Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of 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 outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

Impact of High-Dose Vitamin D3 Supplementation in Patients with Crohn's Disease in Remission: A Pilot Randomized Double-Blind Controlled Study.

PubMed

Narula, Neeraj; Cooray, Mohan; Anglin, Rebecca; Muqtadir, Zack; Narula, Alisha; Marshall, John K

2017-02-01

To assess the tolerability and efficacy of high-dose vitamin D3 in patients with Crohn's disease (CD). This was a randomized, double-blind placebo-controlled trial of high-dose vitamin D3 at 10,000 IU daily (n = 18) compared to 1000 IU daily (n = 16) for 12 months in patients with CD in remission. The primary outcome was change in serum 25-hydroxy-vitamin D levels. Secondary outcomes included clinical relapse rates and changes in mood scores. High-dose vitamin D3 at 10,000 IU daily significantly improved 25-hydroxy-vitamin D levels from a mean of 73.5 nmol/L [standard deviation (SD) 11.7 nmol/L] to 160.8 nmol/L (SD 43.2 nmol/L) (p = 0.02). On an intention-to-treat basis, the rate of relapse was not significantly different between patients receiving low- and high-dose vitamin D3 (68.8 vs 33.3%, p = 0.0844). In per-protocol analysis, clinical relapse of Crohn's disease was less frequently observed in patients receiving a high dose (0/12 or 0%) compared to those receiving a low dose of 1000 IU daily (3/8 or 37.5%) (p = 0.049). Improvement in anxiety and depression scores and a good safety profile were observed in both groups treated with vitamin D3. Oral supplementation with high-dose vitamin D3 at 10,000 IU daily significantly improved serum 25-hydroxy-vitamin D levels. Rates of clinical relapse were similar between both groups. Larger studies using high-dose vitamin D3 for treatment of inflammatory bowel diseases are warranted. CLINICALTRIALS. NCT02615288.

Simultaneous integrated vs. sequential boost in VMAT radiotherapy of high-grade gliomas.

PubMed

Farzin, Mostafa; Molls, Michael; Astner, Sabrina; Rondak, Ina-Christine; Oechsner, Markus

2015-12-01

In 20 patients with high-grade gliomas, we compared two methods of planning for volumetric-modulated arc therapy (VMAT): simultaneous integrated boost (SIB) vs. sequential boost (SEB). The investigation focused on the analysis of dose distributions in the target volumes and the organs at risk (OARs). After contouring the target volumes [planning target volumes (PTVs) and boost volumes (BVs)] and OARs, SIB planning and SEB planning were performed. The SEB method consisted of two plans: in the first plan the PTV received 50 Gy in 25 fractions with a 2-Gy dose per fraction. In the second plan the BV received 10 Gy in 5 fractions with a dose per fraction of 2 Gy. The doses of both plans were summed up to show the total doses delivered. In the SIB method the PTV received 54 Gy in 30 fractions with a dose per fraction of 1.8 Gy, while the BV received 60 Gy in the same fraction number but with a dose per fraction of 2 Gy. All of the OARs showed higher doses (Dmax and Dmean) in the SEB method when compared with the SIB technique. The differences between the two methods were statistically significant in almost all of the OARs. Analysing the total doses of the target volumes we found dose distributions with similar homogeneities and comparable total doses. Our analysis shows that the SIB method offers advantages over the SEB method in terms of sparing OARs.

Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial.

PubMed

Isanaka, Sheila; Mugusi, Ferdinand; Hawkins, Claudia; Spiegelman, Donna; Okuma, James; Aboud, Said; Guerino, Chalamilla; Fawzi, Wafaie W

2012-10-17

Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. INTERVENTION The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. The composite of HIV disease progression or death from any cause. The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96-1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11-1.87) vs standard-dose supplementation. CONCLUSION In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Clinicaltrials.gov Identifier: NCT00383669.

Severe neuropathy after high dose carboplatin in three patients receiving multidrug chemotherapy

PubMed Central

Heinzlef, O.; Lotz, J.; Roullet, E.

1998-01-01

Three patients are described who developed a severe neuropathy after chemotherapy with high dose cis-diamine-(1,1-cyclobutane dicarboxylato) platinum (carboplatin). This toxic side effect, which is unusual at conventional doses, might become more frequent as increasing doses are administered to overcome drug resistance in cancer treatment, and might limit its use at very high doses before haematopoietic stem cell transplantation. 

 PMID:9598687

Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children’s Oncology Group Study AALL0232

PubMed Central

Devidas, Meenakshi; Chen, Si; Salzer, Wanda L.; Raetz, Elizabeth A.; Loh, Mignon L.; Mattano, Leonard A.; Cole, Catherine; Eicher, Alisa; Haugan, Maureen; Sorenson, Mark; Heerema, Nyla A.; Carroll, Andrew A.; Gastier-Foster, Julie M.; Borowitz, Michael J.; Wood, Brent L.; Willman, Cheryl L.; Winick, Naomi J.; Hunger, Stephen P.; Carroll, William L.

2016-01-01

Purpose Survival for children and young adults with high-risk B-acute lymphoblastic leukemia has improved significantly, but 20% to 25% of patients are not cured. Children’s Oncology Group study AALL0232 tested two interventions to improve survival. Patients and Methods Between January 2004 and January 2011, AALL0232 enrolled 3,154 participants 1 to 30 years old with newly diagnosed high-risk B-acute lymphoblastic leukemia. By using a 2 × 2 factorial design, 2,914 participants were randomly assigned to receive dexamethasone (14 days) versus prednisone (28 days) during induction and high-dose methotrexate versus Capizzi escalating-dose methotrexate plus pegaspargase during interim maintenance 1. Results Planned interim monitoring showed the superiority of the high-dose methotrexate regimens, which exceeded the predefined boundary and led to cessation of enrollment in January 2011. At that time, participants randomly assigned to high-dose methotrexate during interim maintenance 1 versus those randomly assigned to Capizzi methotrexate had a 5-year event-free survival (EFS) of 82% versus 75.4% (P = .006). Mature final data showed 5-year EFS rates of 79.6% for high-dose methotrexate and 75.2% for Capizzi methotrexate (P = .008). High-dose methotrexate decreased both marrow and CNS recurrences. Patients 1 to 9 years old who received dexamethasone and high-dose methotrexate had a superior outcome compared with those who received the other three regimens (5-year EFS, 91.2% v 83.2%, 80.8%, and 82.1%; P = .015). Older participants derived no benefit from dexamethasone during induction and experienced excess rates of osteonecrosis. Conclusion High-dose methotrexate is superior to Capizzi methotrexate for the treatment of high-risk B-acute lymphoblastic leukemia, with no increase in acute toxicity. Dexamethasone given during induction benefited younger children but provided no benefit and was associated with a higher risk of osteonecrosis among participants 10 years and older. PMID:27114587

Randomized Comparative Study of Intravenous Infusion of Three Different Fixed Doses of Milrinone in Pediatric Patients with Pulmonary Hypertension Undergoing Open Heart Surgery

PubMed Central

Barnwal, Neeraj Kumar; Umbarkar, Sanjeeta Rajendra; Sarkar, Manjula Sudeep; Dias, Raylene J

2017-01-01

Background: Pulmonary hypertension secondary to congenital heart disease is a common problem in pediatric patients presenting for open heart surgery. Milrinone has been shown to reduce pulmonary vascular resistance and pulmonary artery pressure in pediatric patients and neonates postcardiac surgery. We aimed to evaluate the postoperative outcome in such patients with three different fixed maintenance doses of milrinone. Methodology: Patients were randomized into three groups. All patients received fixed bolus dose of milrinone 50 μg/kg on pump during rewarming. Following this, patients in low-dose group received infusion of milrinone at the rate of 0.375 μg/kg/min, medium-dose group received 0.5 μg/kg/min, and high-dose group received 0.75 μg/kg/min over 24 h. Heart rate, mean arterial pressure (MAP), mean airway pressure (MaP), oxygenation index (OI), and central venous pressure (CVP) were compared at baseline and 24 h postoperatively. Dose of inotropic requirement, duration of ventilatory support and Intensive Care Unit (ICU) stay were noted. Results: MAP, MaP, OI, and CVP were comparable in all three groups postoperatively. All patients in the low-dose group required low inotropic support while 70% of patients in the high-dose group needed high inotropic support to manage episodes of hypotension (P = 0.000). Duration of ventilatory support and ICU stay in all three groups was comparable (P = 0.412, P = 0.165). Conclusion: Low-dose infusions while having a clinical impact were more beneficial in avoiding adverse events and decreasing inotropic requirement without affecting duration of ventilatory support and duration of ICU stay. PMID:28701597

Randomized comparative study of intravenous infusion of three different fixed doses of milrinone in pediatric patients with pulmonary hypertension undergoing open heart surgery.

PubMed

Barnwal, Neeraj Kumar; Umbarkar, Sanjeeta Rajendra; Sarkar, Manjula Sudeep; Dias, Raylene J

2017-01-01

Pulmonary hypertension secondary to congenital heart disease is a common problem in pediatric patients presenting for open heart surgery. Milrinone has been shown to reduce pulmonary vascular resistance and pulmonary artery pressure in pediatric patients and neonates postcardiac surgery. We aimed to evaluate the postoperative outcome in such patients with three different fixed maintenance doses of milrinone. Patients were randomized into three groups. All patients received fixed bolus dose of milrinone 50 μg/kg on pump during rewarming. Following this, patients in low-dose group received infusion of milrinone at the rate of 0.375 μg/kg/min, medium-dose group received 0.5 μg/kg/min, and high-dose group received 0.75 μg/kg/min over 24 h. Heart rate, mean arterial pressure (MAP), mean airway pressure (MaP), oxygenation index (OI), and central venous pressure (CVP) were compared at baseline and 24 h postoperatively. Dose of inotropic requirement, duration of ventilatory support and Intensive Care Unit (ICU) stay were noted. MAP, MaP, OI, and CVP were comparable in all three groups postoperatively. All patients in the low-dose group required low inotropic support while 70% of patients in the high-dose group needed high inotropic support to manage episodes of hypotension (P = 0.000). Duration of ventilatory support and ICU stay in all three groups was comparable (P = 0.412, P = 0.165). Low-dose infusions while having a clinical impact were more beneficial in avoiding adverse events and decreasing inotropic requirement without affecting duration of ventilatory support and duration of ICU stay.

Optimizing bevacizumab dosing in glioblastoma: less is more.

PubMed

Ajlan, Abdulrazag; Thomas, Piia; Albakr, Abdulrahman; Nagpal, Seema; Recht, Lawrence

2017-10-01

Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below maximum tolerated dose. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of 10 mg/kg every other week for glioma patients, there has not been much prior work examining whether the relatively high complication rates reported with this agent can be decreased by lowering the dose without impairing efficacy. We assessed charts from 80 patients who received BEV for glioblastoma to survey the incidence of complications relative to BEV dose. All patients were treated with standard upfront chemoradiation. The toxicity was graded based on the NCI CTCAE, version 4.03. The rate of BEV serious related adverse events was 12.5% (n = 10/80). There were no serious adverse events (≥grade 3) when the administered dose was (<3 mg/kg/week), compared to a 21% incidence in those who received higher doses (≥3 mg/kg/week) (P < 0.01). Importantly, the three patient deaths attributable to BEV administration occurred in patients receiving higher doses. Patients who received lower doses also had a better survival rate, although this did not reach statistical significance [median OS 39 for low dose group vs. 17.3 for high dose group (P = 0.07)]. Lower rates of serious BEV related toxicities are noted when lower dosages are used without diminishing positive clinical impact. Further work aimed at optimizing BEV dosage is justified.

High Dose Vitamin D Therapy for Chronic Pain in Children and Adolescents with Sickle Cell Disease: Results of a Randomized Double Blind Pilot Study

PubMed Central

I, Osunkwo; TR, Ziegler; J, Alvarez; C, McCracken; K, Cherry; CE, Osunkwo; SF, Ofori-Acquah; S, Ghosh; A, Ogunbobode; J, Rhodes; JR, Eckman; CD, Dampier; V, Tangpricha

2012-01-01

Summary We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were followed for 6 months after receiving a six-week course of oral high-dose cholecalciferol or placebo. Vitamin D insufficiency and deficiency was present at baseline in 82.5% and 52.5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects. PMID:22924607

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.

High-dose Versus Low-dose Tranexamic Acid to Reduce Transfusion Requirements in Pediatric Scoliosis Surgery.

PubMed

Johnson, Daniel J; Johnson, Christine C; Goobie, Susan M; Nami, Nina; Wetzler, Joshua A; Sponseller, Paul D; Frank, Steven M

2017-12-01

Our objective was to quantify blood loss and transfusion requirements for high-dose and low-dose tranexamic acid (TXA) dosing regimens in pediatric patients undergoing spinal fusion for correction of idiopathic scoliosis. Previous investigators have established the efficacy of TXA in pediatric scoliosis surgery; however, the dosing regimens vary widely and the optimal dose has not been established. We retrospectively analyzed electronic medical records for 116 patients who underwent spinal fusion surgery for idiopathic scoliosis by a single surgeon and were treated with TXA. In total, 72 patients received a 10 mg/kg loading dose with a 1 mg/kg/h maintenance dose (low-dose) and 44 patients received 50 mg/kg loading dose with a 5 mg/kg/h maintenance dose (high-dose). Estimated blood loss and transfusion requirements were compared between dosing groups. Patient characteristics were nearly identical between the 2 groups. Compared with the low-dose TXA group, the high-dose TXA group had decreased estimated blood loss (695 vs. 968 mL, P=0.01), and a decrease in both intraoperative (0.3 vs. 0.9 units, P=0.01) and whole hospitalization (0.4 vs. 1.0 units, P=0.04) red blood cell transfusion requirements. The higher-dose TXA was associated with decreased intraoperative (P=0.01), and whole hospital transfusion (P=0.01) requirements, even after risk-adjustment for potential confounding variables. High-dose TXA is more effective than low-dose TXA in reducing blood loss and transfusion requirements in pediatric idiopathic scoliosis patients undergoing surgery. Level-III, retrospective cohort study.

Novel high dose rate lip brachytherapy technique to improve dose homogeneity and reduce toxicity by customized mold.

PubMed

Feldman, Jon; Appelbaum, Limor; Sela, Mordechay; Voskoboinik, Ninel; Kadouri, Sarit; Weinberger, Jeffrey; Orion, Itzhak; Meirovitz, Amichay

2014-12-23

The purpose of this study is to describe a novel brachytherapy technique for lip Squamous Cell Carcinoma, utilizing a customized mold with embedded brachytherapy sleeves, which separates the lip from the mandible, and improves dose homogeneity. Seven patients with T2 lip cancer treated with a "sandwich" technique of High Dose Rate (HDR) brachytherapy to the lip, consisting of interstitial catheters and a customized mold with embedded catheters, were reviewed for dosimetry and outcome using 3D planning. Dosimetric comparison was made between the "sandwich" technique to "classic" - interstitial catheters only plan. We compared dose volume histograms for Clinical Tumor Volume (CTV), normal tissue "hot spots" and mandible dose. We are reporting according to the ICRU 58 and calculated the Conformal Index (COIN) to show the advantage of our technique. The seven patients (ages 36-81 years, male) had median follow-up of 47 months. Four patients received Brachytherapy and External Beam Radiation Therapy, 3 patients received brachytherapy alone. All achieved local control, with excellent esthetic and functional results. All patients are disease free. The Customized Mold Sandwich technique (CMS) reduced the high dose region receiving 150% (V150) by an average of 20% (range 1-47%), The low dose region (les then 90% of the prescribed dose) improved by 73% in average by using the CMS technique. The COIN value for the CMS was in average 0.92 as opposed to 0.88 for the interstitial catheter only. All differences (excluding the low dose region) were statistically significant. The CMS technique significantly reduces the high dose volume and increases treatment homogeneity. This may reduce the potential toxicity to the lip and adjacent mandible, and results in excellent tumor control, cosmetic and functionality.

Methylene Blue Facilitates Memory Retention in Zebrafish in a Dose-Dependent Manner.

PubMed

Echevarria, David J; Caramillo, Erika M; Gonzalez-Lima, Francisco

2016-12-01

Methylene blue (MB) is an FDA-grandfathered drug with memory-enhancing effects at low doses, but opposite effects at high doses. We investigated the effects of four MB doses (0.1, 0.5, 5.0, or 10.0 μM) on zebrafish memory retention in the T-maze task. After training fish to swim into a certain arm of the T-maze, the fish were placed into a tank containing one of the four MB doses or a control tank containing blue food dye. Subsequently, fish were placed into the T-maze for memory retention testing. Results indicated that MB produced hormetic dose-response effects on memory. Fish that received the 0.5 μM dose performed significantly better at the T-maze than those that received higher doses. Fish who received 5.0 μM did not exhibit a significant difference in performance from control fish, and the fish that received the 10.0 μM dose performed significantly worse than lower doses. These findings support the utility of zebrafish in comparative research and their potential value for testing of MB and other neuropsychopharmacological treatments in animal models of memory disorders.

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.

Facial exposure to ultraviolet radiation: Predicted sun protection effectiveness of various hat styles.

PubMed

Backes, C; Religi, A; Moccozet, L; Vuilleumier, L; Vernez, D; Bulliard, J-L

2018-04-23

Solar ultraviolet radiation (UVR) doses received by individuals are highly influenced by behavioural and environmental factors. This study aimed at quantifying hats' sun protection effectiveness in various exposure conditions, by predicting UVR exposure doses and their anatomical distributions. A well-defined three-dimensional head morphology and four hat styles (a cap, a helmet, a middle- and a wide-brimmed hat) were added to a previously published model. Midday (12:00-14:00) and daily (08:00 - 17:00) seasonal UVR doses were estimated at various facial skin zones, with and without hat-wear, accounting for each UVR component. Protection effectiveness was calculated by the relative reduction of predicted UVR dose, expressed as a predictive protection factor (PPF). The unprotected entire face received 2.5 times higher UVR doses during a summer midday compared to a winter midday (3.3 vs. 1.3 SED) with highest doses received at the nose (6.1 SED). During a cloudless summer day, the lowest mean UVR dose is received by the entire face protected by a wide-brimmed hat (1.7 SED). No hat reached 100% protection at any facial skin zone (PPF max : 76%). Hats' sun protection effectiveness varied highly with environmental conditions and were mainly limited by the high contribution of diffuse UVR, irrespective of hat style. Larger brim sizes afforded greater facial protection than smaller brim sizes except around midday when the sun position is high. Consideration of diffuse and reflected UVR in sun educational messages could improve sun protection effectiveness. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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

The effects of crude aqueous and alcohol extracts of Aloe vera on growth and abdominal viscera of suckling rats.

PubMed

Beya, Wabeya; Davidson, Bruce; Erlwanger, Kennedy H

2012-01-01

The gastrointestinal tract of neonates is sensitive to dietary manipulations. When nursing mothers use Aloe vera, their babies are at risk of indirect exposure to Aloe vera via breast feeding or directly as health supplements. The effects of orally administered extracts of Aloe vera in unweaned rats were investigated. Six day old Sprague-Dawley rats were gavaged with aqueous or alcohol extracts of Aloe vera (low dose 50mg. kg⁻¹ or high dose 500mg. kg⁻¹) daily for eight days. All data were expressed as mean ± SD and analyzed by one way ANOVA. Pups receiving high doses of either extract had a significantly higher body mass gain than the group receiving lower dose (p < 0.05). Tibial length was significantly increased in the high dose aqueous extract group (15-26%). The differences in growth could not be attributed to circulating insulin-like growth factor-1 as the levels were not significantly different. The caecum was significantly enlarged in the rats that received the high doses of both extracts. Although, there was no significant difference in the non-fasting plasma concentration of glucose and triglycerides, the hepatic lipid and glycogen content were significantly higher (p < 0.001) for the high dose aqueous extract group. The plasma alanine transaminase was not affected by the treatments, however the high doses of the extracts significantly increased plasma alkaline phosphatase activity. Short term administration of Aloe vera extracts resulted in growth promotion, enhanced hepatic storage of metabolic substrates, increased ALP possibly in relation to bone growth and caused hypertrophy of the caecum of neonatal rats. These effects need to be explored further to enhance animal production and health.

Effect of High-Dose vs Standard-Dose Multivitamin Supplementation at the Initiation of HAART on HIV Disease Progression and Mortality in Tanzania

PubMed Central

Isanaka, Sheila; Mugusi, Ferdinand; Hawkins, Claudia; Spiegelman, Donna; Okuma, James; Aboud, Said; Guerino, Chalamilla; Fawzi, Wafaie W.

2013-01-01

Context Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. Objective To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. Design, Setting, and Participants A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. Intervention The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. Main Outcome Measure The composite of HIV disease progression or death from any cause. Results The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96–1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11–1.87) vs standard-dose supplementation. Conclusion In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Trial Registration clinicaltrials.gov Identifier: NCT00383669 PMID:23073950

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.

Older adults and high-risk medication administration in the emergency department.

PubMed

Kim, Mitchell; Mitchell, Steven H; Gatewood, Medley; Bennett, Katherine A; Sutton, Paul R; Crawford, Carol A; Bentov, Itay; Damodarasamy, Mamatha; Kaplan, Stephen J; Reed, May J

2017-01-01

Older adults are susceptible to adverse effects from opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and benzodiazepines (BZDs). We investigated factors associated with the administration of elevated doses of these medications of interest to older adults (≥65 years old) in the emergency department (ED). ED records were queried for the administration of medications of interest to older adults at two academic medical center EDs over a 6-month period. Frequency of recommended versus elevated ("High doses" were defined as doses that ranged between 1.5 and 3 times higher than the recommended starting doses; "very high doses" were defined as higher than high doses) starting doses of medications, as determined by geriatric pharmacy/medicine guidelines and expert consensus, was compared by age groups (65-69, 70-74, 75-79, 80-84, and ≥85 years), gender, and hospital. There were 17896 visits representing 11374 unique patients >65 years of age (55.3% men, 44.7% women). A total of 3394 doses of medications of interest including 1678 high doses and 684 very high doses were administered to 1364 different patients. Administration of elevated doses of medications was more common than that of recommended doses. Focusing on opioids and BZDs, the 65-69-year age group was much more likely to receive very high doses (1481 and 412 doses, respectively) than the ≥85-year age groups (relative risk [RR] 5.52, 95% CI 2.56-11.90), mainly reflecting elevated opioid dosing (RR 8.28, 95% CI 3.69-18.57). Men were more likely than women to receive very high doses (RR 1.47, 95% CI 1.26-1.72), primarily due to BZDs (RR 2.12, 95% CI 2.07-2.16). Administration of elevated doses of opioids and BZDs in the older population occurs frequently in the ED, especially to the 65-69-year age group and men. Further attention to potentially unsafe dosing of high-risk medications to older adults in the ED is warranted.

High-versus low-dose erythropoietin in extremely low birth weight infants. The European Multicenter rhEPO Study Group.

PubMed

Maier, R F; Obladen, M; Kattner, E; Natzschka, J; Messer, J; Regazzoni, B M; Speer, C P; Fellman, V; Grauel, E L; Groneck, P; Wagner, M; Moriette, G; Salle, B L; Verellen, G; Scigalla, P

1998-05-01

To investigate whether a weekly 1500 IU/kg dose of recombinant human erythropoietin (rhEPO) is more effective than a dose of 750 IU/kg/week in preventing anemia and reducing the transfusion need in infants with birth weights less than 1000 gm. In a randomized, double-blind, multicenter trial, 184 infants with birth weights between 500 and 999 gm were treated with either rhEPO 750 (low-dose group) or 1500 IU/kg/week (high-dose group) from day 3 of life until 37 weeks' corrected age. Thirty-two percent of the infants in each group did not receive any transfusion during the treatment period. The total volume of erythrocytes received was similar in each group. The success rate, defined as no transfusion needed and hematocrit value 0.30 L/L or greater, was 27.6% in the low-dose and 29.5% in the high-dose group (p = 0.96). Doubling the rhEPO dose of 750 IU/kg/week is not indicated in infants with birth weights less than 1000 gm.

Equivalent Noise Dose Obtained through Hearing Aids in the Classrooms of Hearing-Impaired Children.

ERIC Educational Resources Information Center

Wilde, Ronald A.

1990-01-01

A commercial noise dose meter was used to estimate the equivalent noise dose received through high-gain hearing aids worn in four classrooms in a school for deaf children. There were no significant differences among nominal saturation sound pressure level (SSPL) settings, and all SSPL settings produced very high equivalent noise doses. (Author/JDD)

High-dose Carboplatin/Etoposide/Melphalan increases risk of thrombotic microangiopathy and organ injury after autologous stem cell transplantation in patients with neuroblastoma.

PubMed

Jodele, Sonata; Dandoy, Christopher E; Myers, Kasiani; Wallace, Gregory; Lane, Adam; Teusink-Cross, Ashley; Weiss, Brian; Davies, Stella M

2018-04-19

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant that can result in multi-organ failure (MOF). Patients undergoing high-dose chemotherapy with autologous stem cell transplant (aHCT) for neuroblastoma require good organ function to receive post-transplant radiation and immunotherapy. We examined TA-TMA incidence and transplant outcomes in patients with neuroblastoma receiving different transplant preparative regimens. Sixty patients underwent aHCT using high-dose chemotherapy: 41 patients received carboplatin/etoposide/melphalan (CEM), 13 patients busulfan/melphalan (Bu/Mel) and six patients received tandem transplant (cyclophosphamide/thiotepa and CEM). TA-TMA with MOF was diagnosed in 13 patients (21.7%) at a median of 18 days after aHCT. TA-TMA occurred in 12 patients receiving CEM and in 1 after cyclophosphamide/thiotepa. There were no incidences of TA-TMA after Bu/Mel regimen. Six of 13 patients with TA-TMA and MOF received terminal complement blocker eculizumab for therapy. They all recovered organ function and received planned post-transplant therapy. Out of seven patients who did not get eculizumab, two died from TA-TMA complications and four progressed to ESRD. We conclude that the CEM regimen is associated with a high incidence of clinically significant TA-TMA after aHCT and eculizumab can be safe and effective treatment option to remediate TA-TMA associated MOF.

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.

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.

Timeliness and risk factors associated with delay for pneumococcal conjugate 10-valent routine immunization in Brazilian children.

PubMed

Sartori, Ana Lucia; Minamisava, Ruth; Afonso, Eliane Terezinha; Policena, Gabriela Moreira; Pessoni, Grécia Carolina; Bierrenbach, Ana Luiza; Andrade, Ana Lucia

2017-02-15

Vaccination coverage is the usual metrics to evaluate the immunization programs performance. For the 10-valent pneumococcal conjugate (PCV10) vaccine, measuring the delay of vaccination is also important, particularly as younger children are at increased risk of disease. Routinely collected administrative data was used to assess the timeliness of PCV10 vaccination, and the factors associated with delay to receive the first and second doses, and the completion of the PCV10 3+1 schedule. A population-based retrospective cohort study was conducted with children born in 2012 in Central Brazil. Children who received the PCV10 first dose in public health services were followed-up until 23months of age. Timeliness of receiving each PCV10 dose at any given age was defined as receiving the dose within 28days grace period from the recommended age by the National Immunization Program. Log-binomial regression models were used to examine risk factors for delays of the first dose and the completion PCV10 3+1 schedule. In total, 14,282 children were included in the cohort of study. Delayed vaccination occurred in 9.4%, 23.8%, 36.8% and 39.9% children for the first, second, third and the booster doses, respectively. A total of 1912 children (12.8% of the cohort) were not adequately vaccinated at the 6months of life; 1,071 (7%) received the second dose after 6months of age, 784 (5.4%) did not receive the second dose, and 57 (0.4%) received the first dose after six months of life. A considerable delay was found in PCV10 third and booster doses. Almost 2 thousand children had not received the recommended PCV10 doses at 6months of age. Timeliness of vaccination is an issue in Brazil although high vaccination coverages. Copyright © 2017 Elsevier Ltd. All rights reserved.

Post-trial apomorphine at an autoreceptor dose level can eliminate apomorphine conditioning and sensitization: support for the critical role of dopamine in re-consolidation.

PubMed

Carrera, Marinete Pinheiro; Carey, Robert J; Cruz Dias, Flávia Regina; dos Santos Sampaio, Maria de Fátima; de Matos, Liana Wermelinger

2013-01-01

Re-exposure to conditioned drug stimuli triggers re-consolidation processes. In the present study post-trial apomorphine treatments were administered in order to interact with the re-consolidation of an apomorphine conditioned/sensitized locomotor response. A low (0.05 mg/kg) and a high (2.0mg/kg) dose were used to inhibit or to enhance dopamine activity, respectively. Initially, groups received 5 daily apomorphine (2.0mg/kg)/vehicle treatments either paired or unpaired to open-field placement. The paired treatments generated a progressive locomotor response. Subsequently, all groups received a 5 min non-drug test for conditioning and a conditioned locomotor response was observed in the paired group. The groups received another apomorphine (2.0mg/kg)/vehicle treatment as a re-induction treatment. At this stage the post-trial protocol was initiated. One set of paired, unpaired and vehicle groups were given a low dose of apomorphine (0.05 mg/kg) post-trial; another set received a high dose of apomorphine (2.0mg/kg) post-trial. The remaining group set received vehicle post-trial. The low dose post-trial treatment eliminated the conditioned and sensitized locomotor response and the high dose post-trial treatment enhanced the conditioned and sensitized locomotor response. The efficacy of the post-trial apomorphine treatments to modify the conditioned and the sensitized response after a brief non-drug exposure to test cues supports the proposition that exteroceptive cues control conditioning and sensitization and that the interoceptive drug cues make little or no associational contribution to apomorphine conditioning and sensitization. In addition, the findings point to the importance of dopamine activation in both the acquisition and re-consolidation of conditioning processes. Copyright © 2012 Elsevier B.V. All rights reserved.

Analysis of Dose at the Site of Second Tumor Formation After Radiotherapy to the Central Nervous System

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

Galloway, Thomas J.; University of Florida Proton Therapy Institute, Jacksonville, FL; Indelicato, Daniel J., E-mail: dindelicato@floridaproton.org

Purpose: Second tumors are an uncommon complication of multimodality treatment of childhood cancer. The present analysis attempted to correlate the dose received as a component of primary treatment and the site of the eventual development of a second tumor. Methods and Materials: We retrospectively identified 16 patients who had received radiotherapy to sites in the craniospinal axis and subsequently developed a second tumor. We compared the historical fields and port films of the primary treatment with the modern imaging of the second tumor locations. We classified the location of the second tumors as follows: in the boost field; marginal tomore » the boost field, but in a whole-brain field; in a whole-brain field; marginal to the whole brain/primary treatment field; and distant to the field. We divided the dose received into 3 broad categories: high dose (>45 Gy), moderate dose (20-36 Gy), and low dose (<20 Gy). Results: The most common location of the second tumor was in the whole brain field (57%) and in the moderate-dose range (81%). Conclusions: Our data contradict previous publications that suggested that most second tumors develop in tissues that receive a low radiation dose. Almost all the second tumors in our series occurred in tissue within a target volume in the cranium that had received a moderate dose (20-36 Gy). These findings suggest that a major decrease in the brain volume that receives a moderate radiation dose is the only way to substantially decrease the second tumor rate after central nervous system radiotherapy.« less

In vitro dermal absorption of di(2-ethylhexyl) adipate (DEHA) in a roll-on deodorant using human skin.

PubMed

Zhou, Simon Ningsun; Moody, Richard P; Aikawa, Bio; Yip, Anna; Wang, Bing; Zhu, Jiping

2013-01-01

In vitro dermal absorption experiments were conducted using a roll-on deodorant that contains 1.56% di(2-ethylhexyl) adipate (DEHA), a plasticizer widely used in consumer products. Human skin specimens were fitted in Bronaugh flow-through Teflon diffusion cells. The diffusion cells were maintained at 32 °C to reflect the skin temperature. Two amounts (low dose: 5 mg of the product; high dose: 100 mg) were applied, in triplicate, each on four different human skins. DEHA was determined in the receiver solution at 6-h intervals, using headspace solid-phase microextraction gas chromatography-mass spectrometry (GC-MS). After 24 h, the experiment was terminated and masses of DEHA in the skin depot, skin wash, and upper and lower chambers of the diffusion cell were determined. A significant portion of applied DEHA, 28% in the low amount application and 34% in the high one, was found in the skin depot. In comparison, only 0.04% and 0.002% of applied DEHA were found in the receiver solutions for the low and high doses, respectively. Under our experimental conditions, an apparent steady-state flux of low DEHA mass penetrating from skin into the receiver solution was observed with a penetration rate of 2.2 ng/cm(2)/h for both the low and high doses. The average mass recovery was 81% for the low dose application and 56% for the high dose.

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.

Anticoagulation and high dose liver radiation. A preliminary report

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

Lightdale, C.J.; Wasser, J.; Coleman, M.

