14.8 (95% confidence interval: 1.4-160; P=.027) for high doses (>25 Gy). Thyroid gland dose was significantly higher in patients with thyroid gland pathologies during follow-up (P=.03). Univariate analysis revealed significant correlations between hypothyroidism and thyroid gland dose (P<.001). Ultrasonographically detectable changes, that is, volume reductions, pathologies, and hypothyroidism, after malignancy treatment during childhood are associated with thyroid gland dose. Both ultrasonography and laboratory follow-up examinations should be performed regularly after tumor therapy during childhood, especially if the treatment included radiation therapy. Copyright © 2016. Published by Elsevier Inc.

Smart Porous Silicon Nanoparticles with Polymeric Coatings for Sequential Combination Therapy.

PubMed

Xu, Wujun; Thapa, Rinez; Liu, Dongfei; Nissinen, Tuomo; Granroth, Sari; Närvänen, Ale; Suvanto, Mika; Santos, Hélder A; Lehto, Vesa-Pekka

2015-11-02

In spite of the advances in drug delivery, the preparation of smart nanocomposites capable of precisely controlled release of multiple drugs for sequential combination therapy is still challenging. Here, a novel drug delivery nanocomposite was prepared by coating porous silicon (PSi) nanoparticles with poly(beta-amino ester) (PAE) and Pluronic F-127, respectively. Two anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX), were separately loaded into the core of PSi and the shell of F127. The nanocomposite displayed enhanced colloidal stability and good cytocompatibility. Moreover, a spatiotemporal drug release was achieved for sequential combination therapy by precisely controlling the release kinetics of the two tested drugs. The release of PTX and DOX occurred in a time-staggered manner; PTX was released much faster and earlier than DOX at pH 7.0. The grafted PAE on the external surface of PSi acted as a pH-responsive nanovalve for the site-specific release of DOX. In vitro cytotoxicity tests demonstrated that the DOX and PTX coloaded nanoparticles exhibited a better synergistic effect than the free drugs in inducing cellular apoptosis. Therefore, the present study demonstrates a promising strategy to enhance the efficiency of combination cancer therapies by precisely controlling the release kinetics of different drugs.

Evidence for the use PET for radiation therapy planning in patients with cervical cancer: a systematic review.

PubMed

Salem, A; Salem, A F; Al-Ibraheem, A; Lataifeh, I; Almousa, A; Jaradat, I

2011-01-01

In recent years, the role of positron emission tomography (PET) in the staging and management of gynecological cancers has been increasing. The aim of this study was to systematically review the role of PET in radiotherapy planning and brachytherapy treatment optimization in patients with cervical cancer. Systematic literature review. Systematic review of relevant literature addressing the utilization of PET and/or PET-computed tomography (CT) in external-beam radiotherapy planning and brachytherapy treatment optimization. We performed an extensive PubMed database search on 20 April 2011. Nineteen studies, including 759 patients, formed the basis of this systematic review. PET/ PET-CT is the most sensitive imaging modality for detecting nodal metastases in patients with cervical cancer and has been shown to impact external-beam radiotherapy planning by modifying the treatment field and customizing the radiation dose. This particularly applies to detection of previously uncovered para-aortic and inguinal nodal metastases. Furthermore, PET/ PET-CT guided intensity-modulated radiation therapy (IMRT) allows delivery of higher doses of radiation to the primary tumor, if brachytherapy is unsuitable, and to grossly involved nodal disease while minimizing treatment-related toxicity. PET/ PET-CT based brachytherapy optimization allows improved tumor-volume dose distribution and detailed 3D dosimetric evaluation of risk organs. Sequential PET/ PET-CT imaging performed during the course of brachytherapy form the basis of “adaptive” brachytherapy in cervical cancer. This review demonstrates the effectiveness of pretreatment PET/ PET-CT in cervical cancer patients treated by radiotherapy. Further prospective studies are required to define the group of patients who would benefit the most from this procedure.

Gantry for medical particle therapy facility

DOEpatents

Trbojevic, Dejan

2013-04-23

A particle therapy gantry for delivering a particle beam to a patient includes a beam tube having a curvature defining a particle beam path and a plurality of superconducting, variable field magnets sequentially arranged along the beam tube for guiding the particle beam along the particle path. In a method for delivering a particle beam to a patient through a gantry, a particle beam is guided by a plurality of variable field magnets sequentially arranged along a beam tube of the gantry and the beam is alternately focused and defocused with alternately arranged focusing and defocusing variable field magnets.

Gantry for medical particle therapy facility

DOEpatents

Trbojevic, Dejan [Wading River, NY

2012-05-08

A particle therapy gantry for delivering a particle beam to a patient includes a beam tube having a curvature defining a particle beam path and a plurality of fixed field magnets sequentially arranged along the beam tube for guiding the particle beam along the particle path. In a method for delivering a particle beam to a patient through a gantry, a particle beam is guided by a plurality of fixed field magnets sequentially arranged along a beam tube of the gantry and the beam is alternately focused and defocused with alternately arranged focusing and defocusing fixed field magnets.

Potential of Proton Therapy to Reduce Acute Hematologic Toxicity in Concurrent Chemoradiation Therapy for Esophageal Cancer.

PubMed

Warren, Samantha; Hurt, Christopher N; Crosby, Thomas; Partridge, Mike; Hawkins, Maria A

2017-11-01

Radiation therapy dose escalation using a simultaneous integrated boost (SIB) is predicted to improve local tumor control in esophageal cancer; however, any increase in acute hematologic toxicity (HT) could limit the predicted improvement in patient outcomes. Proton therapy has been shown to significantly reduce HT in lung cancer patients receiving concurrent chemotherapy. Therefore, we investigated the potential of bone marrow sparing with protons for esophageal tumors. Twenty-one patients with mid-esophageal cancer who had undergone conformal radiation therapy (3D50) were selected. Two surrogates for bone marrow were created by outlining the thoracic bones (bone) and only the body of the thoracic vertebrae (TV) in Eclipse. The percentage of overlap of the TV with the planning treatment volume was recorded for each patient. Additional plans were created retrospectively, including a volumetric modulated arc therapy (VMAT) plan with the same dose as for 3D50; a VMAT SIB plan with a dose prescription of 62.5 Gy to the high-risk subregion within the planning treatment volume; a reoptimized TV-sparing VMAT plan; and a proton therapy plan with the same SIB dose prescription. The bone and TV dose metrics were recorded and compared across all plans and variations with respect to PTV and percentage of overlap for each patient. The 3D50 plans showed the highest bone mean dose and TV percentage of volume receiving ≥30 Gy (V 30Gy ) for each patient. The VMAT plans irradiated a larger bone V 10Gy than did the 3D50 plans. The reoptimized VMAT62.5 VT plans showed improved sparing of the TV volume, but only the proton plans showed significant sparing for bone V 10Gy and bone mean dose, especially for patients with a larger PTV. The results of the present study have shown that proton therapy can reduced bone marrow toxicity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Temperature mapping and thermal dose calculation in combined radiation therapy and 13.56 MHz radiofrequency hyperthermia for tumor treatment

NASA Astrophysics Data System (ADS)

Kim, Jung Kyung; Prasad, Bibin; Kim, Suzy

2017-02-01

To evaluate the synergistic effect of radiotherapy and radiofrequency hyperthermia therapy in the treatment of lung and liver cancers, we studied the mechanism of heat absorption and transfer in the tumor using electro-thermal simulation and high-resolution temperature mapping techniques. A realistic tumor-induced mouse anatomy, which was reconstructed and segmented from computed tomography images, was used to determine the thermal distribution in tumors during radiofrequency (RF) heating at 13.56 MHz. An RF electrode was used as a heat source, and computations were performed with the aid of the multiphysics simulation platform Sim4Life. Experiments were carried out on a tumor-mimicking agar phantom and a mouse tumor model to obtain a spatiotemporal temperature map and thermal dose distribution. A high temperature increase was achieved in the tumor from both the computation and measurement, which elucidated that there was selective high-energy absorption in tumor tissue compared to the normal surrounding tissues. The study allows for effective treatment planning for combined radiation and hyperthermia therapy based on the high-resolution temperature mapping and high-precision thermal dose calculation.

Very High Dose-Rate Radiobiology and Radiation Therapy for Lung Cancer

DTIC Science & Technology

2015-02-01

most dramatic example is stereotactic ablative radiotherapy ( SABR )/ stereotactic body radiation therapy (SBRT), highly focused and accurate...significant motion, thus increasing the precision and accuracy of lung SABR /SBRT. Objective: We propose to develop a new type of RT system for early stage

Simulation of irradiation exposure of electronic devices due to heavy ion therapy with Monte Carlo Code MCNP6

NASA Astrophysics Data System (ADS)

Lapins, Janis; Guilliard, Nicole; Bernnat, Wolfgang; Buck, Arnulf

2017-09-01

During heavy ion irradiation therapy the patient has to be located exactly at the right position to make sure that the Bragg peak occurs in the tumour. The patient has to be moved in the range of millimetres to scan the ill tissue. For that reason a special table was developed which allows exact positioning. The electronic control can be located outside the surgery. But that has some disadvantage for the construction. To keep the system compact it would be much more comfortable to put the electronic control inside the surgery. As a lot of high energetic secondary particles are produced during the therapy causing a high dose in the room it is important to find positions with low dose rates. Therefore, investigations are needed where the electronic devices should be located to obtain a minimum of radiation, help to prevent the failure of sensitive devices. The dose rate was calculated for carbon ions with different initial energy and protons over the entire therapy room with Monte Carlo particle tracking using MCNP6. The types of secondary particles were identified and the dose rate for a thin silicon layer and an electronic mixture material was determined. In addition, the shielding effect of several selected material layers was calculated using MCNP6.

Increasing Use of Dose-Escalated External Beam Radiation Therapy for Men With Nonmetastatic Prostate Cancer

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

Swisher-McClure, Samuel, E-mail: Swisher-Mcclure@uphs.upenn.edu; Leonard Davis Institute of Health Economics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Mitra, Nandita

Purpose: To examine recent practice patterns, using a large national cancer registry, to understand the extent to which dose-escalated external beam radiation therapy (EBRT) has been incorporated into routine clinical practice for men with prostate cancer. Methods and Materials: We conducted a retrospective observational cohort study using the National Cancer Data Base, a nationwide oncology outcomes database in the United States. We identified 98,755 men diagnosed with nonmetastatic prostate cancer between 2006 and 2011 who received definitive EBRT and classified patients into National Comprehensive Cancer Network (NCCN) risk groups. We defined dose-escalated EBRT as total prescribed dose of ≥75.6 Gy. Usingmore » multivariable logistic regression, we examined the association of patient, clinical, and demographic characteristics with the use of dose-escalated EBRT. Results: Overall, 81.6% of men received dose-escalated EBRT during the study period. The use of dose-escalated EBRT did not vary substantially by NCCN risk group. Use of dose-escalated EBRT increased from 70.7% of patients receiving treatment in 2006 to 89.8% of patients receiving treatment in 2011. On multivariable analysis, year of diagnosis and use of intensity modulated radiation therapy were significantly associated with receipt of dose-escalated EBRT. Conclusions: Our study results indicate that dose-escalated EBRT has been widely adopted by radiation oncologists treating prostate cancer in the United States. The proportion of patients receiving dose-escalated EBRT increased nearly 20% between 2006 and 2011. We observed high utilization rates of dose-escalated EBRT within all disease risk groups. Adoption of intensity modulated radiation therapy was strongly associated with use of dose-escalated treatment.« less

Efficacy and safety of fosfomycin plus imipenem as rescue therapy for complicated bacteremia and endocarditis due to methicillin-resistant Staphylococcus aureus: a multicenter clinical trial.

PubMed

del Río, Ana; Gasch, Oriol; Moreno, Asunción; Peña, Carmen; Cuquet, Jordi; Soy, Dolors; Mestres, Carlos A; Suárez, Cristina; Pare, Juan C; Tubau, Fe; Garcia de la Mària, Cristina; Marco, Francesc; Carratalà, Jordi; Gatell, José M; Gudiol, Francisco; Miró, José M

2014-10-15

There is an urgent need for alternative rescue therapies in invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We assessed the clinical efficacy and safety of the combination of fosfomycin and imipenem as rescue therapy for MRSA infective endocarditis and complicated bacteremia. The trial was conducted between 2001 and 2010 in 3 Spanish hospitals. Adult patients with complicated MRSA bacteremia or endocarditis requiring rescue therapy were eligible for the study. Treatment with fosfomycin (2 g/6 hours IV) plus imipenem (1 g/6 hours IV) was started and monitored. The primary efficacy endpoints were percentage of sterile blood cultures at 72 hours and clinical success rate assessed at the test-of-cure visit (45 days after the end of therapy). The combination was administered in 12 patients with endocarditis, 2 with vascular graft infection, and 2 with complicated bacteremia. Therapy had previously failed with vancomycin in 9 patients, daptomycin in 2, and sequential antibiotics in 5. Blood cultures were negative 72 hours after the first dose of the combination in all cases. The success rate was 69%, and only 1 of 5 deaths was related to the MRSA infection. Although the combination was safe in most patients (94%), a patient with liver cirrhosis died of multiorgan failure secondary to sodium overload. There were no episodes of breakthrough bacteremia or relapse. Fosfomycin plus imipenem was an effective and safe combination when used as rescue therapy for complicated MRSA bloodstream infections and deserves further clinical evaluation as initial therapy in these infections. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

High-Dose Intravenous Ribavirin Therapy for Subacute Sclerosing Panencephalitis

PubMed Central

Hosoya, Mitsuaki; Shigeta, Shiro; Mori, Shuichi; Tomoda, Akemi; Shiraishi, Seiji; Miike, Teruhisa; Suzuki, Hitoshi

2001-01-01

Two patients with subacute sclerosing panencephalitis (SSPE) were treated safely and effectively with high doses of intravenous ribavirin combined with intraventricular alpha interferon. The ribavirin concentrations maintained in the serum and cerebrospinal fluid were higher than those which inhibit SSPE virus replication in vitro and in vivo. PMID:11181386

Neuroblastoma Treatment (PDQ®)—Patient Version

Cancer.gov

Neuroblastoma treatment may include surgery, observation, chemotherapy, radiation therapy, radioactive iodine, and high-dose chemotherapy with stem cell transplant and targeted therapy. Treatment also depends on risk category. Learn more in this expert-reviewed summary.

Retinoblastoma Treatment (PDQ®)—Patient Version

Cancer.gov

Retinoblastoma treatment may include cryosurgery, laser therapy (thermotherapy), chemotherapy, radiation therapy, high-dose chemotherapy with stem cell rescue, and sometimes surgery. Learn more about newly diagnosed and recurrent retinoblastoma in this expert-reviewed summary.

Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial

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

Westover, Kenneth D.; Loo, Billy W.; Gerber, David E.

2015-09-01

Purpose: Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. Methods and Materials: Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiationmore » therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. Results: Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59). Conclusions: Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.« less

Helicobacter pylori second-line rescue therapy with levofloxacin- and bismuth-containing quadruple therapy, after failure of standard triple or non-bismuth quadruple treatments.

PubMed

Gisbert, J P; Romano, M; Gravina, A G; Solís-Muñoz, P; Bermejo, F; Molina-Infante, J; Castro-Fernández, M; Ortuño, J; Lucendo, A J; Herranz, M; Modolell, I; Del Castillo, F; Gómez, J; Barrio, J; Velayos, B; Gómez, B; Domínguez, J L; Miranda, A; Martorano, M; Algaba, A; Pabón, M; Angueira, T; Fernández-Salazar, L; Federico, A; Marín, A C; McNicholl, A G

2015-04-01

The most commonly used second-line Helicobacter pylori eradication regimens are bismuth-containing quadruple therapy and levofloxacin-containing triple therapy, both offering suboptimal results. Combining bismuth and levofloxacin may enhance the efficacy of rescue eradication regimens. To evaluate the efficacy and tolerability of a second-line quadruple regimen containing levofloxacin and bismuth in patients whose previous H. pylori eradication treatment failed. This was a prospective multicenter study including patients in whom a standard triple therapy (PPI-clarithromycin-amoxicillin) or a non-bismuth quadruple therapy (PPI-clarithromycin-amoxicillin-metronidazole, either sequential or concomitant) had failed. Esomeprazole (40 mg b.d.), amoxicillin (1 g b.d.), levofloxacin (500 mg o.d.) and bismuth (240 mg b.d.) was prescribed for 14 days. Eradication was confirmed by (13) C-urea breath test. Compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by questionnaires. 200 patients were included consecutively (mean age 47 years, 67% women, 13% ulcer). Previous failed therapy included: standard clarithromycin triple therapy (131 patients), sequential (32) and concomitant (37). A total of 96% took all medications correctly. Per-protocol and intention-to-treat eradication rates were 91.1% (95%CI = 87-95%) and 90% (95%CI = 86-94%). Cure rates were similar regardless of previous (failed) treatment or country of origin. Adverse effects were reported in 46% of patients, most commonly nausea (17%) and diarrhoea (16%); 3% were intense but none was serious. Fourteen-day bismuth- and levofloxacin-containing quadruple therapy is an effective (≥90% cure rate), simple and safe second-line strategy in patients whose previous standard triple or non-bismuth quadruple (sequential or concomitant) therapies have failed. © 2015 John Wiley & Sons Ltd.

Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

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

Appelt, Ane L., E-mail: ane.lindegaard.appelt@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

2013-01-01

Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from themore » histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D{sub 50,i}, and the normalized dose-response gradient, {gamma}{sub 50,i}. Results: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D{sub 50,TRG1} = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), {gamma}{sub 50,TRG1} = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D{sub 50,TRG1} and {sub 2} = 72.1 Gy (CI 65.3-94.0 Gy), {gamma}{sub 50,TRG1} and {sub 2} = 0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. Conclusions: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.« less

Clinical Ion Beam Applications: Basic Properties, Application, Quality Control, Planning

NASA Astrophysics Data System (ADS)

Kraft, Gerhard

2009-03-01

Heavy-ion therapy using beam scanning and biological dose optimization is a novel technique of high-precision external radiotherapy. It yields a better perspective for tumor cure of radio-resistant tumors. However, heavy-ion therapy is not a general solution for all types of tumors. As compared to conventional radiotherapy, heavy-ion radiotherapy has the advantages of higher tumor dose, improved sparing of normal tissue in the entrance channel, a more precise concentration of the dose in the target volume with steeper gradients to the normal tissue, and a higher radiobiological effectiveness for tumors which are radio-resistant in conventional therapy. These properties make it possible to treat radio-resistant tumors with great success, including those in close vicinity to critical organs.

Effect of Boron Neutron Capture Therapy (BNCT) on Normal Liver Regeneration: Towards a Novel Therapy for Liver Metastases

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

Jorge E. Cardoso; Elisa M. Heber; David W. Nigg

2007-10-01

The “TAORMINA project” developed a new method for Boron Neutron Capture Therapy (BNCT) of human multifocal unresectable liver metastases based on whole liver ex-situ BNCT mediated by boronophenylalanine (BPA), followed by whole liver autograft. This technique involved a high risk, prolonged anhepatic phase. The Roffo Institute liver surgeons (JEC) herein propose a novel technique to pursue ex-situ liver BNCT studies with a drastically lower surgical risk for the patient. The technique would involve, sequentially, ex-situ BNCT of left liver segments II and III, partial liver autograft, and induction of partial atrophy of the untreated right liver. The working hypothesis ismore » that the atrophy of the right, untreated, diseased liver would stimulate regeneration of the left, treated, “cured” liver to yield a healthy liver mass, allowing for the resection of the remaining portion of diseased liver. This technique does not involve an anhepatic phase and would thus pose a drastically lower surgical risk to the patient but requires sine qua non that BNCT should not impair the regenerative capacity of normal hepatocytes. The aim of the present study was to assess the effect of therapeutic doses of BNCT mediated by BPA, GB-10 (Na2 10B10H10) or (GB- 10 + BPA) on normal liver regeneration in the Wistar rat employing partial hepatectomy as a regenerative stimulus. BNCT did not cause alterations in the outcome of normal liver regeneration, regenerated liver function or histology. We provide proof of principle to support the development of a novel, promising BNCT technique for the treatment of liver metastases.« less

Revision of orthovoltage chest wall treatment using Monte Carlo simulations.

PubMed

Zeinali-Rafsanjani, B; Faghihi, R; Mosleh-Shirazi, M A; Mosalaei, A; Hadad, K

2017-01-01

Given the high local control rates observed in breast cancer patients undergoing chest wall irradiation by kilovoltage x-rays, we aimed to revisit this treatment modality by accurate calculation of dose distributions using Monte Carlo simulation. The machine components were simulated using the MCNPX code. This model was used to assess the dose distribution of chest wall kilovoltage treatment in different chest wall thicknesses and larger contour or fat patients in standard and mid sternum treatment plans. Assessments were performed at 50 and 100 cm focus surface distance (FSD) and different irradiation angles. In order to evaluate different plans, indices like homogeneity index, conformity index, the average dose of heart, lung, left anterior descending artery (LAD) and percentage target coverage (PTC) were used. Finally, the results were compared with the indices provided by electron therapy which is a more routine treatment of chest wall. These indices in a medium chest wall thickness in standard treatment plan at 50 cm FSD and 15 degrees tube angle was as follows: homogeneity index 2.57, conformity index 7.31, average target dose 27.43 Gy, average dose of heart, lung and LAD, 1.03, 2.08 and 1.60 Gy respectively and PTC 11.19%. Assessments revealed that dose homogeneity in planning target volume (PTV) and conformity between the high dose region and PTV was poor. To improve the treatment indices, the reference point was transferred from the chest wall skin surface to the center of PTV. The indices changed as follows: conformity index 7.31, average target dose 60.19 Gy, the average dose of heart, lung and LAD, 3.57, 6.38 and 5.05 Gy respectively and PTC 55.24%. Coverage index of electron therapy was 89% while it was 22.74% in the old orthovoltage method and also the average dose of the target was about 50 Gy but in the given method it was almost 30 Gy. The results of the treatment study show that the optimized standard and mid sternum treatment for different chest wall thicknesses is with 50 cm FSD and zero (vertical) tube angle, while in large contour patients, it is with 100 cm FSD and zero tube angle. Finally, chest wall kilovoltage and electron therapies were compared, which revealed that electron therapy produces a better dose distribution than kilovoltage therapy.

Comprehensive evaluations of cone-beam CT dose in image-guided radiation therapy via GPU-based Monte Carlo simulations

NASA Astrophysics Data System (ADS)

Montanari, Davide; Scolari, Enrica; Silvestri, Chiara; Jiang Graves, Yan; Yan, Hao; Cervino, Laura; Rice, Roger; Jiang, Steve B.; Jia, Xun

2014-03-01

Cone beam CT (CBCT) has been widely used for patient setup in image-guided radiation therapy (IGRT). Radiation dose from CBCT scans has become a clinical concern. The purposes of this study are (1) to commission a graphics processing unit (GPU)-based Monte Carlo (MC) dose calculation package gCTD for Varian On-Board Imaging (OBI) system and test the calculation accuracy, and (2) to quantitatively evaluate CBCT dose from the OBI system in typical IGRT scan protocols. We first conducted dose measurements in a water phantom. X-ray source model parameters used in gCTD are obtained through a commissioning process. gCTD accuracy is demonstrated by comparing calculations with measurements in water and in CTDI phantoms. Twenty-five brain cancer patients are used to study dose in a standard-dose head protocol, and 25 prostate cancer patients are used to study dose in pelvis protocol and pelvis spotlight protocol. Mean dose to each organ is calculated. Mean dose to 2% voxels that have the highest dose is also computed to quantify the maximum dose. It is found that the mean dose value to an organ varies largely among patients. Moreover, dose distribution is highly non-homogeneous inside an organ. The maximum dose is found to be 1-3 times higher than the mean dose depending on the organ, and is up to eight times higher for the entire body due to the very high dose region in bony structures. High computational efficiency has also been observed in our studies, such that MC dose calculation time is less than 5 min for a typical case.

Impact of dose size in single fraction spatially fractionated (grid) radiotherapy for melanoma

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

Zhang, Hualin, E-mail: hualin.zhang@northwestern.edu, E-mail: hualinzhang@yahoo.com; Zhong, Hualiang; Barth, Rolf F.

2014-02-15

Purpose: To evaluate the impact of dose size in single fraction, spatially fractionated (grid) radiotherapy for selectively killing infiltrated melanoma cancer cells of different tumor sizes, using different radiobiological models. Methods: A Monte Carlo technique was employed to calculate the 3D dose distribution of a commercially available megavoltage grid collimator in a 6 MV beam. The linear-quadratic (LQ) and modified linear quadratic (MLQ) models were used separately to evaluate the therapeutic outcome of a series of single fraction regimens that employed grid therapy to treat both acute and late responding melanomas of varying sizes. The dose prescription point was atmore » the center of the tumor volume. Dose sizes ranging from 1 to 30 Gy at 100% dose line were modeled. Tumors were either touching the skin surface or having their centers at a depth of 3 cm. The equivalent uniform dose (EUD) to the melanoma cells and the therapeutic ratio (TR) were defined by comparing grid therapy with the traditional open debulking field. The clinical outcomes from recent reports were used to verify the authors’ model. Results: Dose profiles at different depths and 3D dose distributions in a series of 3D melanomas treated with grid therapy were obtained. The EUDs and TRs for all sizes of 3D tumors involved at different doses were derived through the LQ and MLQ models, and a practical equation was derived. The EUD was only one fifth of the prescribed dose. The TR was dependent on the prescribed dose and on the LQ parameters of both the interspersed cancer and normal tissue cells. The results from the LQ model were consistent with those of the MLQ model. At 20 Gy, the EUD and TR by the LQ model were 2.8% higher and 1% lower than by the MLQ, while at 10 Gy, the EUD and TR as defined by the LQ model were only 1.4% higher and 0.8% lower, respectively. The dose volume histograms of grid therapy for a 10 cm tumor showed different dosimetric characteristics from those of conventional radiotherapy. A significant portion of the tumor volume received a very large dose in grid therapy, which ensures significant tumor cell killing in these regions. Conversely, some areas received a relatively small dose, thereby sparing interspersed normal cells and increasing radiation tolerance. The radiobiology modeling results indicated that grid therapy could be useful for treating acutely responding melanomas infiltrating radiosensitive normal tissues. The theoretical model predictions were supported by the clinical outcomes. Conclusions: Grid therapy functions by selectively killing infiltrating tumor cells and concomitantly sparing interspersed normal cells. The TR depends on the radiosensitivity of the cell population, dose, tumor size, and location. Because the volumes of very high dose regions are small, the LQ model can be used safely to predict the clinical outcomes of grid therapy. When treating melanomas with a dose of 15 Gy or higher, single fraction grid therapy is clearly advantageous for sparing interspersed normal cells. The existence of a threshold fraction dose, which was found in the authors’ theoretical simulations, was confirmed by clinical observations.« 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

SU-F-J-45: Sparing Normal Tissue with Ultra-High Dose Rate in Radiation Therapy

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

Feng, Y

Purpose: To spare normal tissue by reducing the location uncertainty of a moving target, we proposed an ultra-high dose rate system and evaluated. Methods: High energy electrons generated with a linear accelerator were injected into a storage ring to be accumulated. The number of the electrons in the ring was determined based on the prescribed radiation dose. The dose was delivered within a millisecond, when an online imaging system found that the target was in the position that was consistent with that in a treatment plan. In such a short time period, the displacement of the target was negligible. Themore » margin added to the clinical target volume (CTV) could be reduced that was evaluated by comparing of volumes between CTV and ITV in 14 cases of lung stereotactic body radiation therapy (SBRT) treatments. A design of the ultra-high dose rate system was evaluated based clinical needs and the recent developments of low energy (a few MeV) electron storage ring. Results: This design of ultra-high dose rate system was feasible based on the techniques currently available. The reduction of a target volume was significant by reducing the margin that accounted the motion of the target. ∼50% volume reduction of the internal target volume (ITV) could be achieved in lung SBRT treatments. Conclusion: With this innovation of ultra-high dose rate system, the margin of target is able to be significantly reduced. It will reduce treatment time of gating and allow precisely specified gating window to improve the accuracy of dose delivering.« less

Electromagnetic transponders indicate prostate size increase followed by decrease during the course of external beam radiation therapy.

PubMed

King, Benjamin L; Butler, Wayne M; Merrick, Gregory S; Kurko, Brian S; Reed, Joshua L; Murray, Brian C; Wallner, Kent E

2011-04-01

Real-time image guidance enables more accurate radiation therapy by tracking target movement. This study used transponder positions to monitor changes in prostate volume that may be a source of dosimetric and target inaccuracy. Twenty-four men with biopsy-proven T1c-T3a prostate cancer each had three electromagnetic transponders implanted transperineally. Their coordinates were recorded by the Calypso system, and the perimeter of the triangle formed by the transponders was used to calculate prostate volumes at sequential time points throughout the course of radiation therapy to a dose of 81 Gy in 1.8-Gy fractions. There was a significant decrease in mean prostate volume of 10.9% from the first to the final day of radiation therapy. The volume loss did not occur monotonically but increased in most patients (75%) during the first several weeks to a median maximum on Day 7. The volume increased by a mean of 6.1% before decreasing by a mean maximum difference of 18.4% to nadir (p < 0.001 for both increase and decrease). Glandular shrinkage was asymmetric, with the apex to right base dimension varying more than twice that of the lateral dimension. For all dimensions, the mean change was <0.5 cm. Real-time transponder positions indicated a volume increase during the initial days of radiation therapy and then significant and asymmetric shrinkage by the final day. Understanding and tracking volume fluctuations of the prostate during radiation therapy can help real-time imaging technology perform to its fullest potential. Copyright © 2011 Elsevier Inc. All rights reserved.

Improved speed and stability of ST-segment recovery with reduced-dose tenecteplase and eptifibatide compared with full-dose tenecteplase for acute ST-segment elevation myocardial infarction.

PubMed

Roe, Matthew T; Green, Cynthia L; Giugliano, Robert P; Gibson, C Michael; Baran, Kenneth; Greenberg, Mark; Palmeri, Sebastian T; Crater, Suzanne; Trollinger, Kathleen; Hannan, Karen; Harrington, Robert A; Krucoff, Mitchell W

2004-02-18

This sub-study of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial evaluated of the impact of combination reperfusion therapy with reduced-dose tenecteplase plus eptifibatide on continuous ST-segment recovery and angiographic results. Combination therapy with reduced-dose fibrinolytics and glycoprotein IIb/IIIa inhibitors for ST-segment elevation myocardial infarction improves biomarkers of reperfusion success but has not reduced mortality when compared with full-dose fibrinolytics. We evaluated 140 patients enrolled in the INTEGRITI trial with 24-h continuous 12-lead ST-segment monitoring and angiography at 60 min. The dose-combination regimen of 50% of standard-dose tenecteplase (0.27 microg/kg) plus high-dose eptifibatide (2 boluses of 180 microg/kg separated by 10 min, 2.0 microg/kg/min infusion) was compared with full-dose tenecteplase (0.53 microg/kg). The dose-confirmation regimen of reduced-dose tenecteplase plus high-dose eptifibatide was associated with a faster median time to stable ST-segment recovery (55 vs. 98 min, p = 0.06), improved stable ST-segment recovery by 2 h (89.6% vs. 67.7%, p = 0.02), and less recurrent ischemia (34.0% vs. 57.1%, p = 0.05) when compared with full-dose tenecteplase. Continuously updated ST-segment recovery analyses demonstrated a modest trend toward greater ST-segment recovery at 30 min (57.7% vs. 40.6%, p = 0.13) and 60 min (82.7% vs. 65.6%, p = 0.08) with this regimen. These findings correlated with improved angiographic results at 60 min. Combination therapy with reduced-dose tenecteplase and eptifibatide leads to faster, more stable ST-segment recovery and improved angiographic flow patterns, compared with full-dose tenecteplase. These findings question the relationship between biomarkers of reperfusion success and clinical outcomes.

The future of epigenetic therapy in solid tumours--lessons from the past.

PubMed

Azad, Nilofer; Zahnow, Cynthia A; Rudin, Charles M; Baylin, Stephen B

2013-05-01

The promise of targeting epigenetic abnormalities for cancer therapy has not been realized for solid tumours, although increasing evidence is demonstrating its worth in haematological malignancies. In fact, true clinical efficacy in haematopoietic-related neoplasms has only become evident at low doses of epigenetic-targeting drugs (namely, inhibitors of histone deacetylase and DNA methyltransferases). Describing data from preclinical studies and early clinical trial results, we hypothesize that in using low-dose epigenetic-modulating agents, tumour cells can be reprogrammed, which overrides any immediate cytotoxic and off-target effect observed at high dose. We suggest that such optimization of drug dosing and scheduling of currently available agents could give these agents a prominent place in cancer management--when used alone or in combination with other therapies. If so, optimal use of these known agents might also pave the way for the introduction of other agents that target the epigenome.

Improving Outcomes for Esophageal Cancer using Proton Beam Therapy

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

Chuong, Michael D.; Hallemeier, Christopher L.; Jabbour, Salma K.

Radiation therapy (RT) plays an essential role in the management of esophageal cancer. Because the esophagus is a centrally located thoracic structure there is a need to balance the delivery of appropriately high dose to the target while minimizing dose to nearby critical structures. Radiation dose received by these critical structures, especially the heart and lungs, may lead to clinically significant toxicities, including pneumonitis, pericarditis, and myocardial infarction. Although technological advancements in photon RT delivery like intensity modulated RT have decreased the risk of such toxicities, a growing body of evidence indicates that further risk reductions are achieved with protonmore » beam therapy (PBT). Herein we review the published dosimetric and clinical PBT literature for esophageal cancer, including motion management considerations, the potential for reirradiation, radiation dose escalation, and ongoing esophageal PBT clinical trials. We also consider the potential cost-effectiveness of PBT relative to photon RT.« less

Improving Outcomes for Esophageal Cancer using Proton Beam Therapy.