Two groups of patients were observed for evidence of acute radiation hepatitis during high dose radiation to the liver. The first group of 18 patients with metastatic liver disease received an average of 4,050 rad to the whole liver. Half received anticoagulation with warfarin. One patient on anticoagulation developed evidence of acute radiation hepatitis while 2 patients did so without anticoagulation. Eleven patients with Hodgkin's disease received 4,000 rad to the left lobe of the liver during extended field radiation. Four of these 11 patients were anticoagulated to therapeutic range. Only one of the fully anticoagulated patients showed changes onmore » liver scan consistent with radiation hepatitis whereas three did so without anticoagulation. No serious sequelae from anticoagulation occurred in either group. These preliminary data suggest that anticoagulation may be safely administered with high dose hepatic radiation and that further trials with anticoagulation are warranted.« less

A prospective randomized study of the efficacy and cost-effectiveness of high and low dose regimens of I-131 treatment in hyperthyroidism.

PubMed

Pusuwan, Pawana; Tuntawiroon, Malulee; Sritongkul, Nopamol; Chaudakshetrin, Pachee; Nopmaneejumruslers, Cherdchai; Komoltri, Chulalak; Thepamongkhol, Kullathorn; Khiewvan, Benjapa; Tuchinda, Pongpija; Sriussadaporn, Sutin

2011-03-01

To compare the efficacy and cost-effectiveness of high and low dose regimens of I-131 treatment in patients with hyperthyroidism. One hundred fifty patients with proven hyperthyroidism were randomly allocated into the high (74 patients) and low (76 patients) dose regimen of I-131 treatment. Four patients of the high dose group and one patient of the low dose group were excluded because of lost follow-up. A gland-specific dosage was calculated on the estimated weight of thyroid gland and 24-hour I-131 uptake. The high and low I-131 dose regimens were 150 microCi/gm and 100 microCi/gm, respectively. The first mean radioiodine activity administered to the high and low dose group was 10.2 and 8 mCi, respectively. Repeated treatment was given to 25 patients of the high dose group and 40 patients of the low dose group. Clinical outcome and calculated costs for outpatient attendances, and laboratory tests together with initial and subsequent treatments were evaluated for one year after I-131 treatment. Elimination of hyperthyroidism that resulted in either euthyroidism or hypothyroidism was classified as therapeutic success. The cost effectiveness was also compared. At 6 months after treatment, 45 (64.3%) patients receiving high dose and 59 (78.7%) patients receiving low dose were hyperthyroidism. Clinical outcome at one year showed persistence of hyperthyroidism in 21 (30%) patients of the high dose regimen and 36 (48%) patients of the low dose regimen. At one year post treatment, it was demonstrated that the high dose regimen could eliminate hyperthyroidism in a significantly shorter time than the low dose regimen, i.e., 259.6 days and 305.5 days, respectively, p = 0.008). For the persistent hyperthyroid patients, the average total cost of treatment in the low dose group was significantly higher than that of the high dose group, i.e., 13,422.78 baht and 10,942.79 baht, respectively; p = 0.050). A high dose regimen of radioactive iodine treatment is more effective than the low dose regimen. The successful outcome of a high dose regimen occurred significantly earlier than that of the low dose regimen. For the persistent hyperthyroid patients, the average total cost in the low dose group was significantly higher than that of the high dose group.

High dose vitamin D may improve lower urinary tract symptoms in postmenopausal women.

PubMed

Oberg, Johanna; Verelst, Margareta; Jorde, Rolf; Cashman, Kevin; Grimnes, Guri

2017-10-01

Lower urinary tract symptoms (LUTS) are common in postmenopausal women, and have been reported inversely associated with vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) levels. The aim of this study was to investigate if high dose vitamin D supplementation would affect LUTS in comparison to standard dose. In a randomized controlled study including 297 postmenopausal women with low bone mineral density, the participants were allocated to receive capsules of 20 000IU of vitamin D 3 twice a week (high dose group) or similar looking placebo (standard dose group). In addition, all the participants received 1g of calcium and 800IU of vitamin D daily. A validated questionnaire regarding LUTS was filled in at baseline and after 12 months. At baseline, 76 women in the high dose group and 82 in the standard dose group reported any LUTS. Levels of serum 25(OH)D increased significantly more in the high dose group (from 64.7 to 164.1nmol/l compared to from 64.1 to 81.8nmol/l, p<0.01). No differences between the groups were seen regarding change in LUTS except for a statistically significant reduction in the reported severity of urine incontinence in the high dose group as compared to the standard dose group after one year (p<0.05). The results need confirmation in a study specifically designed for this purpose. Copyright © 2017 Elsevier Ltd. All rights reserved.

The role of concomitant methotrexate dosage and maintenance over time in the therapy of rheumatoid arthritis patients treated with adalimumab or etanercept: retrospective analysis of a local registry.

PubMed

Favalli, Ennio Giulio; Becciolini, Andrea; Biggioggero, Martina; Bertoldi, Ilaria; Crotti, Chiara; Raimondo, Maria Gabriella; Marchesoni, Antonio

2018-01-01

To evaluate the pattern of prescription and maintenance over time of concomitant methotrexate (MTX), and its impact on a 2-year clinical response in a cohort of rheumatoid arthritis (RA) patients treated with a first-line tumor necrosis factor alpha inhibitor (TNFi). The study population included all RA patients receiving adalimumab or etanercept a as first-line biologic drug, extracted from a local registry. Enrolled patients were stratified into 3 subgroups according to baseline concomitant MTX: no MTX, low-dose MTX (≤10 mg/wk), and high-dose MTX (≥12.5 mg/wk). The 2-year persistence of the initial MTX regimen was computed by the Kaplan-Meier method, and a Cox proportional hazard model was developed to examine potential predictors of MTX withdrawal/change of dosage. European League Against Rheumatism remission and good-to-moderate response were evaluated according to baseline MTX regimen and MTX maintenance over time. A total of 330 patients (163 treated with adalimumab and 167 with etanercept) were included; 141 were prescribed TNFi without MTX and 112 received low-dose and 77 high-dose concomitant MTX. Male sex, younger age, and shorter mean disease duration were predictors of high-dose MTX use. Among MTX users (76.2% parenteral and 23.8% oral), initial MTX dose persisted over time in 79.9% at 1 year and 70.2% at 2 years. Fifty-one patients (27%) underwent MTX dose de-escalation/discontinuation because of intolerance/adverse events. The 2-year EULAR remission rate was higher in the patients receiving and maintaining high-dose MTX than in those receiving low-dose or no MTX (46.2% vs 29.5% and 23.4%, respectively; p =0.009). The same was true for good-to-moderate response rate (71.2% vs 52.6% and 50.4%, respectively; p =0.031). In a real-life setting, about one-third of RA patients treated with TNFis experienced dose reduction/discontinuation of concomitant MTX because of intolerance/adverse events over a 2-year follow-up period. Initial high-dose MTX and its maintenance over time are associated with better 2-year clinical response.

Severe palmar-plantar erythrodysesthesia and aplasia in an adult undergoing re-induction treatment with high-dose cytarabine for acute myelogenous leukemia: a possible drug interaction between posaconazole and cytarabine.

PubMed

Alzghari, Saeed K; Seago, Susan E; Cable, Christian T; Herrington, Jon D

2017-09-01

High-dose cytarabine is recommended for re-induction chemotherapy in patients less than 60 years of age with acute myelogenous leukemia. This case describes a patient receiving high-dose cytarabine for re-induction and subsequently developed tingling and numbness in her hands and feet followed by severe pain, swelling, and erythema consistent with a diagnosis of palmar-plantar erythrodysesthesia. Furthermore, the patient's hemoglobin, platelets, and neutrophils did not recover after over 30 days post high-dose cytarabine. The patient was concurrently receiving posaconazole for fungal prophylaxis which was initiated after the induction therapy. We speculate that posaconazole may inhibit the cytarabine efflux through P-glycoprotein inhibition leading to the patient's palmar-plantar erythrodysesthesia and subsequent aplasia. Future pharmacokinetic studies need to be conducted to ascertain if posaconazole does influence the pharmacokinetics of cytarabine.

The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial.

PubMed

Huttner, Angela; Dayer, Julie-Anne; Yerly, Sabine; Combescure, Christophe; Auderset, Floriane; Desmeules, Jules; Eickmann, Markus; Finckh, Axel; Goncalves, Ana Rita; Hooper, Jay W; Kaya, Gürkan; Krähling, Verena; Kwilas, Steve; Lemaître, Barbara; Matthey, Alain; Silvera, Peter; Becker, Stephan; Fast, Patricia E; Moorthy, Vasee; Kieny, Marie Paule; Kaiser, Laurent; Siegrist, Claire-Anne

2015-10-01

Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×10(7) pfu (n=35) or 5 × 10(7) pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold. The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18-65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 × 10(5) pfu or placebo, whereas deployable participants received single-injection 3 × 10(5) pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 10(7) or 5 × 10(7) pfu, 56 participants were given a lower dose (3 × 10(5) pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov, number NCT02287480. Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 × 10(5) pfu) or placebo in a double-blind fashion, whereas 13 deployable participants received 3 × 10(5) pfu open-label. Altogether, in the low-dose group, 51 participants received rVSV-ZEBOV and five received placebo. No serious adverse events occurred. At 3 × 10(5) pfu, early-onset reactogenicity remained frequent (45 [88%] of 51 compared with 50 [98%] of 51 high dose and two [15%] of 13 placebo recipients), but mild. Objective fever was present in one (2%) of 51 low-dose versus 13 (25%) of 51 high-dose vaccinees receiving at least 1 ×10(7) pfu (p<0·0001). Subjective fever (p<0·0001), myalgia (p=0·036), and chills (p=0·026) were significantly reduced and their time of onset delayed, reflecting significantly lower viraemia (p<0·0001) and blood monocyte-activation patterns (p=0·0233). Although seropositivity rates remained similarly high (48 [94%] of 51), day-28 EBOV-glycoprotein-binding and neutralising antibody titres were lower in low-dose versus high-dose vaccinees (geometric mean titres 344·5 [95% CI 229·7-516·4] vs 1064·2 [757·6-1495·1]; p<0·0001; and 35·1 [24·7-50·7] vs 127·0 [86·0-187·6]; p<0·0001, respectively). Furthermore, oligoarthritis again occurred on day 10 (median; IQR 9-14) in 13 (25%) of 51 low-dose vaccinees, with maculopapular, vesicular dermatitis, or both in seven (54%) of 13; arthritis was associated with increasing age in low-dose but not high-dose vaccinees. Two vaccinees presented with purpura of the lower legs; histological findings indicated cutaneous vasculitis. The presence of rVSV in synovial fluid and skin lesions confirmed causality. Reducing the dose of rVSV-ZEBOV improved its early tolerability but lowered antibody responses and did not prevent vaccine-induced arthritis, dermatitis, or vasculitis. Like its efficacy, the safety of rVSV-ZEBOV requires further definition in the target populations of Africa. Wellcome Trust through WHO. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dose-Response Relationship between Radiation Dose and Loco-regional Control in Patients with Stage II-III Esophageal Cancer Treated with Definitive Chemoradiotherapy.

PubMed

Kim, Hyun Ju; Suh, Yang-Gun; Lee, Yong Chan; Lee, Sang Kil; Shin, Sung Kwan; Cho, Byung Chul; Lee, Chang Geol

2017-07-01

The correlation between radiation dose and loco-regional control (LRC) was evaluated in patients with stage II-III esophageal cancer treated with definitive concurrent chemoradiotherapy (CRT). Medical records of 236 stage II-III esophageal cancer patients treated with definitive CRT at Yonsei Cancer Center between 1994 and 2013 were retrospectively reviewed. Among these, 120 received a radiation dose of < 60 Gy (standard-dose group), while 116 received ≥ 60 Gy (high-dose group). The median doses of radiation in the standard- and high-dose groups were 50.4 and 63 Gy, respectively. Concurrent 5-fluorouracil/cisplatin chemotherapy was administered to most patients. There were no differences in patient characteristics between the two groups except for high Karnofsky performance status and lower-thoracic lesions being more prevalent in the standard-dose group. The median progression-free survival (PFS) and overall survival (OS) times were 13.2 months and 26.2 months, respectively. Patients in the high-dose group had significantly better 2-year LRC (69.1% vs. 50.3%, p=0.002), median PFS (16.7 months vs. 11.7 months, p=0.029), and median OS (35.1 months vs. 22.3 months, p=0.043). Additionally, LRC exhibited a dose-response relationship and the complete response rate was significantly higher in the high-dose group (p=0.006). There were no significant differences in treatment-related toxicities between the groups. A higher radiation dose (> 60 Gy) is associated with increased LRC, PFS, and OS in patients with stage II-III esophageal cancer treated with definitive CRT.

Cost-effectiveness and public health impact of alternative influenza vaccination strategies in high-risk adults.

PubMed

Raviotta, Jonathan M; Smith, Kenneth J; DePasse, Jay; Brown, Shawn T; Shim, Eunha; Nowalk, Mary Patricia; Wateska, Angela; France, Glenson S; Zimmerman, Richard K

2017-10-09

High-dose trivalent inactivated influenza vaccine (HD-IIV3) or recombinant trivalent influenza vaccine (RIV) may increase influenza vaccine effectiveness (VE) in adults with conditions that place them at high risk for influenza complications. This analysis models the public health impact and cost-effectiveness (CE) of these vaccines for 50-64year-olds. Markov model CE analysis compared 5 strategies in 50-64year-olds: no vaccination; only standard-dose IIV3 offered (SD-IIV3 only), only quadrivalent influenza vaccine offered (SD-IIV4 only); high-risk patients receiving HD-IIV3, others receiving SD-IIV3 (HD-IIV3 & SD-IIV3); and high-risk patients receiving HD-IIV3, others receiving SD-IIV4 (HD-IIV3 & SD-IIV4). In a secondary analysis, RIV replaced HD-IIV3. Parameters were obtained from U.S. databases, the medical literature and extrapolations from VE estimates. Effectiveness was measured as 3%/year discounted quality adjusted life year (QALY) losses avoided. The least expensive strategy was SD-IIV3 only, with total costs of $99.84/person. The SD-IIV4 only strategy cost an additional $0.91/person, or $37,700/QALY gained. The HD-IIV3 & SD-IIV4 strategy cost $1.06 more than SD-IIV4 only, or $71,500/QALY gained. No vaccination and HD-IIV3 & SD-IIV3 strategies were dominated. Results were sensitive to influenza incidence, vaccine cost, standard-dose VE in the entire population and high-dose VE in high-risk patients. The CE of RIV for high-risk patients was dependent on as yet unknown parameter values. Based on available data, using high-dose influenza vaccine or RIV in middle-aged, high-risk patients may be an economically favorable vaccination strategy with public health benefits. Clinical trials of these vaccines in this population may be warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

PubMed

Iversen, Ole-Erik; Miranda, Maria Jose; Ulied, Angels; Soerdal, Terje; Lazarus, Erica; Chokephaibulkit, Kulkanya; Block, Stan L; Skrivanek, Ales; Nur Azurah, Abdul Ghani; Fong, Siew Moy; Dvorak, Vladimir; Kim, Kyung-Hyo; Cestero, Ramon M; Berkovitch, Matitiahu; Ceyhan, Mehmet; Ellison, Misoo C; Ritter, Michael A; Yuan, Shuai S; DiNubile, Mark J; Saah, Alfred J; Luxembourg, Alain

2016-12-13

Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. clinicaltrials.gov Identifier: NCT01984697.

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

Stomach Cancer Risk After Treatment for Hodgkin Lymphoma

PubMed Central

Morton, Lindsay M.; Dores, Graça M.; Curtis, Rochelle E.; Lynch, Charles F.; Stovall, Marilyn; Hall, Per; Gilbert, Ethel S.; Hodgson, David C.; Storm, Hans H.; Johannesen, Tom Børge; Smith, Susan A.; Weathers, Rita E.; Andersson, Michael; Fossa, Sophie D.; Hauptmann, Michael; Holowaty, Eric J.; Joensuu, Heikki; Kaijser, Magnus; Kleinerman, Ruth A.; Langmark, Frøydis; Pukkala, Eero; Vaalavirta, Leila; van den Belt-Dusebout, Alexandra W.; Fraumeni, Joseph F.; Travis, Lois B.; Aleman, Berthe M.; van Leeuwen, Flora E.

2013-01-01

Purpose Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear. Patients and Methods We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location. Results Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m2) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m2 (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m2; however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses. Conclusion Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly. PMID:23980092

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

PubMed

Ray, Kausik K; Landmesser, Ulf; Leiter, Lawrence A; Kallend, David; Dufour, Robert; Karakas, Mahir; Hall, Tim; Troquay, Roland P T; Turner, Traci; Visseren, Frank L J; Wijngaard, Peter; Wright, R Scott; Kastelein, John J P

2017-04-13

In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).

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.

Aminocaproic Acid (amicar) as an alternative to aprotinin (trasylol) in liver transplantation.

PubMed

Mangus, R S; Kinsella, S B; Fridell, J A; Kubal, C A; Lahsaei, P; Mark, L O; Tector, A J

2014-06-01

This study compared clinical outcomes for a large number of liver transplant patients receiving intraoperative epsilon-aminocaproic acid (EACA), aprotinin, or no antifibrinolytic agent over an 8-year period. Records for deceased donor liver transplants were reviewed. Data included antifibrinolytic agent, blood loss, early graft function, and postoperative complications. Study groups included low-dose aprotinin, high-dose aprotinin, EACA (25 mg/kg, 1-hour infusion), or no antifibrinolytic agent. Data were included for 1170 consecutive transplants. Groups included low-dose aprotinin (n = 324 [28%]), high-dose aprotinin (n = 308 [26%]), EACA (n = 216 [18%]), or no antifibrinolytic (n = 322 [28%]). EACA had the lowest intraoperative blood loss and required the fewest transfusions of plasma. Patients receiving no agent required the most blood transfusions. Early graft loss was lowest in the EACA group, and 90-day and 1-year patient survival rates were significantly higher for the low-dose aprotinin and EACA groups according to Cox regression. Complications were similar, but there were more episodes of deep vein thrombosis in patients receiving EACA. These results suggest that transitioning from aprotinin to EACA did not result in worse outcomes. In addition to decreased intraoperative blood loss, a trend toward improved graft and patient survival was seen in patients receiving EACA. Copyright © 2014 Elsevier Inc. All rights reserved.

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

Radiation bronchitis and stenosis secondary to high dose rate endobronchial irradiation

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

Speiser, B.L.; Spratling, L.

The purpose of the study was to describe a new clinical entity observed in follow-up bronchoscopies in patients who were treated with high dose rate and medium dose rate remote afterloading brachytherapy of the tracheobronchial tree. Patients were treated by protocol with medium dose rate, 47 patients receiving 1000 cGy at a 5 mm depth times three fractions, high dose rate 144 patients receiving 1000 cGy at a 10 mm depth for three fractions and high dose rate 151 patients receiving cGy at a 10 mm depth for three fractions followed by bronchoscopy. Incidence of this entity was 9% formore » the first group, 12% for the second, and 13% for the third group. Reactions were grade 1 consisting of mild inflammatory response with a partial whitish circumferential membrane in an asymptomatic patient; grade 2, thicker complete white circumferential membrane with cough and/or obstructive problems requiring intervention; grade 3, severe inflammatory response with marked membranous exudate and mild fibrotic reaction; and grade 4 a predominant fibrotic reaction with progressive stenosis. Variables associated with a slightly increased incidence of radiation bronchitis and stenosis included: large cell carcinoma histology, curative intent, prior laser photoresection, and/or concurrent external radiation. Survival was the strongest predictor of the reaction. Radiation bronchitis and stenosis is a new clinical entity that must be identified in bronchial brachytherapy patients and treated appropriately. 23 refs., 3 figs., 7 tabs.« less

Cryopreservation of ovarian tissue for fertility preservation in a large cohort of young girls: focus on pubertal development.

PubMed

Jensen, A K; Rechnitzer, C; Macklon, K T; Ifversen, M R S; Birkebæk, N; Clausen, N; Sørensen, K; Fedder, J; Ernst, E; Andersen, C Yding

2017-01-01

Is there an association between the need for medical puberty induction and the diagnosis or treatment received in girls who have undergone cryopreservation of ovarian tissue for fertility preservation? There was a clear association between the intensity of treatment received and requirement for medical puberty induction but no association with the diagnosis. Although it cannot be predicted which girls will become infertile or develop premature ovarian insufficiency (POI) following intensive chemotherapy or irradiation, patients who are at high risk of POI should be offered ovarian tissue cryopreservation (OTC). This includes girls who are planned to receive either high doses of alkylating agents, conditioning regimen before stem cell transplantation (SCT), total body irradiation (TBI) or high radiation doses to the craniospinal, abdominal or pelvic area. This is a retrospective cohort study. In total, 176 Danish girls under 18 years of age have had OTC performed over a period of 15 years. An overview of the girls' diagnoses and mean age at OTC as well as the number of deceased is presented. Of the 176 girls, 38 had died and 46 girls were still younger than 12 years so their pubertal development cannot be evaluated yet. For the 60 girls who had OTC performed after 12 years of age, the incidence of POI was evaluated and in the group of 32 girls who were younger than 12 years at OTC, the association between the diagnosis and received treatment and the requirement for medical puberty induction was examined. The need for medical puberty induction was assessed in 32 girls who were prepubertal at the time of OTC. Indications for OTC were allogeneic SCT for leukaemia, myelodysplastic syndrome or benign haematological disorders, autologous SCT for lymphoma or sarcoma, and irradiation to the pelvis or to the spinal axis. The mean age at OTC of the 176 girls were 11.3 years. The two most prevalent diagnoses of the 176 girls were malignant tumours and malignant haematological diseases. Among the 32 prepubertal girls, 12 received high dose chemotherapy and either TBI prior to SCT or irradiation to the pelvis, abdomen or the spinal axis, 13 received high dose alkylating agents but no irradiation prior to SCT, six received alkylating agents as part of conventional chemotherapy and one patient had a genetic metabolic disorder and did not receive gonadotoxic treatment. Among these 32 girls, 23 did not undergo puberty spontaneously and thus received medical puberty induction. Among the nine girls, who went through spontaneous puberty, four had received high dose alkylating agents and five had received conventional chemotherapy. All information was retrieved retrospectively from patient records, and thus some information was not available. OTC should be recommended to all young girls, who present a high risk of developing ovarian insufficiency and/or infertility following high dose chemotherapy and/or irradiation. The Childhood Cancer Foundation (2012-2016) and the EU interregional project ReproHigh are thanked for having funded this study. They had no role in the study design, collection and analysis of the data or writing of the report. The authors have no conflict of interest to disclose. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Evaluation of growth hormone treatment efficacy in short Japanese children born small for gestational age: Five-year treatment outcome and impact on puberty

PubMed Central

Horikawa, Reiko; Tanaka, Toshiaki; Nishinaga, Hiromi; Ogawa, Yoshihisa; Yokoya, Susumu

2017-01-01

Abstract. Some children born small for gestational age (SGA) have short stature and are at an increased risk of developing psychosocial or behavioral problems. Here we evaluated the efficacy of GH and its effects on the timing of pubertal onset in a 3-yr extension of our previous 2-yr (total 5 yr) multicenter, randomized, double-blind, parallel-group clinical trial of 65 short Japanese children born SGA. Patients received low or high doses of GH (0.033 or 0.067 mg/kg/day, respectively). Age at onset of puberty was not statistically different for male and female patients receiving high- or low-dose GH. After the onset of puberty, no difference in height gain was observed between the two GH dose groups. At the onset of puberty, height standard deviation scores for chronological age of boys and girls improved significantly in both dose groups with evidence of a dose-response effect. Mean bone age/chronological age ratios in the low- and high-dose groups were significantly increased compared with baseline, being significantly greater in the high-dose group at 5 yr after treatment initiation. Delayed bone age at baseline was close to chronological age following GH treatment. GH treatment, especially high-dose GH, induced advanced bone age in short children born SGA. PMID:28458458

Using a treatment diary to improve the medication adherence in patients with chronic myeloid leukaemia.

PubMed

Santoleri, Fiorenzo; Lasala, Ruggero; Logreco, Andrea; Ranucci, Elena; Costantini, Alberto

2018-01-01

Purpose The aim of this study was to verify whether the distribution of a treatment diary by a pharmacist could influence the adherence to oral treatment with imatinib, nilotinib, and dasatinib in patients with chronic myeloid leukaemia. Methods The level of adherence was calculated using the received daily dose/prescribed daily dose ratio and compared between patients who used a diary and those who did not. Results Forty-four (35.8%) of 123 patients with chronic myeloid leukaemia completed the diary: 20 (45.4%) receiving imatinib, 17 (38.6%) receiving nilotinib, and seven (15.9%) receiving dasatinib. Treatment adherence with the diary calculated using received daily dose/prescribed daily dose method was 93.6% (imatinib 94.9%, nilotinib 91.1%, and dasatinib 95.8%). Adherence during the period without a diary was 86.5% (84.9, 87.4, and 90%). Adherence was significantly greater with than without a diary (p < 0.0001). Conclusions The findings of this study that, in the case of chronic diseases, direct pharmacist-patient contact is important in order to maintain high levels of adherence, and a treatment diary is a valid means of doing this. According to these data, it is necessary to support similar patient-oriented programmes in order to ensure high levels of adherence and optimize drug management.

Effect of different doses of nandrolone decanoate on lipid peroxidation, DNA fragmentation, sperm abnormality and histopathology of testes of male Wister rats.

PubMed

Mohamed, Hanaa Mahmoud; Mohamed, Manal Abdul-Hamid

2015-01-01

The present study aims of to investigate the effects of low and high doses of nandrolone decanoate (ND) on histopathology and apoptosis of the spermatogenic cells as well as lipid peroxidation, antioxidant enzyme activities, sperm abnormality and DNA fragmentation. Eighteen animals were divided into three groups each group contain six animals. The rats were divided into three groups as following: Group 1 was administered saline (control). Group 2, received nandrolone decanoate (3 mg/kg/weekly) (low dose) with intramuscular injection. Group 3, received intramuscular injection dose of nandrolone decanoate (10 mg/kg/weekly) (high dose). After 8 weeks, caspase-3 assay was used to determine the apoptotic cells. The sperm parameters, lipid peroxidation, antioxidant enzyme activities and testosterone concentration were also investigated in the experimental groups of both low and high dose compared to the control groups. Treated group with high dose showed degenerated germinal epithelial cells sloughed in the lumina of seminiferous tubules, where almost seminiferous tubules were devoid of spermatids and spermatozoa compared to control and group treated with low dose. Also, a significant increase of lipid peroxidation levels and heat shock proteins was observed in two groups administrated with two different doses of ND while, antioxidant enzyme activities, and testosterone concentration was significantly decreased in two treated group when compared with control. Administration of ND at high and low doses leads to deteriorated sperm parameters, DNA fragmentation and testicular apoptosis. In conclusion, the administration ND at high doses more effective on lipid peroxidation, antioxidant enzyme activities, sperm abnormality, histopathology, apoptotic and DNA changes compared to low dose group and to control group. Published by Elsevier GmbH.

High-dose versus standard-dose radiotherapy with concurrent chemotherapy in stages II-III esophageal cancer.

PubMed

Suh, Yang-Gun; Lee, Ik Jae; Koom, Wong Sub; Cha, Jihye; Lee, Jong Young; Kim, Soo Kon; Lee, Chang Geol

2014-06-01

In this study, we investigated the effects of radiotherapy ≥60 Gy in the setting of concurrent chemo-radiotherapy for treating patients with Stages II-III esophageal cancer. A total of 126 patients treated with 5-fluorouracilbased concurrent chemo-radiotherapy between January 1998 and February 2008 were retrospectively reviewed. Among these patients, 49 received a total radiation dose of <60 Gy (standard-dose group), while 77 received a total radiation dose of ≥60 Gy (high-dose group). The median doses in the standard- and high-dose groups were 54 Gy (range, 45-59.4 Gy) and 63 Gy (range, 60-81 Gy), respectively. The high-dose group showed significantly improved locoregional control (2-year locoregional control rate, 69 versus 32%, P < 0.01) and progression-free survival (2-year progression-free survival, 47 versus 20%, P = 0.01) than the standard-dose group. Median overall survival in the high- and the standard-dose groups was 28 and 18 months, respectively (P = 0.26). In multivariate analysis, 60 Gy or higher radiotherapy was a significant prognostic factor for improved locoregional control, progression-free survival and overall survival. No significant differences were found in frequencies of late radiation pneumonitis, post-treatment esophageal stricture or treatment-related mortality between the two groups. High-dose radiotherapy of 60 Gy or higher with concurrent chemotherapy improved locoregional control and progression-free survival without a significant increase of in treatment-related toxicity in patients with Stages II-III esophageal cancer. Our study could provide the basis for future randomized clinical trials. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Evaluation of aprepitant for acute chemotherapy-induced nausea and vomiting in children and adolescents with acute lymphoblastic leukemia receiving high-dose methotrexate.

PubMed

Felix-Ukwu, Femi; Reichert, Kate; Bernhardt, M Brooke; Schafer, Eric S; Berger, Amanda

2018-02-01

Chemotherapy-induced nausea and vomiting (CINV) negatively impacts patients' quality of life. The emetogenicity of high-dose methotrexate in children and adolescents with cancer is incompletely characterized. At our institution, a number of patients with acute lymphoblastic leukemia (ALL) have received aprepitant with courses of high-dose methotrexate after poor CINV control with prior courses. We conducted a retrospective cohort analysis on patients with ALL who received methotrexate 5 g/m 2 /dose with and without concomitant aprepitant at Texas. Children's Hospital between October 1, 2010 and January 31, 2016. We identified 16 patients who received a total of 69 courses of methotrexate. An enhanced antiemetic regimen containing aprepitant was administered with 42 methotrexate courses and resulted in a 54% reduction in the use of as-needed antiemetics (P = 0.002, 95% CI: 21-89%). There were no statistically significant differences in methotrexate area under the curve values (2,209 μM⋅hr/l ± 151 vs. 2,051 μM⋅hr/l ± 94, P = 0.355) or end-infusion methotrexate concentrations (80.5 μM ± 5.6 vs. 74.7 μM ± 3.2, P = 0.335) in patients receiving a standard versus an enhanced antiemetic regimen. The addition of aprepitant reduces both CINV and the use of rescue antiemetics. Aprepitant does not appear to affect the pharmacokinetics of methotrexate. Granisetron was prescribed more frequently than ondansetron, but selection of secondary and tertiary agents, if any, was highly variable. © 2017 Wiley Periodicals, Inc.

Normal tissue complication probability (NTCP) modelling using spatial dose metrics and machine learning methods for severe acute oral mucositis resulting from head and neck radiotherapy.

PubMed

Dean, Jamie A; Wong, Kee H; Welsh, Liam C; Jones, Ann-Britt; Schick, Ulrike; Newbold, Kate L; Bhide, Shreerang A; Harrington, Kevin J; Nutting, Christopher M; Gulliford, Sarah L

2016-07-01

Severe acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning. Predictive models of severe acute mucositis were generated using radiotherapy dose (dose-volume and spatial dose metrics) and clinical data. Penalised logistic regression, support vector classification and random forest classification (RFC) models were generated and compared. Internal validation was performed (with 100-iteration cross-validation), using multiple metrics, including area under the receiver operating characteristic curve (AUC) and calibration slope, to assess performance. Associations between covariates and severe mucositis were explored using the models. The dose-volume-based models (standard) performed equally to those incorporating spatial information. Discrimination was similar between models, but the RFCstandard had the best calibration. The mean AUC and calibration slope for this model were 0.71 (s.d.=0.09) and 3.9 (s.d.=2.2), respectively. The volumes of oral cavity receiving intermediate and high doses were associated with severe mucositis. The RFCstandard model performance is modest-to-good, but should be improved, and requires external validation. Reducing the volumes of oral cavity receiving intermediate and high doses may reduce mucositis incidence. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.

Dose escalation of definitive radiation is not associated with improved survival for cervical esophageal cancer: a National Cancer Data Base (NCDB) analysis.