PubMed

Chuong, Michael D; Hallemeier, Christopher L; Jabbour, Salma K; Yu, Jen; Badiyan, Shahed; Merrell, Kenneth W; Mishra, Mark V; Li, Heng; Verma, Vivek; Lin, Steven H

2016-05-01

Radiation therapy (RT) plays an essential role in the management of esophageal cancer. Because the esophagus is a centrally located thoracic structure there is a need to balance the delivery of appropriately high dose to the target while minimizing dose to nearby critical structures. Radiation dose received by these critical structures, especially the heart and lungs, may lead to clinically significant toxicities, including pneumonitis, pericarditis, and myocardial infarction. Although technological advancements in photon RT delivery like intensity modulated RT have decreased the risk of such toxicities, a growing body of evidence indicates that further risk reductions are achieved with proton beam therapy (PBT). Herein we review the published dosimetric and clinical PBT literature for esophageal cancer, including motion management considerations, the potential for reirradiation, radiation dose escalation, and ongoing esophageal PBT clinical trials. We also consider the potential cost-effectiveness of PBT relative to photon RT. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of autologous blood stem cells in support of high-dose therapy for multiple myeloma.

PubMed

Fermand, J P; Chevret, S; Levy, Y; Miclea, J M; Tsapis, A; Gerota, J; Benbunan, M; Brouet, J C

1992-04-01

During the last few years, high-dose therapy with hemopoietic stem cell support has become a well-admitted therapeutic option for young patients with MM. The role of allogeneic or autologous graft and of blood rather than bone marrow as the source of hemopoietic stem cells must be further investigated. Autologous PBSC transplantation has, however, both practical and theoretic advantages over allogeneic and autologous BMT: (1) It can be applied to most patients, especially if blood stem cells are collected early in the course of therapy. (2) It usually induces relatively rapid hematologic reconstitution. (3) In comparison with autologous BMT, it appears to minimize the hazard of the reinfusion of malignant cells.

Dimethyl sulfoxide therapy in bronchiolitis.

PubMed

Zúñiga, A; Burdach, R; Rubio, S

1975-01-27

The action of a medicinal spray that contains anti-inflammatory and bacterio-static drugs integrated with the penetrating and potentiating agent DMSO has been evaluated clinically in 60 infants with acute respiratory obstruction. A dose of 2 ml of this spray is applied in the posterior pharynx and the tonsil region; 1 to 4 applications are made, according to the clinical evolution of the case. Two groups were chosen at random; 60 patients were paired off, and one of each pair received the treatment with DMSO spray. All the patients received ampicillin (50-100 mg/kg body weight). The following clinical results were observed. First there was an immediate recovery, after an average lapse of 30 min; improvement of sensorial involvement was observed in 80% of the cases, reduction of the intercostal retraction in 75%, reduction of polypnea in 76%, and transformation of the obstructive syndrome into a catarrhal syndrome in 80% (with fluidification of the secretions, which were expelled more easily by the upper air tracts). There was also a deferred or maintenance effect, which evaluated in comparsion with the control group that received similar treatment except for the nebulizations with DMSO spray. A sequential design, based on whether or not it was necessary to use the croupette, demonstrated the superiority of the DMSO spray over the control treatment in the bronchiolar process; in the group treated with DMSO spray it was not necessary to use the croupette. The sequential design based on the effect of this therapy on the general condition and the tabulated clinical factors permitted the inference that the therapeutic responses are more favorable in the group treated with DMSO spray than in the control group. In the sequential design, the line of significance is cut at the fifteenth pair (an error of 0.05 and P equals 0.95%). Since the application is easy, there are no toxic side effects and in view of the favorable results in the clinical evolution of the acute respiratory obstructive processes, we consider the use of this therapeutic spray very useful and beneficial in bronchiolitis.

Single dose treatment of malaria - current status and perspectives.

PubMed

Mischlinger, Johannes; Agnandji, Selidji T; Ramharter, Michael

2016-07-01

Despite increased international efforts for control and ultimate elimination, malaria remains a major health problem. Currently, artemisinin-based combination therapies are the treatment of choice for uncomplicated malaria exhibiting high efficacy in clinical trial settings in sub-Saharan Africa. However, their administration over a three-day period is associated with important problems of treatment adherence resulting in markedly reduced effectiveness of currently recommended antimalarials under real world settings. Antimalarial drug candidates and antimalarial drug combinations currently under advanced clinical development for the indication as single dose antimalarial therapy. Expert commentary: Several new drug candidates and combinations are currently undergoing pivotal proof-of-concept studies or clinical development programmes. The development of a single dose combination therapy would constitute a breakthrough in the control of malaria. Such an innovative treatment approach would simultaneously close the effectiveness gap of current three-day therapies and revolutionize population based interventions in the context of malaria elimination campaigns.

Radiation Therapy for Cancer

Cancer.gov

Radiation therapy is a type of cancer treatment that uses high doses of radiation to kill cancer cells and shrink tumors. Learn about the types of radiation, why side effects happen, which ones you might have, and more.

Childhood Astrocytoma Treatment (PDQ®)—Patient Version

Cancer.gov

Childhood astrocytoma treatment options include surgery, observation, radiation therapy, chemotherapy, high-dose chemotherapy with stem cell transplant, and targeted therapy. Learn more about the treatment of newly diagnosed and recurrent astrocytoma in this expert-reviewed summary.

Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy.

PubMed

Kumar, Sameera S; Higgins, Kristin A; McGarry, Ronald C

2017-01-01

The current standard of care for locally advanced non-small cell lung cancer (NSCLC) includes radiation, chemotherapy, and surgery in certain individualized cases. In unresectable NSCLC, chemoradiation has been the standard of care for the past three decades. Local and distant failure remains high in this group of patients, so dose escalation has been studied in both single institution and national clinical trials. Though initial studies showed a benefit to dose escalation, phase III studies examining dose escalation using standard fractionation or hyperfractionation have failed to show a benefit. Over the last 17 years, stereotactic body radiation therapy (SBRT) has shown a high degree of safety and local control for stage I lung cancers and other localized malignancies. More recently, phase I/II studies using SBRT for dose escalation after conventional chemoradiation in locally advanced NSCLC have been promising with good apparent safety. Immunotherapy also offers opportunities to address distant disease and preclinical data suggest immunotherapy in tandem with SBRT may be a rational way to induce an "abscopal effect" although there are little clinical data as yet. By building on the proven concept of conventional chemoradiation for patients with locally advanced NSCLC with a subsequent radiation dose intensification to residual disease with SBRT concurrent with immunotherapy, we hope address the issues of metastatic and local failures. This "quadmodality" approach is still in its infancy but appears to be a safe and rational approach to the improving the outcome of NSCLC therapy.

Comparison of three light doses in the photodynamic treatment of actinic keratosis using mathematical modeling

NASA Astrophysics Data System (ADS)

Vignion-Dewalle, Anne-Sophie; Betrouni, Nacim; Tylcz, Jean-Baptiste; Vermandel, Maximilien; Mortier, Laurent; Mordon, Serge

2015-05-01

Photodynamic therapy (PDT) is an emerging treatment modality for various diseases, especially for cancer therapy. Although high efficacy is demonstrated for PDT using standardized protocols in nonhyperkeratotic actinic keratoses, alternative light doses expected to increase efficiency, to reduce adverse effects or to expand the use of PDT, are still being evaluated and refined. We propose a comparison of the three most common light doses in the treatment of actinic keratosis with 5-aminolevulinic acid PDT through mathematical modeling. The proposed model is based on an iterative procedure that involves determination of the local fluence rate, updating of the local optical properties, and estimation of the local damage induced by the therapy. This model was applied on a simplified skin sample model including an actinic keratosis lesion, with three different light doses (red light dose, 37 J/cm2, 75 mW/cm2, 500 s blue light dose, 10 J/cm2, 10 mW/cm2, 1000 s and daylight dose, 9000 s). Results analysis shows that the three studied light doses, although all efficient, lead to variable local damage. Defining reference damage enables the nonoptimal parameters for the current light doses to be refined and the treatment to be more suitable.

Retrospective cohort study of bronchial doses and radiation-induced atelectasis after stereotactic body radiation therapy of lung tumors located close to the bronchial tree.

PubMed

Karlsson, Kristin; Nyman, Jan; Baumann, Pia; Wersäll, Peter; Drugge, Ninni; Gagliardi, Giovanna; Johansson, Karl-Axel; Persson, Jan-Olov; Rutkowska, Eva; Tullgren, Owe; Lax, Ingmar

2013-11-01

To evaluate the dose-response relationship between radiation-induced atelectasis after stereotactic body radiation therapy (SBRT) and bronchial dose. Seventy-four patients treated with SBRT for tumors close to main, lobar, or segmental bronchi were selected. The association between incidence of atelectasis and bronchial dose parameters (maximum point-dose and minimum dose to the high-dose bronchial volume [ranging from 0.1 cm(3) up to 2.0 cm(3)]) was statistically evaluated with survival analysis models. Prescribed doses varied between 4 and 20 Gy per fraction in 2-5 fractions. Eighteen patients (24.3%) developed atelectasis considered to be radiation-induced. Statistical analysis showed a significant correlation between the incidence of radiation-induced atelectasis and minimum dose to the high-dose bronchial volumes, of which 0.1 cm(3) (D(0.1cm3)) was used for further analysis. The median value of D(0.1cm3) (α/β = 3 Gy) was EQD(2,LQ) = 147 Gy3 (range, 20-293 Gy3). For patients who developed atelectasis the median value was EQD(2,LQ) = 210 Gy3, and for patients who did not develop atelectasis, EQD(2,LQ) = 105 Gy3. Median time from treatment to development of atelectasis was 8.0 months (range, 1.1-30.1 months). In this retrospective study a significant dose-response relationship between the incidence of atelectasis and the dose to the high-dose volume of the bronchi is shown. Copyright © 2013 Elsevier Inc. All rights reserved.

Pulsed-dosing with oral sodium phenylbutyrate increases hemoglobin F in a patient with sickle cell anemia.

PubMed

Hines, Patrick; Dover, George J; Resar, Linda M S

2008-02-01

Increasing hemoglobin F (HbF) appears to be beneficial for patients with sickle cell anemia. We previously demonstrated that daily, oral sodium phenylbutyrate (OSPB) induces HbF synthesis in pediatric and adult patients with hemoglobin SS (HbSS). The high doses and need for daily therapy, however, have limited its use. Here, we report a patient treated with pulsed-dosing of OSPB for over 3 years. This patient developed a modest, but sustained elevation in HbF over the course of therapy without side effects. Although larger studies are needed, this case demonstrates that pulsed-dosing with OSPB enhances HbF synthesis. (c) 2007 Wiley-Liss, Inc.

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

Hobbs, R; Le, Y; Armour, E

Purpose: Dose-response studies in radiation therapy are typically using single response values for tumors across ensembles of tumors. Using the high dose rate (HDR) treatment plan dose grid and pre- and post-therapy FDG-PET images, we look for correlations between voxelized dose and FDG uptake response in individual tumors. Methods: Fifteen patients were treated for localized rectal cancer using 192Ir HDR brachytherapy in conjunction with surgery. FDG-PET images were acquired before HDR therapy and 6–8 weeks after treatment (prior to surgery). Treatment planning was done on a commercial workstation and the dose grid was calculated. The two PETs and the treatmentmore » dose grid were registered to each other using non-rigid registration. The difference in PET SUV values before and after HDR was plotted versus absorbed radiation dose for each voxel. The voxels were then separated into bins for every 400 cGy of absorbed dose and the bin average values plotted similarly. Results: Individual voxel doses did not correlate with PET response; however, when group into tumor subregions corresponding to dose bins, eighty percent of the patients showed a significant positive correlation (R2 > 0) between PET uptake difference in the targeted region and the absorbed dose. Conclusion: By considering larger ensembles of voxels, such as organ average absorbed dose or the dose bins considered here, valuable information may be obtained. The dose-response correlations as measured by FDG-PET difference potentially underlines the importance of FDG-PET as a measure of response, as well as the value of voxelized information.« less

Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia.

PubMed

Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas; Rosthøj, Susanne; Nersting, Jacob

2015-05-01

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression.

Asthma: non-responsiveness to conventional therapy.

PubMed

Rebuck, A S

1986-01-01

Despite regular inhalation of beta-agonists, topical steroids and anticholinergic aerosols and the achievement of therapeutic blood levels of theophylline, some asthmatics have rapidly fluctuating levels of peak flow measurements throughout the day. Often little or no improvement is obtained with larger doses of corticosteroids. Before embarking on more intense drug therapy, attention should be paid to conscientious adherence to the prescribed regimen and avoidance of aspirin and tartrazine, as well as to exposure to allergens such as those associated with household pets. A number of newer therapeutic options are related to the use of air jet or ultrasonic nebulizers, that allow liquid forms of inhalation agents to be taken slowly in the home environment. In this regard, combination therapy with a beta-agonist and the anticholinergic ipratropium has been shown to have bronchodilating properties superior to either agent used alone. Secondly, sodium cromoglycate in its liquid form appears to have bronchodilator properties; taken on a regular basis, four times per day, it appears to have a steroid-sparing effect. Two alternatives are available for increasing the intensity of corticosteroid therapy, other than by prolonged, high-dose prednisone. The first is that of high-dose inhaled beclomethasone (up to 2000 micrograms/day) using the 250 micrograms/puff inhaler. The second is that of intravenous therapy with methylprednisolone, recently shown to have lung permeability superior to that of prednisolone. Office patients can be treated with occasional or even regular 'pulse' doses of methylprednisolone, an approach that is now finding acceptance in the management of the inflammatory alveolitides.

Influence of atropine therapy on fenthion-induced pancreatitis.

PubMed

Ela, Yuksel; Fidan, Huseyin; Sahin, Onder; Kilbas, Aynur; Bas, Orhan; Yavuz, Yucel; Kucuker, Hudaverdi; Altuntas, Irfan

2008-02-01

We searched the influence of dose and timing of atropine therapy in fenthion-induced pancreatitis model. All rats were intoxicated with fenthion except the control group. Two milligrams of atropine was administered for 24 hours in a high dose atropine group while a low dose atropine group received 100 micrograms of atropine for 24 hours. One group received 2 milligrams of atropine in the first four hours of intoxication while the other group received 2 milligrams of atropine in the last four hours before sacrifice. All rats were sacrificed 24 hours after intoxication. Pseudo-cholinesterase and lipase concentrations and histopathological markers of pancreatitis were studied. None of the models in this study completely prevented pancreatitis, however high dose atropine that is administered for 24 hours or the first four hours after intoxication prevented severe pancreatitis. Atropine administration influence on fenthion-induced pancreatitis should be studied for other organophosphates in animals and humans.

Potential for focused beam orthovoltage therapy

NASA Astrophysics Data System (ADS)

Mahato, Dip N.; MacDonald, C. A.

2010-08-01

Radiation therapy typically employs high energy photon beams because the low absorption coefficient at these energies minimizes skin dose with a conventional, unfocused beam. At orthovoltage energies less than 150 keV, the maximum dose for a single beam occurs very close to the skin surface. However a well-focused beam of low energy x rays can provide much higher flux at the target depth while sparing dose to the skin. The measured focal spot size for the polycapillary optic was 0.2 mm and was found to remain unchanged through 50 mm of phantom thickness. The calculated depth-dose curve was found to peak several centimeters below the surface with 25-40 keV radiation. Modeling indicates that the tumor dose would remain much higher than the skin dose even after scanning to cover a 1 cm3 tumor.

Relationship Between Radiation Therapy Dose and Outcome in Patients Treated With Neoadjuvant Chemoradiation Therapy and Surgery for Stage IIIA Non-Small Cell Lung Cancer: A Population-Based, Comparative Effectiveness Analysis

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

Sher, David J., E-mail: david_sher@rush.edu; Fidler, Mary Jo; Seder, Christopher W.

Purpose: To compare, using the National Cancer Database, survival, pathologic, and surgical outcomes in patients with stage IIIA non-small cell lung cancer treated with differential doses of neoadjuvant chemoradiation therapy, with the aim to discern whether radiation dose escalation was associated with a comparative effectiveness benefit and/or toxicity risk. Methods and Materials: Patients in the National Cancer Database with stage IIIA non-small cell lung cancer treated with neoadjuvant chemoradiation therapy and surgery between 1998 and 2005 were analyzed. Dose strata were divided between 36 to 45 Gy (low-dose radiation therapy, LD-RT), 45 to 54 Gy (inclusive, standard-dose, SD-RT), and 54 to 74 Gymore » (high-dose, HD-RT). Outcomes included overall survival, residual nodal disease, positive surgical margin status, hospital length of stay, and adverse surgical outcomes (30-day mortality or readmission). Results: The cohort consisted of 1041 patients: 233 (22%) LD-RT, 584 (56%) SD-RT, and 230 (22%) HD-RT. The median, 3-year, and 5-year overall survival outcomes were 34.9 months, 48%, and 37%, respectively. On univariable analysis, patients treated with SD-RT experienced prolonged overall survival (median 38.3 vs 31.8 vs 29.0 months for SD-RT, LD-RT, and HD-RT, respectively, P=.0089), which was confirmed on multivariable analysis (hazard ratios 0.77 and 0.81 vs LD and HD, respectively). Residual nodal disease was seen less often after HD-RT (25.5% vs 31.8% and 37.5% for HD-RT, LD-RT, and SD-RT, respectively, P=.0038). Patients treated with SD-RT had fewer prolonged hospital stays. There were no differences in positive surgical margin status or adverse surgical outcomes between the cohorts. Conclusions: Neoadjuvant chemoradiation therapy between 45 and 54 Gy was associated with superior survival in comparison with doses above and below this threshold. Although this conclusion is limited by selection bias, clear candidates for trimodality therapy do not seem to achieve additional benefit with dose escalation.« less

Tapering off long-term opioid therapy in chronic non-cancer pain patients: a randomized clinical trial.