PubMed

De, B; Rhome, R; Doucette, J; Buckstein, M

2017-04-01

For cervical esophageal cancer (CEC), National Comprehensive Cancer Network guidelines support RT to 50-50.4 Gy with chemotherapy but acknowledge higher doses may be appropriate. This study uses the National Cancer Database (NCDB) to characterize RT practices and identify if a dose-response relationship exists for overall survival (OS) for definitive treatment of CEC. We queried the NCDB for patients diagnosed with Stage I-III CEC from 2004 to 2013, and selected patients receiving definitive RT with doses between 50 and 74 Gy. Using multivariate logistic regression, the database was analyzed to determine factors associated with use of RT > 50.4 Gy. Patients were then stratified into three dose categories. Predictors of OS were analyzed with univariate and multivariate methods using the Kaplan-Meier curves, the log-rank test, and the Cox proportional hazards analysis. We stratified 789 patients with CEC who were treated with definitive radiation ± chemotherapy: 50-50.4 Gy ('standard'), >50.4 and <66 Gy ('medium'), and 66-74 Gy ('high'). Of these patients, 215 (27%) received standard doses, 375 (48%) received medium doses, and 199 (25%) received high doses. Patients with Medicaid insurance and those with Stage II disease were less likely (P < 0.05) to receive >50.4 Gy. Sex, histology, distance to treatment facility, and academic/community facility type were not significantly associated with receipt of >50.4 Gy. There was no association between dose and OS for the medium or high groups when using univariate analysis or analysis adjusted for demographic, facility, and clinical attributes. Stage III disease and the Charlson-Deyo scores of 1 or 2 were associated with higher mortality (P < 0.05), while female sex and use of chemotherapy were associated with lower mortality (P < 0.01). Nearly three-fourths of CEC patients in the United States are treated with RT > 50.4 Gy. Higher radiation doses were not associated with increased OS in CEC patients in the NCDB. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study.

PubMed

Boye, Kjetil; Del Prever, Adalberto Brach; Eriksson, Mikael; Saeter, Gunnar; Tienghi, Amelia; Lindholm, Paula; Fagioli, Franca; Skjeldal, Sigmund; Ferrari, Stefano; Hall, Kirsten Sundby

2014-05-01

Patients with metastatic osteosarcoma at diagnosis or axial primary tumors have a poor prognosis. The aim of the study was to evaluate the feasibility and efficacy of intensified treatment with high-dose chemotherapy (HDCT) and stem cell rescue in this group. From May 1996 to August 2004, 71 patients were included in a Scandinavian-Italian single arm phase II study. Preoperative chemotherapy included methotrexate, doxorubicin, cisplatin and ifosfamide, and postoperative treatment consisted of two cycles of doxorubicin, one cycle of cyclophosphamide and etoposide and two courses of high-dose etoposide and carboplatin with stem cell rescue. Twenty-nine patients (43%) received two courses and 10 patients (15%) received one course of HDCT. HDCT was associated with significant toxicity, but no treatment-related deaths were recorded. Fourteen patients (20%) had disease progression before completion of the study protocol, and only 29/71 patients (41%) received the full planned treatment. Median event-free survival (EFS) was 18 months, and estimated 5-year EFS was 27%. Median overall survival (OS) was 34 months, and estimated 5-year OS was 31%. When patients who did not receive HDCT due to disease progression were excluded, there was no difference in EFS (P = 0.72) or OS (P = 0.49) between patients who did or did not receive HDCT. The administration of high-dose chemotherapy with stem cell rescue was feasible, but associated with significant toxicity. Patient outcome seemed comparable to previous studies using conventional chemotherapy. We conclude that HDCT with carboplatin and etoposide should not be further explored as a treatment strategy in high-risk osteosarcoma. © 2013 Wiley Periodicals, Inc.

Low-dose right unilateral electroconvulsive therapy (ECT): effectiveness of the first treatment.

PubMed

Lapidus, Kyle A B; Shin, Joseph S W; Pasculli, Rosa M; Briggs, Mimi C; Popeo, Dennis M; Kellner, Charles H

2013-06-01

Electroconvulsive therapy (ECT) is a widely used, highly effective antidepressant treatment. Except for the most severely ill patients, right unilateral (RUL) electrode placement is the most frequent initial treatment choice. In current practice, RUL ECT is administered at several multiples of seizure threshold (ST) based on reports that lower stimulus intensity results in lower response/remission rates. Many patients, as part of an initial dose titration to determine ST, will receive a single treatment with low-dose RUL ECT and subsequent treatments with a stimulus at a multiple of ST. To assess response to the first ECT. A retrospective analysis of charts from clinical practice at Mount Sinai Medical Center was performed. A single treatment with low-dose (presumably near ST) RUL ECT had a significant and immediate antidepressant effect in our sample of patients with major depression. We determined that this response is similar to that of patients receiving a single initial treatment with high-dose RUL ECT (at a multiple of ST). These data suggest, contrary to commonly held belief, that RUL ECT may be effective at a low stimulus dose. This argues against restimulating at 6 times ST in the initial session, based on the belief that the near-threshold seizure has no antidepressant efficacy. Our findings suggest a need for further investigation of cases in which low-dose RUL ECT may be an effective antidepressant treatment. Further prospective studies, including larger numbers of patients who receive randomized treatment with low- or high-dose RUL with longer follow-up, are indicated.

Relationship between dose of antithyroid drugs and adverse events in pediatric patients with Graves’ disease

PubMed Central

Yasuda, Kie; Miyoshi, Yoko; Tachibana, Makiko; Namba, Noriyuki; Miki, Kazunori; Nakata, Yukiko; Takano, Toru; Ozono, Keiichi

2017-01-01

Abstract. Graves’ disease (GD) accounts for a large proportion of pediatric hyperthyroidism, and the first-line treatment is antithyroid drug (ATD) therapy. Methimazole (MMI) is effective in most patients but is associated with significant adverse events (AEs). We reviewed the medical records of GD patients (n = 56) with onset age of <15 yr and investigated the relationship between MMI dose and AEs. The study population comprised 11 male and 45 female patients and the median age at diagnosis was 11 yr. All patients were initially treated with ATDs. Among the 52 patients initially treated with MMI, 20 received a low dose, and 32 received a high dose of MMI (< 0.7 vs ≥ 0.7 mg/kg/day, respectively). AEs occurred in 20% of the patients in the low-dose MMI group, and in 50% patients in the high-dose MMI group (p = 0.031). A greater variety of AEs was observed in the high-dose group. Neutropenia and rash were observed in both groups. With treatment transition to low-dose MMI according to the Japanese Society for Pediatric Endocrinology guidelines, we expect a decrease in the incidence of AEs in future. However, we should be careful as neutropenia and rash can occur independently of the MMI dose. PMID:28203042

Relationship between dose of antithyroid drugs and adverse events in pediatric patients with Graves' disease.

PubMed

Yasuda, Kie; Miyoshi, Yoko; Tachibana, Makiko; Namba, Noriyuki; Miki, Kazunori; Nakata, Yukiko; Takano, Toru; Ozono, Keiichi

2017-01-01

Graves' disease (GD) accounts for a large proportion of pediatric hyperthyroidism, and the first-line treatment is antithyroid drug (ATD) therapy. Methimazole (MMI) is effective in most patients but is associated with significant adverse events (AEs). We reviewed the medical records of GD patients (n = 56) with onset age of <15 yr and investigated the relationship between MMI dose and AEs. The study population comprised 11 male and 45 female patients and the median age at diagnosis was 11 yr. All patients were initially treated with ATDs. Among the 52 patients initially treated with MMI, 20 received a low dose, and 32 received a high dose of MMI (< 0.7 vs ≥ 0.7 mg/kg/day, respectively). AEs occurred in 20% of the patients in the low-dose MMI group, and in 50% patients in the high-dose MMI group (p = 0.031). A greater variety of AEs was observed in the high-dose group. Neutropenia and rash were observed in both groups. With treatment transition to low-dose MMI according to the Japanese Society for Pediatric Endocrinology guidelines, we expect a decrease in the incidence of AEs in future. However, we should be careful as neutropenia and rash can occur independently of the MMI dose.

Comparative assessment of onion and garlic extracts on endogenous hepatic and renal antioxidant status in rat.

PubMed

Suru, Stephen M; Ugwu, Chidiebere E

2015-07-01

Despite growing claims of functional health benefits in folkloric medicine, the safety of chronic/elevated intakes of onion and garlic cannot be assumed. Therefore, this study assesses oral administration of varied doses of onion and garlic on some biomarkers of hepatic and renal functions in rats. Animals were divided into five groups: control group received vehicle and extract-treated groups received varied doses of onion or garlic extract (0.5 mL and 1.0 mL/100 g bwt/day) for 6 weeks. Both doses of onion caused marked (p<0.05) increase in hepatic and renal levels of glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and marked (p<0.05) decrease in malondialdehyde (MDA). Treatment with low dose of garlic elicited similar trend except in hepatic CAT, renal SOD and GST levels. A high dose of garlic only caused marked (p<0.05) increase in hepatic GST, renal GST, and SOD. Both doses of onion and low dose of garlic significantly (p<0.05) enhanced renal Na+/K+-ATPase activity. Only a high dose of onion caused significant (p<0.05) increase in hepatic aspartate transaminase (AST), alkaline phosphatase (ALP), and decrease in plasma AST activities. These findings suggest antioxidant enhancing capability for both doses of onion and low dose of garlic, while high dose of garlic elicited pro-oxidant conditions.

Estimation of the Dose and Dose Rate Effectiveness Factor

NASA Technical Reports Server (NTRS)

Chappell, L.; Cucinotta, F. A.

2013-01-01

Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

Beneficial effects of low dose Musa paradisiaca on the semen quality of male Wistar rats.

PubMed

Alabi, A S; Omotoso, Gabriel O; Enaibe, B U; Akinola, O B; Tagoe, C N B

2013-03-01

This study aimed at determining the effects of administration of mature green fruits of Musa paradisiaca on the semen quality of adult male Wistar rats. THE ANIMALS USED FOR THE STUDY WERE GROUPED INTO THREE: the control group, given 2 ml of double distilled water, a low dose group given 500 mg/kg/day and a high dose group given 1000 mg/kg/day of the plantain fruits, which was made into flour, and dissolved in 2 ml of double distilled water for easy oral administration. Significant increment in the semen parameters was noticed in animals that received a lower dose of the plantain flour, but those animals who received the high dose had marked and very significant reduction in sperm cell concentration and percentage of morphologically normal spermatozoa. Musa paradisiaca should be consumed in moderate quantities in order to derive its beneficial effects of enhancing male reproductive functions.

Older adults and high-risk medication administration in the emergency department

PubMed Central

Kim, Mitchell; Mitchell, Steven H; Gatewood, Medley; Bennett, Katherine A; Sutton, Paul R; Crawford, Carol A; Bentov, Itay; Damodarasamy, Mamatha; Kaplan, Stephen J; Reed, May J

2017-01-01

Background Older adults are susceptible to adverse effects from opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and benzodiazepines (BZDs). We investigated factors associated with the administration of elevated doses of these medications of interest to older adults (≥65 years old) in the emergency department (ED). Patients and methods ED records were queried for the administration of medications of interest to older adults at two academic medical center EDs over a 6-month period. Frequency of recommended versus elevated (“High doses” were defined as doses that ranged between 1.5 and 3 times higher than the recommended starting doses; “very high doses” were defined as higher than high doses) starting doses of medications, as determined by geriatric pharmacy/medicine guidelines and expert consensus, was compared by age groups (65–69, 70–74, 75–79, 80–84, and ≥85 years), gender, and hospital. Results There were 17896 visits representing 11374 unique patients >65 years of age (55.3% men, 44.7% women). A total of 3394 doses of medications of interest including 1678 high doses and 684 very high doses were administered to 1364 different patients. Administration of elevated doses of medications was more common than that of recommended doses. Focusing on opioids and BZDs, the 65–69-year age group was much more likely to receive very high doses (1481 and 412 doses, respectively) than the ≥85-year age groups (relative risk [RR] 5.52, 95% CI 2.56–11.90), mainly reflecting elevated opioid dosing (RR 8.28, 95% CI 3.69–18.57). Men were more likely than women to receive very high doses (RR 1.47, 95% CI 1.26–1.72), primarily due to BZDs (RR 2.12, 95% CI 2.07–2.16). Conclusion Administration of elevated doses of opioids and BZDs in the older population occurs frequently in the ED, especially to the 65–69-year age group and men. Further attention to potentially unsafe dosing of high-risk medications to older adults in the ED is warranted. PMID:29184448

Comparative evaluation of two-dimensional radiography and three dimensional computed tomography based dose-volume parameters for high-dose-rate intracavitary brachytherapy of cervical cancer: a prospective study.

PubMed

Madan, Renu; Pathy, Sushmita; Subramani, Vellaiyan; Sharma, Seema; Mohanti, Bidhu Kalyan; Chander, Subhash; Thulkar, Sanjay; Kumar, Lalit; Dadhwal, Vatsla

2014-01-01

Dosimetric comparison of two dimensional (2D) radiography and three-dimensional computed tomography (3D-CT) based dose distributions with high-dose-rate (HDR) intracavitry radiotherapy (ICRT) for carcinoma cervix, in terms of target coverage and doses to bladder and rectum. Sixty four sessions of HDR ICRT were performed in 22 patients. External beam radiotherapy to pelvis at a dose of 50 Gray in 27 fractions followed by HDR ICRT, 21 Grays to point A in 3 sessions, one week apart was planned . All patients underwent 2D-orthogonal and 3D-CT simulation for each session. Treatment plans were generated using 2D-orthogonal images and dose prescription was made at point A. 3D plans were generated using 3D-CT images after delineating target volume and organs at risk. Comparative evaluation of 2D and 3D treatment planning was made for each session in terms of target coverage (dose received by 90%, 95% and 100% of the target volume: D90, D95 and D100 respectively) and doses to bladder and rectum: ICRU-38 bladder and rectum point dose in 2D planning and dose to 0.1cc, 1cc, 2cc, 5cc, and 10cc of bladder and rectum in 3D planning. Mean doses received by 100% and 90% of the target volume were 4.24 ± 0.63 and 4.9 ± 0.56 Gy respectively. Doses received by 0.1cc, 1cc and 2cc volume of bladder were 2.88 ± 0.72, 2.5 ± 0.65 and 2.2 ± 0.57 times more than the ICRU bladder reference point. Similarly, doses received by 0.1cc, 1cc and 2cc of rectum were 1.80 ± 0.5, 1.48 ± 0.41 and 1.35 ± 0.37 times higher than ICRU rectal reference point. Dosimetric comparative evaluation of 2D and 3D CT based treatment planning for the same brachytherapy session demonstrates underestimation of OAR doses and overestimation of target coverage in 2D treatment planning.

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

PubMed

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

2013-08-11

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

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

PubMed Central

2013-01-01

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

Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate.

PubMed

Joerger, Markus; Ferreri, Andrés J M; Krähenbühl, Stephan; Schellens, Jan H M; Cerny, Thomas; Zucca, Emanuele; Huitema, Alwin D R

2012-02-01

There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h. A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10,000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX) . These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four. The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C(24) < 0.5 µmol l(-1) up to -35% in patients with MTX C(24) > 12 µmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC(MTX) target between 1000 and 1100 µmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure. A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC(MTX) and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL). © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.

PubMed

Teinturier, C; Hartmann, O; Valteau-Couanet, D; Benhamou, E; Bougneres, P F

1998-11-01

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.

Incidence of Hypoglycemia in Patients With Low eGFR Treated With Insulin and Dextrose for Hyperkalemia.

PubMed

Pierce, Dwayne A; Russell, Greg; Pirkle, James L

2015-12-01

Hyperkalemia is a potentially life-threatening condition that is common in kidney disease patients. Insulin is used to treat hyperkalemia, but may cause hypoglycemia, especially in kidney disease when insulin may be metabolized more slowly. We compared the rates of hypoglycemia in patients with low estimated glomerular filtration rate (eGFR) using high versus low doses of insulin for hyperkalemia to determine if lower doses of insulin would decrease the incidence of hypoglycemia. This was a retrospective study of hospitalized patients receiving intravenous insulin for hyperkalemia during a 6-month period. Patients with low eGFR were analyzed based on how much insulin they received: high dose (10 units, n = 78) versus low dose (5 units, n = 71). Postdose nadir blood glucose values were examined for up to 8 hours after the dose. The percentage of hypoglycemia (blood glucose ≤70 mg/dl) and a subset of severe hypoglycemia (blood glucose <50 mg/dl) were then reported for each dose group. A total of 149 doses were identified in patients with low eGFR. The rates of hypoglycemia were 16.7% and 19.7% (P = 0.79), respectively, among high-dose (n = 78) and low-dose (n = 71) groups. Rates of severe hypoglycemia were 8.9% and 7.0%, respectively (P = 0.90). More than 28% of hypoglycemic episodes with high doses occurred after 4 hours (median = 2.5 hours) compared with 14.3% with low doses (median = 2.38 hours). There was no difference in the rate of hypoglycemia or severe hypoglycemia between high or low doses of insulin in patients with low eGFR. We recommend monitoring up to 6 hours after insulin use in hyperkalemia. © The Author(s) 2015.

The financial impact of increasing home-based high dose haemodialysis and peritoneal dialysis.

PubMed

Liu, Frank Xiaoqing; Treharne, Catrin; Culleton, Bruce; Crowe, Lydia; Arici, Murat

2014-10-02

Evidence suggests that high dose haemodialysis (HD) may be associated with better health outcomes and even cost savings (if conducted at home) versus conventional in-centre HD (ICHD). Home-based regimens such as peritoneal dialysis (PD) are also associated with significant cost reductions and are more convenient for patients. However, the financial impact of increasing the use of high dose HD at home with an increased tariff is uncertain. A budget impact analysis was performed to investigate the financial impact of increasing the proportion of patients receiving home-based dialysis modalities from the perspective of the England National Health Service (NHS) payer. A Markov model was constructed to investigate the 5 year budget impact of increasing the proportion of dialysis patients receiving home-based dialysis, including both high dose HD at home and PD, under the current reimbursement tariff and a hypothetically increased tariff for home HD (£575/week). Five scenarios were compared with the current England dialysis modality distribution (prevalent patients, 14.1% PD, 82.0% ICHD, 3.9% conventional home HD; incident patients, 22.9% PD, 77.1% ICHD) with all increases coming from the ICHD population. Under the current tariff of £456/week, increasing the proportion of dialysis patients receiving high dose HD at home resulted in a saving of £19.6 million. Conducting high dose HD at home under a hypothetical tariff of £575/week was associated with a budget increase (£19.9 million). The costs of high dose HD at home were totally offset by increasing the usage of PD to 20-25%, generating savings of £40.0 million - £94.5 million over 5 years under the increased tariff. Conversely, having all patients treated in-centre resulted in a £172.6 million increase in dialysis costs over 5 years. This analysis shows that performing high dose HD at home could allow the UK healthcare system to capture the clinical and humanistic benefits associated with this therapy while limiting the impact on the dialysis budget. Increasing the usage of PD to 20-25%, the levels observed in 2005-2008, will totally offset the additional costs and generate further savings.

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

High doses of nandrolone decanoate reduce volume of testis and length of seminiferous tubules in rats.

PubMed

Noorafshan, Ali; Karbalay-Doust, Saied; Ardekani, Fakhrodin Mesbah

2005-02-01

Anabolic-androgenic steroid (AAS) compounds rank among the drugs most widely abused with the goal of improving athletic ability, appearance, or muscle mass. It has been shown that these compounds have adverse effects on human and animal physiology and sperm quality, but quantitative structural changes of the testis have received less attention. The present study was conducted to evaluate the effects of nandrolone decanoate, which is one of the AAS compounds, on testis weight and volume, diameter and length of seminiferous tubules in rats by unbiased stereological methods. Adult rats were divided into three groups. The first comprised control rats; the second and third groups received low and high doses of nandrolone decanoate for 14 weeks. The rats were then left untreated for 14 weeks. After removal of the testis, stereological study of these tissues showed that the mean volume of testis and length of the seminiferous tubules in the animals that received high doses of nandrolone decanoate were reduced approximately 32% (p<0.01) and approximately 31% (p<0.04), respectively, in comparison with the control group. It can be concluded that the high doses of nandrolone decanoate produce structural changes in the rat testis that remain 14 weeks after stopping injection of the drug.

Coverage and cost of a large oral cholera vaccination program in a high-risk cholera endemic urban population in Dhaka, Bangladesh.

PubMed

Khan, Iqbal Ansary; Saha, Amit; Chowdhury, Fahima; Khan, Ashraful Islam; Uddin, Md Jasim; Begum, Yasmin A; Riaz, Baizid Khoorshid; Islam, Sanjida; Ali, Mohammad; Luby, Stephen P; Clemens, John D; Cravioto, Alejandro; Qadri, Firdausi

2013-12-09

A feasibility study of an oral cholera vaccine was carried out to test strategies to reach high-risk populations in urban Mirpur, Dhaka, Bangladesh. The study was cluster randomized, with three arms: vaccine, vaccine plus safe water and hand washing practice, and no intervention. High risk people of age one year and above (except pregnant woman) from the two intervention arms received two doses of the oral cholera vaccine, Shanchol™. Vaccination was conducted between 17th February and 16th April 2011, with a minimum interval of fourteen days between two doses. Interpersonal communication preceded vaccination to raise awareness amongst the target population. The number of vaccine doses used, the population vaccinated, left-out, drop out, vaccine wastage and resources required were documented. Fixed outreach site vaccination strategy was adopted as the mode of vaccine delivery. Additionally, mobile vaccination sites and mop-up activities were carried out to reach the target communities. Of the 172,754 target population, 141,839 (82%) and 123,666 (72%) received complete first and second doses of the vaccine, respectively. Dropout rate from the first to the second dose was 13%. Two complete doses were received by 123,661 participants. Vaccine coverage in children was 81%. Coverage was significantly higher in females than in males (77% vs. 66%, P<0.001). Vaccine wastage for delivering the complete doses was 1.2%. The government provided cold-chain related support at no cost to the project. Costs for two doses of vaccine per-person were US$3.93, of which US$1.63 was spent on delivery. Cost for delivering a single dose was US$0.76. We observed no serious adverse events. Mass vaccination with oral cholera vaccine is feasible for reaching high risk endemic population through the existing national immunization delivery system employed by the government. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Clinical Pharmacokinetics of IPX066: Evaluation of Dose Proportionality and Effect of Food in Healthy Volunteers

PubMed Central

Yao, Hsuan-Ming; Hsu, Ann; Gupta, Suneel; Modi, Nishit B.

2016-01-01

Objectives IPX066 is an oral, extended-release capsule formulation of carbidopa-levodopa (CD-LD) available in 4 strengths. The goals of this investigation were to assess the dose proportionality of IPX066 and to study the effects of a high-fat, high-calorie meal and of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 in healthy volunteers. Methods Three open-label studies were conducted. In the first study, subjects received 1 capsule of each IPX066 strength (23.75–95, 36.25–145, 48.75–195, and 61.25–245 mg of CD-LD). In the second study, subjects received 1 and 2 capsules of IPX066 245-mg LD under fasting conditions. In the third study, subjects received 2 capsules of IPX066 245-mg LD under 3 conditions: fasting; following a high-fat, high-calorie breakfast; and with the capsule contents sprinkled on applesauce under fasting conditions. Results Peak plasma concentrations (Cmax) and systemic exposure (AUCt, AUCinf) for LD and CD increased dose-proportionally over the range of the IPX066 capsule strengths. Comparison of 1 and 2 IPX066 245-mg LD capsules showed dose-proportional pharmacokinetics for Cmax and AUCt. Sprinkling the capsule contents on applesauce did not affect the pharmacokinetics. A high-fat, high-calorie meal delayed the initial increase in LD concentration by approximately 1 to 2 hours, reduced Cmax by 21%, and increased AUCinf by 13% compared with the fasted state. Conclusions IPX066 shows dose-proportional pharmacokinetics. Sprinkling the capsule contents on applesauce does not affect the pharmacokinetics; a high-fat, high-calorie meal delayed absorption by 1 to 2 hours, slightly reduced Cmax, and slightly increased extent of absorption. PMID:26626430

Clinical Pharmacokinetics of IPX066: Evaluation of Dose Proportionality and Effect of Food in Healthy Volunteers.

PubMed

Yao, Hsuan-Ming; Hsu, Ann; Gupta, Suneel; Modi, Nishit B

2016-01-01

IPX066 is an oral, extended-release capsule formulation of carbidopa-levodopa (CD-LD) available in 4 strengths. The goals of this investigation were to assess the dose proportionality of IPX066 and to study the effects of a high-fat, high-calorie meal and of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 in healthy volunteers. Three open-label studies were conducted. In the first study, subjects received 1 capsule of each IPX066 strength (23.75-95, 36.25-145, 48.75-195, and 61.25-245 mg of CD-LD). In the second study, subjects received 1 and 2 capsules of IPX066 245-mg LD under fasting conditions. In the third study, subjects received 2 capsules of IPX066 245-mg LD under 3 conditions: fasting; following a high-fat, high-calorie breakfast; and with the capsule contents sprinkled on applesauce under fasting conditions. Peak plasma concentrations (Cmax) and systemic exposure (AUCt, AUCinf) for LD and CD increased dose-proportionally over the range of the IPX066 capsule strengths. Comparison of 1 and 2 IPX066 245-mg LD capsules showed dose-proportional pharmacokinetics for Cmax and AUCt. Sprinkling the capsule contents on applesauce did not affect the pharmacokinetics. A high-fat, high-calorie meal delayed the initial increase in LD concentration by approximately 1 to 2 hours, reduced Cmax by 21%, and increased AUCinf by 13% compared with the fasted state. IPX066 shows dose-proportional pharmacokinetics. Sprinkling the capsule contents on applesauce does not affect the pharmacokinetics; a high-fat, high-calorie meal delayed absorption by 1 to 2 hours, slightly reduced Cmax, and slightly increased extent of absorption.

Tolerance to 3,4-Methylenedioxymethamphetamine (MDMA) in Rats Exposed to Single High-Dose Binges

PubMed Central

Baumann, Michael H.; Clark, Robert D.; Franken, Frederick H.; Rutter, John J.; Rothman, Richard B.

2008-01-01

3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) stimulates the transporter-mediated release of monoamines, including serotonin (5-HT). High-dose exposure to MDMA causes persistent 5-HT deficits (e.g., depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-induced 5-HT depletions in rats. Male rats received binges of 3 ip injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kg × 3, low dose) or at a 5-fold higher amount (7.5 mg/kg × 3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute iv challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by iv MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting ~50% loss of forebrain 5-HT two weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of iv MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with iv MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation. PMID:18313226

Evaluation of incidence and risk factors for high-dose methotrexate-induced nephrotoxicity.

PubMed

Wiczer, Tracy; Dotson, Emily; Tuten, Amy; Phillips, Gary; Maddocks, Kami

2016-06-01

High-dose methotrexate (doses ≥1 g/m(2)) is a key component of several chemotherapy regimens used to treat patients with leukemia or lymphoma. Despite appropriate precautions with hydration, urine alkalinization, and leucovorin, nephrotoxicity remains a risk which can lead to significant morbidity and mortality. Current reports of risk factors for nephrotoxicity focus on patients with nephrotoxicity with a lack of comparison to those without toxicity. This study aimed to describe the incidence of high-dose methotrexate-induced nephrotoxicity at our institution and determined risk factors for high-dose methotrexate-induced nephrotoxicity by examining characteristics of patients with and without nephrotoxicity. This was a retrospective, single-center, chart review. Adult patients with a diagnosis of leukemia or lymphoma who received high-dose methotrexate were included. Serum creatinine values were used to evaluate nephrotoxicity according to Common Terminology Criteria for Adverse Events criteria v4.03. Data related to the following proposed risk factors were collected: age, sex, body mass index, methotrexate dose, number of high-dose methotrexate exposures, leucovorin administration route, baseline renal function, albumin, hydration status, Clostridium difficile infection, urine pH, and concomitant interacting and nephrotoxic medications. The primary endpoint was evaluated with exact binomial methods and risk factors were identified using multivariable random-effects logistic regression. Final analyses included 140 patients with 432 high-dose methotrexate exposures. There were no differences in baseline demographical characteristics. Fifty-four patients (38.6%) experienced nephrotoxicity of any grade: 27.9% with grade 1, 5.7% with grade 2, 3.6% grade 3, 0% with grade 4, and 1.4% with grade 5 toxicity. More patients in the toxicity group received doses of methotrexate ≥3 g/m(2) (58.3% versus 57.2%, p < 0.001), had an albumin level <3 g/dL (31.9% versus 15.9%, p = 0.04), and received an interacting medication during high-dose methotrexate clearance (44.4% versus 24.7%, p = 0.003). Male gender (OR 2.3, 95% CI: 1.27-4.18, p = 0.006), albumin (OR 0.44, 95% CI: 0.26-0.75, p = 0.002), number of drug interactions (OR 1.60, 95% CI: 1.15-2.21, p = 0.005), and use of furosemide (OR 2.56, 95% CI 1.46-4.48, p = 0.001) were all independent risk factors for the development of nephrotoxicity. Nephrotoxicity is a possible complication of therapy with high-dose methotrexate with most instances comprising grade 1-2 toxicity. Male gender, low albumin, and administration of interacting drugs or furosemide during high-dose methotrexate clearance may predispose patients to nephrotoxicity. © The Author(s) 2015.

The effect of duration of dose delivery with patient-controlled analgesia on the incidence of nausea and vomiting after hysterectomy

PubMed Central

Woodhouse, Annie; Mather, Laurence E

1998-01-01

Aims Postoperative nausea and vomiting (PONV) may be exacerbated by postoperative opioid analgesics and may limit patients’ successful use of these medications when used with patient controlled analgesia (PCA). We tested the hypothesis that the rapid change in blood morphine concentration associated with PCA bolus delivery contributed to PONV, and that prolonging its delivery to a brief infusion would result in decreased PONV. Methods Patients, who were receiving morphine for pain relief via patient-controlled analgesia (PCA) after total abdominal hysterectomy, received 1 mg morphine sulphate incremental doses either over 40 s with a 5 min lockout interval or over 5 min delivery with a 1 min lockout interval. Episodes of nausea, retching and vomiting, along with the use of morphine and the pain relief obtained, were recorded. Results Data from 20 patients in each group were analysed. Contrary to expectations, most patients in both groups reported nausea postoperatively. Those patients receiving morphine over 5 min experienced more episodes of emesis (36) than those receiving the dose over 40 s (17). Most patients receiving the 40 s doses vomited in the first 12 h (median time 8 h), while those receiving the 5 min doses vomited between 12 and 24 h (median time 19 h) (P=0.01). There were no differences between groups in the visual analogue pain scores or use of morphine between groups. Conclusions Reasons for these unexpected findings remain speculative. The high incidence of PONV appears to be inherently high in gynaecological surgery patients and standard antiemetic medication regimens appear to be poorly efficacious. Reasons for the differences in the time-course of emetic episodes between the two groups may be related to differences in the time-course of central opioid receptor occupancy. PMID:9489595

[Efficacy and safety of vaccination against hepatitis A and B in patients with chronic liver disease].

PubMed

de Artaza Varasa, Tomás; Sánchez Ruano, Juan José; García Vela, Almudena; Gómez Rodríguez, Rafael; Romero Gutiérrez, Marta; de la Cruz Pérez, Gema; Gómez Moreno, Ana Zaida; Carrobles Jiménez, José María

2009-01-01

Vaccination to protect against hepatitis A and B should be part of the routine management of patients with chronic liver disease (CLD). To evaluate the efficacy and safety of hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccination in a group of patients with CLD and to assess the presence of factors predictive of response. We performed a prospective, single-center study in 194 patients (123 men, 71 women; mean age, 48.9+/-10.7 years) with CLD: 107 with chronic hepatitis (CH) and 87 with hepatic cirrhosis (HC), all Child-Pugh class A. The most frequent causes of CLD were HCV infection and alcohol. Patients negative for anti-HAV IgG received the HAV vaccination (1440 ELISA units in two doses) and those with negative HBV serology received the HBV vaccination ( three 20 microg doses). Patients with inadequate response to the latter vaccine received an additional double dose. Thirty patients received a combination vaccine (three doses). Sixty patients (31%) received the HAV vaccine and 150 (77%) patients received the HBV vaccine. Seroconversion was achieved by 91.6% of patients for HAV and by 57% of the patients for HBV. After the additional dose, the response increased to 74%. Efficacy was similar between CH and HC. HBV vaccination was less effective in HC than in CH and the seroconversion rate was significantly lower in patients with HC and previous decompensation. The combination vaccine (30 patients) was highly immunogenic. No adverse effects were registered. HAV vaccination has high efficacy in patients with CLD. Patients with HC respond weakly to HBV vaccination compared with those with CH and especially if there is prior decompensation. The combination vaccine seems particularly effective in patients with CLD. The three vaccines are safe.

High Dose Cytosine Arabinoside in the consolidation of adult acute myeloid leukemia.

PubMed

Rahman, M H; Khan, M A; Islam, M S; Afrose, S; Ara, T

2012-04-01

This interventional study was done to evaluate the duration of remission with High Dose Cytosine Arabinoside (Ara-C) as post-remission chemotherapy in the consolidation of adult acute myeloid leukemia. A total of 32 patients were included in this study. Among them, 19 were male and 13 were female and the age of the patients ranges from 15-60 years. We use High Dose Cytosine Arabinoside 1.5-2.5 g/m2 i.v, 12 hourly, over 2-3 hours on day 1, 3 and 5 in a 28 days cycle. This study was done during the period of April 2007 to March 2009 in the department of hematology, Dhaka Medical College & Hospital. History, clinical features and laboratory investigations were included. Among 32 patients, 5 patients (15.6%) received one cycle, 20 patients (62.5%) received two cycles and 7 patients (21.9%) received three cycles. The mean ± SD duration of remission (disease free survival) was 5.20 ± 3.83 months who received one cycle, 9.55 ± 3.30 months and 10.71 ± 1.70 months who received two cycles and three cycles respectively. The adverse effects of the therapy were neutropenia and neutropenic fever, purpuric rash, gum bleeding, mucositis and peripheral neuropathy. The supportive materials needed were antibiotics (both prophylactic and treatment) 86.13%, blood and blood products 51.7% and G-CSF 14.9% patients of all cycles. High Dose Ara-C (HiDAC) is a safe and cost effective consolidation treatment for AML patients in complete remission. This therapy merits multi-center control study to define its efficacy and cost-effectiveness in contrast to our socio-economic condition.

Evaluation of an every-other-day palonosetron schedule to control emesis in multiple-day high-dose chemotherapy.

PubMed

Mirabile, Aurora; Celio, Luigi; Magni, Michele; Bonizzoni, Erminio; Gianni, Alessandro Massimo; Di Nicola, Massimo

2014-12-01

Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated. Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion). Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome. Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

[Optimization of ventricular function during anesthesia induction by administering crystalloids and colloids to heart surgery patients].

PubMed

Ballesteros, M; Boldt, J; Zickmann, B; Knothe, C; Hempelmann, G

1995-01-01

To describe the changes in cardiac function after administration of three different solutions infused after anesthetic induction. Thirty-six patients scheduled for elective aortocoronary bypass surgery were randomly distributed into three groups. Over a period of 25 min after anesthetic induction, 12 received 10 ml/kg of Ringer solution (low dose crystalloid group), 12 received 20 ml/kg of Ringer solution (high dose crystalloid group), and 12 received 10 ml/kg of Ringer solution with 10 ml/kg of hydroxi-ethyl-almidon solution 450,000 D, 0.7 substitution grade (group C-HEA). Minute volume, systemic and pulmonary pressures, osmolality of blood and urine, and plasma and urine sodium concentrations were measured before and after infusion of the assigned liquid. In spite of the volume infused, low dose crystalloid group showed a high incidence of oliguria, increased urinary osmolality and decreased sodium in urine. Cardiac and systolic indices and left ventricular work load remained stable after infusion of the assigned liquid in low and high dose crystalloid groups, whereas they increased significantly ion group C-HEA (+23%, +16% and +20%). Administration of restricted doses of crystalloids after anesthetic induction favors the retention of water and sodium. Higher doses of crystalloids weaken this effect. However, neither of these two regimens leads to a more effective cardiac work load. A combination of crystalloids and colloids administered immediately after anesthetic induction temporarily improves cardiac performance during surgery.

Typical doses and dose rates in studies pertinent to radiation risk inference at low doses and low dose rates

PubMed Central

Rühm, Werner; Azizova, Tamara; Bouffler, Simon; Cullings, Harry M; Grosche, Bernd; Little, Mark P; Shore, Roy S; Walsh, Linda; Woloschak, Gayle E

2018-01-01

Abstract In order to quantify radiation risks at exposure scenarios relevant for radiation protection, often extrapolation of data obtained at high doses and high dose rates down to low doses and low dose rates is needed. Task Group TG91 on ‘Radiation Risk Inference at Low-dose and Low-dose Rate Exposure for Radiological Protection Purposes’ of the International Commission on Radiological Protection is currently reviewing the relevant cellular, animal and human studies that could be used for that purpose. This paper provides an overview of dose rates and doses typically used or present in those studies, and compares them with doses and dose rates typical of those received by the A-bomb survivors in Japan. PMID:29432579

Cardiac Function After Multimodal Breast Cancer Therapy Assessed With Functional Magnetic Resonance Imaging and Echocardiography Imaging

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

Heggemann, Felix, E-mail: felix.heggemann@umm.de; German Center for Cardiovascular Research, Mannheim; Grotz, Hanna

Purpose: Breast intensity modulated radiation therapy (IMRT) reduces high-dose heart volumes but increases low-dose volumes. We prospectively assessed heart changes after 3D conformal RT (3DCRT) and IMRT for left-sided breast cancer. Heart dose was analyzed individually, 3DCRT patients were moderately exposed, and IMRT was performed only in patients with unacceptably high heart doses upon 3DCRT planning. Methods and Materials: In 49 patients (38 patients received 3DCRT; 11 patients received IMRT; and 20 patients received neoadjuvant or adjuvant chemotherapy) magnetic resonance imaging (MRI) and echocardiography were performed before and at 6, 12, and 24 months after treatment. Results: Mean heart dose formore » IMRT was 12.9 ± 3.9 Gy versus 4.5 ± 2.4 Gy for 3DCRT. Heart volumes receiving >40 Gy were 2.6% (3DCRT) versus 1.3% (IMRT); doses were >50 Gy only with 3DCRT. Temporary ejection fraction (EF) decrease was observed on MRI after 6 months (63%-59%, P=.005) resolving at 24 months. Only 3 patients had pronounced largely transient changes of EF and left ventricular enddiastolic diameter (LVEDD). Mitral (M) and tricuspid (T) annular plane systolic excursion (MAPSE and TAPSE) were reduced over the whole cohort (still within normal range). After 24 months left ventricular remodeling index decreased in patients receiving chemotherapy (0.80 vs 0.70, P=.028). Neither wall motion abnormalities nor late enhancements were found. On echocardiography, in addition to EF findings that were similar to those on MRI, global strain was unchanged over the whole cohort at 24 months after a transient decrease at 6 and 12 months. Longitudinal strain decreased in the whole cohort after 24 months in some segments, whereas it increased in others. Conclusions: Until 24 months after risk-adapted modern multimodal adjuvant therapy, only subclinical cardiac changes were observed in both 3DCRT patients with inclusion of small to moderate amounts of heart volume in RT tangents and in the patients treated with IMRT and reduced high-dose heart exposure.« less

RADIATION-INDUCED CHROMOSOME ABERRATIONS IN MAN

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

Sasaki, M.; Ottoman, R.E.; Norman, A.

1963-10-01

A study was made of the production and elimination of radioinduced chromosomal aberrations in leukocytes from the peripheral blood of persons exposed to chronic or acute doses of high-energy radiation. Included in the group were radiologists and laboratory scientists, for whom there were available complete records of the radiation dose received during their working life, and a number of distinguished radiologists who have practiced more than 25 yrs and who may have received substantial doses One of seven leukocytes from a distinguished radiologist contained a pair of chromosomes that could be classified as pseudo- diploid. In laboratory personnel for whommore » the doses received were significantly within the prescribed limits, the incidence of pseudo-diploid cells, of dicentrics, and of other chroNonemosomal aberrations was significantly higher than in a more or less comparable control group. (tr-auth)« less

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

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

Chandrasekara, S; Pella, S; Hyvarinen, M

2016-06-15

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

High Dose Atorvastatin Decreases Cellular Markers of Immune Activation Without Affecting HIV-1 RNA Levels: Results of a Double-Blind Randomized Placebo Controlled Clinical Trial

DTIC Science & Technology

2011-02-15

M A J O R A R T I C L E High Dose Atorvastatin Decreases Cellular Markers of Immune Activation without Affecting HIV-1 RNA Levels: Results of a... atorvastatin on HIV-1 RNA (primary objective) and cellular markers of immune activation (secondary objective). HIV-infected individuals not receiving...antiretroviral therapy were randomized to receive either 8 weeks of atorvastatin (80 mg) or placebo daily. After a 4–6 week washout phase, participants

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

PubMed

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

2005-06-01

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

Impact of angiotensin-converting enzyme gene polymorphism on neurohormonal responses to high- versus low-dose enalapril in advanced heart failure.

PubMed

Tang, W H Wilson; Vagelos, Randall H; Yee, Yin-Gail; Fowler, Michael B

2004-11-01

The impact of angiotensin-converting enzyme (ACE) gene polymorphism on neurohormonal dose response to ACE inhibitor therapy is unclear. ACE Insertion (I) or Deletion (D) genotype was determined in 74 patients with chronic heart failure who were randomly assigned to receive either high-dose or low-dose enalapril over a period of 6 months. Monthly pre-enalapril and post-enalapril neurohormone levels (serum ACE activity (sACE), plasma angiotensin II (A-II), plasma renin activity (PRA), and serum aldosterone (ALDO) were compared between genotype subgroups and between patients who received high- or low-dose enalapril within each genotype subgroup. At baseline, predose/postdose sACE and postdose PRA were significantly higher in the DD genotype. At 6-month follow-up, postdose sACE was reduced in a dose-dependent fashion in all three genotypes (P < .05). However, predose and postdose ALDO and A-II levels did not differ between each genotype subgroup at baseline or by enalapril dose within each genotype subgroup. ALDO escape and A-II reactivation were not affected by ACE genotype or enalapril dosage. Predose sACE were consistently higher in the DD genotype when compared with ID or II subgroups. Despite a dose-dependent suppression of sACE, there were no observed statistically significant differences in ALDO and A-II suppression or escape with escalating doses of enalapril within each subgroup.

Radiation Doses from the Norwegian Diet.

PubMed

Komperød, Mari; Skuterud, Lavrans

2018-06-13

Ingestion doses between and within countries are expected to vary significantly due to differences in dietary habits and geographical variations in radionuclide concentrations. This paper presents the most comprehensive assessment to date of the effective radiation dose from the Norwegian diet, from natural as well as anthropogenic radionuclides. Ingestion doses to the Norwegian public are calculated using national dietary statistics and the most relevant radionuclide concentration data for the various food products. The age-weighted average effective dose received by the Norwegian population from the diet is estimated at 0.41 mSv y from naturally occurring radionuclides and 0.010 mSv y from anthropogenic radionuclides. This is approximately 50% higher than the estimated world average. Fish and shellfish is the food group that provides the largest dose contribution from the average Norwegian diet. Although the average dose from anthropogenic radionuclides today is low, the exposure may still be significant for certain critical groups-especially persons who consume large amounts of reindeer meat from the regions that received significant radioactive fallout after the Chernobyl accident. Furthermore, persons with high Rn concentrations in their drinking water are among those receiving the highest ingestion doses in Norway.

Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study.

PubMed

Lublin, Fred D; Bowen, James D; Huddlestone, John; Kremenchutzky, Marcelo; Carpenter, Adam; Corboy, John R; Freedman, Mark S; Krupp, Lauren; Paulo, Corri; Hariri, Robert J; Fischkoff, Steven A

2014-11-01

Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer.

PubMed

Shilkrut, Mark; Merrick, Gregory S; McLaughlin, P William; Stenmark, Matthew H; Abu-Isa, Eyad; Vance, Sean M; Sandler, Howard M; Feng, Felix Y; Hamstra, Daniel A

2013-02-01

The objective of this study was to determine whether the addition of low-dose-rate brachytherapy or androgen-deprivation therapy (ADT) improves clinical outcome in patients with high-risk prostate cancer (HiRPCa) who received dose-escalated radiotherapy (RT). Between 1995 and 2010, 958 patients with HiRPCa were treated at Schiffler Cancer Center (n = 484) or at the University of Michigan (n = 474) by receiving either dose-escalated external-beam RT (EBRT) (n = 510; minimum prescription dose, 75 grays [Gy]; median dose, 78 Gy) or combined-modality RT (CMRT) consisting of (103) Pd implants (n = 369) or (125) I implants (n = 79) both with pelvic irradiation (median prescription dose, 45 Gy). The cumulative incidences of biochemical failure (BF) and prostate cancer-specific mortality (PCSM) were estimated by using the Kaplan-Meier method and Fine and Gray regression analysis. The median follow-up was 63.2 months (interquartile range, 35.4-99.0 months), and 250 patients were followed for >8 years. Compared with CMRT, patients who received EBRT had higher prostate-specific antigen levels, higher tumor classification, lower Gleason sum, and more frequent receipt of ADT for a longer duration. The 8-year incidence BF and PCSM among patients who received EBRT was 40% (standard error, 38%-44%) and 13% (standard error, 11%-15%) compared with 14% (standard error, 12%-16%; P < .0001) and 7% (standard error 6%-9%; P = .003) among patients who received CMRT. On multivariate analysis, the hazard ratios (HRs) for BF and PCSM were 0.35 (95% confidence interval [CI], 0.23-0.52; P < .0001) and 0.41 (95% CI, 0.23-0.75; P < .003), favoring CMRT. Increasing duration of ADT predicted decreased BF (P = .04) and PCSM (P = .001), which was greatest with long-term ADT (BF: HR, 0.33; P < .0001; 95% CI, 0.21-0.52; PCSM: HR, 0.30; P = .001; 95% CI, 0.15-0.6) even in the subgroup that received CMRT. In this retrospective comparison, both low-dose-rate brachytherapy boost and ADT were associated with decreased risks of BF and PCSM compared with EBRT. Copyright © 2012 American Cancer Society.

The usefulness of sLORETA in evaluating the effect of high-dose ARA-C on brain connectivity in patients with acute myeloid leukemia: an exploratory study

PubMed Central

Zarabla, Alessia; Ungania, Sara; Cacciatore, Alessandra; Maialetti, Andrea; Petreri, Gianluca; Mengarelli, Andrea; Spadea, Antonio; Marchesi, Francesco; Renzi, Daniela; Gumenyuk, Svitlana; Strigari, Lidia; Maschio, Marta

2017-01-01

Summary Cytosine arabinoside (Ara-C) is one of the key drugs for treating acute myeloid leukemia (AML). High intravenous doses may produce a number of central nervous system (CNS) toxicities and contribute to modifications in brain functional connectivity. sLORETA is a software used for localizing brain electrical activity and functional connectivity. The aim of this study was to apply sLORETA in the evaluation of possible effects of Ara-C on brain connectivity in patients with AML without CNS involvement. We studied eight patients with AML; four were administered standard doses of Ara-C while the other four received high doses. sLORETA was computed from computerized EEG data before treatment and after six months of treatment. Three regions of interest, corresponding to specific combinations of Brodmann areas, were defined. In the patients receiving high-dose Ara-C, a statistically significant reduction in functional connectivity was observed in the frontoparietal network, which literature data suggest is involved in attentional processes. Our data highlight the possibility of using novel techniques to study potential CNS toxicity of cancer therapy.

Identification of Differential Gene Expression Patterns after Acute Exposure to High and Low Doses of Low-LET Ionizing Radiation in a Reconstituted Human Skin Tissue

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

Tilton, Susan C.; Markillie, Lye Meng; Hays, Spencer

Our goal here was to identify dose and temporal dependent radiation responses in a complex tissue, reconstituted human skin. Direct sequencing of RNA (RNA-seq) was used to quantify altered transcripts following exposure to 0.1, 2 and 10 Gy of ionizing radiation at 3 and 8 hours. These doses include a low dose in the range of some medical diagnostic procedures (0.1 Gy), a dose typically received during radiotherapy (2.0 Gy) and a lethal dose (10 Gy). These doses could be received after an intentional or accidental radiation exposure and biomarkers are needed to rapidly and accurately triage exposed individuals. Amore » total of 1701 genes were deemed to be significantly affected by high dose radiation exposure with the majority of genes affected at 10 Gy. A group of 29 genes including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA, and AEN were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at multiple time points. A much larger group of up regulated genes, including those involved in inflammatory responses, was significantly altered only after a 10 Gy exposure. At high doses, down regulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a handful of genes were significantly affected by 0.1 Gy exposure using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to the high dose exposures. Differential regulation of PLK1 signaling at low and high doses was confirmed using qRT-PCR. These results indicate that some alterations in gene expression are qualitatively different at low and high doses of radiation in this model system.« less

An evaluation of hyperkalemia and serum creatinine elevation associated with different dosage levels of outpatient trimethoprim-sulfamethoxazole with and without concomitant medications.

PubMed

Gentry, Chris A; Nguyen, Ann T

2013-12-01

Adverse events associated with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) for outpatient infections, particularly those likely caused by community-acquired methicillin-resistant Staphylococcus aureus, have not been adequately characterized. Describe hyperkalemia and acute renal injury associated with high-dose TMP-SMX. An electronic medical record database retrospective study was conducted of outpatients receiving high-dose or low-dose TMP-SMX, comparing the incidences of hyperkalemia and acute renal injury. Of 6162 patients, more developed hyperkalemia (3.06% vs 1.05%, P < .0001) or acute renal injury (1.99% vs 0.700%, P = .0001) in the high-dose TMP-SMX group. Variables independently associated with hyperkalemia included age >58 years (odds ratio [OR] = 3.44; 95% CI = 1.86-7.0; P < .0001), concomitant receipt of an NSAID (OR = 1.71; 95% CI = 1.02-2.79; P = .044) or an ACE inhibitor (OR = 3.27; 95% CI = 2.06-5.14; P < .0001), high-dose TMP-SMX prescribed (OR = 2.92; 95% CI = 1.85-4.60; P < .0001), and baseline elevated serum creatinine (OR = 45.1; 95% CI = 21.7-93.2; P < .0001). Variables independently associated with acute renal injury included concomitant receipt of an ACE inhibitor (OR = 2.36; 95% CI = 1.01-5.24; P = .048) or a potassium supplement (OR = 4.10; 95% CI = 1.45-10.1; P = .010), high-dose TMP-SMX prescribed (OR = 3.70; 95% CI = 1.70-8.12; P = .0012), and baseline elevated serum creatinine (OR = 2110; 95% CI = 724-7980; P < .0001). Serum creatinine and potassium concentrations should be monitored in outpatients receiving high-dose TMP-SMX.

Beneficial effects of low dose Musa paradisiaca on the semen quality of male Wistar rats

PubMed Central

Alabi, A. S.; Omotoso, Gabriel O.; Enaibe, B. U.; Akinola, O. B.; Tagoe, C. N. B.

2013-01-01

Background: This study aimed at determining the effects of administration of mature green fruits of Musa paradisiaca on the semen quality of adult male Wistar rats. Materials and Methods: The animals used for the study were grouped into three: the control group, given 2 ml of double distilled water, a low dose group given 500 mg/kg/day and a high dose group given 1000 mg/kg/day of the plantain fruits, which was made into flour, and dissolved in 2 ml of double distilled water for easy oral administration. Results: Significant increment in the semen parameters was noticed in animals that received a lower dose of the plantain flour, but those animals who received the high dose had marked and very significant reduction in sperm cell concentration and percentage of morphologically normal spermatozoa. Conclusion: Musa paradisiaca should be consumed in moderate quantities in order to derive its beneficial effects of enhancing male reproductive functions. PMID:23798793

Does motivational interviewing counseling time influence HIV-positive persons' self-efficacy to practice safer sex?

PubMed

Chariyeva, Zulfiya; Golin, Carol E; Earp, Jo Anne; Suchindran, Chirayath

2012-04-01

This study examined the impact of motivational interviewing (MI) counseling time on self-efficacy to practice safer sex for people living with HIV/AIDS (PLWHA). In 4 month intervals we followed a cohort of 490 PLWHA for 12 months. We conducted hierarchical linear regression models to examine changes in safer sex self-efficacy when participants received zero, low to moderate (5-131 min) and high (132-320 min) doses of MI time. We conducted a similar analysis using number of counseling sessions as the predictor variable. Participants with low to moderate doses of MI counseling had 0.26 higher self-efficacy scores than participants with zero MI time (p=0.01). Also, they had 0.26 lower self-efficacy scores than participants with high amounts of MI time (p=0.04). Participants with high doses of MI had a 0.5 higher self-efficacy score than participants with zero amount of MI time (p<0.0001). Participants who received 3-4 counseling sessions had 0.41 greater self-efficacy scores than participants who did not receive any sessions (p<0.0001) but did not differ from participants receiving 1-2 sessions. MI time is a key to enhancing safer sex self-efficacy among PLWHA. Safer sex self-efficacy improves the more MI counseling time and sessions PLWHA receive. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The effects of recombinant activated factor VII dose on the incidence of thromboembolic events in patients with coagulopathic bleeding.

PubMed

Bucklin, Mason H; Acquisto, Nicole M; Nelson, Catherine

2014-05-01

Previous studies have suggested the used of off-label recombinant factor VII (rFVIIa) increases the risk of thromboembolic events, but the effect of the dose of rFVIIa is not well described in the literature. All adult patients that received off-label rFVIIa from 2005-2012 were included in this single-center, retrospective cohort study. The primary endpoint was the incidence of a thromboembolic event in the low dose (<50 mcg/kg) compared to the high dose (≥50 mcg/kg) cohort. Secondary endpoints compared time to thromboembolic event, incidence of arterial compared to venous events, and mortality. There were 152 patients that received rFVIIa during the study period with 66 in the low dose cohort and 86 in the high dose cohort. Mean total dose of rFVIIa was 30.2 mcg/kg (SD ± 9.5 mcg/kg) in the low dose and 99.8 mcg/kg (SD ± 64.7 mcg/kg) in the high dose cohort (p=0.0001). The overall incidence of thromboembolic events was 12.5%. There were 12 (14%) events in the low dose cohort and seven (10.6%) in the high dose cohort, RR=0.76 (95% CI 0.31-1.82). There were no differences in any of the secondary outcomes. A higher incidence of thromboembolic events in cardiothoracic surgery (20.8%) and penetrating trauma patients (21.4%) was seen compared to the remaining cohort (6.7%). No significant difference in the incidence of thromboembolic events was seen between low dose versus high dose rFVIIa over a seven year period at our institution. However, due to the relatively low overall incidence and a small sample size, type II error may be present. Copyright © 2014 Elsevier Ltd. All rights reserved.

Patterns of zolpidem use among Iraq and Afghanistan veterans: A retrospective cohort analysis.

PubMed

Shayegani, Ramona; Song, Kangwon; Amuan, Megan E; Jaramillo, Carlos A; Eapen, Blessen C; Pugh, Mary Jo

2018-01-01

Although concern exists regarding the adverse effects and rate of zolpidem use, especially long-term use, limited information is available concerning patterns of zolpidem use. To examine the prevalence and correlates of zolpidem exposure in Iraq and Afghanistan Veterans (IAVs). A retrospective cohort study of zolpidem prescriptions was performed with National Veterans Health Administration (VHA) data. We gathered national VA inpatient, outpatient, and pharmacy data files for IAV's who received VA care between fiscal years (FY) 2013 and 2014. The VA pharmacy database was used to identify the prevalence of long term (>30 days), high-dose zolpidem exposure (>10mg immediate-release; >12.5mg extended-release) and other medications received in FY14. Baseline characteristics (demographics, diagnoses) were identified in FY13. Bivariate and multivariable analyses were used to examine the demographic, clinical, and medication correlates of zolpidem use. Of 493,683 IAVs who received VHA care in FY 2013 and 2014, 7.6% (n = 37,422) were prescribed zolpidem in FY 2014. Women had lower odds of high-dose zolpidem exposure than men. The majority (77.3%) of IAVs who received zolpidem prescriptions had long-term use with an average days' supply of 189.3 days and a minority (0.9%) had high-dose exposure. In multivariable analyses, factors associated with long-term zolpidem exposure included age greater than 29 years old, PTSD, insomnia, Selim Index, physical 2-3 conditions, opioids, antidepressants, benzodiazepines, atypical antipsychotics, and stimulants. High dose exposure was associated with PTSD, depression, substance use disorder, insomnia, benzodiazepines, atypical antipsychotics, and stimulant prescriptions. The current practices of insomnia pharmacotherapy in IAVs fall short of the clinical guidelines and may reflect high-risk zolpidem prescribing practices that put Iraq and Afghanistan Veterans at risk for adverse effects of zolpidem and poor health outcomes.

Primate paneth cell degeneration following methylmercury hydroxide ingestion.

PubMed Central

Mottet, N. K.; Body, R. L.

1976-01-01

The effects of methylmercury on the intestinal epithelium were studied in 14 adolescent male Macaca mulatta monkeys weighing 3 to 5 kg. They were divided into three groups: two controls received daily applesauce vehicle without methylmercury. Nine chronic low-dose animals received 0.2 to 1.0 mg of methylmercury per day for 80 to 491 days. Three acute high-dose animals received 2.0 mg methylmercury for 17 to 18 days, when they became terminally ill. Light and electron microscopic observations were made on samples of duodenum and ileum following perfusion and immersion fixation in a glutaraldehyde-paraformaldehyde fixative. Numerous uniquely structured inclusions were prominent in the Paneth cells of the chronic low-dose animals and some necrotic Paneth cells were seen, especially in the most chronic and higher dosed animals of the group. Acute high-dose treatment produced some inclusions in the Paneth cells similar to those of the chronic low-dose group, but degenerative and necrotic cells were more frequently seen. These alterations were not seen in other intestinal epithelial cells. Paneth cells are selectively altered. These findings suggest that a function of Paneth cells may be to eliminate metals from the body. Images Figure 11 Figure 12 Figure 13 Figure 1 Figure 2 Figure 3 Figures 4 and 5 Figure 14 Figure 15 Figures 16-18 Figures 6-10 PMID:820204

Randomized comparison of 5 and 10 microgram doses of two recombinant hepatitis B vaccines.

PubMed

Bryan, J P; Craig, P G; Reyes, L; Hakre, S; Jaramillo, R; Harlan, H; MacArthy, P; Legters, L J

1995-08-01

The high cost of hepatitis B vaccines remains an obstacle to their use. Since the recommended adult dose of Recombivax HB (MSD) is 10 micrograms and that of Engerix B (SKB) is 20 micrograms, we sought to determine if 10 microgram doses of each vaccine are equally immunogenic. Further, since 5 microgram doses of Recombivax are routinely used in those < or = 29 years of age in the US military, we sought to compare this dose with 5 microgram doses of Engerix B. Lower doses of Engerix would result in vaccine cost savings. members of the Belize Defence Force who were > or = 18 years of age (median 24) without detectable anti-HBc were randomly assigned to receive Recombivax, 5 or 10 micrograms, or ENgerix, 5 or 10 micrograms IM at 0, 1, and 6 months. Randomization was weighted toward Engerix. after 3 doses, geometric mean concentrations (GMC) of anti-HBs were highest among those receiving Recombivax 10 micrograms (n=22) or 5 micrograms (n=46) with GMC anti-HBs of 744 and 570 mIU ml-1, respectively. Similar proportions in the two groups developed > or = 10 mIU m-1 anti-HBs (100 and 98%). Among the 91 people who received Engerix 10 micrograms, the GMC anti-HBs was 325 mIU ml-1 and 91% developed > or = 10 mIU ml-1. The 87 people who received Engerix 5 micrograms had the lowest GMC, 177 mIU ml-1 (p < 0.05 compared with either Recombivax group). Only 86% attained > or = 10 mIU ml-1 anti-HBs (p > 0.05 compared with other regimens). The proportion attaining > or = 100 mIU ml-1 was lower in the 5 microgram Engerix group (63%) compared with 80% in the 5 microgram or 95% in the 10 microgram Recombivax groups (p < 0.05). Engerix administered in 5 microgram doses is less immunogenic than 5 or 10 microgram doses of Recombivax. In healthy populations < 30 years of age, regimens of half the recommended adult dose (5 micrograms of Recombivax or 10 micrograms of Engerix) are highly immunogenic and may result in significant vaccine cost savings.

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

Cardiac systolic dysfunction in doxorubicin-challenged rats is associated with upregulation of MuRF2 and MuRF3 E3 ligases

PubMed Central

da Silva, Marcia Gracindo; Mattos, Elisabete; Camacho-Pereira, Juliana; Domitrovic, Tatiana; Galina, Antonio; Costa, Mauro W; Kurtenbach, Eleonora

2012-01-01

Doxorubicin (DOXO) is an efficient and low-cost chemotherapeutic agent. The use of DOXO is limited by its side effects, including cardiotoxicity, that may progress to cardiac failure as a result of multifactorial events that have not yet been fully elucidated. In the present study, the effects of DOXO at two different doses were analyzed to identify early functional and molecular markers of cardiac distress. One group of rats received 7.5 mg/kg of DOXO (low-dose group) and was followed for 20 weeks. A subset of these animals was then subjected to an additional cycle of DOXO treatment, generating a cumulative dose of 20 mg/kg (high-dose group). Physiological and biochemical parameters were assessed in both treatment groups and in a control group that received saline. Systolic dysfunction was observed only in the high-dose group. Mitochondrial function analysis showed a clear reduction in oxidative cellular respiration for animals in both DOXO treatment groups, with evidence of complex I damage being observed. Transcriptional analysis by quantitative polymerase chain reaction revealed an increase in atrial natriuretic peptide transcript in the high-dose group, which is consistent with cardiac failure. Analysis of transcription levels of key components of the cardiac ubiquitin-proteasome system found that the ubiquitin E3 ligase muscle ring finger 1 (MuRF1) was upregulated in both the low- and high-dose DOXO groups. MuRF2 and MuRF3 were also upregulated in the high-dose group but not in the low-dose group. This molecular profile may be useful as an early physiological and energetic cardiac failure indicator for testing therapeutic interventions in animal models. PMID:23620696

Daily Palonosetron Is Superior to Ondansetron in the Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting in Patients With Acute Myelogenous Leukemia

PubMed Central

Mattiuzzi, Gloria N.; Cortes, Jorge E.; Blamble, Deborah A.; Bekele, B. Nebiyou; Xiao, Lianchun; Cabanillas, Maria; Borthakur, Gautam; O’Brien, Susan; Kantarjian, Hagop

2014-01-01

BACKGROUND Nausea and vomiting in patients with acute myelogenous leukemia (AML) can be from various causes, including the use of high-dose cytarabine. METHODS The authors compared 2 schedules of palonosetron versus ondansetron in the treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with AML receiving high-dose cytarabine. Patients were randomized to: 1) ondansetron, 8 mg intravenously (IV), followed by 24 mg continuous infusion 30 minutes before high-dose cytarabine and until 12 hours after the high-dose cytarabine infusion ended; 2) palonosetron, 0.25 mg IV 30 minutes before chemotherapy, daily from Day 1 of high-dose cytarabine up to Day 5; or 3) palonosetron, 0.25 mg IV 30 minutes before high-dose cytarabine on Days 1, 3, and 5. RESULTS Forty-seven patients on ondansetron and 48 patients on each of the palonosetron arms were evaluable for efficacy. Patients in the palonosetron arms achieved higher complete response rates (no emetic episodes plus no rescue medication), but the difference was not statistically significant (ondansetron, 21%; palonosetron on Days 1–5, 31%; palonosetron on Days 1, 3, and 5, 35%; P = .32). Greater than 77% of patients in each arm were free of nausea on Day 1; however, on Days 2 through 5, the proportion of patients without nausea declined similarly in all 3 groups. On Days 6 and 7, significantly more patients receiving palonosetron on Days 1 to 5 were free of nausea (P = .001 and P = .0247, respectively). CONCLUSIONS The daily assessments of emesis did not show significant differences between the study arms. Patients receiving palonosetron on Days 1 to 5 had significantly less severe nausea and experienced significantly less impact of CINV on daily activities on Days 6 and 7. PMID:21218459

Rectal bleeding after high-dose-rate brachytherapy combined with hypofractionated external-beam radiotherapy for localized prostate cancer: Impact of rectal dose in high-dose-rate brachytherapy on occurrence of grade 2 or worse rectal bleeding

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

Akimoto, Tetsuo; Katoh, Hiroyuki; Kitamoto, Yoshizumi

2006-06-01

Purpose: To evaluate the incidence of Grade 2 or worse rectal bleeding after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiotherapy (EBRT), with special emphasis on the relationship between the incidence of rectal bleeding and the rectal dose from HDR brachytherapy. Methods and Materials: The records of 100 patients who were treated by HDR brachytherapy combined with EBRT for {>=}12 months were analyzed. The fractionation schema for HDR brachytherapy was prospectively changed, and the total radiation dose for EBRT was fixed at 51 Gy. The distribution of the fractionation schema used in the patients was as follows: 5 Gy xmore » 5 in 13 patients; 7 Gy x 3 in 19 patients; and 9 Gy x 2 in 68 patients. Results: Ten patients (10%) developed Grade 2 or worse rectal bleeding. Regarding the correlation with dosimetric factors, no significant differences were found in the average percentage of the entire rectal volume receiving 30%, 50%, 80%, and 90% of the prescribed radiation dose from EBRT between those with bleeding and those without. The average percentage of the entire rectal volume receiving 10%, 30%, 50%, 80%, and 90% of the prescribed radiation dose from HDR brachytherapy in those who developed rectal bleeding was 77.9%, 28.6%, 9.0%, 1.5%, and 0.3%, respectively, and was 69.2%, 22.2%, 6.6%, 0.9%, and 0.4%, respectively, in those without bleeding. The differences in the percentages of the entire rectal volume receiving 10%, 30%, and 50% between those with and without bleeding were statistically significant. Conclusions: The rectal dose from HDR brachytherapy for patients with prostate cancer may have a significant impact on the incidence of Grade 2 or worse rectal bleeding.« less

Immunogenicity and safety of a high-dose hepatitis B vaccine among patients receiving methadone maintenance treatment: A randomized, double-blinded, parallel-controlled trial.