PubMed

Kurita, Geana Paula; Højsted, Jette; Sjøgren, Per

2018-05-13

The indications for initiating long-term opioid treatment (L-TOT) for chronic non-cancer pain (CNCP) are often unclear and associated with problematic use. This study aimed at evaluating the efficacy of stabilizing opioid therapy followed by a sequential opioid tapering off program in CNCP patients. A randomized clinical trial with a medications stabilization period (Phase 1) followed by a opioid tapering off program (Phase 2). In Phase 2, patients were randomized to Control Group (stable treatment) or Taper off Group (sequential opioid dose reduction) and assessed at baseline, after stabilization and up to six months. Primary outcomes: measures of cognitive function; secondary outcomes: pain, sleep, rest, quality of life, depression, anxiety, opioid misuse, and opioid withdrawal symptoms. Two hundred seventy-four patients were screened; 75 were included, out of which 40 dropped out before Phase 2. Those who succeeded Phase 1 (n=35) had weak/moderate improvements of psychomotor function (p=0.020), sleeping hours (p=0.031), opioid withdrawal symptoms (p=0.019), measures of quality of life (p≤0.043) and opioid misuse scores (p=0.003). In Phase 2, patients in Taper off Group (n=15) experienced stable pain intensity and felt significantly more rested at third assessment than the Control Group (n=20). The opioid tapering off program was not successful due to the vast number of dropouts. Phase 1 was associated with weak to moderate improvements on psychomotor function, sleeping, opioid withdrawal symptoms, quality of life, and reduced risk of opioid misuse. In the intervention group of Phase 2, pain intensity was stable and patients felt more rested. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Radiation dosimetry with fiber Bragg gratings

NASA Astrophysics Data System (ADS)

Avino, S.; D'Avino, V.; Giorgini, A.; Pacelli, R.; Liuzzi, R.; Cella, L.; Gagliardi, G.; De Natale, P.

2014-05-01

The measurement and monitoring of radiation dose delivered in patient tissues is a critical aspect in radiation therapy. Various dosimeters have proven effective in measuring radiations at low doses. However, there is a growing demand for new dosimeters based on small, non-invasive and high resolution devices. Here we report on a miniature dosimeter based on an optical fiber cavity. We demonstrate an ultimate detection limit of 160 mGy with an effective interaction region of 6 x 10-4 mm3. Due to its reliability, compactness and biomedical dose level sensitivity, our system shows itself suitable for applications in radiation therapy dosimetry.

Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma

PubMed Central

Dudley, Mark E.; Wunderlich, John R.; Yang, James C.; Sherry, Richard M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Royal, Richard E.; Kammula, Udai; White, Don E.; Mavroukakis, Sharon A.; Rogers, Linda J.; Gracia, Gerald J.; Jones, Stephanie A.; Mangiameli, David P.; Pelletier, Michelle M.; Gea-Banacloche, Juan; Robinson, Michael R.; Berman, David M.; Filie, Armando C.; Abati, Andrea; Rosenberg, Steven A.

2006-01-01

Purpose We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. Patients and Methods Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL)-2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m2). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. Results Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 ± 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. Conclusion Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma. PMID:15800326

Dosimetric effects of patient rotational setup errors on prostate IMRT treatments

NASA Astrophysics Data System (ADS)

Fu, Weihua; Yang, Yong; Li, Xiang; Heron, Dwight E.; Saiful Huq, M.; Yue, Ning J.

2006-10-01

The purpose of this work is to determine dose delivery errors that could result from systematic rotational setup errors (ΔΦ) for prostate cancer patients treated with three-phase sequential boost IMRT. In order to implement this, different rotational setup errors around three Cartesian axes were simulated for five prostate patients and dosimetric indices, such as dose-volume histogram (DVH), tumour control probability (TCP), normal tissue complication probability (NTCP) and equivalent uniform dose (EUD), were employed to evaluate the corresponding dosimetric influences. Rotational setup errors were simulated by adjusting the gantry, collimator and horizontal couch angles of treatment beams and the dosimetric effects were evaluated by recomputing the dose distributions in the treatment planning system. Our results indicated that, for prostate cancer treatment with the three-phase sequential boost IMRT technique, the rotational setup errors do not have significant dosimetric impacts on the cumulative plan. Even in the worst-case scenario with ΔΦ = 3°, the prostate EUD varied within 1.5% and TCP decreased about 1%. For seminal vesicle, slightly larger influences were observed. However, EUD and TCP changes were still within 2%. The influence on sensitive structures, such as rectum and bladder, is also negligible. This study demonstrates that the rotational setup error degrades the dosimetric coverage of target volume in prostate cancer treatment to a certain degree. However, the degradation was not significant for the three-phase sequential boost prostate IMRT technique and for the margin sizes used in our institution.

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

PubMed

Taguchi, Isao; Iimuro, Satoshi; Iwata, Hiroshi; Takashima, Hiroaki; Abe, Mitsuru; Amiya, Eisuke; Ogawa, Takanori; Ozaki, Yukio; Sakuma, Ichiro; Nakagawa, Yoshihisa; Hibi, Kiyoshi; Hiro, Takafumi; Fukumoto, Yoshihiro; Hokimoto, Seiji; Miyauchi, Katsumi; Yamazaki, Tsutomu; Ito, Hiroshi; Otsuji, Yutaka; Kimura, Kazuo; Takahashi, Jun; Hirayama, Atsushi; Yokoi, Hiroyoshi; Kitagawa, Kazuo; Urabe, Takao; Okada, Yasushi; Terayama, Yasuo; Toyoda, Kazunori; Nagao, Takehiko; Matsumoto, Masayasu; Ohashi, Yasuo; Kaneko, Tetsuji; Fujita, Retsu; Ohtsu, Hiroshi; Ogawa, Hisao; Daida, Hiroyuki; Shimokawa, Hiroaki; Saito, Yasushi; Kimura, Takeshi; Inoue, Teruo; Matsuzaki, Masunori; Nagai, Ryozo

2018-05-08

Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group ( P <0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; P =0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; P =0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730. © 2018 The Authors.

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

Rational design and adaptive management of combination therapies for Hepatitis C virus infection

DOE PAGES

Ke, Ruian; Loverdo, Claude; Qi, Hangfei; ...

2015-06-30

Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensatemore » when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design.« less

Pulsatile crizotinib treatment for brain metastasis in a patient with non-small-cell lung cancer.

PubMed

Wang, S; Chen, J; Xie, Z; Xia, L; Luo, W; Li, J; Li, Q; Yang, Z

2017-10-01

Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is a distinct subtype with patients showing peculiar clinicopathological features and dramatic responses to the ALK tyrosine kinase inhibitor crizotinib. Patients with this cancer variant have a dismal prognosis and limited treatment options when it has progressed to intracranial metastasis because of inadequate drug penetration into the central nervous system (CNS). Factors associated with response to TKI therapy have been reported to include pharmacokinetic and biodynamic resistance phenomena. In our NSCLC patient with multiple intracranial metastases, we administered high-dose pulsatile crizotinib therapy (1000 mg/d) on a one-day-on/one-day-off basis. A significant central nervous system (CNS) response was achieved, and time to neurological progression was prolonged to 6 months. High-dose pulsatile therapy may be an effective dosing strategy for crizotinib in NSCLC showing progression to metastasis in the brain. © 2017 John Wiley & Sons Ltd.

Hypertensive crisis due to contrast-enhanced computed tomography in a patient with malignant pheochromocytoma.

PubMed

Nakano, Sachiko; Tsushima, Yoshito; Taketomi-Takahashi, Ayako; Higuchi, Tetsuya; Amanuma, Makoto; Oriuchi, Noboru; Endo, Keigo

2011-07-01

A 63-year-old man underwent computed tomography (CT) using intravenous low-osmolar iodine contrast medium (LOCM) 6 days after undergoing high-dose (131)I-MIBG therapy for metastatic pheochromocytoma. Immediately after the CT examination, his blood pressure increased to 260/160 mmHg (from 179/101 mmHg before the examination). Phentolamine mesilate was administered, and the blood pressure rapidly went back to normal. Although hypertensive crisis after administration of LOCM is rare, this case suggests that high-dose (131)IMIBG therapy may be a risk factor for hypertensive crisis after administration of intravenous LOCM.

A polymorphism within the promoter of the TGFβ1 gene is associated with radiation sensitivity using an objective radiologic endpoint.

PubMed

Kelsey, Chris R; Jackson, Lauren; Langdon, Scott; Owzar, Kouros; Hubbs, Jessica; Vujaskovic, Zeljko; Das, Shiva; Marks, Lawrence B

2012-02-01

To evaluate whether single nucleotide polymorphisms (SNPs) in the transforming growth factor-β1 (TGFβ1) gene are associated with radiation sensitivity using an objective radiologic endpoint. Preradiation therapy and serial postradiation therapy single photon emission computed tomography (SPECT) lung perfusion scans were obtained in patients undergoing treatment for lung cancer. Serial blood samples were obtained to measure circulating levels of TGFβ1. Changes in regional perfusion were related to regional radiation dose yielding a patient-specific dose-response curve, reflecting the patient's inherent sensitivity to radiation therapy. Six TGFβ1 SNPs (-988, -800, -509, 869, 941, and 1655) were assessed using high-resolution melting assays and DNA sequencing. The association between genotype and slope of the dose-response curve, and genotype and TGFβ1 ratio (4-week/preradiation therapy), was analyzed using the Kruskal-Wallis test. 39 white patients with preradiation therapy and ≥ 6-month postradiation therapy SPECT scans and blood samples were identified. Increasing slope of the dose-response curve was associated with the C(-509)T SNP (p = 0.035), but not the other analyzed SNPs. This SNP was also associated with higher TGFβ1 ratios. This study suggests that a polymorphism within the promoter of the TGFβ1 gene is associated with increased radiation sensitivity (defined objectively by dose-dependent changes in SPECT lung perfusion). Copyright © 2012 Elsevier Inc. All rights reserved.

A Polymorphism Within the Promoter of the TGF{beta}1 Gene Is Associated With Radiation Sensitivity Using an Objective Radiologic Endpoint

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

Kelsey, Chris R., E-mail: kelse003@mc.duke.edu; Jackson, Lauren; Langdon, Scott

2012-02-01

Purpose: To evaluate whether single nucleotide polymorphisms (SNPs) in the transforming growth factor-{beta}1 (TGF{beta}1) gene are associated with radiation sensitivity using an objective radiologic endpoint. Methods and Materials: Preradiation therapy and serial postradiation therapy single photon emission computed tomography (SPECT) lung perfusion scans were obtained in patients undergoing treatment for lung cancer. Serial blood samples were obtained to measure circulating levels of TGF{beta}1. Changes in regional perfusion were related to regional radiation dose yielding a patient-specific dose-response curve, reflecting the patient's inherent sensitivity to radiation therapy. Six TGF{beta}1 SNPs (-988, -800, -509, 869, 941, and 1655) were assessed using high-resolutionmore » melting assays and DNA sequencing. The association between genotype and slope of the dose-response curve, and genotype and TGF{beta}1 ratio (4-week/preradiation therapy), was analyzed using the Kruskal-Wallis test. Results: 39 white patients with preradiation therapy and {>=}6-month postradiation therapy SPECT scans and blood samples were identified. Increasing slope of the dose-response curve was associated with the C(-509)T SNP (p = 0.035), but not the other analyzed SNPs. This SNP was also associated with higher TGF{beta}1 ratios. Conclusions: This study suggests that a polymorphism within the promoter of the TGF{beta}1 gene is associated with increased radiation sensitivity (defined objectively by dose-dependent changes in SPECT lung perfusion).« less

Childhood Central Nervous System Embryonal Tumors Treatment (PDQ®)—Patient Version

Cancer.gov

Childhood central nervous system embryonal tumors and pineal tumors are treated with surgery, radiation therapy, chemotherapy, high-dose chemotherapy with stem cell rescue and targeted therapy. Learn more in this expert-reviewed summary.

[Electronic data processing-assisted high dosage therapy with stem cell transplantation at the Donauspital].

PubMed

Habertheuer, K H; Kier, P; Ruckser, R; Scherz, M; Höniger, S; Sebesta, C; Tiefengraber, E; Schmid, A; Mandl, A; Sterz, M

1995-01-01

Organization of high dose chemotherapy with stem cell transplantation essentially requires EDV-support. "ONCOBASE" has been adapted into the Donauspital network on May 1, 1992. We report about the 2-year clinical experience with ONCOBASE: 1. ONCOBASE effectively supports communication between the ward, ambulance and hospital pharmacy (where all cytostatics are prepared). 2. ONCOBASE provides better surveillance concerning all therapeutic procedures including cytostatic drugs and supportive therapies. 3. ONCOBASE allows the generation of medical letters which include all drugs and supportive therapies delivered. 4. Since ONCOBASE is a database program, all informations concerning the patients are registered. These include cumulative drug doses, information on side effects, blood cell kinetics after previous therapies, kinetics of tumor markers and results of further examinations. 5. ONCOBASE permits rapid data exchange with other hospital networks using the communication data record governed by the "Arbeitskreis für EDV der deutschen Gesellschaft für Hämatoonkologie".

Repeated high-dose chemotherapy followed by purged autologous bone marrow transplantation as consolidation therapy in metastatic neuroblastoma.

PubMed

Hartmann, O; Benhamou, E; Beaujean, F; Kalifa, C; Lejars, O; Patte, C; Behard, C; Flamant, F; Thyss, A; Deville, A

1987-08-01

Among 62 children over 1 year of age at diagnosis, who were treated for stage IV neuroblastoma, 33 entered complete remission (CR) or good partial remission (GPR) after conventional therapy and received high-dose chemotherapy (HDC) with in vitro purged autologous bone marrow transplantation (ABMT) as consolidation therapy. The HDC was a combination of carmustine (BCNU), teniposide (VM-26), and melphalan. Thirty-three patients received one course of this regimen, and 18 received two courses. At present, 16 of the 33 grafted patients are alive in continuous CR, with a median follow-up of 28 months. Toxicity of this regimen was tolerable, principally marked by bone marrow depression and gastrointestinal (GI) tract complications. Four complication-related deaths were observed. Relapse post-ABMT occurred most often in the bone marrow. Under this treatment, actuarial disease-free survival is improved compared with that observed under conventional therapy.

Evaluation of LiF:Mg,Ti (TLD-100) for Intraoperative Electron Radiation Therapy Quality Assurance

PubMed Central

Liuzzi, Raffaele; Savino, Federica; D’Avino, Vittoria; Pugliese, Mariagabriella; Cella, Laura

2015-01-01

Background Purpose of the present work was to investigate thermoluminescent dosimeters (TLDs) response to intraoperative electron radiation therapy (IOERT) beams. In an IOERT treatment, a large single radiation dose is delivered with a high dose-per-pulse electron beam (2–12 cGy/pulse) during surgery. To verify and to record the delivered dose, in vivo dosimetry is a mandatory procedure for quality assurance. The TLDs feature many advantages such as a small detector size and close tissue equivalence that make them attractive for IOERT as in vivo dosimeters. Methods LiF:Mg,Ti dosimeters (TLD-100) were irradiated with different IOERT electron beam energies (5, 7 and 9 MeV) and with a 6 MV conventional photon beam. For each energy, the TLDs were irradiated in the dose range of 0–10 Gy in step of 2Gy. Regression analysis was performed to establish the response variation of thermoluminescent signals with dose and energy. Results The TLD-100 dose-response curves were obtained. In the dose range of 0–10 Gy, the calibration curve was confirmed to be linear for the conventional photon beam. In the same dose region, the quadratic model performs better than the linear model when high dose-per-pulse electron beams were used (F test; p<0.05). Conclusions This study demonstrates that the TLD dose response, for doses ≤10Gy, has a parabolic behavior in high dose-per-pulse electron beams. TLD-100 can be useful detectors for IOERT patient dosimetry if a proper calibration is provided. PMID:26427065

Evaluation of LiF:Mg,Ti (TLD-100) for Intraoperative Electron Radiation Therapy Quality Assurance.