PubMed

Shi, Jing; Feng, Yongliang; Gao, Linying; Feng, Dan; Yao, Tian; Shi, Shan; Zhang, Yawei; Liang, Xiaofeng; Wang, Suping

2017-04-25

To explore whether the immunization with high-dose (60μg) hepatitis B vaccines in patients receiving methadone maintenance treatment (MMT) could yield a superior protection against hepatitis B infection than did the standard dose (20μg). We conducted a randomized, double-blinded, parallel-controlled trial in MMT patients. Patients with serologically negative hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were randomized in a ratio of 1:1 to receive three intramuscular injections of 20μg or 60μg recombinant hepatitis B vaccine at months 0, 1, and 6. Serum HBsAg and anti-HBs were measured at months 7 and 12 post-vaccination to assess the immunogenicity. A total of 196 MMT patients were randomized and 195 received at least one injection (98 and 97 in 20 and 60μg vaccine groups, respectively). The 60μg vaccine group showed a seroconversion of anti-HBs of 87.3%, high-level response rate of 56.3%, and GMC of 742.9mIU/mL at month 7. While these results were numerically higher than the 20μg group, a statistical difference was not found. HIV infection and concomitant drug abuse were negatively associated with the robust immune responses. 7.7% of MMT patients receiving at least one dose of vaccine reported solicited adverse reactions within 7days after vaccination, 2.6% reported unsolicited adverse reactions within 28days after vaccination. None of the MMT patients reported serious adverse events or became HBsAg positive during the follow-up. The three-dose regimen of 60μg recombinant hepatitis B vaccine at months 0, 1, and 6 can yield a similar immunogenicity among MMT patients as compared to the 20μg vaccine. ClinicalTrials.gov identifier: NCT02991599. Copyright © 2017. Published by Elsevier Ltd.

Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Bennett, Gary J; Ware, Mark A; Gandhi, Wiebke; Bley, Keith; Schweinhardt, Petra; Coderre, Terence J

2016-10-01

This double-blind randomized controlled study was designed to evaluate the analgesic effects of topical treatments with clonidine (CLON) and pentoxifylline (PTX) tested alone or as low- and high-dose combinations in a human experimental model of pain. Of 69 healthy subjects aged 18 to 60 years, 23 each were randomly allocated to low-dose (0.04% + 2%) and high-dose (0.1% + 5%) CLON + PTX groups. Both of these groups also received their corresponding placebos in one of 2 treatment periods separated by at least 48 hours. Twenty-three additional subjects received either CLON (0.1%) or PTX (5%) as single drug treatments, in each of 2 treatment periods. Assessment of analgesic efficacy was based on allodynic effects of previous intraepidermal capsaicin injection, as well as postcapsaicin tourniquet-induced pain 50 minutes following capsaicin injection. Visual Analogue Scale (VAS) ratings of pain intensity and the area of dynamic mechanical allodynia were the primary outcome measures, whereas area of punctate mechanical allodynia (PMA) served as a secondary outcome measure. Topical treatments with high- or low-dose combinations significantly reduced VAS ratings compared with corresponding placebo treatments throughout the period of postcapsaicin tourniquet-induced pain. Importantly, the high-dose combination produced lower VAS ratings than CLON alone, which were lower than PTX alone. Results also revealed significant inhibition of postcapsaicin dynamic mechanical allodynia and PMA for the high-dose combination compared with placebo, and of PMA for CLON compared with the low-dose combination. Hence, the present data are supportive of further clinical investigation of the high-dose topical combination of CLON + PTX in complex regional pain syndrome and neuropathic pain patients, for which our preclinical data predict efficacy.

Oral Cryotherapy for Preventing Oral Mucositis in Patients Receiving Cancer Treatment.

PubMed

Riley, Philip; McCabe, Martin G; Glenny, Anne-Marie

2016-10-01

In patients receiving treatment for cancer, does oral cryotherapy prevent oral mucositis? Oral cryotherapy is effective for the prevention of oral mucositis in adults receiving fluorouracil-based chemotherapy for solid cancers, and for the prevention of severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT).

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

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

Wu, V; Epelman, M; Feng, M

2014-06-15

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

Final report of the 70.2-Gy and 75.6-Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer.

PubMed

Rosenzweig, K E; Mychalczak, B; Fuks, Z; Hanley, J; Burman, C; Ling, C C; Armstrong, J; Ginsberg, R; Kris, M G; Raben, A; Leibel, S

2000-01-01

Three-dimensional conformal radiotherapy (3D-CRT) is a mode of high-precision radiotherapy designed to increase the tumor dose and decrease the dose to normal tissues. This study reports the final results of the first two dose levels (70.2 Gy and 75.6 Gy) of a phase I dose-escalation study using 3D-CRT for the treatment of non-small cell lung cancer. Fifty-two patients were treated with 3D-CRT without chemotherapy. The median age was 67 years (range, 39-82 years). The majority of patients had locally advanced cancer. Tumor was staged as I/II in 10%, IIIA in 40%, and IIIB in 50%. Radiation was delivered in daily fractions of 1.8 Gy, 5 days a week. A radiation dose level was considered complete when 10 patients received the intended dose without unacceptable acute morbidity. Toxicity was scored according to the Radiation Therapy Oncology Group grading scheme. Twenty patients were initially assigned to the 70.2-Gy level; 14 of them received the intended dose. Three patients experienced severe acute toxicity, two with grade 3 (requiring steroids or oxygen) and a third with grade 5 (fatal) acute radiation pneumonitis. Because of the grade 5 pulmonary toxicity, the protocol was modified, and only patients with a calculated risk of normal tissue complication of less than 25% were eligible for dose escalation. Patients who had a normal tissue complication probability (NTCP) of greater than 25% received a lower dose of radiation. An additional 18 patients were entered on the modified study; 11 of them received 70.2 Gy. One patient experienced grade 3 acute pneumonitis. Despite dose reduction in four patients because of an unacceptably high NTCP, two additional patients developed grade 3 pulmonary toxicity. Fourteen patients were accrued to the 75.6-Gy dose level, and 10 received the intended dose. One of the 10 patients experienced grade 3 pulmonary toxicity and one developed grade 3 esophageal toxicity. Three patients were treated to lower doses as a result of their calculated NTCP without toxicity, and one patient refused treatment. The 2-year local control, disease-free survival, and overall survival rates were 37%, 12%, and 24%, respectively. The median survival time was 11 months. Treatment to 70.2 Gy and 75.6 Gy using 3D-CRT was delivered with acceptable morbidity when NTCP constraints were observed. Local control was encouraging in these patients with locally advanced disease. Patients are currently being accrued to the 81-Gy level of the study.

High-precision γ -ray spectroscopy of the cardiac PET imaging isotope Rb 82 and its impact on dosimetry

DOE PAGES

Nino, M. N.; McCutchan, E. A.; Smith, S. V.; ...

2016-02-01

82Rb is a positron-emitting isotope used in cardiac positron emission tomography (PET) imaging which has been reported to deliver a significantly lower effective radiation dose than analogous imaging isotopes like 201Tl and 99mTc sestamibi. High-quality β-decay data are essential to accurately appraise the total dose received by the patients. A source of 82Sr was produced at the Brookhaven Linac Isotope Producer (BLIP), transported to Argonne National Laboratory, and studied with the Gammasphere facility. Significant revisions have been made to the level scheme of 82Kr including 12 new levels, 50 new γ-ray transitions, and the determination of many new spin assignmentsmore » through angular correlations. Lastly, these new high-quality data allow a precise reappraisal of the β-decay strength function and thus the consequent dose received by patients.« less

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

NASA Astrophysics Data System (ADS)

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

2017-08-01

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

Treating KSHV-Associated Multicentric Castleman Disease

Cancer.gov

In this study, patients with KSHV-associated multicentric Castleman disease will receive IV tocilizumab every other week for up to 12 weeks. Patients who do not benefit may go on to receive high-dose AZT and valganciclovir as well.

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

PubMed Central

Slichter, Sherrill J.; Kaufman, Richard M.; Assmann, Susan F.; McCullough, Jeffrey; Triulzi, Darrell J.; Strauss, Ronald G.; Gernsheimer, Terry B.; Ness, Paul M.; Brecher, Mark E.; Josephson, Cassandra D.; Konkle, Barbara A.; Woodson, Robert D.; Ortel, Thomas L.; Hillyer, Christopher D.; Skerrett, Donna L.; McCrae, Keith R.; Sloan, Steven R.; Uhl, Lynne; George, James N.; Aquino, Victor M.; Manno, Catherine S.; McFarland, Janice G.; Hess, John R.; Leissinger, Cindy; Granger, Suzanne

2010-01-01

BACKGROUND We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1×1011, 2.2×1011, or 4.4×1011 platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25×1011) than in the medium-dose group (11.25×1011) or the high-dose group (19.63×1011) (P = 0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1×1011 and 4.4×1011 platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.) PMID:20164484

Double oral esomeprazole after a 3-day intravenous esomeprazole infusion reduces recurrent peptic ulcer bleeding in high-risk patients: a randomised controlled study.

PubMed

Cheng, Hsiu-Chi; Wu, Chung-Tai; Chang, Wei-Lun; Cheng, Wei-Chun; Chen, Wei-Ying; Sheu, Bor-Shyang

2014-12-01

Patients with high Rockall scores have increased risk of ulcer rebleeding after 3-day esomeprazole infusions. To investigate whether double oral esomeprazole given after a 3-day esomeprazole infusion decreases ulcer rebleeding for patients with high Rockall scores. We prospectively enrolled 293 patients with peptic ulcer bleeding who had achieved endoscopic haemostasis. After a 3-day esomeprazole infusion, patients with Rockall scores ≥6 were randomised into the oral double-dose group (n=93) or the oral standard-dose group (n=94) to receive 11 days of oral esomeprazole 40 mg twice daily or once daily, respectively. The patients with Rockall scores <6 served as controls (n=89); they received 11 days of oral esomeprazole 40 mg once daily. Thereafter, all patients received oral esomeprazole 40 mg once daily for two more weeks until the end of the 28-day study period. The primary end point was peptic ulcer rebleeding. Among patients with Rockall scores ≥6, the oral double-dose group had a higher cumulative rebleeding-free proportion than the oral standard-dose group (p=0.02, log-rank test). The proportion of patients free from recurrent bleeding during the 4th-28th day in the oral double-dose group remained lower than that of the group with Rockall scores <6 (p=0.03, log-rank test). Among patients with Rockall scores ≥6, the rebleeding rate was lower in the oral double-dose group than in the oral standard-dose group (4th-28th day: 10.8% vs 28.7%, p=0.002). Double oral esomeprazole at 40 mg twice daily after esomeprazole infusion reduced recurrent peptic ulcer bleeding in high-risk patients with Rockall scores ≥6. NCT01591083. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Process evaluation results from the HEALTHY physical education intervention

PubMed Central

Hall, William J.; Zeveloff, Abigail; Steckler, Allan; Schneider, Margaret; Thompson, Deborah; Pham, Trang; Volpe, Stella L.; Hindes, Katie; Sleigh, Adriana; McMurray, Robert G.

2012-01-01

Process evaluation is an assessment of the implementation of an intervention. A process evaluation component was embedded in the HEALTHY study, a primary prevention trial for Type 2 diabetes implemented over 3 years in 21 middle schools across the United States. The HEALTHY physical education (PE) intervention aimed at maximizing student engagement in moderate-to-vigorous physical activity through delivery of structured lesson plans by PE teachers. Process evaluation data collected via class observations and interventionist interviews assessed fidelity, dose delivered, implementor participation, dose received and barriers. Process evaluation results indicate a high level of fidelity in implementing HEALTHY PE activities and offering 225 min of PE every 10 school days. Concerning dose delivered, students were active for approximately 33 min of class, representing an average of 61% of the class time. Results also indicate that PE teachers were generally engaged in implementing the HEALTHY PE curriculum. Data on dose received showed that students were highly engaged with the PE intervention; however, student misbehavior was the most common barrier observed during classes. Other barriers included teacher disengagement, large classes, limited gym space and poor classroom management. Findings suggest that the PE intervention was generally implemented and received as intended despite several barriers. PMID:22156231

Reduction in radiation-induced brain injury by use of pentobarbital or lidocaine protection

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

Oldfield, E.H.; Friedman, R.; Kinsella, T.

1990-05-01

To determine if barbiturates would protect brain at high doses of radiation, survival rates in rats that received whole-brain x-irradiation during pentobarbital- or lidocaine-induced anesthesia were compared with those of control animals that received no medication and of animals anesthetized with ketamine. The animals were shielded so that respiratory and digestive tissues would not be damaged by the radiation. Survival rates in rats that received whole-brain irradiation as a single 7500-rad dose under pentobarbital- or lidocaine-induced anesthesia was increased from between from 0% and 20% to between 45% and 69% over the 40 days of observation compared with the othermore » two groups (p less than 0.007). Ketamine anesthesia provided no protection. There were no notable differential effects upon non-neural tissues, suggesting that pentobarbital afforded protection through modulation of ambient neural activity during radiation exposure. Neural suppression during high-dose cranial irradiation protects brain from acute and early delayed radiation injury. Further development and application of this knowledge may reduce the incidence of radiation toxicity of the central nervous system (CNS) and may permit the safe use of otherwise unsafe doses of radiation in patients with CNS neoplasms.« less

Process evaluation results from the HEALTHY physical education intervention.

PubMed

Hall, William J; Zeveloff, Abigail; Steckler, Allan; Schneider, Margaret; Thompson, Deborah; Pham, Trang; Volpe, Stella L; Hindes, Katie; Sleigh, Adriana; McMurray, Robert G

2012-04-01

Process evaluation is an assessment of the implementation of an intervention. A process evaluation component was embedded in the HEALTHY study, a primary prevention trial for Type 2 diabetes implemented over 3 years in 21 middle schools across the United States. The HEALTHY physical education (PE) intervention aimed at maximizing student engagement in moderate-to-vigorous physical activity through delivery of structured lesson plans by PE teachers. Process evaluation data collected via class observations and interventionist interviews assessed fidelity, dose delivered, implementor participation, dose received and barriers. Process evaluation results indicate a high level of fidelity in implementing HEALTHY PE activities and offering 225 min of PE every 10 school days. Concerning dose delivered, students were active for approximately 33 min of class, representing an average of 61% of the class time. Results also indicate that PE teachers were generally engaged in implementing the HEALTHY PE curriculum. Data on dose received showed that students were highly engaged with the PE intervention; however, student misbehavior was the most common barrier observed during classes. Other barriers included teacher disengagement, large classes, limited gym space and poor classroom management. Findings suggest that the PE intervention was generally implemented and received as intended despite several barriers.

Hepatoprotective effect of Crocus sativus (saffron) petals extract against acetaminophen toxicity in male Wistar rats

PubMed Central

Omidi, Arash; Riahinia, Narges; Montazer Torbati, Mohammad Bagher; Behdani, Mohammad-Ali

2014-01-01

Objectives: Acetaminophen (APAP) toxicity is known to be common and potentially fatal. This study aims to investigate the protective effects of hydroalcoholic extract, remaining from Crocus sativus petals (CSP) against APAP-induced hepatotoxicity by measuring the blood parameters and studying the histopathology of liver in male rats. Materials and Methods: Wister rats (24) were randomly assigned into four groups including: I) healthy, receiving normal saline; II) Intoxicated, receiving only APAP (600 mg/kg); III) pre-treated with low dose of CSP (10 mg /kg) and receiving APAP (600 mg/kg); IV) pre-treated with high dose of CSP (20 mg/kg) and receiving APAP (600 mg/kg). Results: The APAP treatment resulted in higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin, along with lower total protein and albumin concentration than the control group. The administration of CSP with a dose of 20 mg/kg was found to result in lower levels of AST, ALT and bilirubin, with a significant higher concentration of total protein and albumin. The histopathological results regarding liver pathology, revealed sever conditions including cell swelling, severe inflammation and necrosis in APAP-exposed rats, which was quiet contrasting compared to the control group. The pre-treated rats with low doses of ‍CSP showed hydropic degeneration with mild necrosis in centrilobular areas of the liver, while the same subjects with high doses of ‍CSP appeared to have only mild hepatocyte degeneration. Conclusions: Doses of 20 mg/kg of CSP ameliorates APAP–induced acute liver injury in rats. It was concluded that the antioxidant property of CSP resulted in reducing the oxidative stress complications of toxic levels of APAP in intoxicated rats. PMID:25386395

Comparison of Immunogenicity Between Inactivated and Live Attenuated Hepatitis A Vaccines Among Young Adults: A 3-Year Follow-up Study.

PubMed

Liu, Xue-en; Chen, Hai-ying; Liao, Zheng; Zhou, Yisheng; Wen, Hairong; Peng, Shihui; Liu, Yan; Li, Rui; Li, Jie; Zhuang, Hui

2015-10-15

A randomized clinical trial of hepatitis A vaccines (1 or 2 doses of inactivated vaccine [Healive] or 1 dose of live attenuated vaccine [Biovac]) was conducted among adults to evaluate seroprotection rates and geometric mean concentrations of antibody against hepatitis A virus for 36 months. High rates of seroprotection persisted for at least 36 months among adults who received 1 or 2 doses of inactivated hepatitis A vaccine but not among adults who received 1 dose of live attenuated hepatitis A vaccine. The long-term serial monitoring of immunogenicity induced by 1 dose of inactivated hepatitis A vaccine is needed to determine an effective alternative to a 2-dose schedule. NCT01865968. © The Author 2015. 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.

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.

Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus.

PubMed

Miles, Clifford D; Skorupa, Jill Y; Sandoz, John P; Rigley, Theodore H; Nielsen, Kathleen J; Stevens, R Brian

2011-01-01

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications. © 2010 John Wiley & Sons A/S.

A summary of evidence on radiation exposures received near to the Semipalatinsk nuclear weapons test site in Kazakhstan.

PubMed

Simon, Steven L; Baverstock, Keith F; Lindholm, Carita

2003-06-01

The presently available evidence about the magnitude of doses received by members of the public living in villages in the vicinity of Semipalatinsk nuclear test in Kazakhstan, particularly with respect to external radiation, while preliminary, is conflicting. The village of Dolon, in particular, has been identified for many years as the most highly exposed location in the vicinity of the test site. Previous publications cited external doses of more than 2 Gy to residents of Dolon while an expert group assembled by the WHO in 1997 estimated that external doses were likely to have been less than 0.5 Gy. In 2001, a larger expert group workshop was held in Helsinki jointly by the WHO, the National Cancer Institute of the United States, and the Radiation and Nuclear Safety Authority of Finland, with the expressed purpose to acquire data to evaluate the state of knowledge concerning doses received in Kazakhstan. This paper summarizes evidence presented at that workshop. External dose estimates from calculations based on sparse physical measurements and bio-dosimetric estimates based on chromosome abnormalities and electron paramagnetic resonance from a relatively small sample of teeth do not agree well. The physical dose estimates are generally higher than the biodosimetric estimates (1 Gy or more compared to 0.5 Gy or less). When viewed in its entirety, the present body of evidence does not appear to support external doses greater than 0.5 Gy; however, research is continuing to try and resolve the difference in dose estimates from the different methods. Thyroid doses from internal irradiation, which can only be estimated via calculation, are expected to have been several times greater than the doses from external irradiation, especially where received by small children.

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.

Methods for Probabilistic Radiological Dose Assessment at a High-Level Radioactive Waste Repository.

NASA Astrophysics Data System (ADS)

Maheras, Steven James

Methods were developed to assess and evaluate the uncertainty in offsite and onsite radiological dose at a high-level radioactive waste repository to show reasonable assurance that compliance with applicable regulatory requirements will be achieved. Uncertainty in offsite dose was assessed by employing a stochastic precode in conjunction with Monte Carlo simulation using an offsite radiological dose assessment code. Uncertainty in onsite dose was assessed by employing a discrete-event simulation model of repository operations in conjunction with an occupational radiological dose assessment model. Complementary cumulative distribution functions of offsite and onsite dose were used to illustrate reasonable assurance. Offsite dose analyses were performed for iodine -129, cesium-137, strontium-90, and plutonium-239. Complementary cumulative distribution functions of offsite dose were constructed; offsite dose was lognormally distributed with a two order of magnitude range. However, plutonium-239 results were not lognormally distributed and exhibited less than one order of magnitude range. Onsite dose analyses were performed for the preliminary inspection, receiving and handling, and the underground areas of the repository. Complementary cumulative distribution functions of onsite dose were constructed and exhibited less than one order of magnitude range. A preliminary sensitivity analysis of the receiving and handling areas was conducted using a regression metamodel. Sensitivity coefficients and partial correlation coefficients were used as measures of sensitivity. Model output was most sensitive to parameters related to cask handling operations. Model output showed little sensitivity to parameters related to cask inspections.

Whole-brain radiotherapy and high-dose methylprednisolone for elderly patients with primary central nervous system lymphoma: Results of North Central Cancer Treatment Group (NCCTG) 96-73-51

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

Laack, Nadia N.; Ballman, Karla V.; Mayo Clinic Cancer Center, Rochester, MN

Purpose: The aim of this study was to evaluate the efficacy, toxicity, and survival of whole-brain radiotherapy-treated (WBRT) and high-dose methylprednisolone (HDMP)-treated in elderly patients with primary central nervous system lymphoma (PCNSL). Methods and Materials: Patients with PCNSL who were 70 years and older received 1 g of methylprednisolone daily for 5 days, 30 days after WBRT. Patients then received 1 g of methylprednisolone every 28 days until progression. The primary endpoint was overall survival (OS) at 6 months. Results were compared with those in patients on the previous North Central Cancer Treatment Group (NCCTG) trial who received pre-WBRT cytoxan,more » adriamycin, vincristine, prednisone (CHOP) and high-dose cytarabine (CHOP-WBRT). A planned interim analysis was performed. The current regimen would be considered inactive if survival was not improved from patients treated with CHOP-WBRT. Results: Nineteen patients were accrued between 1998 and 2003. Median age was 76 years. Interim analysis revealed a 6-month survival of 33%, resulting in closure of the trial. Toxicity, OS, and event-free survival (EFS) were similar to those in patients more than 70 years of age who received CHOP-WBRT. The subgroup of patients who received HDMP had longer OS (12.1 vs. 7.0 months, p = 0.76) and EFS (11.7 vs. 4.0 months, p = 0.04) compared with the CHOP-WBRT patients alive 60 days after the start of treatment. Conclusions: Patients on-study long enough to receive HDMP had prolongation of OS and EFS compared to patients receiving CHOP-WBRT. Although the numbers of patients are too small for statistical conclusions, the HDMP regimen deserves further study.« less

Prevention of febrile neutropenia: use of prophylactic antibiotics.

PubMed

Cullen, M; Baijal, S

2009-09-01

Febrile neutropenia (FN) causes significant morbidity and mortality in patients receiving cytotoxic chemotherapy and can lead to reduced chemotherapy dose intensity and increased overall treatment costs. Antibiotic prophylaxis reduces the incidence of FN. Recent research and meta-analyses confirm that prophylactic fluoroquinolones decrease FN and infection-related mortality in patients with acute leukaemia and those receiving high-dose chemotherapy. Fluoroquinolone prophylaxis also lowers the incidence of FN and all-cause mortality following the first cycle of myelosuppressive chemotherapy for solid tumours. Levofloxacin has been the agent studied most thoroughly in this context. Although there is no convincing evidence that colonisation of individuals with resistant organisms due to antibiotic prophylaxis increases FN or mortality, such concerns must be taken seriously and the use of prophylaxis should be limited responsibly for patients with the greatest chance of benefit. Fluoroquinolone prophylaxis is well tolerated and cost-effective and should be offered to patients receiving chemotherapy for haematological malignancies and high-dose chemotherapy for solid tumours in which prolonged (>7 days) neutropenia is expected. It should also be considered for those receiving chemotherapy for solid tumours and lymphomas during the first cycle of chemotherapy when grade 4 neutropenia is anticipated.

Prevention of febrile neutropenia: use of prophylactic antibiotics

PubMed Central

Cullen, M; Baijal, S

2009-01-01

Febrile neutropenia (FN) causes significant morbidity and mortality in patients receiving cytotoxic chemotherapy and can lead to reduced chemotherapy dose intensity and increased overall treatment costs. Antibiotic prophylaxis reduces the incidence of FN. Recent research and meta-analyses confirm that prophylactic fluoroquinolones decrease FN and infection-related mortality in patients with acute leukaemia and those receiving high-dose chemotherapy. Fluoroquinolone prophylaxis also lowers the incidence of FN and all-cause mortality following the first cycle of myelosuppressive chemotherapy for solid tumours. Levofloxacin has been the agent studied most thoroughly in this context. Although there is no convincing evidence that colonisation of individuals with resistant organisms due to antibiotic prophylaxis increases FN or mortality, such concerns must be taken seriously and the use of prophylaxis should be limited responsibly for patients with the greatest chance of benefit. Fluoroquinolone prophylaxis is well tolerated and cost-effective and should be offered to patients receiving chemotherapy for haematological malignancies and high-dose chemotherapy for solid tumours in which prolonged (>7 days) neutropenia is expected. It should also be considered for those receiving chemotherapy for solid tumours and lymphomas during the first cycle of chemotherapy when grade 4 neutropenia is anticipated. PMID:19756000

A Live Attenuated Influenza A(H5N1) Vaccine Induces Long-Term Immunity in the Absence of a Primary Antibody Response

PubMed Central

Talaat, Kawsar R.; Luke, Catherine J.; Khurana, Surender; Manischewitz, Jody; King, Lisa R.; McMahon, Bridget A.; Karron, Ruth A.; Lewis, Kristen D. C.; Qin, Jing; Follmann, Dean A.; Golding, Hana; Neuzil, Kathleen M.; Subbarao, Kanta

2014-01-01

Background. Highly pathogenic avian influenza A(H5N1) causes severe infections in humans. We generated 2 influenza A(H5N1) live attenuated influenza vaccines for pandemic use (pLAIVs), but they failed to elicit a primary immune response. Our objective was to determine whether the vaccines primed or established long-lasting immunity that could be detected by administration of inactivated subvirion influenza A(H5N1) vaccine (ISIV). Methods. The following groups were invited to participate in the study: persons who previously received influenza A(H5N1) pLAIV; persons who previously received an irrelevant influenza A(H7N3) pLAIV; and community members who were naive to influenza A(H5N1) and LAIV. LAIV-experienced subjects received a single 45-μg dose of influenza A(H5N1) ISIV. Influenza A(H5N1)– and LAIV-naive subjects received either 1 or 2 doses of ISIV. Results. In subjects who had previously received antigenically matched influenza A(H5N1) pLAIV followed by 1 dose of ISIV compared with those who were naive to influenza A(H5N1) and LAIV and received 2 doses of ISIV, we observed an increased frequency of antibody response (82% vs 50%, by the hemagglutination inhibition assay) and a significantly higher antibody titer (112 vs 76; P = .04). The affinity of antibody and breadth of cross-clade neutralization was also enhanced in influenza A(H5N1) pLAIV–primed subjects. Conclusions. ISIV administration unmasked long-lasting immunity in influenza A(H5N1) pLAIV recipients, with a rapid, high-titer, high-quality antibody response that was broadly cross-reactive across several influenza A(H5N1) clades. Clinical Trials Registration. NCT01109329. PMID:24604819

Immune response and reactogenicity of intradermal administration versus subcutaneous administration of varicella-zoster virus vaccine: an exploratory, randomised, partly blinded trial.

PubMed

Beals, Chan R; Railkar, Radha A; Schaeffer, Andrea K; Levin, Yotam; Kochba, Efrat; Meyer, Brian K; Evans, Robert K; Sheldon, Eric A; Lasseter, Kenneth; Lang, Nancy; Weinberg, Adriana; Canniff, Jennifer; Levin, Myron J

2016-08-01

The licensed live, attenuated varicella-zoster virus vaccine prevents herpes zoster in adults older than 50 years. We aimed to determine whether intradermal administration of zoster vaccine could enhance vaccine immunogenicity compared with conventional needle subcutaneous administration. In this randomised, dose-ranging study, adults aged 50 years or older who had a history of varicella or who had resided in a country with endemic varicella-zoster virus infection for 30 years or more were eligible. Participants received the approved full or a 1/3 dose of zoster vaccine given subcutaneously or one of four intradermal doses (full, 1/3, 1/10, or 1/27 dose) using the MicronJet600 device. The two subcutaneous doses and the four intradermal doses were randomised (1·5:1:1:1:1:1) by computer generated sequence with randomisation stratified by age (50-59 years or 60 years or older). The primary immunogenicity endpoint was the change from baseline in IgG antibody to varicella-zoster virus-specific glycoproteins (gpELISA) measured at 6 weeks. All patients were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01385566. Between Sept 2, 2011, and Jan 13, 2012, 224 participants were enrolled from three clinics in the USA and 223 were randomly assigned: 52 to receive the full dose subcutaneous zoster vaccine, 34 to receive the 1/3 dose subcutaneous zoster vaccine, 34 to receive the full dose intradermal zoster vaccine, 35 to receive the 1/3 dose intradermal zoster vaccine, 34 to receive the 1/10 dose intradermal zoster vaccine, and 34 to receive the 1/27 dose intradermal zoster vaccine. Full dose zoster vaccine given subcutaneously resulted in a gpELISA geometric mean fold-rise (GMFR) of 1·74 (90% CI 1·48-2·04) at 6 weeks post-vaccination compared with intradermal administration which resulted in a significantly higher gpELISA GMFR of 3·25 (2·68-3·94; p<0·0001), which also remained high at 18 months. An apparent dose-response relation was observed with intradermal administration (1/3 dose subcutaneous GMFR 1·64 [90% CI 1·36-1·99], 1/3 dose intradermal 2·58 (2·13-3·13), 1/10 dose intradermal 2·22 [1·83-2·69], and 1/27 dose intradermal 1·64 [1·35-2·00]). Each partial dose of zoster vaccine given intradermaly had a gpELISA GMFR comparable to that of full dose zoster vaccine given subcutaneously. Transient erythema and induration were more common after intradermal administration (31% erythema for full subcutaneous dose and 77% for intradermal dose). Intradermal zoster vaccine showed a greater increase in varicella-zoster virus gpELISA antibody compared with subcutaneous zoster vaccine at comparable doses. Larger and longer studies of intradermal administration of live, attenuated zoster vaccine are needed to provide convincing evidence of improved cell mediated immunity. Merck & Co Inc. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

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

Gay, H; Dyk, P; Mullen, D

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

Effect of amphetamine on human macronutrient intake.

PubMed

Foltin, R W; Kelly, T H; Fischman, M W

1995-11-01

Six male subjects participated in a 15-day residential study examining the effects of amphetamine on macronutrient intake. During the first 11 days, carbohydrate intake was manipulated by providing lunch meals high (155 g) or low (25 g) in carbohydrate. Subjects received oral d-amphetamine (5, 10 mg/70 kg, BID) or placebo. Total daily caloric intake was similar under both lunch conditions (approximately 3400/Kcal), but carbohydrate contributed more energy under the high-carbohydrate condition. Both doses of amphetamine decreased total caloric intake to approximately 2600 Kcal, by decreasing the number of eating bouts, without affecting macronutrient selection. During the last four days subjects received a higher daily dose of amphetamine (30 mg/70 kg in four doses) or placebo, and were allowed to self-select lunch. Although 30 mg amphetamine decreased intake of all macronutrients, the relative contribution of carbohydrate to total caloric intake was increased from 54% to 62%, while the contribution of fat was decreased from 32% to 26% and the contribution of protein was decreased from 14% to 12%. Thus, at a high dose, amphetamine altered the relative contribution of specific macronutrients to total caloric intake.

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

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

Pak, Daniel; Vineberg, Karen; Feng, Felix

2012-08-01

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

Risperidone dosing in children and adolescents with autistic disorder: a double-blind, placebo-controlled study.

PubMed

Kent, Justine M; Kushner, Stuart; Ning, Xiaoping; Karcher, Keith; Ness, Seth; Aman, Michael; Singh, Jaskaran; Hough, David

2013-08-01

Efficacy and safety of 2 risperidone doses were evaluated in children and adolescents with autism. Patients (N = 96; 5-17 years), received risperidone (low-dose: 0.125 mg/day [20 to <45 kg], 0.175 mg/day [>45 kg] or high-dose: 1.25 mg/day [20 to <45 kg], 1.75 mg/day [>45 kg]) or placebo. Mean baseline (range 27-29) to endpoint change in Aberrant Behavior Checklist-Irritability (primary endpoint) was significantly greater in the high-dose-(-12.4 [6.5]; p < 0.001), but not low-dose (-7.4 [8.1]; p = 0.164) group, versus placebo (-3.5 [10.7]). Clinical Global Impressions-Severity and Children's Yale-Brown Obsessive Compulsive Scale scores improved significantly only in the high-dose group, consistent with ABC-I results. Somnolence, sedation and increased appetite occurred more frequently in high-versus low-dose groups. Overall, increased appetite occurred most frequently.