PubMed

Liuzzi, Raffaele; Savino, Federica; D'Avino, Vittoria; Pugliese, Mariagabriella; Cella, Laura

2015-01-01

Purpose of the present work was to investigate thermoluminescent dosimeters (TLDs) response to intraoperative electron radiation therapy (IOERT) beams. In an IOERT treatment, a large single radiation dose is delivered with a high dose-per-pulse electron beam (2-12 cGy/pulse) during surgery. To verify and to record the delivered dose, in vivo dosimetry is a mandatory procedure for quality assurance. The TLDs feature many advantages such as a small detector size and close tissue equivalence that make them attractive for IOERT as in vivo dosimeters. LiF:Mg,Ti dosimeters (TLD-100) were irradiated with different IOERT electron beam energies (5, 7 and 9 MeV) and with a 6 MV conventional photon beam. For each energy, the TLDs were irradiated in the dose range of 0-10 Gy in step of 2 Gy. Regression analysis was performed to establish the response variation of thermoluminescent signals with dose and energy. The TLD-100 dose-response curves were obtained. In the dose range of 0-10 Gy, the calibration curve was confirmed to be linear for the conventional photon beam. In the same dose region, the quadratic model performs better than the linear model when high dose-per-pulse electron beams were used (F test; p<0.05). This study demonstrates that the TLD dose response, for doses ≤10 Gy, has a parabolic behavior in high dose-per-pulse electron beams. TLD-100 can be useful detectors for IOERT patient dosimetry if a proper calibration is provided.

Dual Chemodrug-Loaded Single-Walled Carbon Nanohorns for Multimodal Imaging-Guided Chemo-Photothermal Therapy of Tumors and Lung Metastases

PubMed Central

Yang, Jingxing; Su, Huilan; Sun, Wenshe; Cai, Jiali; Liu, Shiyuan; Chai, Yimin; Zhang, Chunfu

2018-01-01

Tumor combination therapy using nano formulations with multimodal synergistic therapeutic effects shows great potential for complete ablation of tumors. However, targeting tumor metastases with nano structures is a major obstacle for therapy. Therefore, developing a combination therapy system able to target both primary tumors and their metastases at distant sites with synergistic therapy is desirable for the complete eradication of tumors. To this end, a dual chemodrug-loaded theranostic system based on single walled carbon nanohorns (SWNHs) is developed for targeting both primary breast tumors and their lung metastases. Methods: SWNHs were first modified simultaneously with poly (maleic anhydride-alt-1-octadecene) (C18PMH) and methoxypolyethyleneglycol-b-poly-D, L-lactide (mPEG-PLA) via hydrophobic-hydrophobic interactions and π-π stacking. Then cisplatin and doxorubicin (DOX) (2.9:1 molar ratio) were sequentially loaded onto the modified nanohorns in a noninterfering way. After careful examinations of the release profiles of the loaded drugs and the photothermal performance of the dual chemodrug-loaded SWNHs, termed SWNHs/C18PMH/mPEG-PLA-DOX-Pt, the dual drug chemotherapeutic and chemo-photothermal synergetic therapeutic effects on tumor cells were evaluated. Subsequently, the in vivo behavior and tumor accumulation of the drug-loaded SWNHs were studied by photoacoustic imaging (PAI). For chemo-photothermal therapy of tumors, 4T1 tumor bearing mice were intravenously injected with SWNHs/C18PMH/mPEG-PLA-DOX-Pt at a dose of 10 mg/kg b.w. (in SWNHs) and tumors were illuminated by an 808 nm laser (1W/cm2 for 5 min) 24 h post-injection. Results: DOX and cisplatin were loaded onto the modified SWNHs with high efficiency (44 wt% and 66 wt%, respectively) and released in a pH-sensitive, tandem and sustainable manner. The SWNHs/C18PMH/mPEG-PLA-DOX-Pt had a hydrodynamic diameter of 182 ± 3.2 nm, were highly stable in physiological environment, and had both dual drug chemotherapeutic (CI = 0.439) and chemo-photothermal synergistic antitumor effects (CI = 0.396) in vitro. Moreover, the dual drug-loaded SWNHs had a long blood half-life (10.9 h) and could address both the primary breast tumors and their lung metastases after intravenous administration. Consequently, chemo-photothermal combination therapy ablated the primary tumors and simultaneously eradicated the metastatic lung nodules. Conclusion: Our study demonstrates that SWNHs/C18PMH/mPEG-PLA-DOX-Pt is highly potent for chemo-photothermal combination therapy of primary tumors and cocktail chemotherapy of their metastases at a distant site. PMID:29556368

Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment.

PubMed

Hendriksz, Christian; Santra, Saikat; Jones, Simon A; Geberhiwot, Tarekegn; Jesaitis, Lynne; Long, Brian; Qi, Yulan; Hawley, Sara M; Decker, Celeste

2018-04-01

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

[Treatment and results of therapy in chronic idiopathic thrombocytopenic purpura].

PubMed

Tasić, J; Milenović, M; Drasković, S; Vukicević, T; Macukanović, L; Kitić, Lj; Bakić, M

1994-01-01

Basic principles in the therapy of chronic idiopathic thrombocytopenic purpura are glucocorticoides and splenectomy. Other measures: Intravenous high doses gamma globulin therapy, attenuated androgenes, immunosupresive drugs and plasmaferesis are less effective. During the period of 1989-1992 we treated 34 patients. From 34 patients, 23 were women and 11 were men. We treated patients primarily by prednisolon approximaly for 2 - 4 weeks. Rarely we use doses of 3 mg/kg per day for short periods of time (5 to 10 days) or "pulse therapy" of 500 mg per day. Those doses may be effective in elevating platelet count if the response is poor. If response occurs, high dosages of steroides should be tareped to determine the amount that will maintain the platelet count in the range of 30x10(9)/l to 50x10(9)/l (to minimaze the toxic sade effects of steroides). If steroides are ineffective, we perform splenectomy. From 34 treated patients by glucocorticoides, in 16 we got remission and in 11 partial response. We discussed in detailes relationship duration of treatment with glucocorticoides and level of platelets, and also correlation duration of treatment with prognosis. From 6 splenectomized patients 3 were successful. In two patients we applied intravenous gamma globulin therapy and attenuated androgen successfuly. In one patients therapy with gamma globulin, immunosupresive drugs, androgen and other measures was ineffective. In one patients without splenectomy we administrated successfuly gamma globulin therapy and androgen for peroid of two years.

A REVIEW ON THE RADIATION THERAPY TECHNOLOGIST RECEIVED DOSE FROM INDUCED ACTIVATION IN HIGH-ENERGY MEDICAL LINEAR ACCELERATORS.

PubMed

Nourmohammadi, Bahareh; Mesbahi, Asghar

2018-06-01

Despite all advantages for using high-energy photons for radiotherapy, high-energy photon beams (≥10 MV) induce photonuclear and neutron capture interactions, which result in producing radionuclide byproducts inside the Linac head and bunker, exposing radiation therapy technologists (RTTs) and patients to excessive dose. By the use of higher photon energy, greater number of monitor unit, greater field size and adding treatment accessories, induced dose rate become greater in the isocenter mainly due to activation of high-Z materials inside the Linac head. Activated radionuclides disintegrate with γ, β+ and β- rays with half-lives between 2 min up to more than 5 years. Several researches estimated additional exposure to an RTT depend on treatment strategies, beam energy, and delay time before entrance to the treatment room between 0.1 and 4.9 mSv/y and proposed at least 2 min delay before entrance to the treatment room after treatments with high-energy photon beams.

Optimization of Monte Carlo dose calculations: The interface problem

NASA Astrophysics Data System (ADS)

Soudentas, Edward

1998-05-01

High energy photon beams are widely used for radiation treatment of deep-seated tumors. The human body contains many types of interfaces between dissimilar materials that affect dose distribution in radiation therapy. Experimentally, significant radiation dose perturbations has been observed at such interfaces. The EGS4 Monte Carlo code was used to calculate dose perturbations at boundaries between dissimilar materials (such as bone/water) for 60Co and 6 MeV linear accelerator beams using a UNIX workstation. A simple test of the reliability of a random number generator was also developed. A systematic study of the adjustable parameters in EGS4 was performed in order to minimize calculational artifacts at boundaries. Calculations of dose perturbations at boundaries between different materials showed that there is a 12% increase in dose at water/bone interface, and a 44% increase in dose at water/copper interface. with the increase mainly due to electrons produced in water and backscattered from the high atomic number material. The dependence of the dose increase on the atomic number was also investigated. The clinically important case of using two parallel opposed beams for radiation therapy was investigated where increased doses at boundaries has been observed. The Monte Carlo calculations can provide accurate dosimetry data under conditions of electronic non-equilibrium at tissue interfaces.

Positron emission tomography-guided conformal fast neutron therapy for glioblastoma multiforme

PubMed Central

Stelzer, Keith J.; Douglas, James G.; Mankoff, David A.; Silbergeld, Daniel L.; Krohn, Kenneth A.; Laramore, George E.; Spence, Alexander M.

2008-01-01

Glioblastoma multiforme (GBM) continues to be a difficult therapeutic challenge. Our study was conducted to determine whether improved survival and tumor control could be achieved with modern delivery of fast neutron radiation using three-dimensional treatment planning. Ten patients were enrolled. Eligibility criteria included pathologic diagnosis of GBM, age ≥ 18 years, and KPS ≥60. Patients underwent MRI and 18F-fluorodeoxyglucose PET (FDG PET) as part of initial three-dimensional treatment planning. Sequential targets were treated with noncoplanar fields to a total dose of 18 Gy in 16 fractions over 4 weeks. Median and 1-year overall survival were 55 weeks and 60%, respectively. One patient remains alive at last follow-up 255 weeks after diagnosis. Median progression-free survival was 16 weeks, and all patients had tumor progression by 39 weeks. Treatment was clinically well tolerated, but evidence of mild to moderate gliosis and microvascular sclerosis consistent with radiation injury was observed at autopsy in specimens taken from regions of contralateral brain that received approximately 6–10 Gy. Fast neutron radiation using modern imaging, treatment planning, and beam delivery was feasible to a total dose of 18 Gy, but tumor control probability was poor in comparison to that predicted from a dose-response model based on older studies. Steep dose-response curves for both tumor control and neurotoxicity continue to present a challenge to establishing a therapeutic window for fast neutron radiation in GBM, even with modern techniques. PMID:18055860

Improving medication titration in heart failure by embedding a structured medication titration plan.

PubMed

Hickey, Annabel; Suna, Jessica; Marquart, Louise; Denaro, Charles; Javorsky, George; Munns, Andrew; Mudge, Alison; Atherton, John J

2016-12-01

To improve up-titration of medications to target dose in heart failure patients by improving communication from hospital to primary care. This quality improvement project was undertaken within three heart failure disease management (HFDM) services in Queensland, Australia. A structured medication plan was collaboratively designed and implemented in an iterative manner, using methods including awareness raising and education, audit and feedback, integration into existing work practice, and incentive payments. Evaluation was undertaken using sequential audits, and included process measures (use of the titration plan, assignment of responsibility) and outcome measures (proportion of patients achieving target dose) in HFDM service patients with reduced left ventricular ejection fraction. Comparison of the three patient cohorts (pre-intervention cohort A n=96, intervention cohort B n=95, intervention cohort C n=89) showed increase use of the titration plan, a shift to greater primary care responsibility for titration, and an increase in the proportion of patients achieving target doses of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) (A 37% vs B 48% vs C 55%, p=0.051) and beta-blockers (A 38% vs B 33% vs C 51%, p=0.045). Combining all three cohorts, patients not on target doses when discharged from hospital were more likely to achieve target doses of ACEI/ARB (p<0.0001) and beta blockers (p<0.0001) within six months if they received a medication titration plan. A medication titration plan was successfully implemented in three HFDM services and improved transitional communication and achievement of target doses of evidence-based therapies within six months of hospital discharge. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Bioequivalence between two serum-free recombinant factor VIII preparations (N8 and ADVATE®)--an open-label, sequential dosing pharmacokinetic study in patients with severe haemophilia A.

PubMed

Martinowitz, U; Bjerre, J; Brand, B; Klamroth, R; Misgav, M; Morfini, M; Santagostino, E; Tiede, A; Viuff, D

2011-11-01

Recombinant coagulation factor VIII (rFVIII) concentrates provide a safe and efficacious replacement therapy for treatment and prevention of bleeding in patients with severe haemophilia A. The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of two serum-free rFVIII products: N8, a new rFVIII manufactured by Novo Nordisk and Advate(®), a marketed product. Patients with severe haemophilia A with >150 exposure days to FVIII, without current or past inhibitors, were enrolled in an open-label, first human dose (FHD), multicentre trial. Twenty-three patients first received a single dose of 50 IU kg(-1) body weight Advate(®) followed by 50 IU kg(-1) body weight N8 at the next visit. A 4-day washout period was required prior to each dosing. Blood samples for PK and safety analyses were drawn prior to dosing and at intervals up until 48 h postdosing. The PK parameters were based on FVIII clotting activity (FVIII:C) measurements. Occurrence of adverse events was closely monitored. The mean profiles of FVIII:C and all primary and secondary parameters for Advate(®) and N8 were comparable. The 90% CI for the treatment ratio (Advate(®)/N8) for all primary endpoints (incremental recovery, t(1/2), AUC and Cl), and the secondary endpoints (AUC(last) and C(max)) were within the bioequivalence interval of 0.8-1.25. There were no safety concerns in the study and no reports of inhibitor formation in the 72-h period following exposure to a single N8 dose. In conclusion, N8 is bioequivalent to Advate(®). Furthermore, N8 is well tolerated in the FHD trial. © 2011 Blackwell Publishing Ltd.

Refractory immune thrombocytopenia successfully treated with high-dose vitamin D supplementation and hydroxychloroquine: two case reports

PubMed Central

2013-01-01

Introduction Immune thrombocytopenic purpura is thought to be characterized by an immune response against the host’s own platelets. If the thrombocytopenia is severe, patients are initially treated with high-dose steroids. Other more toxic second line treatments are considered if steroids fail. Here, we report the case of two patients in whom conventional treatment was unsuccessful but who responded to hydroxychloroquine and high-dose vitamin D replacement therapy. To the best of our knowledge, this is the first description of successful treatment for immune thrombocytopenia with high-dose vitamin D and hydroxychloroquine. Case presentation Case 1: We report the case of a 79-year-old Caucasian man who presented with high titer antinuclear antibodies, positive anti-SSA/Ro autoantibodies and clinically was felt to have an overlap of systemic lupus erythematosus and/or Sjögren’s syndrome with profound life-threatening thrombocytopenia. There was no evidence of underlying malignancy. The patient’s platelet count significantly increased with vitamin D and hydroxychloroquine treatment, but upon vitamin D discontinuation his platelet levels plummeted. Hydroxychloroquine therapy was maintained throughout treatment. With reinstitution of high-dose vitamin D therapy, platelet counts were restored to normal levels. Case 2: We also report the case of an 87-year-old Caucasian woman who presented with high titer antinuclear antibodies, positive anti-SSA/Ro autoantibodies and was felt to have an overlap of systemic lupus erythematosus and/or Sjögren’s syndrome with immune thrombocytopenia; she also had severely low levels of 25-hydroxy vitamin D (17ng/mL). There was no evidence of underlying malignancy. She responded to high-dose vitamin D replacement and hydroxychloroquine treatment, thereby alleviating the need for high-dose steroid treatment. She remains in remission while taking vitamin D, hydroxychloroquine and very low-dose prednisone. No untoward side effects were observed in either patient. Conclusions In our two case reports, we found an association between vitamin D deficiency and immune thrombocytopenia where platelet levels responded to vitamin D treatment and hydroxychloroquine but not to prednisone. We believe there may be synergism between vitamin D supplementation and hydroxychloroquine. The mechanism by which high-dose vitamin D results in increased platelet counts in immune thrombocytopenia patients is unknown. However, vitamin D has long been thought to play an immunomodulatory role, which may include a dampened immune response in patients with immune thrombocytopenia or other autoimmune diseases. PMID:23556539

Radiation dose to the esophagus from breast cancer radiation therapy, 1943-1996: an international population-based study of 414 patients.

PubMed

Lamart, Stephanie; Stovall, Marilyn; Simon, Steven L; Smith, Susan A; Weathers, Rita E; Howell, Rebecca M; Curtis, Rochelle E; Aleman, Berthe M P; Travis, Lois; Kwon, Deukwoo; Morton, Lindsay M

2013-07-15

To provide dosimetric data for an epidemiologic study on the risk of second primary esophageal cancer among breast cancer survivors, by reconstructing the radiation dose incidentally delivered to the esophagus of 414 women treated with radiation therapy for breast cancer during 1943-1996 in North America and Europe. We abstracted the radiation therapy treatment parameters from each patient's radiation therapy record. Treatment fields included direct chest wall (37% of patients), medial and lateral tangentials (45%), supraclavicular (SCV, 64%), internal mammary (IM, 44%), SCV and IM together (16%), axillary (52%), and breast/chest wall boosts (7%). The beam types used were (60)Co (45% of fields), orthovoltage (33%), megavoltage photons (11%), and electrons (10%). The population median prescribed dose to the target volume ranged from 21 Gy to 40 Gy. We reconstructed the doses over the length of the esophagus using abstracted patient data, water phantom measurements, and a computational model of the human body. Fields that treated the SCV and/or IM lymph nodes were used for 85% of the patients and delivered the highest doses within 3 regions of the esophagus: cervical (population median 38 Gy), upper thoracic (32 Gy), and middle thoracic (25 Gy). Other fields (direct chest wall, tangential, and axillary) contributed substantially lower doses (approximately 2 Gy). The cervical to middle thoracic esophagus received the highest dose because of its close proximity to the SCV and IM fields and less overlying tissue in that part of the chest. The location of the SCV field border relative to the midline was one of the most important determinants of the dose to the esophagus. Breast cancer patients in this study received relatively high incidental radiation therapy doses to the esophagus when the SCV and/or IM lymph nodes were treated, whereas direct chest wall, tangentials, and axillary fields contributed lower doses. Published by Elsevier Inc.