Immunogenicity, reactogenicity, and safety of a human rotavirus vaccine, Rotarix, in Taiwanese infants who received a dose of hepatitis B immunoglobulin after birth.

PubMed

Lu, Chun-Yi; Chang, Luan-Yin; Shao, Pei-Lan; Suryakiran, Pemmaraju Venkata; Han, Htay-Htay; Huang, Li-Min

2013-09-01

This Phase-IV study evaluated the human rotavirus (RV) vaccine Rotarix (RIX4414) to provide additional local clinical data to the Taiwan Food and Drug Association (NCT01198769). Healthy infants aged 6-12 weeks who were given a hepatitis B immunoglobulin (HBIg) dose after birth, received two doses of RIX4414 (0, 2-month schedule). Anti-RV IgA antibody concentrations were measured using ELISA. A total of 15 infants were enrolled, and included in the according-to-protocol cohort. The anti-RV IgA antibody seroconversion rate 2 months post-Dose 2 was 100% (95% confidence interval = 78.2-100) and the geometric mean concentration was 254.7 U/ml (95% confidence interval = 145.0-447.7). Two episodes of gastroenteritis were reported, and one stool sample was tested for RV, which was negative. No fatal serious adverse events were reported during the study period between November 2010 and April 2011. The two-dose regimen of RIX4414 was highly immunogenic and safe when administered to healthy Taiwanese infants who received a HBIg dose after birth. NCT01198769. Copyright © 2012. Published by Elsevier B.V.

Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study.

PubMed

Eisbruch, A; Shewach, D S; Bradford, C R; Littles, J F; Teknos, T N; Chepeha, D B; Marentette, L J; Terrell, J E; Hogikyan, N D; Dawson, L A; Urba, S; Wolf, G T; Lawrence, T S

2001-02-01

To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Predictors of Excess Patient Radiation Exposure During Chronic Total Occlusion Coronary Intervention: Insights from a Contemporary Multicenter Registry

PubMed Central

Christakopoulos, Georgios E.; Christopoulos, Georgios; Karmpaliotis, Dimitri; Alaswad, Khaldoon; Yeh, Robert W.; Jaffer, Farouc A.; Wyman, Michael R.; Lombardi, William L.; Tarar, Muhammad Nauman J.; Grantham, J. Aaron; Kandzari, David; Lembo, Nicholas; Moses, Jeffrey W.; Kirtane, Ajay; Parikh, Manish; Green, Philip; Finn, Matthew; Garcia, Santiago; Doing, Anthony; Hatem, Raja; Thompson, Craig A.; Banerjee, Subhash; Brilakis, Emmanouil S.

2016-01-01

Background High patient radiation dose during chronic total occlusion (CTO) percutaneous coronary intervention (PCI) may lead to procedural failure and radiation skin injury. Methods We examined the association between several clinical and angiographic variables on patient air kerma (AK) radiation dose among 748 consecutive CTO PCIs performed at 9 experienced US centers between May 2012 and May 2015. Results Mean age was 65±10 years, 87% of patients were men, and 35% had prior coronary artery bypass graft surgery (CABG). Technical and procedural success was 92% and 90%, respectively. The median patient AK dose was 3.40 (2.00, 5.40) Gray and 34% of the patients received >4.8 Gray (high radiation exposure). On univariable analysis male gender (p=0.016), high body mass index (p<0.001), history of hyperlipidemia (p=0.023), prior CABG (p<0.001), moderate or severe calcification (p<0.001), tortuosity (p<0.001), proximal cap ambiguity (p=0.001), distal cap at a bifurcation (p=0.006), longer CTO occlusion length (p<0.001), blunt/no blunt stump (p<0.001), and center (<0.001) were associated with higher patient AK dose. On multivariable analysis high body mass index (p<0.001), prior CABG (p=0.005), moderate or severe calcification (p=0.005), longer CTO occlusion length (p<0.001), and center (p<0.001) were independently associated with higher patient AK dose. Conclusions Approximately 1 in 3 patients undergoing CTO PCI receives high AK radiation dose (>4.8 Gray). Several baseline clinical and angiographic characteristics can help predict the likelihood of high radiation dose and assist with intensifying efforts to reduce radiation exposure for the patient and the operator. PMID:28169091

A cross-sectional vaccination coverage study in preschool children attending nurseries-kindergartens: Implications on economic crisis effect

PubMed Central

Menegas, Damianos; Katsioulis, Antonis; Theodoridou, Maria; Kremastinou, Jenny; Hadjichristodoulou, Christos

2017-01-01

ABSTRACT Vaccination coverage studies are important in determining a population's vaccination status and strategically adjusting national immunization programs. This study assessed full and timely vaccination coverage of preschool children aged 2–3 y attending nurseries-kindergartens (N-K) nationwide at the socioeconomic crisis onset. Geographically stratified cluster sampling was implemented considering prefectures as strata and N-K as clusters. The N-K were selected by simple random sampling from the sampling frame while their number was proportional to the stratum size. In total, 185 N-K (response rate 93.9%) and 2539 children (response rate 81.5%) participated. Coverage with traditional vaccines for diphtheria-tetanus-pertussis, polio and measles-mumps-rubella was very high (>95%), followed by Haemophilus influenzae type b and varicella vaccines. Despite very high final coverage, delayed vaccination was observed for hepatitis B (48.3% completed by 12 months). Significant delay was observed for the booster dose of pneumococcal conjugate vaccines (PCV) and meningococcal C conjugate vaccines (MCC). Of the total population studied, 82.3% received 3 PCV doses by 12 months, while 62.3% received the fourth dose by 24 months and 76.2% by 30 months. However, 89.6% received at least one MCC dose over 12 months. Timely vaccinated for hepatitis A with 2 doses by 24 months were 6.1%. Coverage was significantly low for Rotavirus (<20%) and influenza (23.1% one dose). High vaccination coverage is maintained for most vaccines at the beginning of the crisis in Greece. Coverage and timeliness show an increasing trend compared to previous studies. Sustained efforts are needed to support the preventive medicine system as socioeconomic instability continues. PMID:27669156

Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program.

PubMed

Payne, Roxanne; Glenn, Lyn; Hoen, Helena; Richards, Beverley; Smith, John W; Lufkin, Robert; Crocenzi, Todd S; Urba, Walter J; Curti, Brendan D

2014-01-01

High-dose interleukin-2 (IL-2) has been FDA-approved for over 20 years, but it is offered only at a small number of centers with expertise in its administration. We analyzed the outcomes of patients receiving high-dose IL-2 in relation to the severity of toxicity to ascertain if response or survival were adversely affected. A retrospective analysis of the outcomes of 500 patients with metastatic renal cell carcinoma (RCC) (n = 186) or melanoma (n = 314) treated with high-dose IL-2 between 1997 and 2012 at Providence Cancer Center was performed. IL-2 was administered at a dose of 600,000 international units per kg by IV bolus every 8 hours for up to 14 doses. A second cycle was administered 16 days after the first and patients with tumor regression could receive additional cycles. Survival and anti-tumor response were analyzed by diagnosis, severity of toxicity, number of IL-2 cycles and subsequent therapy. The objective response rate in melanoma was 28% (complete 12% and partial 16%), and in RCC was 24% (complete 7% and partial 17%). The 1-, 2- and 3-year survivals were 59%, 41% and 31%, for melanoma and 75%, 56% and 44%, for RCC, respectively. The proportion of patients with complete or partial response in both melanoma and RCC was higher in patients who a) required higher phenylephrine doses to treat hypotension (p < 0.003), b) developed acidosis (bicarbonate < 19 mmol (p < 0.01)), or c) thrombocytopenia (<50, 50-100, >100,000 platelets; p < 0.025). The proportion achieving a complete or partial response was greater in patients with melanoma who received 5 or more compared with 4 or fewer IL-2 cycles (p < 0.0001). The incidence of death from IL-2 was less than 1% and was not higher in patients who required phenylephrine. High-dose IL-2 can be administered safely; severe toxicity including hypotension is reversible and can be managed in a community hospital. The tumor response and survival reported here are superior to the published literature and support treating patients to their individualized maximum tolerated dose. IL-2 should remain part of the treatment paradigm in selected patients with melanoma and RCC.

Developing a virtual reality application for training nuclear power plant operators: setting up a database containing dose rates in the refuelling plant.

PubMed

Ródenas, J; Zarza, I; Burgos, M C; Felipe, A; Sánchez-Mayoral, M L

2004-01-01

Operators in Nuclear Power Plants can receive high doses during refuelling operations. A training programme for simulating refuelling operations will be useful in reducing the doses received by workers as well as minimising operation time. With this goal in mind, a virtual reality application is developed within the framework of the CIPRES project. The application requires doses, both instantaneous and accumulated, to be displayed at all times during operator training. Therefore, it is necessary to set up a database containing dose rates at every point in the refuelling plant. This database is based on radiological protection surveillance data measured in the plant during refuelling operations. Some interpolation routines have been used to estimate doses through the refuelling plant. Different assumptions have been adopted in order to perform the interpolation and obtain consistent data. In this paper, the procedures developed to set up the dose database for the virtual reality application are presented and analysed.

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

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

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

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

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

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

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

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

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

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

Baker, D. A.

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

Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. The Granisetron Study Group.

PubMed Central

Riviere, A.

1994-01-01

The efficacy and safety of three different doses of granisetron (2 micrograms kg-1, group A; 10 micrograms kg-1, group B; 40 micrograms kg-1, group C) were compared in a randomised, double-blind study of 157 patients due to receive high-dose cisplatin therapy (mean dose > 97 mg m-2). In each group, up to two 3 mg rescue doses of granisetron were allowed if more than mild nausea or vomiting occurred. In group A 30.8%, in group B 61.5% and in group C 67.9% of patients were complete responders (i.e. no vomiting or nothing worse than mild nausea) during the first 24 h. These differences are significant between groups A and B, and A and C. There were no statistically significant differences in any efficacy variable between the 10 micrograms kg-1 and 40 micrograms kg-1 groups, although in each case the trend favoured the higher dose. Additional rescue doses resulted in resolved or improved symptoms in 95.3% for the first rescue dose and 93.3% for the second. Over the 7 days of the study, 82.7%, 82.7% and 86.8% of patients in groups A, B and C respectively were treated with granisetron alone. Headache was the most common side-effect, reported by 9.6% of patients; the majority of headaches were mild. There was no difference between the treatment groups regarding the adverse event rate. We concluded that prophylactic doses of 10 or 40 micrograms kg-1 lead to a safe and satisfactory degree of control of nausea and vomiting induced by high-dose cisplatin. PMID:8180032

Thermal Dose is Related to Duration of Local Control in Canine Sarcomas Undergoing Thermoradiotherapy

PubMed Central

Thrall, Donald E.; LaRue, Susan M.; Yu, Daohai; Samulski, Thaddeus; Sanders, Linda; Case, Beth; Rosner, Gary; Azuma, Chieko; Poulson, Jeannie; Pruitt, Amy F.; Stanley, Wilma; Hauck, Marlene L.; Williams, Laurel; Hess, Paul; Dewhirst, Mark W.

2009-01-01

Purpose To test that prospective delivery of higher thermal dose is associated with longer tumor control duration. Experimental Design 122 dogs with a heatable soft tissue sarcoma were randomized to receive a low (2–5 CEM43°CT90) or high (20–50 CEM43°CT90) thermal dose in combination with radiotherapy. Most dogs (90%) received 4–6 hyperthermia treatments over 5 weeks. Results In the primary analysis, median (95% CI) duration of local control in the low dose group was 1.2 (0.7–2.1) years versus 1.9 (1.4–3.2) years in the high dose group (logrank p=0.28). The probability (95% CI) of tumor control at one year in the low vs. high dose groups was 0.57 (0.43–0.70) vs. 0.74 (0.62–0.86), respectively. Using multivariable procedure, thermal dose group (p=0.023), total duration of heating (p=0.008), tumor volume (p=0.041) and tumor grade (p=0.027) were significantly related to duration of local tumor control. When correcting for volume, grade and duration of heating, dogs in the low dose group were 2.3 times as likely to experience local failure. Conclusions Thermal dose is directly related to local control duration in irradiated canine sarcomas. Longer heating being associated with shorter local tumor control was unexpected. However, the effect of thermal dose on tumor control was stronger than for heating duration. The heating duration effect is possibly mediated through deleterious effects on tumor oxygenation. These results are the first to show the value of prospectively controlled thermal dose in achieving local tumor control with thermoradiotherapy, and they establish a paradigm for prescribing thermoradiotherapy and writing a thermal prescription. PMID:16033838

Effects of Dose Frequency of Early Communication Intervention in Young Children with and without Down Syndrome

ERIC Educational Resources Information Center

Yoder, Paul; Woynaroski, Tiffany; Fey, Marc; Warren, Steven

2014-01-01

Children with intellectual disability were randomly assigned to receive Milieu Communication Teaching (MCT) at one 1-hr session per week (low dose frequency, LDF) or five 1-hr sessions per week (high dose frequency, HDF) over 9 months (Fey, Yoder, Warren, & Bredin-Oja, 2013. Non-Down syndrome (NDS) and Down syndrome (DS) subgroups were matched…

Effective Dose of Radon 222 Bottled Water in Different Age Groups Humans: Bandar Abbas City, Iran.

PubMed

Fakhri, Yadolah; Mahvi, Amir Hossein; Langarizadeh, Ghazaleh; Zandsalimi, Yahya; Amirhajeloo, Leila Rasouli; Kargosha, Morteza; Moradi, Mahboobeh; Moradi, Bigard; Mirzaei, Maryam

2015-06-04

Radon 222 is a natural radioactive element with a half-life of 3.8 days. It is odorless and colorless as well as water-soluble. Consuming waters which contain high concentration of 222Rn would increase the effective dose received by different age groups. It would also be followed by an increased prevalence of cancer. In this research, 72 samples of the most commonly used bottled water in Bandar Abbas were collected in 3 consecutive months, May, June and July of 2013. Concentration 222Rn of was measured by radon-meter model RTM166-2. The effective dose received by the 4 age groups, male and female adults as well as children and infants was estimated using the equation proposed by UNSCEAR. The results revealed that the mean and range concentration of 222Rn in bottled waters were 641±9 Bq/m3 and 0-901 Bq/m3, respectively. The mean concentration of 222Rn in the well-known Marks followed this Zam Zam>Bishe>Koohrng>Dassani>Christal>Polour>Damavand>Sivan. Infants were observed to receive a higher effective dose than children. The highest and lowest effective dose received was found to belong to male adults and children, respectively.

Effective Dose of Radon 222 Bottled Water in Different Age Groups Humans: Bandar Abbas City, Iran

PubMed Central

Fakhri, Yadolah; Mahvi, Amir Hossein; Langarizadeh, Ghazaleh; Zandsalimi, Yahya; Amirhajeloo, Leila Rasouli; Kargosha, Morteza; Moradi, Mahboobeh; Moradi, Bigard; Mirzaei, Maryam

2016-01-01

Radon 222 is a natural radioactive element with a half-life of 3.8 days. It is odorless and colorless as well as water-soluble. Consuming waters which contain high concentration of 222Rn would increase the effective dose received by different age groups. It would also be followed by an increased prevalence of cancer. In this research, 72 samples of the most commonly used bottled water in Bandar Abbas were collected in 3 consecutive months, May, June and July of 2013. Concentration 222Rn of was measured by radon-meter model RTM166-2. The effective dose received by the 4 age groups, male and female adults as well as children and infants was estimated using the equation proposed by UNSCEAR. The results revealed that the mean and range concentration of 222Rn in bottled waters were 641±9 Bq/m3 and 0-901 Bq/m3, respectively. The mean concentration of 222Rn in the well-known Marks followed this Zam Zam>Bishe>Koohrng>Dassani>Christal>Polour>Damavand>Sivan. Infants were observed to receive a higher effective dose than children. The highest and lowest effective dose received was found to belong to male adults and children, respectively. PMID:26383192

Analysis of clinical efficacy, side effects, and laboratory changes among patients with acne vulgaris receiving single versus twice daily dose of oral isotretinoin.

PubMed

Ahmad, Hesham M

2015-01-01

Acne vulgaris is a debilitating disorder and requires proper treatment. This work evaluates the clinical efficacy, side effects, and laboratory changes of serum lipids and liver function during oral isotretinoin therapy for acne vulgaris, comparing single versus twice daily dose. Fifty-eight patients with acne vulgaris were included and randomized into group I (26 patients), who received once daily dose, and group II (32 patients), who received twice daily dose of oral isotretinoin. Global acne scoring system was used to evaluate acne severity and post-treatment improvement. Both regimens resulted in highly significant clinical improvement of acne with no significant difference. However, side effects were significantly more common among patients of group I. Both regimens caused mild rise of serum cholesterol, alanine transaminase (ALT), and aspartate aminotransferase (AST) with more prominent rise of triglycerides especially with twice daily dose. Oral isotretinoin is a very effective treatment for acne vulgaris with no statistically significant difference in clinical efficacy between once and twice daily doses. However, dividing dose to twice per day might cause fewer incidence of side effects without reducing clinical efficacy. The drug causes mild clinically insignificant rise of serum cholesterol, triglycerides, AST, and ALT. © 2015 Wiley Periodicals, Inc.

Risperidone Dosing in Children and Adolescents with Autistic Disorder: A Double-Blind, Placebo-Controlled Study

ERIC Educational Resources Information Center

Kent, Justine M.; Kushner, Stuart; Ning, Xiaoping; Karcher, Keith; Ness, Seth; Aman, Michael; Singh, Jaskaran; Hough, David

2013-01-01

Efficacy and safety of 2 risperidone doses were evaluated in children and adolescents with autism. Patients (N = 96; 5-17 years), received risperidone (low-dose: 0.125 mg/day [20 to <45 kg], 0.175 mg/day [>45 kg] or high-dose: 1.25 mg/day [20 to <45 kg], 1.75 mg/day [>45 kg]) or placebo. Mean baseline (range 27-29) to endpoint change…

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

PubMed Central

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

1982-01-01

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

Protective effects of selenium on acrylamide toxicity in the liver of the rat. Effects on the oxidative stress.

PubMed

Teodor, V; Cuciureanu, Magdalena; Filip, Cristiana; Zamosteanu, Nina; Cuciureanu, Rodica

2011-01-01

Acrylamide (AA), obtained for the first time by Moureu in Germany in 1893, is presently used as polyacrylamide in water treatment and wastewater treatment, paper and pulp processing, mineral processing, crude-oil production processes. Acrylamide is a chemical product formed when frying, roasting, grilling or baking carbohydrate-rich foods at temperatures above 120 degrees C. Acrylamide is thus found in a number of foods, such as bread, crisps, French fries and coffee. Tobacco smoking also generates substantial amounts of acrylamide. Acrylamide administration is associated with significant increase of oxidative stress parameters; acrylamide caused disturbances in the oxidative status and enzyme activities and the effect was pronounced with the high doses. This study investigates the effect of selenium (as sodium selenite and as a selenium dietary supplements--Celnium) on the oxidative stress in Wistar rats which received high doses of acrylamide. The administration of sodium selenite and selenium dietary supplements (Celnium) significantly increased GSH and GPx levels and decreased MDA compared to group which received only acrylamide. Our results show that sodium selenite and selenium dietary supplements (Celnium) can partially prevent the biochemical changes in the liver of the rats which received high doses of acrylamide.

Correlation between measles vaccine doses: implications for the maintenance of elimination.

PubMed

McKee, A; Ferrari, M J; Shea, K

2018-03-01

Measles eradication efforts have been successful at achieving elimination in many countries worldwide. Such countries actively work to maintain this elimination by continuing to improve coverage of two routine doses of measles vaccine following measles elimination. While improving measles vaccine coverage is always beneficial, we show, using a steady-state analysis of a dynamical model, that the correlation between populations receiving the first and second routine dose also has a significant impact on the population immunity achieved by a specified combination of first and second dose coverage. If the second dose is administered to people independently of whether they had the first dose, high second-dose coverage improves the proportion of the population receiving at least one dose, and will have a large effect on population immunity. If the second dose is administered only to people who have had the first dose, high second-dose coverage reduces the rate of primary vaccine failure, but does not reach people who missed the first dose; this will therefore have a relatively small effect on population immunity. When doses are administered dependently, and assuming the first dose has higher coverage, increasing the coverage of the first dose has a larger impact on population immunity than does increasing the coverage of the second. Correlation between vaccine doses has a significant impact on the level of population immunity maintained by current vaccination coverage, potentially outweighing the effects of age structure and, in some cases, recent improvements in vaccine coverage. It is therefore important to understand the correlation between vaccine doses as such correlation may have a large impact on the effectiveness of measles vaccination strategies.

Antibiotic dosing in critically ill patients receiving CRRT: underdosing is overprevalent.

PubMed

Lewis, Susan J; Mueller, Bruce A

2014-01-01

Published CRRT drug dosing algorithms and other dosing guidelines appear to result in underdosed antibiotics, leading to failure to attain pharmacodynamic targets. High mortality rates persist with inadequate antibiotic therapy as the most important risk factor for death. Reasons for unintended antibiotic underdosing in patients receiving CRRT are many. Underdosing may result from lack of the recognition that better hepatic function in AKI patients yields higher nonrenal antibiotic clearance compared to ESRD patients. Other factors include the variability in body size and fluid composition of patients, the serious consequence of delayed achievement of antibiotic pharmacodynamic targets in septic patients, potential subtherapeutic antibiotic concentrations at the infection site, and the influence of RRT intensity on antibiotic concentrations. Too often, clinicians weigh the benefits of overcautious antibiotic dosing to avoid antibiotic toxicity too heavily against the benefits of rapid attainment of therapeutic antibiotic concentrations in critically ill patients receiving CRRT. We urge clinicians to prescribe antibiotics aggressively for these vulnerable patients. © 2014 Wiley Periodicals, Inc.

Serum tocopherol levels in very preterm infants after a single dose of vitamin E at birth.

PubMed

Bell, Edward F; Hansen, Nellie I; Brion, Luc P; Ehrenkranz, Richard A; Kennedy, Kathleen A; Walsh, Michele C; Shankaran, Seetha; Acarregui, Michael J; Johnson, Karen J; Hale, Ellen C; Messina, Lynn A; Crawford, Margaret M; Laptook, Abbot R; Goldberg, Ronald N; Van Meurs, Krisa P; Carlo, Waldemar A; Poindexter, Brenda B; Faix, Roger G; Carlton, David P; Watterberg, Kristi L; Ellsbury, Dan L; Das, Abhik; Higgins, Rosemary D

2013-12-01

Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage. Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing. Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs. 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL. A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

Radiation optic neuropathy after megavoltage external-beam irradiation: Analysis of time-dose factors

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

Parsons, J.T.; Bova, F.J.; Million, R.R.

1994-11-15

To investigate the risk of radiation-induced optic neuropathy according to total radiotherapy dose and fraction size, based on both retrospective and prospectively collected data. Between October 1964 and May 1989, 215 optic nerves in 131 patients received fractionated external-beam irradiation during the treatment of primary extracranial head and neck tumors. All patients had a minimum of 3 years of ophthalmologic follow-up (range, 3 to 21 years). The clinical end point was visual acuity of 20/100 or worse as a result of optic nerve injury. Anterior ischemic optic neuropathy developed in five nerves (at mean and median times of 32 andmore » 30 months, respectively, and a range of 2-4 years). Retrobulbar optic neuropathy developed in 12 nerves (at mean and median times of 47 and 28 months, respectively, and a range of 1-14 years). No injuries were observed in 106 optic nerves that received a total dose of <59 Gy. Among nerves that received doses of {ge} 60 Gy, the dose per fraction was more important than the total dose in producing optic neuropathy. The 15-year actuarial risk of optic compared with 47% when given in fraction sizes {ge}1.9 Gy. The data also suggest an increased risk of optic nerve injury with increasing age. As there is no effective treatment of radiation-induced optic neuropathy, efforts should be directed at its prevention by minimizing the total dose, paying attention to the dose per fraction to the nerve, and using reduced field techniques where appropriate to limit the volume of tissues that receive high-dose irradiation. 32 refs., 5 figs., 5 tabs.« less

Clinical and Immune Responses to Inactivated Influenza A(H1N1)pdm09 Vaccine in Children

PubMed Central

Kotloff, Karen L.; Halasa, Natasha B.; Harrison, Christopher J.; Englund, Janet A.; Walter, Emmanuel B.; King, James C.; Creech, C. Buddy; Healy, Sara A.; Dolor, Rowena J.; Stephens, Ina; Edwards, Kathryn M.; Noah, Diana L.; Hill, Heather; Wolff, Mark

2014-01-01

Background As the influenza AH1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years. Methods Children received two doses of approximately 15 μg or 30 μg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition (HAI) titers were measured on days 0 (pre-vaccination), 8, 21, 29, and 42. Results A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 μg dosage elicited a seroprotective HAI (≥1:40) in 20%, 47%, and 93% of children in the 6-35 month, 3-9 year, and 10-17 year age strata 21 days after dose 1 and in 78%, 82%, and 98% of children 21 days after dose 2, respectively. The 30 μg vaccine dosage induced similar responses. Conclusions The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 μg dose induced seroprotective antibody responses in most 10-17 year olds, younger children required 2 doses, even when receiving dosages 4-6 fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics. PMID:25222307

Gabapentin pharmacotherapy for antipsychotic-induced akathisia: single-patient experiment and case report.

PubMed

Sullivan, Maria A; Wilbur, Robert

2014-04-01

This clinical study reports upon the efficacy of gabapentin (Neurontin) for treating severe akathisia (3 on the Barnes Akathisia Rating Scale) in two patients receiving quetiapine (Seroquel), one of whom also received olanzapine (Zyprexa) for a short period. The first patient participated in an open-label experiment in which the bedtime dose of gabapentin was discontinued three times at intervals 1 week apart, resulting in severe akathisia which was quickly terminated by taking his usual 1200 mg gabapentin dose. This patient was also taking high doses of two benzodiazepines and a beta blocker, without therapeutic effect upon his akathisia; only gabapentin was efficacious. The second case is a report of a woman taking a high dose of quetiapine for anxiety who experienced severe akathisia which was relieved by taking 1200 mg of gabapentin. Possible mechanisms of action of gabapentin are discussed. Particular attention is drawn to the difference between neuroleptic-induced akathisia and the neurological condition of restless legs syndrome.

Influence of exposure and geometric parameters on absorbed doses associated with common neuro-interventional procedures.

PubMed

Safari, Mohammad Javad; Wong, Jeannie Hsiu Ding; Jong, Wei Loong; Thorpe, Nathan; Cutajar, Dean; Rosenfeld, Anatoly; Ng, Kwan Hoong

2017-03-01

The purpose of this study was to investigate the effects of routine exposure parameters on patient's dose during neuro-interventional radiology procedures. We scrutinized the routine radiological exposure parameters during 58 clinical neuro-interventional procedures such as, exposure direction, magnification, frame rate, and distance between image receptor to patient's body and evaluate their effects on patient's dose using an anthropomorphic phantom. Radiation dose received by the occipital region, ears and eyes of the phantom were measured using MOSkin detectors. DSA imaging technique is a major contributor to patient's dose (80.9%) even though they are used sparingly (5.3% of total frame number). The occipital region of the brain received high dose largely from the frontal tube constantly placed under couch (73.7% of the total KAP). When rotating the frontal tube away from under the couch, the radiation dose to the occipital reduced by 40%. The use of magnification modes could increase radiation dose by 94%. Changing the image receptor to the phantom surface distance from 10 to 40cm doubled the radiation dose received by the patient's skin at the occipital region. Our findings provided important insights into the contribution of selected fluoroscopic exposure parameters and their impact on patient's dose during neuro-interventional radiology procedures. This study showed that the DSA imaging technique contributed to the highest patient's dose and judicial use of exposure parameters might assist interventional radiologists in effective skin and eye lens dose reduction for patients undergoing neuro-interventional procedures. Copyright © 2017 Associazione Italiana di Fisica Medica. All rights reserved.

Waning immunity of one-dose measles-mumps-rubella vaccine to mumps in children from kindergarten to early school age: a prospective study.

PubMed

Liu, Yuanbao; Liu, Zhihao; Deng, Xiuying; Hu, Ying; Wang, Zhiguo; Lu, Peishan; Guo, Hongxiong; Sun, Xiang; Xu, Yan; Tang, Fenyang; Zhu, Feng-Cai

2018-05-01

In China, one dose measles-mumps-rubella vaccine (MMR) was administered to children aged 18-24 months. The mumps incidence was still high. Data on the waning immunity to mumps after MMR vaccination are limited. This study aimed to describe the waning immunity to mumps in kindergarten and primary school children to provide a scientific basis for confirming an optimal age for a second dose. An observational, prospective study on one-dose MMR in children in kindergarten and primary school was conducted from 2015 to 2016. Waning immunity to mumps in terms of seropositivity and geometric antibody concentration (GMC) with time was analyzed. In total, 7436 eligible subjects in kindergarten (3435) and primary school (4001) were included in 2015. The overall GMC (201.7 U/ml) and seropositivity (75.4%) to mumps antibodies in 2016 were significantly lower compared to those in 2015 (218.7 U/ml, 78.4%). Asymptomatic infection occurred within one year in 8.8% of children who received one-dose MMR. Children who received one-dose MMR in kindergarten and primary school were at high risk of mumps infection, and waning immunity occurred with time. Determining the optimal age for the second dose of MMR in children should be prioritized to prevent mumps epidemics.

Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients.

PubMed

Reichel, Felix F; Peters, Tobias; Wilhelm, Barbara; Biel, Martin; Ueffing, Marius; Wissinger, Bernd; Bartz-Schmidt, Karl U; Klein, Reinhild; Michalakis, Stylianos; Fischer, M Dominik

2018-04-01

To study longitudinal changes of anti-drug antibody (ADA) titers to recombinant adeno-associated virus serotype 8 (rAAV8) capsid epitopes in nonhuman primates (NHP) and patients. Three groups of six NHP each received subretinal injections (high dose: 1 × 1012 vector genomes [vg], low dose: 1 × 1011 vg, or vehicle only). Four additional animals received intravitreal injections of the high dose (1 × 1012 vg). Three patients received 1 × 1010 vg as subretinal injections. ELISA quantified ADA levels at baseline and 1, 2, 3, 7, 28, and 90 days after surgery in NHP and at baseline and 1, 3, and 6 months after surgery in patients. Two out of 22 animals lacked ADA titers at baseline and developed low ADA titers toward the end of the study. Titers in the low-dose group stayed constant, while two of six animals from the high-dose group developed titers that rose beyond the range of the assay. All animals from the intravitreal control group showed a rise in ADA titer by day 7 that peaked at day 28. Preliminary data from the clinical trial (NCT02610582) show no humoral immune response in patients following subretinal delivery of 1 × 1010 vg. No significant induction of ADA occurred in NHP when mimicking the clinical scenario of subretinal delivery with a clinical-grade rAAV8 and concomitant immunosuppression. Likewise, clinical data showed no humoral immune response in patients. In contrast, intravitreal delivery was associated with a substantial humoral immune response. Subretinal delivery might be superior to an intravitreal application regarding immunologic aspects.

The use of TLD-700H dosemeters in the assessment of external doses at the former Semipalatinsk nuclear test site.

PubMed

Hill, P; Dederichs, H; Pillath, J; Schlecht, W; Hille, R; Artemev, O; Ptitskaya, L; Akhmetov, M

2002-01-01

The joint projects performed since 1995 by the Jülich Research Centre in co-operation with the Kazakh National Nuclear Centre in the area of the former nuclear test site near Semipalatinsk, in eastern Kazakhstan, have assessed the current dose rate of the population at and around the test site, as well as determining retrospectively the dose rate of persons affected by the atmospheric tests. Measurements of the population by personal dosemeters depend on reliably wearing these dosemeters over prolonged periods of time, and of a sufficient dosemeter return. In the past, such measurements have been particularly successful whenever short wearing times were possible. This requires high sensitivity of the dosemeters. The suitability of the highly sensitive TLD material of the BICRON TLD 700H type for such personal dosimetry measurements was investigated. It was tested in practical field application at the Semipalatinsk nuclear test site in September 2000. Initial results are available from individual doses received by a group of geologists and a group of herdsmen at the test site. For the first time, the individual dose was measured directly in these population groups. Detection limits below 1 microSv permit informative measurements for wearing times of less than two weeks. Most individual doses did not arise significantly out of local fluctuations of natural background. A conservative assessment from the aspect of practical health physics yielded a mean personal dose of 0.55 microSv per day for the herdsmen, whereas the geologists received a mean personal dose of 0.45 microSv per day. For an annual exposure period of typically, about three months, the radiation dose received by the persons investigated, in addition to the natural radiation exposure, is thus well below the international limit value of 1 mSv x a(-1) for the population dose.