Radiation Dose to the Esophagus From Breast Cancer Radiation Therapy, 1943-1996: An International Population-Based Study of 414 Patients

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

Lamart, Stephanie, E-mail: stephanie.lamart@nih.gov; Stovall, Marilyn; Simon, Steven L.

2013-07-15

Purpose: To provide dosimetric data for an epidemiologic study on the risk of second primary esophageal cancer among breast cancer survivors, by reconstructing the radiation dose incidentally delivered to the esophagus of 414 women treated with radiation therapy for breast cancer during 1943-1996 in North America and Europe. Methods and Materials: We abstracted the radiation therapy treatment parameters from each patient’s radiation therapy record. Treatment fields included direct chest wall (37% of patients), medial and lateral tangentials (45%), supraclavicular (SCV, 64%), internal mammary (IM, 44%), SCV and IM together (16%), axillary (52%), and breast/chest wall boosts (7%). The beam typesmore » used were {sup 60}Co (45% of fields), orthovoltage (33%), megavoltage photons (11%), and electrons (10%). The population median prescribed dose to the target volume ranged from 21 Gy to 40 Gy. We reconstructed the doses over the length of the esophagus using abstracted patient data, water phantom measurements, and a computational model of the human body. Results: Fields that treated the SCV and/or IM lymph nodes were used for 85% of the patients and delivered the highest doses within 3 regions of the esophagus: cervical (population median 38 Gy), upper thoracic (32 Gy), and middle thoracic (25 Gy). Other fields (direct chest wall, tangential, and axillary) contributed substantially lower doses (approximately 2 Gy). The cervical to middle thoracic esophagus received the highest dose because of its close proximity to the SCV and IM fields and less overlying tissue in that part of the chest. The location of the SCV field border relative to the midline was one of the most important determinants of the dose to the esophagus. Conclusions: Breast cancer patients in this study received relatively high incidental radiation therapy doses to the esophagus when the SCV and/or IM lymph nodes were treated, whereas direct chest wall, tangentials, and axillary fields contributed lower doses.« less

Comparison of 10 efficient protocols for photodynamic therapy of actinic keratosis: How relevant are effective light dose and local damage in predicting the complete response rate at 3 months?

PubMed

Vignion-Dewalle, Anne-Sophie; Baert, Gregory; Thecua, Elise; Lecomte, Fabienne; Vicentini, Claire; Abi-Rached, Henry; Mortier, Laurent; Mordon, Serge

2018-04-18

Topical photodynamic therapy is an established treatment modality for various dermatological conditions, including actinic keratosis. In Europe, the approved protocols for photodynamic therapy of actinic keratosis involve irradiation with either an Aktilite CL 128 lamp or daylight, whereas irradiation with the Blu-U illuminator is approved in the United States. Many other protocols using irradiation by a variety of light sources are also clinically efficient. This paper aims to compare 10 different protocols with clinically proven efficacy for photodynamic therapy of actinic keratosis and the available spectral irradiance of the light source. Effective irradiance, effective light dose, and local damage are compared. We also investigate whether there is an association between the complete response rate at 3 months and the effective light dose or local damage. The effective irradiance, also referred to as protoporphyrin IX-weighted irradiance, is obtained by integrating the spectral irradiance weighted by the normalized absorption spectrum of protoporphyrin IX over the wavelength. Integrating the effective irradiance over the irradiation time yields the effective light dose, which is also known as the protoporphyrin IX-weighted light dose. Local damage, defined as the total cumulative singlet oxygen molecules produced during treatment, is estimated using mathematical modeling of the photodynamic therapy process. This modeling is based on an iterative procedure taking into account the spatial and temporal variations in the protoporphyrin IX absorption spectrum during treatment. The protocol for daylight photodynamic therapy on a clear sunny day, the protocol for daylight photodynamic therapy on an overcast day, the photodynamic therapy protocol for a white LED lamp for operating rooms and the photodynamic therapy protocol for the Blu-U illuminator perform better than the six other protocols-all involving red light illumination-in terms of both effective light dose and local damage. However, no association between the complete response rate at 3 months and the effective light dose or local damage was found. Protocols that achieve high complete response rates at 3 months and low pain scores should be preferred regardless of the effective light dose and local damage. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

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

Small, Katherine; Kelly, Chris; Beldham-Collins, Rachael

A comparative study was conducted comparing the difference between (1) conformal radiotherapy (CRT) to the whole breast with sequential boost excision cavity plans and (2) intensity-modulated radiation therapy (IMRT) to the whole breast with simultaneously integrated boost to the excision cavity. The computed tomography (CT) data sets of 25 breast cancer patients were used and the results analysed to determine if either planning method produced superior plans. CT data sets from 25 past breast cancer patients were planned using (1) CRT prescribed to 50 Gy in 25 fractions (Fx) to the whole-breast planning target volume (PTV) and 10 Gy inmore » 5Fx to the excision cavity and (2) IMRT prescribed to 60 Gy in 25Fx, with 60 Gy delivered to the excision cavity PTV and 50 Gy delivered to the whole-breast PTV, treated simultaneously. In total, 50 plans were created, with each plan evaluated by PTV coverage using conformity indices, plan maximum dose, lung dose, and heart maximum dose for patients with left-side lesions. CRT plans delivered the lowest plan maximum doses in 56% of cases (average CRT = 6314.34 cGy, IMRT = 6371.52 cGy). They also delivered the lowest mean lung dose in 68% of cases (average CRT = 1206.64 cGy, IMRT = 1288.37 cGy) and V20 in 88% of cases (average CRT = 20.03%, IMRT = 21.73%) and V30 doses in 92% of cases (average CRT = 16.82%, IMRT = 17.97%). IMRT created more conformal plans, using both conformity index and conformation number, in every instance, and lower heart maximum doses in 78.6% of cases (average CRT = 5295.26 cGy, IMRT = 5209.87 cGy). IMRT plans produced superior dose conformity and shorter treatment duration, but a slightly higher planning maximum and increased lung doses. IMRT plans are also faster to treat on a daily basis, with shorter fractionation.« less

Osteomyelitis of the head and neck: sequential radionuclide scanning in diagnosis and therapy

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

Strauss, M.; Kaufman, R.A.; Baum, S.

1985-01-01

Sequential technetium and gallium scans of the head and neck were used to confirm the diagnosis of osteomyelitis and as an important therapeutic aid to delineate the transformation of active osteomyelitis to inactive osteomyelitis in 11 cases involving sites in the head and neck. Illustrative cases are presented of frontal sinus and cervical spine osteomyelitis and laryngeal osteochondritis.

Application of an inline dry powder inhaler to deliver high dose pharmaceutical aerosols during low flow nasal cannula therapy.

PubMed

Farkas, Dale; Hindle, Michael; Longest, P Worth

2018-05-05

Inline dry powder inhalers (DPIs) offer a potentially effective option to deliver high dose inhaled medications simultaneously with mechanical ventilation. The objective of this study was to develop an inline DPI that is actuated using a low volume of air (LV-DPI) to efficiently deliver pharmaceutical aerosols during low flow nasal cannula (LFNC) therapy. A characteristic feature of the new inline LV-DPIs was the use of hollow capillary tubes that both pierced the capsule and provided a pathway for inlet air and exiting aerosol. Aerosolization characteristics, LFNC depositional losses and emitted dose (ED) were determined using 10 mg powder masses of a small-particle excipient enhanced growth (EEG) formulation. While increasing the number of inlet capillaries from one to three did not improve performance, retracting the inlet and outlet capillaries did improve ED by over 30%. It was theorized that high quality performance requires both high turbulent energy to deaggregate the powder and high wall shear stresses to minimize capsule retention. Best case performance included a device ED of approximately 85% (of loaded dose) and device emitted mass median aerodynamic diameter of 1.77 µm. Maximum ED through the LFNC system and small diameter (4 mm) nasal cannula was approximately 65% of the loaded dose. Potential applications of this device include the delivery of high dose inhaled medications such as surfactants, antibiotics, mucolytics, and anti-inflammatories. Copyright © 2018 Elsevier B.V. All rights reserved.

SU-E-T-410: Evaluation of Treatment Modalities for Stereotactic Lung Radiation Therapy: A Phantom Study

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

Mohatt, D; Malhotra, H

Purpose: To evaluate and verify the accuracy of alternative treatment modalities for stereotactic lung therapy with end-to-end testing. We compared three dimensional conformal therapy (3DCRT), dynamic conformal arc therapy (DCAT), intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) treatment using 6 MV, 6 MV flattening filter free (FFF) and 10 MV FFF photons. Methods: A QUASAR respiratory motion phantom was utilized with custom ion chamber and gafchromatic EBT2 film inserts. The phantom contained a low density lung medium with a cylindrical polystyrene tumor (35 cc). Pseudo representative structures for various organs at risk (OAR) were created. Allmore » treatment plans were created using Eclipse ver. 11 using the same image and structure sets, and delivered via Varian TrueBeam STx linear accelerator equipped with high definition MLC. Evaluation of plan quality followed ROTG 0813 criterion for conformity index (CI100%), high dose spillage, D2cm, and R50%. Results: All treatment plans met the OAR dose constraints per protocol and could be delivered without any beam hold offs or other interlocks and hence were deemed clinically safe. For equivalent beam energies, target conformity was improved for all modalities when switching to FFF mode. Treatment efficiency increased for VMAT FFF by a factor of 3–4 over IMRT, and up to factor of 7 when compared to 3DCRT. Pass rates were > 97% for all treatment using gamma criteria of 3%, 3mm. Absolute dose at iso-center was verified with ion chamber, and found to be within 2% of the treatment planning system. Conclusion: The higher dose rate associated with FFF not only reduces delivery times, but in most cases enhances plan quality. The one modality with succeeding best results for all RTOG criterions was VMAT 6 MV FFF. This end-to-end testing provides necessary confidence in the entire dose delivery chain for lung SBRT patients.« less

Re-Examining Group Development in Adventure Therapy Groups.

ERIC Educational Resources Information Center

DeGraaf, Don; Ashby, Jeff

1998-01-01

Small-group development is an important aspect of adventure therapy. Supplementing knowledge of sequential stages of group development with knowledge concerning within-stage nonsequential development yields a richer understanding of groups. Integrating elements of the individual counseling relationship (working alliance, transference, and real…

Exploring Radiotherapy Targeting Strategy and Dose: A Pooled Analysis of Cooperative Group Trials of Combined Modality Therapy for Stage III Non-Small Cell Lung Cancer.

PubMed

Schild, Steven E; Fan, Wen; Stinchcombe, Thomas E; Vokes, Everett E; Ramalingam, Suresh S; Bradley, Jeffrey D; Kelly, Karen; Pang, Herbert H; Wang, Xiaofei

2018-04-21

Concurrent chemoradiotherapy(CRT) is standard therapy for locally-advanced non-small-cell lung cancer(LA-NSCLC)patients. This study was performed to examine thoracic radiotherapy(TRT) parameters and their impact on patient survival. We collected Individual patient data(IPD) from 3600LA-NSCLC patients participating in 16 cooperative group trials of concurrent CRT. The primary TRT parameters examined included field design strategy(elective nodal irradiation(ENI) compared to involved field TRT(IF-TRT)), total dose, and biologically effective dose(BED). Hazard ratios(HRs) for overall survival were calculated with univariable and multivariable Cox models. TRT doses ranged from 60 to 74 Gy with most treatments administered once-daily. ENI was associated with poorer survival than IF-TRT(univariable HR,1.37;95%CI,1.24-1.51,p<0.0001;multivariable HR,1.31;95%CI,1.08-1.59,p=0.002). The median survival of the IF and ENI patients were 24 and 16 months, respectively. Patients were divided into 3 dose groups: low total dose(60 Gy), medium total dose(>60Gy-66Gy) and high total dose(>66Gy-74 Gy). With reference to the low dose group, the multivariable HR's were 1.08 for the medium dose group(95%CI=0.93-1.25) and 1.12 for the high dose group(CI=0.97-1.30).The univariate p=0.054 and multivariable p=0.17. BED was grouped as follows: low(<55.5Gy 10 ), medium(=55.5 Gy 10) , or high(>55.5 Gy 10 ). With reference to the low BED group, the HR was 1.00(95%CI=0.85-1.18) for the medium BED group and 1.10(95%CI=0.93-1.31) for the high BED group. The univariable p=0.076 and multivariable p=0.16. For LA-NSCLC patients treated with concurrent CRT, IF-TRT was associated with significantly better survival than ENI-TRT. TRT total and BED dose levels were not significantly associated with patient survival. Future progress will require research focusing on better systemic therapy and TRT. Copyright © 2018. Published by Elsevier Inc.

Bilateral implant reconstruction does not affect the quality of postmastectomy radiation therapy

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

Ho, Alice Y., E-mail: hoa1234@mskcc.org; Patel, Nisha; Ohri, Nisha

To determine if the presence of bilateral implants, in addition to other anatomic and treatment-related variables, affects coverage of the target volume and dose to the heart and lung in patients receiving postmastectomy radiation therapy (PMRT). A total of 197 consecutive women with breast cancer underwent mastectomy and immediate tissue expander (TE) placement, with or without exchange for a permanent implant (PI) before radiation therapy at our center. PMRT was delivered with 2 tangential beams + supraclavicular lymph node field (50 Gy). Patients were grouped by implant number: 51% unilateral (100) and 49% bilateral (97). The planning target volume (PTV)more » (defined as implant + chest wall + nodes), heart, and ipsilateral lung were contoured and the following parameters were abstracted from dose-volume histogram (DVH) data: PTV D{sub 95%} > 98%, Lung V{sub 20}Gy > 30%, and Heart V{sub 25}Gy > 5%. Univariate (UVA) and multivariate analyses (MVA) were performed to determine the association of variables with these parameters. The 2 groups were well balanced for implant type and volume, internal mammary node (IMN) treatment, and laterality. In the entire cohort, 90% had PTV D{sub 95%} > 98%, indicating excellent coverage of the chest wall. Of the patients, 27% had high lung doses (V{sub 20}Gy > 30%) and 16% had high heart doses (V{sub 25}Gy > 5%). No significant factors were associated with suboptimal PTV coverage. On MVA, IMN treatment was found to be highly associated with high lung and heart doses (both p < 0.0001), but implant number was not (p = 0.54). In patients with bilateral implants, IMN treatment was the only predictor of dose to the contralateral implant (p = 0.001). In conclusion, bilateral implants do not compromise coverage of the target volume or increase lung and heart dose in patients receiving PMRT. The most important predictor of high lung and heart doses in patients with implant-based reconstruction, whether unilateral or bilateral, is treatment of the IMNs. Refinement of radiation techniques in reconstructed patients who require comprehensive nodal irradiation is warranted.« less

Lack of Benefit for the Addition of Androgen Deprivation Therapy to Dose-Escalated Radiotherapy in the Treatment of Intermediate- and High-Risk Prostate Cancer

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

Krauss, Daniel, E-mail: dkrauss@beaumont.edu; Kestin, Larry; Ye, Hong

2011-07-15

Purpose: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). Methods and Materials: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA {>=}20, or Stage T3. Patients were additionally divided specifically by Gleason score, presencemore » of palpable disease, and PSA level to further define subgroups benefitting from ADT. Results: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason {>=}8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. Conclusion: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.« less

Pharmacokinetic and pharmacodynamic model for analysis of adalimumab administered for Crohn's disease.

PubMed

Kimura, Koji; Yoshida, Atsushi; Takayanagi, Risa; Yamada, Yasuhiko

2018-05-23

Adalimumab (ADA) is used as a therapeutic agent for Crohn's disease (CD). Although that dosage regimen has been established through clinical trial experience, it has not been analyzed theoretically. In the present study, we analyzed of sequential changes of the Crohn's disease activity index (CDAI) after repeated administrations of ADA using a pharmacokinetic and pharmacodynamic model. In addition, we analyzed the validity of the dosage regimen, and potential efficacy gained by increasing the dose and reducing the interval of administration. The sequential changes in CDAI values obtained with our model were in good agreement with observed CDAI values, which was considered to show the validity of our analysis. We considered that our results showed the importance of the loading dose of ADA to obtain remission in an early stage of active CD. In addition, we showed that patients who have an incomplete response to ADA can obtain similar efficacy from increasing the dose and reducing the dose interval. In conclusion, our results showed that the present model may be applied to predict the CDAI values of ADA for CD. They indicated the validity of the dosage regimen, as well as the efficacy of increasing the dose and reducing the dose interval. This article is protected by copyright. All rights reserved.