Real-life GH dosing patterns in children with GHD, TS or born SGA: a report from the NordiNet® International Outcome Study

PubMed Central

Snajderova, Marta; Blair, Jo; Pournara, Effie; Pedersen, Birgitte Tønnes; Petit, Isabelle Oliver

2017-01-01

Objective To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016. Design This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n = 425/61/316/119), France (n = 1404/188/970/206), Germany (n = 2603/351/1387/411) and the UK (n = 259/60/87/35). Methods GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications. Results In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown (P < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%). Conclusions GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations. PMID:28522645

Long-term results of high-dose conformal radiotherapy for patients with medically inoperable T1-3N0 non-small-cell lung cancer: is low incidence of regional failure due to incidental nodal irradiation?

PubMed

Chen, Ming; Hayman, James A; Ten Haken, Randall K; Tatro, Daniel; Fernando, Shaneli; Kong, Feng-Ming

2006-01-01

To report the results of high-dose conformal irradiation and examine incidental nodal irradiation and nodal failure in patients with inoperable early-stage non-small-cell lung cancer (NSCLC). This analysis included patients with inoperable CT-staged T1-3N0M0 NSCLC treated on our prospective dose-escalation trial. Patients were treated with radiation alone (total dose, 63-102.9 Gy in 2.1-Gy daily fractions) with a three-dimensional conformal technique without intentional nodal irradiation. Bilateral highest mediastinal and upper/lower paratracheal, prevascular and retrotracheal, sub- and para-aortic, subcarinal, paraesophageal, and ipsilateral hilar regions were delineated individually. Nodal failure and doses of incidental irradiation were studied. The potential median follow-up was 104 months. For patients who completed protocol treatment, median survival was 31 months. The actuarial overall survival rate was 86%, 61%, 43%, and 21% and the cause-specific survival rate was 89%, 70%, 53%, and 35% at 1, 2, 3, and 5 years, respectively. Weight loss (p = 0.008) and radiation dose in Gy (p = 0.013) were significantly associated with overall survival. In only 22% and 13% of patients examined did ipsilateral hilar and paratracheal (and subaortic for left-sided tumor) nodal regions receive a dose of > or = 40 Gy, respectively. Less than 10% of all other nodal regions received a dose of > or = 40 Gy. No patients failed initially at nodal sites. Radiation dose is positively associated with overall survival in patients with medically inoperable T1-3N0 NSCLC, though long-term results remain poor. The nodal failure rate is low and does not seem to be due to high-dose incidental irradiation.

Method for microbeam radiation therapy

DOEpatents

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

1994-08-16

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

Efficacy and Tolerability of High-Dose Escitalopram in Posttraumatic Stress Disorder.

PubMed

Qi, Wei; Gevonden, Martin; Shalev, Arieh

2017-02-01

Open-label trials suggest that escitalopram (up to 20 mg/d) is an effective treatment for some, but not all posttraumatic stress disorder (PTSD) patients. Higher doses of escitalopram effectively reduced major depression symptoms in patients who had not responded to regular doses. The current study examines the efficacy, tolerability, and adherence to high-dose escitalopram in PTSD. Forty-five PTSD patients received 12 weeks of gradually increasing doses of escitalopram reaching 40 mg daily at 4 weeks. Among those, 12 participants received regular doses of antidepressants at study onset including escitalopram (n = 7). The Clinician-Administered PTSD Scale (CAPS) evaluated PTSD symptoms severity before treatment, at 3 months (upon treatment termination), and at 6 months (maintenance effect). A 20% reduction in CAPS scores was deemed clinically significant. Adverse events and medication adherence were monitored at each clinical session. Linear mixed-models analysis showed a significant reduction of mean CAPS scores (11.5 ± 18.1 points) at 3 months and maintenance of gains by 6 months (F2,34.56 = 8.15, P = 0.001). Eleven participants (34.3%) showed clinically significant improvement at 3 months. Only 9 participants (20%) left the study. There were no serious adverse events and few mild ones with only 2 adverse events (diarrhea, 11.1%; drowsiness, 11.1%) reported by more than 10% of participants. High doses of escitalopram are tolerable and well adhered to in PTSD. Their beneficial effect at a group level is due to a particularly good response in a subset of patients.Variability in prior pharmacological treatment precludes a definite attribution of the results to high doses of escitalopram.

Medical management with diazepam for electrical status epilepticus during slow wave sleep in children.

PubMed

Francois, Densley; Roberts, Jessica; Hess, Stephany; Probst, Luke; Eksioglu, Yaman

2014-03-01

Oral diazepam, administered in varying doses, is among the few proposed treatment options for electrical status epilepticus during slow wave sleep in children. We sought to retrospectively evaluate the long-term efficacy of high-dose oral diazepam in reducing electrographic and clinical evidence of electrical status epilepticus during slow wave sleep in children. Additionally, we surveyed caregivers to assess safety and behavioral outcomes related to ongoing therapy. We collected demographic and clinical data on children treated for electrical status epilepticus during slow wave sleep between October 2010 and March 2013. We sought to identify the number of patients who achieved at least a 50% reduction in spike wave index on electroencephalograph after receiving high-dose oral diazepam. We also administered a questionnaire to caregivers to assess for behavioral problems and side effects. We identified 42 evaluable patients who received high-dose diazepam (range 0.23-2.02 mg/kg per day) to treat electrical status epilepticus during slow wave sleep. Twenty-six patients had spike reduction data and 18/26 (69.2%) children achieved a greater than 50% reduction in spike wave count from an average of 15.54 to 5.05 (P = 0.001). We received 28 responses to the questionnaire. Some patients experienced new onset of difficulties with problem-solving and speech and writing development. Sleep disturbances (50%) and irritability (57.1%) were the most frequent side effects reported. There did not appear to be a dose-related effect with electroencephalograph changes, behavioral effects, or side effects. High-dose oral diazepam significantly reduces the spike wave count on electroencephalograph in children with electrical status epilepticus during slow wave sleep. Although this therapy improves electroencephalograph-related findings, it can be associated with concerning neurological and behavioral side effects in some individuals, so further study is warranted. Copyright © 2014 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.

Patterns of zolpidem use among Iraq and Afghanistan veterans: A retrospective cohort analysis

PubMed Central

Amuan, Megan E.; Jaramillo, Carlos A.; Eapen, Blessen C.

2018-01-01

Background Although concern exists regarding the adverse effects and rate of zolpidem use, especially long-term use, limited information is available concerning patterns of zolpidem use. Objective To examine the prevalence and correlates of zolpidem exposure in Iraq and Afghanistan Veterans (IAVs). Methods A retrospective cohort study of zolpidem prescriptions was performed with National Veterans Health Administration (VHA) data. We gathered national VA inpatient, outpatient, and pharmacy data files for IAV’s who received VA care between fiscal years (FY) 2013 and 2014. The VA pharmacy database was used to identify the prevalence of long term (>30 days), high-dose zolpidem exposure (>10mg immediate-release; >12.5mg extended-release) and other medications received in FY14. Baseline characteristics (demographics, diagnoses) were identified in FY13. Bivariate and multivariable analyses were used to examine the demographic, clinical, and medication correlates of zolpidem use. Results Of 493,683 IAVs who received VHA care in FY 2013 and 2014, 7.6% (n = 37,422) were prescribed zolpidem in FY 2014. Women had lower odds of high-dose zolpidem exposure than men. The majority (77.3%) of IAVs who received zolpidem prescriptions had long-term use with an average days’ supply of 189.3 days and a minority (0.9%) had high-dose exposure. In multivariable analyses, factors associated with long-term zolpidem exposure included age greater than 29 years old, PTSD, insomnia, Selim Index, physical 2–3 conditions, opioids, antidepressants, benzodiazepines, atypical antipsychotics, and stimulants. High dose exposure was associated with PTSD, depression, substance use disorder, insomnia, benzodiazepines, atypical antipsychotics, and stimulant prescriptions. Conclusion The current practices of insomnia pharmacotherapy in IAVs fall short of the clinical guidelines and may reflect high-risk zolpidem prescribing practices that put Iraq and Afghanistan Veterans at risk for adverse effects of zolpidem and poor health outcomes. PMID:29360821

Animal Studies of Residual Hematopoietic and Immune System Injury from Low Dose/Low Dose Rate Radiation and Heavy Metals.

DTIC Science & Technology

1998-09-01

accidents and industrial accidents (e.g., Chernobyl ) who receive high doses of radiation over a relatively short period of time, there are thousands of...several years after exposure may have been terminated. Examples of such groups include those affected by the fallout near Chernobyl , those living near...cohorts (e.g., Chernobyl victims) particular damage from low dose irradiation, especially membrane damage and mismatched DNA repair. Dosimetric Problems

TU-AB-201-06: Evaluation of Electromagnetically Guided High- Dose Rate Brachytherapy for Ablative Treatment of Lung Metastases

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

Pinkham, D.W.; Shultz, D.; Loo, B.W.

Purpose: The advent of electromagnetic navigation bronchoscopy has enabled minimally invasive access to peripheral lung tumors previously inaccessible by optical bronchoscopes. As an adjunct to Stereotactic Ablative Radiosurgery (SABR), implantation of HDR catheters can provide focal treatments for multiple metastases and sites of retreatments. The authors evaluate a procedure to deliver ablative doses via Electromagnetically-Guided HDR (EMG-HDR) to lung metastases, quantify the resulting dosimetry, and assess its role in the comprehensive treatment of lung cancer. Methods: A retrospective study was conducted on ten patients, who, from 2009 to 2011, received a hypo-fractionated SABR regimen with 6MV VMAT to lesions inmore » various lobes ranging from 1.5 to 20 cc in volume. A CT visible pathway was delineated for EM guided placement of an HDR applicator (catheter) and dwell times were optimized to ensure at least 98% prescription dose coverage of the GTV. Normal tissue doses were calculated using inhomogeneity corrections via a grid-based Boltzmann solver (Acuros-BV-1.5.0). Results: With EMG-HDR, an average of 83% (+/−9% standard deviation) of each patient’s GTV received over 200% of the prescription dose, as compared to SABR where the patients received an average maximum dose of 125% (+/−5%). EMG-HDR enabled a 59% (+/−12%) decrease in the aorta maximum dose, a 63% (+/−26%) decrease in the spinal cord max dose, and 57% (+/−23%) and 70% (+/−17%) decreases in the volume of the body receiving over 50% and 25% of the prescription dose, respectively. Conclusion: EMG-HDR enables delivery of higher ablative doses to the GTV, while concurrently reducing surrounding normal tissue doses. The single catheter approach shown here is limited to targets smaller than 20 cc. As such, the technique enables ablation of small lesions and a potentially safe and effective retreatment option in situations where external beam utility is limited by normal tissue constraints.« less

Comparison of high-dose intermittent and low-dose continuous oral artemisinin in dogs with naturally occurring tumors.

PubMed

Hosoya, Kenji; Couto, C Guillermo; London, Cheryl A; Kisseberth, William C; Phelps, Mitchell A; Dalton, James T

2014-01-01

To evaluate the clinical toxicity and activity of orally administered artemisinin in dogs with spontaneous tumors, 24 client-owned dogs were randomly divided into two groups and received either low-continuous dose (3 mg/kg q 24 hr) or high-dose intermittent (three doses of 45 mg/kg q 6 hr repeated q 1 wk) of artemisinin per os. Treatment was continued for 21 days. Dogs were evaluated weekly for clinical effect and at the end of the treatment for hematologic and biochemical adverse events. Whole blood concentrations of artemisinin and dihydroartemisinin were measured by liquid chromatography/tandem mass spectrometry after the first dose of artemisinin in three dogs in each group. Blood concentrations of artemisinin and dihydroartemisinin were <0.1 μM at all time points, and there was no difference in blood concentration between the two dosing groups. The most frequent adverse event was anorexia, which was observed in 11% of the low-dose group and 29% of the high-dose group. Oral artemisinin, both in low-dose continuous and high-dose intermittent, is well tolerated in dogs but results in low bioavailability. Parenteral administration should be considered for future studies.

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

PubMed

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

2015-10-13

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

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

PubMed Central

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

2015-01-01

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

The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu-DOTATOC.

PubMed

Schuchardt, Christiane; Kulkarni, Harshad R; Prasad, Vikas; Zachert, Carolin; Müller, Dirk; Baum, Richard P

2013-01-01

The objective of this study is to analyze the in vivo behavior of the (177)Lu-labeled peptides DOTATATE, DOTANOC, and DOTATOC used for peptide receptor radionuclide therapy (PRRNT) of neuroendocrine tumors (NETs), by measuring organ and tumor kinetics and by performing dosimetric calculations. Two hundred fifty-three patients (group 1) with metastasized NET who underwent PRRNT were examined. Out of these, 185 patients received (177)Lu-DOTATATE, 9 were treated with (177)Lu-DOTANOC, and 59 with (177)Lu-DOTATOC. Additionally, 25 patients receiving, in consecutive PRRNT cycles, DOTATATE followed by DOTATOC (group 2) and 3 patients receiving DOTATATE and DOTANOC (group 3) were analyzed. Dosimetric calculations (according to MIRD scheme) were performed using OLINDA software. In group 1, DOTATOC exhibited the lowest and DOTANOC the highest uptake and therefore mean absorbed dose in normal organs (whole body, kidney, and spleen). In group 2, there was a significant difference between DOTATATE and DOTATOC concerning kinetics and normal organ doses. (177)Lu-DOTATOC had the lowest uptake/dose delivered to normal organs and highest tumor-to-kidney ratio. There were no significant differences between the three peptides concerning tumor kinetics and mean absorbed tumor dose. The study demonstrates a correlation between high affinity of DOTANOC in vitro and high uptake in normal organs/whole body in vivo, resulting in a higher whole-body dose. DOTATOC exhibited the lowest uptake and dose delivered to normal tissues and the best tumor-to-kidney ratio. Due to large interpatient variability, individual dosimetry should be performed for each therapy cycle.

High Dose Hyperfractionated Radiotherapy for Adults with Glioblastomas

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

Koukourakis, Michael; Scarlatos, John; Yiannakakis, Dimitrios

2015-01-15

From 1989 to 1991, 27 patients with glioblastoma multiforme or anaplastic astrocytoma of the brain were treated with radiotherapy. Fifteen of twenty-seven patients were treated through limited volume fields, with a thrice-a-day (1.1 Gy/f) or twice-a-day (1.4 Gy/f) hyperfractionated regimen to a total physical dose of 62–92 Gy (median dose 76 Gy). The remaining 12 were treated with whole brain irradiation (40 Gy of total conventionally fractionated dose) and a localised boost to a total dose of 60 Gy. The hyperfractionated regimen was well tolerated and there was no sign of increased brain oedema to indicate the insertion of amore » split. Of six patients who received a NTD10 (normalised total dose for α/β =10) higher than 71 Gy, five showed CR (83% CR rate) versus three of 21 patients who received a lower NTD10 (14% CR rate). For 13 patients who received a NTD10 higher than 66 Gy, the 18-months survival was 61% (8/13) versus 28% (4/14) for 14 patients who received a NTD10 less than 66 Gy. As far as the late morbidity is concerned, of six patients treated with 76-92 Gy of physical dose, none died because of radiation-induced brain necrosis within 18-42 months of follow-up, and three of them are without evidence of disease 18-31 months after the end of radiation treatment. None of our 15 patients who received less than whole brain irradiation relapsed outside the radiation portals. The present study strongly suggests the use of limited volume hyperfractionated radiotherapy schemes, so as to increase the local tumor dose (NTD10) to values higher than 79 Gy, at the same time keeping the NTD2 (NTD for α/β = 2) below 68 Gy.« less

Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study.

PubMed

Furlanetto, J; Eiermann, W; Marmé, F; Reimer, T; Reinisch, M; Schmatloch, S; Stickeler, E; Thomssen, C; Untch, M; Denkert, C; von Minckwitz, G; Lederer, B; Nekljudova, V; Weber, K; Loibl, S; Möbus, V

2016-11-01

In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m 2 or adjusted to an ideal weight for obese patients due to safety reasons. Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of ≥30 for safety and outcome. Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m 2 . A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications. © The Author 2016. 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.

Texture analysis of T1-w and T2-w MR images allows a quantitative evaluation of radiation-induced changes of internal obturator muscles after radiotherapy for prostate cancer.

PubMed

Scalco, Elisa; Rancati, Tiziana; Pirovano, Ileana; Mastropietro, Alfonso; Palorini, Federica; Cicchetti, Alessandro; Messina, Antonella; Avuzzi, Barbara; Valdagni, Riccardo; Rizzo, Giovanna

2018-04-01

To investigate the potential of texture analysis applied on T2-w and postcontrast T1-w images acquired before radiotherapy for prostate cancer (PCa) and 12 months after its completion in quantitatively characterizing local radiation effect on the muscular component of internal obturators, as organs potentially involved in urinary toxicity. T2-w and postcontrast T1-w MR images were acquired at 1.5 T before treatment (MRI1) and at 12 months of follow-up (MRI2) in 13 patients treated with radiotherapy for PCa. Right and left internal obturator muscle contours were manually delineated upon MRI1 and then automatically propagated on MRI2 by an elastic registration method. Planning CT images were coregistered to both MRIs and dose maps were deformed accordingly. A high-dose region receiving >55 Gy and a low-dose region receiving <55 Gy were identified in each muscle volume. Eighteen textural features were extracted from each region of interest and differences between MRI1 and MRI2 were evaluated. A signal increase was highlighted in both T2-w and T1-w images in the portion of the obturators near the prostate, i.e., in the region receiving medium-high doses. A change in the spatial organization was identified, as an increase in homogeneity and a decrease in contrast and complexity, compatible with an inflammatory status. In particular, the region receiving medium-high doses presented more significant or, at least, stronger differences. Texture analysis applied on T1-w and T2-w MR images has demonstrated its ability in quantitative evaluating radiation-induced changes in obturator muscles after PCa radiotherapy. © 2018 American Association of Physicists in Medicine.

Long-term effectiveness of plasma-derived hepatitis B vaccine 22-28 years after immunization in a hepatitis B virus endemic rural area: is an adult booster dose needed?

PubMed

Li, H; Li, G J; Chen, Q Y; Fang, Z L; Wang, X Y; Tan, C; Yang, Q L; Wang, F Z; Wang, F; Zhang, S; Bi, S L; Shen, L P

2017-04-01

Longan County is considered a highly endemic area for hepatitis B virus (HBV). The plasma-derived vaccine has been used in newborns in this area since 1987. A cross-sectional survey was conducted to evaluate the long-term effectiveness of this vaccine. In total, 1634 participants born during 1987-1993 and who had received a series of plasma-derived HB vaccinations at ages 0, 1, and 6 months were enrolled. Serological HBV markers were detected and compared with previous survey data. Overall the prevalence of hepatitis B surface antigen (HBsAg) in all participants was 3·79%; 3·47% of subjects who had received the first dose within 24 h were HBsAg positive, and 8·41% of subjects who had received a delayed first dose were also HBsAg positive. There were 1527 subjects identified who had received the first dose within 24 h and whose HBsAg and anti-HBc prevalence increased yearly after immunization, while the anti-HBs-positive rate and vaccine effectiveness declined. The geometric mean concentration of antibody in the anti-HB-positive participants was 55·13 mIU/ml and this declined after immunization. Fewer than 2·0% of participants had anti-HB levels ⩾1000 mIU/ml. The data show that the protective efficacy of the plasma-derived vaccinations declined and administration of HB vaccine within 24 h of birth was very important. To reduce the risk of HBV infection in this highly endemic area, a booster dose might be necessary if anti-HBs levels fall below 10 mIU/ml after age 18 years. Furthermore, studies on the immune memory induced by plasma-derived HB vaccine are needed.

Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols.

PubMed

Nichols, C R; Breeden, E S; Loehrer, P J; Williams, S D; Einhorn, L H

1993-01-06

Case reports have suggested that treatment with high-dose etoposide can result in development of a unique secondary leukemia. This study was designed to estimate the risk of developing leukemia for patients receiving conventional doses of etoposide along with cisplatin and bleomycin. We reviewed the records at Indiana University of all untreated patients entering clinical trials using etoposide at conventional doses (cumulative dose, 2000 mg/m2 or less) for germ cell cancer between 1982 and 1991. The records of all patients who received a chemotherapy regimen containing etoposide, ifosfamide, or cisplatin after failing to respond to primary chemotherapy were also reviewed. Between 1982 and 1991, 538 patients entered serial clinical trials with planned cumulative etoposide doses of 1500-2000 mg/m2 in combination with cisplatin plus either ifosfamide or bleomycin. Of these 538 patients, 348 received an etoposide combination as initial chemotherapy and 190 received etoposide as part of salvage treatment. To date, 315 patients are alive, with median follow-up of 4.9 years, and 337 patients have had follow-up beyond 2 years. Two patients (0.37%) developed leukemia. One developed acute undifferentiated leukemia with a t(4;11) (q21;q23) cytogenetic abnormality 2.0 years after starting etoposide-based therapy, and one developed acute myelomonoblastic leukemia with no chromosome abnormalities 2.3 years after beginning chemotherapy. During this period, several hundred patients were treated with etoposide-based chemotherapy and did not enter clinical trials. Three of these patients are known to have developed hematologic abnormalities, including one patient with acute monoblastic leukemia with a t(11;19)(q13;p13) abnormality. Secondary leukemia after treatment with a conventional dose of etoposide does occur, but the low incidence does not alter the risk-to-benefit ratio of etoposide-based chemotherapy in germ cell cancer. The reports of leukemia associated with high doses of etoposide emphasize the need for diligent follow-up of patients and make careful risk-to-benefit analysis imperative.

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

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.

Trends in opioid use and dosing among socio-economically disadvantaged patients

PubMed Central

Gomes, Tara; Juurlink, David N; Dhalla, Irfan A; Mailis-Gagnon, Angela; Paterson, J Michael; Mamdani, Muhammad M

2011-01-01

Background Opioid therapy for patients with chronic nonmalignant pain remains controversial, primarily because of safety concerns and the potential for abuse. The objective of this study was to examine trends in opioid utilization for nonmalignant pain among recipients of social assistance and to explore the relation between dose of analgesic and mortality. Methods Using a cross-sectional study design, we characterized annual trends in prescriptions for and daily dose of opioid analgesics between 2003 and 2008 for beneficiaries (aged 15 to 64 years) of Ontario’s public drug plan. We defined moderate, high and very high dose thresholds as daily doses of up to 200, 201 to 400, and more than 400 mg oral morphine (or equivalent), respectively. In an exploratory cohort study, we followed, over a 2-year period, patients who received at least one prescription for an opioid in 2004 to investigate the relation between opioid dose and opioid-related mortality. Results Over the study period, opioid prescribing rates rose by 16.2%, and 180 974 individuals received nearly 1.5 million opioid prescriptions in 2008. Also by 2008, the daily dose dispensed exceeded 200 mg morphine equivalent for almost a third (32.6%) of recipients of long-acting oxycodone but only 20.3% of those treated with fentanyl or other long-acting opioids. Among patients for whom high or very high doses of opioids were dispensed in 2004, 19.3% of deaths during the subsequent 2 years were opioid-related, occurring at a median age of 46 years. Two-year opioid-related mortality rates were 1.63 per 1000 population (95% confidence interval [CI] 1.42–1.85) among people with moderate-dose prescriptions, 7.92 per 1000 population (95% CI 5.25–11.49) among those with high-dose prescriptions, and 9.94 per 1000 population (95% CI 2.78–25.12) among those with very-high-dose prescriptions. Interpretation Among socio-economically disadvantaged patients in Ontario, the use and dose of opioids for nonmalignant pain has increased substantially, driven primarily by the use of long-acting oxycodone and, to a lesser extent, fentanyl. The findings of our exploratory study suggested a strong association between opioid-related mortality and the dose of opioid dispensed. PMID:22046214

[Clinical application of high-pitch excretory phase images during dual-source CT urography with stellar photon detector].

PubMed

Sun, Hao; Xue, Hua-dan; Jin, Zheng-yu; Wang, Xuan; Chen, Yu; He, Yong-lan; Zhang, Da-ming; Zhu, Liang; Wang, Yun; Qi, Bing; Xu, Kai; Wang, Ming

2014-10-01

To retrospectively evaluate the clinical feasibility of high-pitch excretory phase images during dual-source CT urography with Stellar photon detector. Totally 100 patients received dual-source CT high-pitch urinary excretory phase scanning with Stellar photon detector [80 kV, ref.92 mAs, CARE Dose 4D and CARE kV, pitch of 3.0, filter back projection reconstruction algorithm (FBP)] (group A). Another 100 patients received dual-source CT high-pitch urinary excretory phase scanning with common detector(100 kV, ref.140 mAs, CARE Dose 4D, pitch of 3.0, FBP) (group B). Quantitative measurement of CT value of urinary segments (Hounsfield units), image noise (Hounsfield units), and effective radiation dose (millisievert) were compared using independent-samples t test between two groups. Urinary system subjective opacification scores were compared using Mann-Whitney U test between two groups. There was no significant difference in subjective opacification score of intrarenal collecting system and ureters between two groups (all P>0.05). The group A images yielded significantly higher CT values of all urinary segments (all P<0.01). There was no significant difference in image noise (P>0.05). The effective radiation dose of group A (1.1 mSv) was significantly lower than that of group B (3.79 mSv) (P<0.01). High-pitch low-tube-voltage during excretory phase dual-source CT urography with Stellar photon detector is feasible, with acceptable image noise and lower radiation dose.

Chimpanzee Adenovirus Vector Ebola Vaccine.

PubMed

Ledgerwood, Julie E; DeZure, Adam D; Stanley, Daphne A; Coates, Emily E; Novik, Laura; Enama, Mary E; Berkowitz, Nina M; Hu, Zonghui; Joshi, Gyan; Ploquin, Aurélie; Sitar, Sandra; Gordon, Ingelise J; Plummer, Sarah A; Holman, LaSonji A; Hendel, Cynthia S; Yamshchikov, Galina; Roman, Francois; Nicosia, Alfredo; Colloca, Stefano; Cortese, Riccardo; Bailer, Robert T; Schwartz, Richard M; Roederer, Mario; Mascola, John R; Koup, Richard A; Sullivan, Nancy J; Graham, Barney S

2017-03-09

The unprecedented 2014 epidemic of Ebola virus disease (EVD) prompted an international response to accelerate the availability of a preventive vaccine. A replication-defective recombinant chimpanzee adenovirus type 3-vectored ebolavirus vaccine (cAd3-EBO), encoding the glycoprotein from Zaire and Sudan species, that offers protection in the nonhuman primate model, was rapidly advanced into phase 1 clinical evaluation. We conducted a phase 1, dose-escalation, open-label trial of cAd3-EBO. Twenty healthy adults, in sequentially enrolled groups of 10 each, received vaccination intramuscularly in doses of 2×10 10 particle units or 2×10 11 particle units. Primary and secondary end points related to safety and immunogenicity were assessed throughout the first 8 weeks after vaccination; in addition, longer-term vaccine durability was assessed at 48 weeks after vaccination. In this small study, no safety concerns were identified; however, transient fever developed within 1 day after vaccination in two participants who had received the 2×10 11 particle-unit dose. Glycoprotein-specific antibodies were induced in all 20 participants; the titers were of greater magnitude in the group that received the 2×10 11 particle-unit dose than in the group that received the 2×10 10 particle-unit dose (geometric mean titer against the Zaire antigen at week 4, 2037 vs. 331; P=0.001). Glycoprotein-specific T-cell responses were more frequent among those who received the 2×10 11 particle-unit dose than among those who received the 2×10 10 particle-unit dose, with a CD4 response in 10 of 10 participants versus 3 of 10 participants (P=0.004) and a CD8 response in 7 of 10 participants versus 2 of 10 participants (P=0.07) at week 4. Assessment of the durability of the antibody response showed that titers remained high at week 48, with the highest titers in those who received the 2×10 11 particle-unit dose. Reactogenicity and immune responses to cAd3-EBO vaccine were dose-dependent. At the 2×10 11 particle-unit dose, glycoprotein Zaire-specific antibody responses were in the range reported to be associated with vaccine-induced protective immunity in challenge studies involving nonhuman primates, and responses were sustained to week 48. Phase 2 studies and efficacy trials assessing cAd3-EBO are in progress. (Funded by the Intramural Research Program of the National Institutes of Health; VRC 207 ClinicalTrials.gov number, NCT02231866 .).

Postlumpectomy Focal Brachytherapy for Simultaneous Treatment of Surgical Cavity and Draining Lymph Nodes

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

Hrycushko, Brian A.; Li Shihong; Shi Chengyu

2011-03-01

Purpose: The primary objective was to investigate a novel focal brachytherapy technique using lipid nanoparticle (liposome)-carried {beta}-emitting radionuclides (rhenium-186 [{sup 186}Re]/rhenium-188 [{sup 188}Re]) to simultaneously treat the postlumpectomy surgical cavity and draining lymph nodes. Methods and Materials: Cumulative activity distributions in the lumpectomy cavity and lymph nodes were extrapolated from small animal imaging and human lymphoscintigraphy data. Absorbed dose calculations were performed for lumpectomy cavities with spherical and ellipsoidal shapes and lymph nodes within human subjects by use of the dose point kernel convolution method. Results: Dose calculations showed that therapeutic dose levels within the lumpectomy cavity wall can covermore » 2- and 5-mm depths for {sup 186}Re and {sup 188}Re liposomes, respectively. The absorbed doses at 1 cm sharply decreased to only 1.3% to 3.7% of the doses at 2 mm for {sup 186}Re liposomes and 5 mm for {sup 188}Re liposomes. Concurrently, the draining sentinel lymph nodes would receive a high focal therapeutic absorbed dose, whereas the average dose to 1 cm of surrounding tissue received less than 1% of that within the nodes. Conclusions: Focal brachytherapy by use of {sup 186}Re/{sup 188}Re liposomes was theoretically shown to be capable of simultaneously treating the lumpectomy cavity wall and draining sentinel lymph nodes with high absorbed doses while significantly lowering dose to surrounding healthy tissue. In turn, this allows for dose escalation to regions of higher probability of containing residual tumor cells after lumpectomy while reducing normal tissue complications.« less

Non-induction of radioadaptive response in zebrafish embryos by neutrons

PubMed Central

Ng, Candy Y.P.; Kong, Eva Y.; Kobayashi, Alisa; Suya, Noriyoshi; Uchihori, Yukio; Cheng, Shuk Han; Konishi, Teruaki; Yu, Kwan Ngok

2016-01-01

In vivo neutron-induced radioadaptive response (RAR) was studied using zebrafish (Danio rerio) embryos. The Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility at the National Institute of Radiological Sciences (NIRS), Japan, was employed to provide 2-MeV neutrons. Neutron doses of 0.6, 1, 25, 50 and 100 mGy were chosen as priming doses. An X-ray dose of 2 Gy was chosen as the challenging dose. Zebrafish embryos were dechorionated at 4 h post fertilization (hpf), irradiated with a chosen neutron dose at 5 hpf and the X-ray dose at 10 hpf. The responses of embryos were assessed at 25 hpf through the number of apoptotic signals. None of the neutron doses studied could induce RAR. Non-induction of RAR in embryos having received 0.6- and 1-mGy neutron doses was attributed to neutron-induced hormesis, which maintained the number of damaged cells at below the threshold for RAR induction. On the other hand, non-induction of RAR in embryos having received 25-, 50- and 100-mGy neutron doses was explained by gamma-ray hormesis, which mitigated neutron-induced damages through triggering high-fidelity DNA repair and removal of aberrant cells through apoptosis. Separate experimental results were obtained to verify that high-energy photons could disable RAR. Specifically, 5- or 10-mGy X-rays disabled the RAR induced by a priming dose of 0.88 mGy of alpha particles delivered to 5-hpf zebrafish embryos against a challenging dose of 2 Gy of X-rays delivered to the embryos at 10 hpf. PMID:26850927

Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

PubMed

Mori, Takehiko; Yamazaki, Rie; Aisa, Yoshinobu; Nakazato, Tomonori; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Ikeda, Yasuo; Okamoto, Shinichiro

2006-04-01

We previously reported the efficacy of oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis. The purpose of this study was to evaluate whether the further shortening of the duration of oral cryotherapy could minimize its side effects while sparing its efficacy. Seventeen consecutive recipients of allogeneic hematopoieic stem cell transplant conditioned with high-dose melphalan in combination with fludarabine alone or with fludarabine and additional radiation were enrolled in the study. The severity of stomatitis was graded according to the National Cancer Institute-Common Toxicity Criteria. Patients were kept on oral cryotherapy shortly before, during, and for additional 30 min after the completion of melphalan administration (60-min oral cryotherapy). Patients who were also enrolled in our previous study received the same type of oral cryotherapy but for additional 90 min after the completion of melphalan administration (120-min oral cryotherapy), and they served as controls. Only 2 (11.8%) of 17 patients receiving 60-min oral cryotherapy and 2 (11.1%) of 18 patients receiving 120-min oral cryotherapy developed grade 2 or 3 stomatitis, respectively. The difference between groups was not statistically significant (P = 0.677). The incidence of unpleasant symptoms such as chills and nausea during oral cryotherapy decreased significantly with 60-min oral cryotherapy, as compared with that associated with 120-min oral cryotherapy (P < 0.01). These results suggest that 60-min oral cryotherapy is as effective as 120-min oral cryotherapy at preventing high-dose melphalan-induced stomatitis, and shorter treatment might have contributed to relieve patient discomfort during oral cryotherapy.