A point kernel algorithm for microbeam radiation therapy

NASA Astrophysics Data System (ADS)

Debus, Charlotte; Oelfke, Uwe; Bartzsch, Stefan

2017-11-01

Microbeam radiation therapy (MRT) is a treatment approach in radiation therapy where the treatment field is spatially fractionated into arrays of a few tens of micrometre wide planar beams of unusually high peak doses separated by low dose regions of several hundred micrometre width. In preclinical studies, this treatment approach has proven to spare normal tissue more effectively than conventional radiation therapy, while being equally efficient in tumour control. So far dose calculations in MRT, a prerequisite for future clinical applications are based on Monte Carlo simulations. However, they are computationally expensive, since scoring volumes have to be small. In this article a kernel based dose calculation algorithm is presented that splits the calculation into photon and electron mediated energy transport, and performs the calculation of peak and valley doses in typical MRT treatment fields within a few minutes. Kernels are analytically calculated depending on the energy spectrum and material composition. In various homogeneous materials peak, valley doses and microbeam profiles are calculated and compared to Monte Carlo simulations. For a microbeam exposure of an anthropomorphic head phantom calculated dose values are compared to measurements and Monte Carlo calculations. Except for regions close to material interfaces calculated peak dose values match Monte Carlo results within 4% and valley dose values within 8% deviation. No significant differences are observed between profiles calculated by the kernel algorithm and Monte Carlo simulations. Measurements in the head phantom agree within 4% in the peak and within 10% in the valley region. The presented algorithm is attached to the treatment planning platform VIRTUOS. It was and is used for dose calculations in preclinical and pet-clinical trials at the biomedical beamline ID17 of the European synchrotron radiation facility in Grenoble, France.

Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013.

PubMed

Taylor, Carolyn W; Wang, Zhe; Macaulay, Elizabeth; Jagsi, Reshma; Duane, Frances; Darby, Sarah C

2015-11-15

Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this "mean heart dose." In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose. Copyright © 2015 Elsevier Inc. All rights reserved.

Growth and development after hematopoietic cell transplant in children.

PubMed

Sanders, J E

2008-01-01

Hematopoietic cell transplantation (HCT) following high-dose chemotherapy or chemoradiotherapy for children with malignant or nonmalignant hematologic disorders has resulted in an increasing number of long-term disease-free survivors. The preparative regimens include high doses of alkylating agents, such as CY with or without BU, and may include TBI. These agents impact the neuroendocrine system in growing children and their subsequent growth and development. Children receiving high-dose CY or BUCY have normal thyroid function, but those who receive TBI-containing regimens may develop thyroid function abnormalities. Growth is not impacted by chemotherapy-only preparative regimens, but TBI is likely to result in growth hormone deficiency and decreased growth rates that need to be treated with synthetic growth hormone therapy. Children who receive high-dose CY-only have normal development through puberty, whereas those who receive BUCY have a high incidence of delayed pubertal development. Following fractionated TBI preparative regimens, approximately half of the patients have normal pubertal development. These data demonstrate that the growth and development problems after HCT are dependent upon the preparative regimen received. All children should be followed for years after HCT for detection of growth and development abnormalities that are treatable with appropriate hormone therapy.

Chronic pain treatment with opioid analgesics: benefits versus harms of long-term therapy.

PubMed

Sehgal, Nalini; Colson, James; Smith, Howard S

2013-11-01

Chronic non-cancer pain (CNCP) is a disabling chronic condition with a high prevalence rate around the world. Opioids are routinely prescribed for treatment of chronic pain (CP). In the past two decades there has been a massive increase in the number of opioid prescriptions, prescribed daily opioid doses and overall opioid availability. Many more patients with CNCP receive high doses of long-acting opioids on a long-term basis. Yet CP and related disability rates remain high, and majority of the patients with CNCP are dissatisfied with their treatments. Intersecting with the upward trajectory in opioid use are the increasing trends in opioid related adverse effects, especially prescription drug abuse, addiction and overdose deaths. This complex situation raises questions on the relevance of opioid therapy in the treatment of CNCP. This article reviews current evidence on opioid effectiveness, the benefits and harms of long-term therapy in CNCP.

Integration of chemotherapy and radiation therapy for small cell carcinoma of the lung

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

Holoye, P.Y.; Libnoch, J.A.; Byhardt, R.W.

1982-09-01

Two chemotherapy trials using cyclophosphamide, doxorubicine hydrochloride and high-dose vincristine sulfate with or without methotrexate have induced a 93% incidence of complete remission in limited disease presentation of small cell bronchogenic carcinoma of the lung and 39% incidence in extensive disease. The first without consolidation radiotherapy had a local failure rate of 65%, which dropped to 17% with consolidation radiotherapy to the primary and mediastinum. Prophylactic whole brain radiotherapy prevented local recurrence in 98% of evaluable patients. One carcinomatous meningitis and 5 intraspinal recurrences were noted among the 38 patients in the CAV-M trial. We conclude that high-dose vincristine sulfatemore » is associated with an improved incidence of complete remission; that prophylactic whole brain radiotherapy has been highly successful; that prevention of intraspinal recurrence will necessitate the use of craniospinal axis radiation therapy and consolidation radiation therapy improves local control of primary and mediastinum.« less

Incidence of oral thrush in patients with COPD prescribed inhaled corticosteroids: Effect of drug, dose, and device.

PubMed

Dekhuijzen, P N Richard; Batsiou, Maria; Bjermer, Leif; Bosnic-Anticevich, Sinthia; Chrystyn, Henry; Papi, Alberto; Rodríguez-Roisin, Roberto; Fletcher, Monica; Wood, Lucy; Cifra, Alessandra; Soriano, Joan B; Price, David B

2016-11-01

Little information is available on real-life occurrence of oral thrush in COPD patients treated with ICS. We investigated oral thrush incidence in COPD patients prescribed FDC ICS/LABA therapies and assessed whether it is modulated by the ICS type, dose, and delivery device. We conducted a historical, observational, matched cohort study (one baseline year before and one outcome year after initiation of therapy) using data from the UK Optimum Patient Care Research Database. We assessed oral thrush incidence in patients initiating long-acting bronchodilators or FDC ICS/LABA therapy. We then compared different combination therapies (budesonide/formoterol fumarate dihydrate [BUD/FOR] and fluticasone propionate/salmeterol xinafoate [FP/SAL]) and devices (DPI and pMDI). Patients prescribed FDC ICS/LABA had significantly greater odds of experiencing oral thrush than those prescribed long-acting bronchodilators alone (adjusted OR 2.18 [95% CI 1.84-2.59]). Significantly fewer patients prescribed BUD/FOR DPI developed oral thrush compared with FP/SAL DPI (OR 0.77 [0.63-0.94]) when allowing for differences in prescribed doses between the drugs. A significantly smaller proportion of patients developed oral thrush in the FP/SAL pMDI arm than in the FP/SAL DPI arm (OR 0.67 [0.55-0.82]). Additionally, in the FP/SAL cohort (both DPI and pMDI), increased risk of oral thrush was significantly associated with high ICS daily dose (OR 1.97 [1.22-3.17] vs low daily dose). ICS use increases oral thrush incidence in COPD and this effect is dose-dependent for FP/SAL therapies. Of the therapies assessed, FP/SAL pMDI and BUD/FOR DPI may be more protective against oral thrush. Copyright © 2016 Elsevier Ltd. All rights reserved.

Boron Neutron Capture Therapy for HER2+ breast cancers: A feasibility study evaluating BNCT for potential role in breast conservation therapies

NASA Astrophysics Data System (ADS)

Jenkins, Peter Anthony

A novel Boron Neutron Capture Therapy (BNCT) regimen for the treatment of HER2+ breast cancers has been proposed as an alternative to whole breast irradiation for breast conservation therapy patients. The proposed therapy regimen is based on the assumed production of boron delivery agents that would be synthesized from compounds of Trastuzumab (Herceptin ®) and oligomeric phosphate diesters (OPDs). The combination of the anti-HER2 monoclonal antibody and the high boron loading capability of OPDs has led to the assumption that boron could be delivered to the HER2+ cancer cells at Tumor to Healthy Tissue ratios (T:H) of up to 35:1 and boron concentrations above 50 μg/g. This significantly increased boron delivery efficiency has opened new BNCT possibilities. This proof of concept study examined treatment parameters derived as the results in previous efforts in the context of patient-specific geometry and compared calculated dose results to those observed during actual patient therapy. These results were based on dose calculations performed with a set of calculated Kerma coefficients derived from tissues specific to the regions of interest for breast cancer. A comparison was made of the dose to the tumor region, the patient's skin, and the peripheral organs. The results of this study demonstrated that, given the performance of the proposed boron delivery agent, the BNCT treatment regimen is feasible. The feasibility is based on the findings that the equivalent dose could be delivered to the treatment volume with less dose to the skin and peripheral organs. This is anticipated to improve the treatment outcomes by maintaining local control of tumor cells while reducing dose to healthy tissues.

The FIND-CKD study--a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale.

PubMed

Macdougall, Iain C; Bock, Andreas; Carrera, Fernando; Eckardt, Kai-Uwe; Gaillard, Carlo; Van Wyck, David; Roubert, Bernard; Cushway, Timothy; Roger, Simon D

2014-04-01

Rigorous data are sparse concerning the optimal route of administration and dosing strategy for iron therapy with or without concomitant erythropoiesis-stimulating agent (ESA) therapy for the management of iron deficiency anaemia in patients with non-dialysis dependent chronic kidney disease (ND-CKD). FIND-CKD was a 56-week, open-label, multicentre, prospective, randomized three-arm study (NCT00994318) of 626 patients with ND-CKD and iron deficiency anaemia randomized to (i) intravenous (IV) ferric carboxymaltose (FCM) at an initial dose of 1000 mg iron with subsequent dosing as necessary to target a serum ferritin level of 400-600 µg/L (ii) IV FCM at an initial dose of 200 mg with subsequent dosing as necessary to target serum ferritin 100-200 µg/L or (iii) oral ferrous sulphate 200 mg iron/day. The primary end point was time to initiation of other anaemia management (ESA therapy, iron therapy other than study drug or blood transfusion) or a haemoglobin (Hb) trigger (two consecutive Hb values <10 g/dL without an increase of ≥ 0.5 g/dL). The background, rationale and study design of the trial are presented here. The study has been completed and results are expected in late 2013. FIND-CKD was the longest randomized trial of IV iron therapy to date. Its findings will address several unanswered questions regarding iron therapy to treat iron deficiency anaemia in patients with ND-CKD. It was also the first randomized trial to utilize both a high and low serum ferritin target range to adjust IV iron dosing, and the first not to employ Hb response as its primary end point.

Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.

PubMed

Narita, Aya; Shirai, Kentarou; Itamura, Shinji; Matsuda, Atsue; Ishihara, Akiko; Matsushita, Kumi; Fukuda, Chisako; Kubota, Norika; Takayama, Rumiko; Shigematsu, Hideo; Hayashi, Anri; Kumada, Tomohiro; Yuge, Kotaro; Watanabe, Yoriko; Kosugi, Saori; Nishida, Hiroshi; Kimura, Yukiko; Endo, Yusuke; Higaki, Katsumi; Nanba, Eiji; Nishimura, Yoko; Tamasaki, Akiko; Togawa, Masami; Saito, Yoshiaki; Maegaki, Yoshihiro; Ohno, Kousaku; Suzuki, Yoshiyuki

2016-03-01

Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme-replacement and substrate-reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD. This open-label pilot study included five patients who received high-dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies. High-dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood-brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again. Pharmacological chaperone therapy with high-dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.

Impact of Dose to the Bladder Trigone on Long-Term Urinary Function After High-Dose Intensity Modulated Radiation Therapy for Localized Prostate Cancer

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

Ghadjar, Pirus; Zelefsky, Michael J.; Spratt, Daniel E.

2014-02-01

Purpose: To determine the potential association between genitourinary (GU) toxicity and planning dose–volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients. Methods and Materials: A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose–volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analysesmore » were done by the Kaplan-Meier method and Cox proportional hazard models, respectively. Results: Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19). Conclusions: The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the bladder trigone seems to be associated with a reduction in late GU toxicity.« less

Haloperidol Treatment with Chronically Medicated Residents: Dose Effects on Clinical Behavior and Reinforcement Contingencies.

ERIC Educational Resources Information Center

Aman, Michael G.; And Others

1989-01-01

The study of effects of haloperidol drug therapy with 20 institutionalized mentally retarded persons found clinical changes confined to a slight reduction in stereotypic behavior and an increase in gross motor activity under the high dose condition. Subjects with high initial levels of stereotypy showed the best response to the drug. (Author/DB)

PSA Response to Neoadjuvant Androgen Deprivation Therapy Is a Strong Independent Predictor of Survival in High-Risk Prostate Cancer in the Dose-Escalated Radiation Therapy Era

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

McGuire, Sean E., E-mail: semcguir@mdanderson.org; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; Lee, Andrew K.

2013-01-01

Purpose: The aim of the study was to evaluate the prognostic value of prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer. Methods and Materials: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specificmore » mortality (PCSM) and overall survival (OS) were examined. Results: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs {>=}0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL. Conclusions: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level {>=}0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level {>=}0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation.« less

Androgen Deprivation Therapy Use in the Setting of High-dose Radiation Therapy and the Risk of Prostate Cancer–Specific Mortality Stratified by the Extent of Competing Mortality

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

Rose, Brent S., E-mail: brose44@gmail.com; Chen, Ming-Hui; Wu, Jing

Purpose: The addition of androgen deprivation therapy (ADT) to radiation therapy (RT) is the standard of care for men with intermediate- and high-risk prostate cancer (PC). However, whether competing mortality (CM) affects the ability of ADT to improve, survival remains unanswered. Methods and Materials: We calculated a CM risk score using a Fine-Gray semiparametric model that included age and cardiometabolic comorbidities from a cohort of 17,669 men treated with high-dose RT with or without supplemental ADT for nonmetastatic PC. Fine and Gray competing risk regression analysis was used to assess whether ADT reduced the risk of PC-specific mortality for menmore » with a low versus a high risk of CM among the 4550 patients within the intermediate- and high-risk cohort after adjustment for established PC prognostic factors, year of treatment, site, and ADT propensity score. Results: After a median follow-up of 8.4 years, 1065 men had died, 89 (8.36%) of PC. Among the men with a low CM score, ADT use was associated with a significant reduction in the risk of PC-specific mortality (adjusted hazard ratio 0.35, 95% confidence interval 0.14-0.87, P=.02) but was not for men with high CM (adjusted hazard ratio 1.33, 95% confidence interval 0.77-2.30, P=.30). Conclusions: Adding ADT to high-dose RT appears to be associated with decreased PC-specific mortality risk in men with a low but not a high CM score. These data should serve to heighten awareness about the importance of considering competing risks when determining whether to add ADT to RT for older men with intermediate- or high-risk PC.« less

Alternative methods for the median lethal dose (LD(50)) test: the up-and-down procedure for acute oral toxicity.

PubMed

Rispin, Amy; Farrar, David; Margosches, Elizabeth; Gupta, Kailash; Stitzel, Katherine; Carr, Gregory; Greene, Michael; Meyer, William; McCall, Deborah

2002-01-01

The authors have developed an improved version of the up-and-down procedure (UDP) as one of the replacements for the traditional acute oral toxicity test formerly used by the Organisation for Economic Co-operation and Development member nations to characterize industrial chemicals, pesticides, and their mixtures. This method improves the performance of acute testing for applications that use the median lethal dose (classic LD50) test while achieving significant reductions in animal use. It uses sequential dosing, together with sophisticated computer-assisted computational methods during the execution and calculation phases of the test. Staircase design, a form of sequential test design, can be applied to acute toxicity testing with its binary experimental endpoints (yes/no outcomes). The improved UDP provides a point estimate of the LD50 and approximate confidence intervals in addition to observed toxic signs for the substance tested. It does not provide information about the dose-response curve. Computer simulation was used to test performance of the UDP without the need for additional laboratory validation.

Nonlinear system identification for prostate cancer and optimality of intermittent androgen suppression therapy.

PubMed

Suzuki, Taiji; Aihara, Kazuyuki

2013-09-01

These days prostate cancer is one of the most common types of malignant neoplasm in men. Androgen ablation therapy (hormone therapy) has been shown to be effective for advanced prostate cancer. However, continuous hormone therapy often causes recurrence. This results from the progression of androgen-dependent cancer cells to androgen-independent cancer cells during the continuous hormone therapy. One possible method to prevent the progression to the androgen-independent state is intermittent androgen suppression (IAS) therapy, which ceases dosing intermittently. In this paper, we propose two methods to estimate the dynamics of prostate cancer, and investigate the IAS therapy from the viewpoint of optimality. The two methods that we propose for dynamics estimation are a variational Bayesian method for a piecewise affine (PWA) system and a Gaussian process regression method. We apply the proposed methods to real clinical data and compare their predictive performances. Then, using the estimated dynamics of prostate cancer, we observe how prostate cancer behaves for various dosing schedules. It can be seen that the conventional IAS therapy is a way of imposing high cost for dosing while keeping the prostate cancer in a safe state. We would like to dedicate this paper to the memory of Professor Luigi M. Ricciardi. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Safety of three sequential whole bladder photodynamic therapy (WBPDT) treatments in the management of resistant bladder cancer

NASA Astrophysics Data System (ADS)

Mejia, Maria C.; Nseyo, Unyime O.

2009-02-01

INTRODUCTION: WBPDT has been used to treat resistant superficial bladder cancer, with clinical benefits and associated dose-dependent side effects. OBJECTIVE: The objective of this study was to assess the safety of three sequential WBPDT treatments in patients with resistant non-muscle invasive (NMI) bladder cancer. MATERIALS AND METHODS: 12 males and one female provided written informed consent in this Phase II study. Each patient received intravenous injection of Photofrin® (AXCAN Parma Inc, Canada) at 1.5 mg/kg two days prior to whole bladder laser (630nm) treatment. Assessment of safety and efficacy included weekly urinary symptoms; cystoscopy, biopsy and cytology; and measurement of bladder volume quarterly after each treatment at baseline, six and 12 months. Treatment #2 and/or #3 occurred only in the absence of bladder contracture, and/or disease progression. RESULTS: 13 patients: 12 males and one female have been enrolled and average age of enrollees is 67.1(52 - 87) years. Four patients had Ta-T1/Grade I-III tumors; two patients had CIS associated with T1/GI-III; and seven patients had carcinoma in situ (CIS) only. Three patients received 3/3 treatments, and are evaluable for toxicity; three patients received two treatments only; and seven patients received one treatment only. There was no bladder contracture; transient mild to moderate bladder irritative voiding symptoms of dysuria, urinary frequency, nocturia and urgency occurred in all patients. The three evaluable patients were without evidence of disease at average of 13.1 (7-20) months. CONCLUSION: Three sequential WBPDT treatments might have a favorable toxicity profile in the management of recurrent/ refractory non-muscle invasive bladder cancer.

Proton therapy - Present and future.

PubMed

Mohan, Radhe; Grosshans, David

2017-01-15

In principle, proton therapy offers a substantial clinical advantage over conventional photon therapy. This is because of the unique depth-dose characteristics of protons, which can be exploited to achieve significant reductions in normal tissue doses proximal and distal to the target volume. These may, in turn, allow escalation of tumor doses and greater sparing of normal tissues, thus potentially improving local control and survival while at the same time reducing toxicity and improving quality of life. Protons, accelerated to therapeutic energies ranging from 70 to 250MeV, typically with a cyclotron or a synchrotron, are transported to the treatment room where they enter the treatment head mounted on a rotating gantry. The initial thin beams of protons are spread laterally and longitudinally and shaped appropriately to deliver treatments. Spreading and shaping can be achieved by electro-mechanical means to treat the patients with "passively-scattered proton therapy" (PSPT) or using magnetic scanning of thin "beamlets" of protons of a sequence of initial energies. The latter technique can be used to treat patients with optimized intensity modulated proton therapy (IMPT), the most powerful proton modality. Despite the high potential of proton therapy, the clinical evidence supporting the broad use of protons is mixed. It is generally acknowledged that proton therapy is safe, effective and recommended for many types of pediatric cancers, ocular melanomas, chordomas and chondrosarcomas. Although promising results have been and continue to be reported for many other types of cancers, they are based on small studies. Considering the high cost of establishing and operating proton therapy centers, questions have been raised about their cost effectiveness. General consensus is that there is a need to conduct randomized trials and/or collect outcomes data in multi-institutional registries to unequivocally demonstrate the advantage of protons. Treatment planning and plan evaluation of PSPT and IMPT require special considerations compared to the processes used for photon treatment planning. The differences in techniques arise from the unique physical properties of protons but are also necessary because of the greater vulnerability of protons to uncertainties, especially from inter- and intra-fractional variations in anatomy. These factors must be considered in designing as well as evaluating treatment plans. In addition to anatomy variations, other sources of uncertainty in dose delivered to the patient include the approximations and assumptions of models used for computing dose distributions for planning of treatments. Furthermore, the relative biological effectiveness (RBE) of protons is simplistically assumed to have a constant value of 1.1. In reality, the RBE is variable and a complex function of the energy of protons, dose per fraction, tissue and cell type, end point, etc. These uncertainties, approximations and current technological limitations of proton therapy may limit the achievement of its true potential. Ongoing research is aimed at better understanding the consequences of the various uncertainties on proton therapy and reducing the uncertainties through image-guidance, adaptive radiotherapy, further study of biological properties of protons and the development of novel dose computation and optimization methods. However, residual uncertainties will remain in spite of the best efforts. To increase the resilience of dose distributions in the face of uncertainties and improve our confidence in dose distributions seen on treatment plans, robust optimization techniques are being developed and implemented. We assert that, with such research, proton therapy will be a commonly applied radiotherapy modality for most types of solid cancers in the near future. Copyright © 2016 Elsevier B.V. All rights reserved.

Asymmetric inner wedge group sequential tests with applications to verifying whether effective drug concentrations are similar in adults and children.

PubMed

Hampson, Lisa V; Fisch, Roland; Van, Linh M; Jaki, Thomas

2017-02-10

Extrapolating from information available on one patient group to support conclusions about another is common in clinical research. For example, the findings of clinical trials, often conducted in highly selective patient cohorts, are routinely extrapolated to wider populations by policy makers. Meanwhile, the results of adult trials may be used to support conclusions about the effects of a medicine in children. For example, if the effective concentration of a drug can be assumed to be similar in adults and children, an appropriate paediatric dosing rule may be found by 'bridging', that is, by matching the adult effective concentration. However, this strategy may result in children receiving an ineffective or hazardous dose if, in fact, effective concentrations differ between adults and children. When there is uncertainty about the equality of effective concentrations, some pharmacokinetic-pharmacodynamic data may be needed in children to verify that differences are small. In this paper, we derive optimal group sequential tests that can be used to verify this assumption efficiently. Asymmetric inner wedge tests are constructed that permit early stopping to accept or reject an assumption of similar effective drug concentrations in adults and children. Asymmetry arises because the consequences of under- and over-dosing may differ. We show how confidence intervals can be obtained on termination of these tests and illustrate the small sample operating characteristics of designs using simulation. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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

Hata, Masaharu; Tokuuye, Koichi; Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki

Purpose: To present treatment outcomes of hypofractionated high-dose proton beam therapy for Stage I non-small-cell lung cancer (NSCLC). Methods and Materials: Twenty-one patients with Stage I NSCLC (11 with Stage IA and 10 with Stage IB) underwent hypofractionated high-dose proton beam therapy. At the time of irradiation, patient age ranged from 51 to 85 years (median, 74 years). Nine patients were medically inoperable because of comorbidities, and 12 patients refused surgical resection. Histology was squamous cell carcinoma in 6 patients, adenocarcinoma in 14, and large cell carcinoma in 1. Tumor size ranged from 10 to 42 mm (median, 25 mm)more » in maximum diameter. Three and 18 patients received proton beam irradiation with total doses of 50 Gy and 60 Gy in 10 fractions, respectively, to primary tumor sites. Results: Of 21 patients, 2 died of cancer and 2 died of pneumonia at a median follow-up period of 25 months. The 2-year overall and cause-specific survival rates were 74% and 86%, respectively. All but one of the irradiated tumors were controlled during the follow-up period. Five patients showed recurrences 6-29 months after treatment, including local progression and new lung lesions outside of the irradiated volume in 1 and 4 patients, respectively. The local progression-free and disease-free rates were 95% and 79% at 2 years, respectively. No therapy-related toxicity of Grade {>=}3 was observed. Conclusions: Hypofractionated high-dose proton beam therapy seems feasible and effective for Stage I NSCLC. Proton beams may contribute to enhanced efficacy and lower toxicity in the treatment of patients with Stage I NSCLC.« less

Azithromycin in the treatment of uncomplicated genital chlamydial infections.

PubMed

Stamm, W E

1991-09-12

Chlamydia trachomatis is among the most prevalent of sexually transmitted diseases and causes serious sequelae, especially in women. A major difficulty facing the clinician has been the effective treatment of patients with chlamydial infections, since existing drugs require 7 or more days of multidose therapy, and hence considerable commitment from the patient. Many patients, especially those who are minimally symptomatic or asymptomatic, are likely to be noncompliant when given such multiple day regimens and thus may fail therapy. Azithromycin is an azalide antibiotic that has a minimum inhibitory concentration against C. trachomatis of between 0.03 and 0.25 mg/L, as well as good in vitro activity against other sexually transmitted pathogens that are often present concurrently. Azithromycin also achieves high intracellular concentrations, which may be beneficial in eradicating Chlamydia, an obligate intracellular pathogen. More importantly, azithromycin has high tissue bioavailability and a tissue half-life of between 2 and 4 days. These pharmacokinetic properties imply that the dosing period for azithromycin can be greatly reduced while still achieving high antimicrobial activity at sites of infection. Clinical experience to date shows that a single 1 g oral dose of azithromycin is as effective as a standard 7-day twice daily regimen of doxycycline and more effective than 7 days of ciprofloxacin in eradicating uncomplicated chlamydial genital infections. As such, azithromycin is the first single-dose therapy for the treatment of urethritis and cervicitis due to C. trachomatis. Single-dose therapy for chlamydial infection, which could be administered under supervision in the clinic, would be a significant advance in the management and public health control of chlamydial infections.

Treatment strategy for metastatic prostate cancer with extremely high PSA level: reconsidering the value of vintage therapy.

PubMed

Yamada, Yasutaka; Sakamoto, Shinichi; Amiya, Yoshiyasu; Sasaki, Makoto; Shima, Takayuki; Komiya, Akira; Suzuki, Noriyuki; Akakura, Koichiro; Ichikawa, Tomohiko; Nakatsu, Hiroomi

2018-05-04

The prognostic significance of initial prostate-specific antigen (PSA) level for metastatic prostate cancer remains uncertain. We investigated the differences in prognosis and response to hormonal therapies of metastatic prostate cancer patients according to initial PSA levels. We analyzed 184 patients diagnosed with metastatic prostate cancer and divided them into three PSA level groups as follows: low (<100 ng ml -1 ), intermediate (100-999 ng ml -1 ), and high (≥1000 ng ml -1 ). All patients received androgen deprivation therapy (ADT) immediately. We investigated PSA progression-free survival (PFS) for first-line ADT and overall survival (OS) within each of the three groups. Furthermore, we analyzed response to antiandrogen withdrawal (AW) and alternative antiandrogen (AA) therapies after development of castration-resistant prostate cancer (CRPC). No significant differences in OS were observed among the three groups (P = 0.654). Patients with high PSA levels had significantly short PFS for first-line ADT (P = 0.037). Conversely, patients in the high PSA level group had significantly longer PFS when treated with AW than those in the low PSA level group (P = 0.047). Furthermore, patients with high PSA levels had significantly longer PFS when provided with AA therapy (P = 0.049). PSA responders to AW and AA therapies had significantly longer survival after CRPC development than nonresponders (P = 0.011 and P < 0.001, respectively). Thus, extremely high PSA level predicted favorable response to vintage sequential ADT and AW. The current data suggest a novel aspect of extremely high PSA value as a favorable prognostic marker after development of CRPC.

Health Care Utilization Among Complementary and Alternative Medicine Users in a Large Military Cohort

DTIC Science & Technology

2011-01-01

Sources In addition to our longitudinal survey instrument , other data sources include the Standard Inpatient Data Record (SIDR), which is an...therapy, high-dose megavita- min therapy, homeopathic remedies, hypnosis , massage therapy, relaxation, and spiritual healing. For the pur- poses of these...analyses, acupuncture, biofeedback, chiro- practic care, energy healing, folk medicine, hypnosis , and massage therapy were grouped together as practi

Impact of high-dose atorvastatin therapy and clinical risk factors on incident aortic valve stenosis in patients with cardiovascular disease (from TNT, IDEAL, and SPARCL).

PubMed

Arsenault, Benoit J; Boekholdt, S Matthijs; Mora, Samia; DeMicco, David A; Bao, Weihang; Tardif, Jean-Claude; Amarenco, Pierre; Pedersen, Terje; Barter, Philip; Waters, David D

2014-04-15

Clinical trials have not provided evidence for a role of statin therapy in reducing aortic valve stenosis (AVS) severity in patients with documented AVS. However, whether statin therapy could prevent the onset of AVS is unknown. Our objectives were (1) to compare the incidence rates of AVS among patients treated with high-dose versus usual-dose statin or placebo and (2) to identify clinical risk factors associated with the development of AVS. We conducted post hoc analyses in 23,508 participants from 3 large-scale multicenter atorvastatin randomized blinded clinical trials: Treating to New Targets, the Incremental Decrease in End Points Through Aggressive Lipid Lowering, and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels. The main outcome measure was the incidence of clinical AVS over a median follow-up of 4.9 years (82 cases). Among patients who developed AVS, 39 (47.6%) were treated with atorvastatin 80 mg and 43 (52.4%) were treated with lower dose statin (atorvastatin 10 mg in Treating to New Targets, simvastatin 20 to 40 mg in Incremental Decrease in End Points Through Aggressive Lipid Lowering, or placebo in Stroke Prevention by Aggressive Reduction in Cholesterol Levels; hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.59 to 1.41, p=0.67). In multivariate analyses forcing treatment, sex, and race into the model, factors that were significantly associated with AVS included age (HR 2.17, 95% CI 1.61 to 2.93, p<0.0001 per 1-SD increment), diabetes (HR 1.67, 95% CI 1.00 to 2.80, p=0.05), vitamin K antagonist use (HR 3.25, 95% CI 2.06 to 5.16, p<0.0001), and previous statin use (HR 2.65, 95% CI 1.54 to 4.60, p=0.0008). In conclusion, random allocation to high-dose versus usual-dose statin therapy or placebo did not impact the incidence of AVS among patients without known AVS. Age, diabetes, vitamin K antagonists, and previous statin use were significant predictors of incident AVS in these high-risk patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Dysphagia after sequential chemoradiation therapy for advanced head and neck cancer.

PubMed

Goguen, Laura A; Posner, Marshall R; Norris, Charles M; Tishler, Roy B; Wirth, Lori J; Annino, Donald J; Gagne, Adele; Sullivan, Christopher A; Sammartino, Daniel E; Haddad, Robert I

2006-06-01

Assess impact of sequential chemoradiation therapy (SCRT) for advanced head and neck cancer (HNCA) on swallowing, nutrition, and quality of life. Prospective cohort study of 59 patients undergoing SCRT for advanced head and neck cancer. Follow-up median was 47.5 months. Regional Cancer Center. Median time to gastrostomy tube removal was 21 weeks. Eighteen of 23 patients who underwent modified barium swallow demonstrated aspiration; none developed pneumonia. Six of 7 with pharyngoesophageal stricture underwent successful dilatation. Functional Assessment of Cancer Therapy-Head and Neck Scale questionnaires at median 6 months after treatment revealed "somewhat" satisfaction with swallowing. At the time of analysis, 97% have the gastronomy tube removed and take soft/regular diet. Early after treatment dysphagia adversely affected weight, modified barium swallow results, and quality of life. Diligent swallow therapy, and dilation as needed, allowed nearly all patients to have their gastronomy tubes removed and return to a soft/regular diet. Dysphagia is significant after SCRT but generally slowly recovers 6 to 12 months after SCRT. C-4.

Hormonal priming, induction of ovulation and in-vitro fertilization of the endangered Wyoming toad (Bufo baxteri)

PubMed Central

Browne, Robert K; Seratt, Jessica; Vance, Carrie; Kouba, Andrew

2006-01-01

The endangered Wyoming toad (Bufo baxteri) is the subject of an extensive captive breeding and reintroduction program. Wyoming toads in captivity rarely ovulate spontaneously and hormonal induction is used to ovulate females or to stimulate spermiation in males. With hormonal induction, ovulation is unreliable and egg numbers are low. The sequential administration of anovulatory doses of hormones (priming) has increased egg numbers and quality in both anurans and fish. Consequently, we tested the efficacy of a combination of human Chorionic Gonadotrophin (hCG) and Luteinizing Hormone Releasing Hormone analogue (LHRHa) administered as one dose, or two or three sequential doses to Bufo baxteri on egg numbers, fertilization and early embryo development. Spawning toads deposited eggs into Simplified Amphibian Ringers (SAR) solution to enable controlled in-vitro fertilization (IVF) with sperm from hormonally induced male toads. Unprimed females receiving a single mixed normally ovulatory dose of 500 IU hCG plus 4 micrograms of LHRHa produced no eggs. Whereas females primed with this dose and an anovulatory dose (100 IU hCG and 0.8 micrograms of LHRHa) of the same hormones, or primed only with an anovulatory dose, spawned after then receiving an ovulatory dose. Higher total egg numbers were produced with two primings than with one priming. Moreover, two primings produced significantly more eggs from each individual female than one priming. The cleavage rate of eggs was not found to differ between one or two primings. Nevertheless, embryo development with eggs from two primings gave a significantly greater percentage neurulation and swim-up than those from one priming. Of the male toads receiving a single dose of 300 IU hCG, 80% produced spermic urine with the greatest sperm concentration 7 hours post-administration (PA). However, peak sperm motility (95%) was achieved at 5 hours PA and remained relatively constant until declining 20 hours PA. In conclusion, Bufo baxteri egg numbers and quality benefited from sequential priming with LHRHa and hCG whereas spermic urine for IVF was produced from males with a single dose of hCG. The power of assisted reproduction technology in the conservation of endangered amphibians is shown by the release of nearly 2000 tadpoles produced by IVF during this study. PMID:16790071