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

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

Baker, D.A.

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

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

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

Baker, D.A.

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

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

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

Baker, D.A.

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

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

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

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

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

Fractionated changes in prostate cancer radiotherapy using cone-beam computed tomography

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

Huang, Tzung-Chi, E-mail: tzungchi.huang@mail.cmu.edu.tw; Department of Biomedical Informatics, Asia University, Taichung City, Taiwan; Chou, Kuei-Ting

2015-10-01

The high mobility of the bladder and the rectum causes uncertainty in radiation doses prescribed to patients with prostate cancer who undergo radiotherapy (RT) multifraction treatments. The purpose of this study was to estimate the dose received by the bladder, rectum, and prostate from multifraction treatments using daily cone-beam computed tomography (CBCT). Overall, 28 patients with prostate cancer who planned to receive radiation treatments were enrolled in the study. The acquired CBCT before the treatment delivery was registered with the planning CT to map the dose distribution used in the treatment plan for estimating the received dose during clinical treatment.more » For all 28 patients with 112 data sets, the mean percentage differences (± standard deviation) in the volume and radiation dose were 44% (± 41) and 18% (± 17) for the bladder, 20% (± 21) and 2% (± 2) for the prostate, and 36% (± 29) and 22% (± 15) for the rectum, respectively. Substantial differences between the volumes and radiation dose and those specified in treatment plans were observed. Besides the use of image-guided RT to improve patient setup accuracy, further consideration of large changes in bladder and rectum volumes is strongly suggested when using external beam radiation for prostate cancer.« less

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

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

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

Eye doses to staff in a nuclear medicine department.

PubMed

Summers, Elizabeth C; Brown, Janis L E; Bownes, Peter J; Anderson, Shona E

2012-05-01

Occupational radiation doses to the Nuclear Medicine Department staff at Mount Vernon Hospital are routinely measured using optically stimulated luminescence dosemeters for whole-body effective dose and ring thermoluminescence dosemeters (TLDs) for finger dose. In 2002, a project was carried out using LiF:Mg,Cu,P Chinese TLDs to measure the dose to the lens of the eye received by staff during normal working procedures. Separate pairs of TLDs were worn by staff on their forehead between their eyes while dispensing and releasing in the radiopharmacy, injecting, and when administering I-131 capsules to patients. The dose received was calculated using calibration data from identical TLDs irradiated with Tc-99m, I-131, and the Ir-192 source of a Gammamed High Dose Rate (HDR) treatment unit. Data were collected over a 5-month period and the mean dose to the eye was calculated for each procedure. Using a typical yearly workload, the annual dose to the eye for a single member of staff was calculated and found to be 4.5 mSv. The occupational eye dose limit was, at the time, 150 mSv; therefore, staff were well below the level (3/10th of this limit) that would have required them to be classified. However, there have been large increases in radiopharmacy production and I-131 therapies administered at Mount Vernon in subsequent years. It is therefore expected that the eye dose received by staff will have increased to be significantly higher than 4.5 mSv and will in fact be greater than 6 mSv, which is 3/10th of the proposed new dose limit and would require these staff to become classified workers.

Evaluation of the subchronic toxicity of kefir by oral administration in Wistar rats.

PubMed

Diniz Rosa, Damiana; Gouveia Peluzio, Maria do Carmo; Pérez Bueno, Tania; Vega Cañizares, Ernesto; Sánchez Miranda, Lilian; Mancebo Dorbignyi, Betty; Chong Dubí, Dainé; Espinosa Castaño, Ivette; Marcin Grzes Kowiak, Lukasz; Fortes Ferreira, Célia Lucia de Luces

2014-06-01

Kefir is obtained by fermentation of milk with complex microbial populations present in kefir grains. Several health-promoting benefits have been attributed to kefir consumption. The objective of this work was to conduct a subchronic toxicity study, offering the rats normal or high-doses of kefir and evaluating growth, hematology and blood chemistry, as well as assessing bacterial translocation and the integrity of the intestinal mucosa of animals. Wistar rats were randomly divided into three groups (n = 6/group): control group received 0.7 mL of water, kefir group received 0.7 mL/day of kefir, (normodose), and Hkefir group received 3.5 mL/day of kefir (fivefold higher dose). Feeding was carried out by gavage. The animals were housed in individual cages and maintained under standard conditions for 4 weeks. The normodose and high-dose of kefir supplementation did not harm the animals since growth, hematology and blood chemistry in rats, as well as the potential pathogenicity in tissues were within normal limits, demonstrating that consumption of normodose and highdose of kefir are safe. In addition, administration of the normodose of kefir reduced cholesterol levels and improved the intestinal mucosa of the rats. These results demonstrate that the consumption of kefir is safe. Importantly, while damages are not seen for the high-dose, the normodose consumption is recommended due to the pronounced beneficial effects, as safety is concerned. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Testosterone Dose Dependently Prevents Bone and Muscle Loss in Rodents after Spinal Cord Injury

PubMed Central

Conover, Christine F.; Beggs, Luke A.; Beck, Darren T.; Otzel, Dana M.; Balaez, Alexander; Combs, Sarah M.; Miller, Julie R.; Ye, Fan; Aguirre, J. Ignacio; Neuville, Kathleen G.; Williams, Alyssa A.; Conrad, Bryan P.; Gregory, Chris M.; Wronski, Thomas J.; Bose, Prodip K.; Borst, Stephen E.

2014-01-01

Abstract Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0 mg/week), or (4) SCI+High-dose TE (7.0 mg/week). Twenty-one days post-injury, SCI animals exhibited a 77–85% reduction in hindlimb cancellous bone volume at the distal femur (measured via μCT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13–27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI. PMID:24378197

Pedestrians in Traffic Environments: Ultrafine Particle Respiratory Doses

PubMed Central

Manigrasso, Maurizio; Natale, Claudio; Vitali, Matteo; Protano, Carmela; Avino, Pasquale

2017-01-01

Particulate matter has recently received more attention than other pollutants. PM10 and PM2.5 have been primarily monitored, whereas scientists are focusing their studies on finer granulometric sizes due both to their high number concentration and their high penetration efficiency into the respiratory system. The purpose of this study is to investigate the population exposure to UltraFine Particles (UFP, submicrons in general) in outdoor environments. The particle number doses deposited into the respiratory system have been compared between healthy individuals and persons affected by Chronic Obstructive Pulmonary Disease (COPD). Measurements were performed by means of Dust Track and Nanoscan analyzers. Forty minute walking trails through areas with different traffic densities in downtown Rome have been considered. Furthermore, particle respiratory doses have been estimated for persons waiting at a bus stop, near a traffic light, or along a high-traffic road, as currently occurs in a big city. Large differences have been observed between workdays and weekdays: on workdays, UFP number concentrations are much higher due to the strong contribution of vehicular exhausts. COPD-affected individuals receive greater doses than healthy individuals due to their higher respiratory rate. PMID:28282961

High-pressure liquid chromatography and microbiological assay of serum ofloxacin levels in adults receiving intravenous and oral therapy for skin infections.

PubMed Central

Auten, G M; Preheim, L C; Sookpranee, M; Bittner, M J; Sookpranee, T; Vibhagool, A

1991-01-01

Thirty-two adults hospitalized with skin and skin structure infections received intravenous ofloxacin followed by oral ofloxacin. The standard treatment was 400 mg every 12 h. One patient with renal failure received 400 mg every 24 h. Serum ofloxacin levels were measured (1.5 h postdose and 1 h predose) during intravenous (32 patients) and oral (30 patients) therapy. Levels were assayed by high-pressure liquid chromatography (HPLC) and microbiological assay (MBA). Mean levels +/- standard deviation (in micrograms per milliliter) when measured by MBA after intravenous dosing were (postdose versus predose) 6.23 +/- 2.49 versus 2.42 +/- 1.56, and those after oral dosing were 6.17 +/- 3.25 versus 3.49 +/- 2.77. When measured by HPLC, mean levels +/- standard deviation after intravenous dosing were 5.81 +/- 2.08 versus 2.14 +/- 1.26 and those after oral dosing were 5.63 +/- 2.92 versus 3.41 +/- 2.98. There were no significant differences between levels achieved with oral or intravenous dosing when measured by either MBA or HPLC. Levels in serum did not correlate with side effects. The MICs for 50 and 90% of the 40 aerobic pathogens isolated from 21 patients were 0.5 and 2.0 micrograms/ml, respectively. Cure or improvement was achieved in 30 patients. Intravenous and oral administration of ofloxacin yielded similar levels in serum which were safe and effective in the therapy of skin infections in adult patients. PMID:1810189

Pneumonitis: a serious adverse effect of PD-L1 inhibitors including pembrolizumab.

PubMed

Rickard, Frances; Hyams, Catherine; Low, Andrew T

2018-05-07

A 70-year-old man presented with breathlessness, cough and fever while receiving pembrolizumab for melanoma. A CT pulmonary angiogram demonstrated small bilateral upper lobe segmental pulmonary emboli with patchy ground-glass opacities and basal perilobular consolidation, in keeping with organising pneumonia. He was treated for community-acquired pneumonia and pulmonary emboli but rapidly deteriorated, with increasing hypoxia and dyspnoea. He was admitted to the intensive care unit for support with continuous positive airway pressure and high flow nasal oxygen. His clinical condition improved once he received high-dose intravenous methylprednisolone to treat pneumonitis. His treatment was continued with a weaning course of high-dose oral steroids, and he was discharged with a persistent oxygen requirement. The patient maintained a requirement for high doses of oral steroids and continued to deteriorate. He was referred to palliative care for symptom management and died a month following hospital discharge, as a result of pneumonitis due to pembrolizumab. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Correlation of Clinical and Dosimetric Factors With Adverse Pulmonary Outcomes in Children After Lung Irradiation

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

Venkatramani, Rajkumar, E-mail: rvenkatramani@chla.usc.edu; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; Kamath, Sunil

Purpose: To identify the incidence and the risk factors for pulmonary toxicity in children treated for cancer with contemporary lung irradiation. Methods and Materials: We analyzed clinical features, radiographic findings, pulmonary function tests, and dosimetric parameters of children receiving irradiation to the lung fields over a 10-year period. Results: We identified 109 patients (75 male patients). The median age at irradiation was 13.8 years (range, 0.04-20.9 years). The median follow-up period was 3.4 years. The median prescribed radiation dose was 21 Gy (range, 0.4-64.8 Gy). Pulmonary toxic chemotherapy included bleomycin in 58.7% of patients and cyclophosphamide in 83.5%. The followingmore » pulmonary outcomes were identified and the 5-year cumulative incidence after irradiation was determined: pneumonitis, 6%; chronic cough, 10%; pneumonia, 35%; dyspnea, 11%; supplemental oxygen requirement, 2%; radiographic interstitial lung disease, 40%; and chest wall deformity, 12%. One patient died of progressive respiratory failure. Post-irradiation pulmonary function tests available from 44 patients showed evidence of obstructive lung disease (25%), restrictive disease (11%), hyperinflation (32%), and abnormal diffusion capacity (12%). Thoracic surgery, bleomycin, age, mean lung irradiation dose (MLD), maximum lung dose, prescribed dose, and dosimetric parameters between V{sub 22} (volume of lung exposed to a radiation dose ≥22 Gy) and V{sub 30} (volume of lung exposed to a radiation dose ≥30 Gy) were significant for the development of adverse pulmonary outcomes on univariate analysis. MLD, maximum lung dose, and V{sub dose} (percentage of volume of lung receiving the threshold dose or greater) were highly correlated. On multivariate analysis, MLD was the sole significant predictor of adverse pulmonary outcome (P=.01). Conclusions: Significant pulmonary dysfunction occurs in children receiving lung irradiation by contemporary techniques. MLD rather than prescribed dose should be used to perform risk stratification of patients receiving lung irradiation.« less

Gonad dose in AP pelvis radiography: Impact of anode heel orientation.

PubMed

Mraity, H A A B; England, A; Hogg, P

2017-02-01

For antero posterior (AP) pelvis radiographic examination, determine the impact of anode heel orientation on female/male gonad dose. High sensitivity thermo-luminescent dosimeters (TLDs) were used with an ATOM dosimetry phantom; the phantom was positioned for AP pelvis. TLDs were placed into the testes and ovaries. Radiation dose received by these organs was measured with the feet toward anode and feet toward the cathode. kVp, mAs and SID were manipulated to generate a range of exposures. A dose profile was also generated using Unfors Mult-O-Meter 401 along the long axis of the phantom. A decrease in dose from the central ray toward the anode was noted, with a marked increase toward the cathode. A significant reduction in dose was received by the testes with feet towards the anode compared with feet towards cathode (P˂0.001). No difference was seen for ovarian dose (P˃0.05). kVp, mAs and SID all have an effect on male and female gonad dose. For male pelvis imaging, placing feet towards the anode can be used as a simple dose reduction method. Copyright © 2016 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.

[Safety and immunogenicity of a 7-valent pneumococcal conjugate vaccine (Prevenar) booster dose in healthy Chinese toddlers].

PubMed

Li, Rong-cheng; Li, Feng-xiang; Li, Yan-ping

2009-06-01

To evaluate the safety and immunogenicity of the booster dose of 7 valent pneumococcal conjugate vaccine (PCV7) to the healthy Chinese toddlers who had received 3 primary doses. Four hundred and eighty-eight Chinese toddlers received a booster dose of PCV7 at age of 12-15 months following a primary series of the vaccine given at ages 3, 4, 5 months separately with Diphtheria Tetanus Acellular Pertussis Combined Vaccine (DTaP) in Group 1 or concurrently with DTaP in Group 2. Following the booster dose immunization, each subject was followed up for 30 days to observe the safety of the vaccine. Blood samples were taken from a subset of subjects prior and post 30 days the booster dose immunization to evaluate immunogenicity. A high proportion of subjects in Group 1 (89%) and Group 2 (91%) remained afebrile after the booster dose. Local reactions to the PCV7 booster dose were generally mild. For each serotype, the rise in GMC (post-/pre-vaccination) showed a statistically significant difference (P<0.0001) between both groups. PCV7 administered as a booster dose is generally safe, well tolerate, and immunogenic in healthy Chinese toddlers.

Effectiveness of a Third Dose of MMR Vaccine for Mumps Outbreak Control.

PubMed

Cardemil, Cristina V; Dahl, Rebecca M; James, Lisa; Wannemuehler, Kathleen; Gary, Howard E; Shah, Minesh; Marin, Mona; Riley, Jacob; Feikin, Daniel R; Patel, Manisha; Quinlisk, Patricia

2017-09-07

The effect of a third dose of the measles-mumps-rubella (MMR) vaccine in stemming a mumps outbreak is unknown. During an outbreak among vaccinated students at the University of Iowa, health officials implemented a widespread MMR vaccine campaign. We evaluated the effectiveness of a third dose for outbreak control and assessed for waning immunity. Of 20,496 university students who were enrolled during the 2015-2016 academic year, mumps was diagnosed in 259 students. We used Fisher's exact test to compare unadjusted attack rates according to dose status and years since receipt of the second MMR vaccine dose. We used multivariable time-dependent Cox regression models to evaluate vaccine effectiveness, according to dose status (three vs. two doses and two vs. no doses) after adjustment for the number of years since the second dose. Before the outbreak, 98.1% of the students had received at least two doses of MMR vaccine. During the outbreak, 4783 received a third dose. The attack rate was lower among the students who had received three doses than among those who had received two doses (6.7 vs. 14.5 cases per 1000 population, P<0.001). Students had more than nine times the risk of mumps if they had received the second MMR dose 13 years or more before the outbreak. At 28 days after vaccination, receipt of the third vaccine dose was associated with a 78.1% lower risk of mumps than receipt of a second dose (adjusted hazard ratio, 0.22; 95% confidence interval, 0.12 to 0.39). The vaccine effectiveness of two doses versus no doses was lower among students with more distant receipt of the second vaccine dose. Students who had received a third dose of MMR vaccine had a lower risk of mumps than did those who had received two doses, after adjustment for the number of years since the second dose. Students who had received a second dose of MMR vaccine 13 years or more before the outbreak had an increased risk of mumps. These findings suggest that the campaign to administer a third dose of MMR vaccine improved mumps outbreak control and that waning immunity probably contributed to propagation of the outbreak. (Funded by the Centers for Disease Control and Prevention.).

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

PubMed

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

1995-07-01

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

Tumor Control Outcomes Following Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases from Renal Cell Carcinoma

PubMed Central

Zelefsky, Michael J; Greco, Carlo; Motzer, Robert; Magsanoc, Juan Martin; Pei, Xin; Lovelock, Michael; Mechalakos, Jim; Zatcky, Joan; Fuks, Zvi; Yamada, Yoshiya

2014-01-01

Purpose To report tumor local progression-free outcomes following treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Methods and Materials Between 2004 and 2010, a total of 105 lesions from renal cell carcinomas were treated with either SD-IGRT to prescription doses of 18–24 Gy (median, 24 Gy) or hypofractionation (3 or 5 fractions) with prescription doses ranging between 20 and 30 Gy. The median follow-up was 12 months (range, 1–48 months). Results The overall 3-year actuarial local progression-free survival (LPFS) for all lesions was 44%. The 3-year LPFS for those who received high single-dose (24 Gy; n = 45), low single-dose (< 24 Gy; n = 14), and hypofractionation regimens (n = 46) were 88%, 21%, and 17%, respectively (high single dose versus low single dose, p = 0.001; high single dose versus hypofractionation, p < 0.001). Multivariate analysis revealed the following variables as significant predictors of improved LPFS: dose of 24 Gy compared with lower dose (p = 0.009), and single dose versus hypofractionation (p = 0.008). Conclusion High-dose SD-IGRT is a non-invasive procedure resulting in high probability of local tumor control for metastatic renal cell cancers, generally considered radioresistant according to classical radiobiological ranking. PMID:21596489

High-dose oxytocin is not associated with maternal temperature elevation: a retrospective cohort study of mid-trimester pregnancy with intrauterine fetal demise.

PubMed

Frölich, M A; Esame, A; Warren Iii, W M; Owen, J

2011-01-01

Maternal intrapartum fever has been associated with an increased incidence of neonatal morbidity. In this retrospective cohort study, we evaluated whether intravenous oxytocin has a fever-inducing effect. Oxytocin augments secretion of prostaglandins E(2) and F(2α) which are inflammatory mediators known to elevate body temperature. Between January 2005 and June 2008, 279 patients were admitted with mid-trimester fetal demise. Patients meeting inclusion criteria included 34 women who received a high-dose intravenous oxytocin regimen and 29 patients who delivered after spontaneous labor without the need for augmentation. Oral temperatures were measured on admission and at delivery. The median length of oxytocin infusion was 5.3h. The calculated temperature change was -0.14°C in the oxytocin group and +0.12°C in the control group. These findings were confirmed in a model adjusted for patients' white blood cell count and duration of labor. We did not observe an effect of analgesia type, epidural versus intravenous analgesia, on duration of labor. Based on this comparative analysis of pregnant women who received high-doses of oxytocin, we found insufficient evidence to support that high-dose intravenous oxytocin elevates intrapartum maternal temperature. Copyright © 2010 Elsevier Ltd. All rights reserved.

Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism.

PubMed

Otto, Sven; Pautke, Christoph; Opelz, Christine; Westphal, Ines; Drosse, Inga; Schwager, Joanna; Bauss, Frieder; Ehrenfeld, Michael; Schieker, Matthias

2010-11-01

Osteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro. The effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy. Both types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P < .01), with more pronounced effects for zoledronate. Equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in the patients in the control group who did not receive bisphosphonates. Our results have shown that high concentrations of N-BPs and a local acidic milieu, which is commonly present in infections of the jaw, might play a key role in the pathogenesis of osteonecrosis of the jaw in patients receiving high doses of N-BPs for malignant diseases. Also the potency of N-BPs might be different, suggesting a greater risk of osteonecrosis of the jaw with zoledronate. Copyright © 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

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.

131I-tositumomab myeloablative radioimmunotherapy for non-Hodgkin’s lymphoma: radiation dose to the testes

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

Hattori, Naoya; Gopal, Ajay K.; Shields, Andrew T.

Purpose: To investigate radiation doses to the testes delivered by a radiolabeled anti-CD20 antibody and its effects on male sex hormone levels. Materials and methods: Testicular uptake and retention of 131I-tositumomab were measured, and testicular absorbed doses were calculated for 67 male patients (54+/-11 years of age) with non-Hodgkin's lymphoma who had undergone myeloablative radioimmunotherapy (RIT) using 131I-tositumomab. Time-activity curves for the major organs, testes, and whole body were generated from planar imaging studies. In a subset of patients, male sex hormones were measured before and 1 year after the therapy. Results: The absorbed dose to the testes showed considerablemore » variability (range=4.4-70.2 Gy). Pretherapy levels of total testosterone were below the lower limit of the reference range, and post-therapy evaluation demonstrated further reduction [4.6+/-1.8 nmol/l (pre-RIT) vs. 3.8+/-2.9 nmol/l (post-RIT), P<0.05]. Patients receiving higher radiation doses to the testes (>=25 Gy) showed a greater reduction [4.7+/-1.6 nmol/l (pre-RIT) vs. 3.3+/-2.7 nmol/l (post-RIT), P<0.05] compared with patients receiving lower doses (<25 Gy), who showed no significant change in total testosterone levels. Conclusion: The testicular radiation absorbed dose varied highly among individual patients. Finally, patients receiving higher doses to the testes were more likely to show post-RIT suppression of testosterone levels.« less

Recent resurgence of mumps in the United States.

PubMed

Dayan, Gustavo H; Quinlisk, M Patricia; Parker, Amy A; Barskey, Albert E; Harris, Meghan L; Schwartz, Jennifer M Hill; Hunt, Kae; Finley, Carol G; Leschinsky, Dennis P; O'Keefe, Anne L; Clayton, Joshua; Kightlinger, Lon K; Dietle, Eden G; Berg, Jeffrey; Kenyon, Cynthia L; Goldstein, Susan T; Stokley, Shannon K; Redd, Susan B; Rota, Paul A; Rota, Jennifer; Bi, Daoling; Roush, Sandra W; Bridges, Carolyn B; Santibanez, Tammy A; Parashar, Umesh; Bellini, William J; Seward, Jane F

2008-04-10

The widespread use of a second dose of mumps vaccine among U.S. schoolchildren beginning in 1990 was followed by historically low reports of mumps cases. A 2010 elimination goal was established, but in 2006 the largest mumps outbreak in two decades occurred in the United States. We examined national data on mumps cases reported during 2006, detailed case data from the most highly affected states, and vaccination-coverage data from three nationwide surveys. A total of 6584 cases of mumps were reported in 2006, with 76% occurring between March and May. There were 85 hospitalizations, but no deaths were reported; 85% of patients lived in eight contiguous midwestern states. The national incidence of mumps was 2.2 per 100,000, with the highest incidence among persons 18 to 24 years of age (an incidence 3.7 times that of all other age groups combined). In a subgroup analysis, 83% of these patients reported current college attendance. Among patients in eight highly affected states with known vaccination status, 63% overall and 84% between the ages of 18 and 24 years had received two doses of mumps vaccine. For the 12 years preceding the outbreak, national coverage of one-dose mumps vaccination among preschoolers was 89% or more nationwide and 86% or more in highly affected states. In 2006, the national two-dose coverage among adolescents was 87%, the highest in U.S. history. Despite a high coverage rate with two doses of mumps-containing vaccine, a large mumps outbreak occurred, characterized by two-dose vaccine failure, particularly among midwestern college-age adults who probably received the second dose as schoolchildren. A more effective mumps vaccine or changes in vaccine policy may be needed to avert future outbreaks and achieve the elimination of mumps. Copyright 2008 Massachusetts Medical Society.

Patient dose estimation from CT scans at the Mexican National Neurology and Neurosurgery Institute

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

Alva-Sánchez, Héctor, E-mail: halva@ciencias.unam.mx; Reynoso-Mejía, Alberto; Casares-Cruz, Katiuzka

In the radiology department of the Mexican National Institute of Neurology and Neurosurgery, a dedicated institute in Mexico City, on average 19.3 computed tomography (CT) examinations are performed daily on hospitalized patients for neurological disease diagnosis, control scans and follow-up imaging. The purpose of this work was to estimate the effective dose received by hospitalized patients who underwent a diagnostic CT scan using typical effective dose values for all CT types and to obtain the estimated effective dose distributions received by surgical and non-surgical patients. Effective patient doses were estimated from values per study type reported in the applications guidemore » provided by the scanner manufacturer. This retrospective study included all hospitalized patients who underwent a diagnostic CT scan between 1 January 2011 and 31 December 2012. A total of 8777 CT scans were performed in this two-year period. Simple brain scan was the CT type performed the most (74.3%) followed by contrasted brain scan (6.1%) and head angiotomography (5.7%). The average number of CT scans per patient was 2.83; the average effective dose per patient was 7.9 mSv; the mean estimated radiation dose was significantly higher for surgical (9.1 mSv) than non-surgical patients (6.0 mSv). Three percent of the patients had 10 or more brain CT scans and exceeded the organ radiation dose threshold set by the International Commission on Radiological Protection for deterministic effects of the eye-lens. Although radiation patient doses from CT scans were in general relatively low, 187 patients received a high effective dose (>20 mSv) and 3% might develop cataract from cumulative doses to the eye lens.« less

Patient dose estimation from CT scans at the Mexican National Neurology and Neurosurgery Institute

NASA Astrophysics Data System (ADS)

Alva-Sánchez, Héctor; Reynoso-Mejía, Alberto; Casares-Cruz, Katiuzka; Taboada-Barajas, Jesús

2014-11-01

In the radiology department of the Mexican National Institute of Neurology and Neurosurgery, a dedicated institute in Mexico City, on average 19.3 computed tomography (CT) examinations are performed daily on hospitalized patients for neurological disease diagnosis, control scans and follow-up imaging. The purpose of this work was to estimate the effective dose received by hospitalized patients who underwent a diagnostic CT scan using typical effective dose values for all CT types and to obtain the estimated effective dose distributions received by surgical and non-surgical patients. Effective patient doses were estimated from values per study type reported in the applications guide provided by the scanner manufacturer. This retrospective study included all hospitalized patients who underwent a diagnostic CT scan between 1 January 2011 and 31 December 2012. A total of 8777 CT scans were performed in this two-year period. Simple brain scan was the CT type performed the most (74.3%) followed by contrasted brain scan (6.1%) and head angiotomography (5.7%). The average number of CT scans per patient was 2.83; the average effective dose per patient was 7.9 mSv; the mean estimated radiation dose was significantly higher for surgical (9.1 mSv) than non-surgical patients (6.0 mSv). Three percent of the patients had 10 or more brain CT scans and exceeded the organ radiation dose threshold set by the International Commission on Radiological Protection for deterministic effects of the eye-lens. Although radiation patient doses from CT scans were in general relatively low, 187 patients received a high effective dose (>20 mSv) and 3% might develop cataract from cumulative doses to the eye lens.

Comparison of image quality, myocardial perfusion, and LV function between standard imaging and single-injection ultra-low-dose imaging using a high-efficiency SPECT camera: the MILLISIEVERT study

PubMed Central

Einstein, Andrew J.; Blankstein, Ron; Andrews, Howard; Fish, Mathews; Padgett, Richard; Hayes, Sean W.; Friedman, John D.; Qureshi, Mehreen; Rakotoarivelo, Harivony; Slomka, Piotr; Nakazato, Ryo; Bokhari, Sabahat; Di Carli, Marcello; Berman, Daniel S.

2015-01-01

SPECT myocardial perfusion imaging (MPI) plays a central role in coronary artery disease diagnosis; but concerns exist regarding its radiation burden. Compared to standard Anger-SPECT (A-SPECT) cameras, new high-efficiency (HE) cameras with specialized collimators and solid-state cadmium-zinc-telluride detectors offer potential to maintain image quality (IQ), while reducing administered activity and thus radiation dose to patients. No previous study has compared IQ, interpretation, total perfusion deficit (TPD), or ejection fraction (EF) in patients receiving both ultra-low-dose (ULD) imaging on a HE-SPECT camera and standard low-dose (SLD) A-SPECT imaging. Methods We compared ULD-HE-SPECT to SLD-A-SPECT imaging by dividing the rest dose in 101 patients at 3 sites scheduled to undergo clinical A-SPECT MPI using a same day rest/stress Tc-99m protocol. Patients received HE-SPECT imaging following an initial ~130 MBq (3.5mCi) dose, and SLD-A-SPECT imaging following the remainder of the planned dose. Images were scored visually by 2 blinded readers for IQ and summed rest score (SRS). TPD and EF were assessed quantitatively. Results Mean activity was 134 MBq (3.62 mCi) for ULD-HE-SPECT (effective dose 1.15 mSv) and 278 MBq (7.50 mCi, 2.39 mSv) for SLD-A-SPECT. Overall IQ was superior for ULD-HE-SPECT (p<0.0001), with twice as many studies graded excellent quality. Extracardiac activity and overall perfusion assessment were similar. Between-method correlations were high for SRS (r=0.87), TPD (r=0.91), and EF (r=0.88). Conclusion ULD-HE-SPECT rest imaging correlates highly with SLD-A-SPECT. It has improved image quality, comparable extracardiac activity, and achieves radiation dose reduction to 1 mSv for a single injection. PMID:24982439

Radiation exposure from diagnostic imaging in young patients with testicular cancer.

PubMed

Sullivan, C J; Murphy, K P; McLaughlin, P D; Twomey, M; O'Regan, K N; Power, D G; Maher, M M; O'Connor, O J

2015-04-01

Risks associated with high cumulative effective dose (CED) from radiation are greater when imaging is performed on younger patients. Testicular cancer affects young patients and has a good prognosis. Regular imaging is standard for follow-up. This study quantifies CED from diagnostic imaging in these patients. Radiological imaging of patients aged 18-39 years, diagnosed with testicular cancer between 2001 and 2011 in two tertiary care centres was examined. Age at diagnosis, cancer type, dose-length product (DLP), imaging type, and frequency were recorded. CED was calculated from DLP using conversion factors. Statistical analysis was performed with SPSS. In total, 120 patients with a mean age of 30.7 ± 5.2 years at diagnosis had 1,410 radiological investigations. Median (IQR) surveillance was 4.37 years (2.0-5.5). Median (IQR) CED was 125.1 mSv (81.3-177.5). Computed tomography accounted for 65.3 % of imaging studies and 98.3 % of CED. We found that 77.5 % (93/120) of patients received high CED (>75 mSv). Surveillance time was associated with high CED (OR 2.1, CI 1.5-2.8). Survivors of testicular cancer frequently receive high CED from diagnostic imaging, mainly CT. Dose management software for accurate real-time monitoring of CED and low-dose CT protocols with maintained image quality should be used by specialist centres for surveillance imaging. • CT accounted for 98.3 % of CED in patients with testicular cancer. • Median CED in patients with testicular cancer was 125.1 mSv • High CED (>75 mSv) was observed in 77.5 % (93/120) of patients. • Dose tracking and development of low-dose CT protocols are recommended.

Ocular lesions in canine mucopolysaccharidosis I and response to enzyme replacement therapy.

PubMed

Newkirk, Kim M; Atkins, Rosalie M; Dickson, Patti I; Rohrbach, Barton W; McEntee, Michael F

2011-07-11

Mucopolysaccharidosis I (MPS I) is an inherited metabolic disorder resulting from deficiency of α-L-iduronidase and lysosomal accumulation of glycosaminoglycans (GAG) in multiple tissues. Accumulation of GAG in corneal stromal cells causes corneal opacity and reduced vision. The purpose of this study was to determine the extent of ocular GAG accumulation and investigate the effectiveness of intravenous enzyme replacement therapy (ERT) on corneal GAG accumulation in dogs. Ocular tissues were obtained from 58 dogs with mucopolysaccharidosis I and four unaffected controls. Affected dogs received either low-dose ERT, high-dose ERT, or no treatment; some low-dose dogs also received intrathecal treatments. Histologic severity of corneal stromal GAG accumulation was scored. Accumulation of GAG was found in corneal stromal cells and scleral fibroblasts but not in corneal epithelium, endothelium, ciliary epithelium, choroid, retina, retinal pigment epithelium, or optic nerve. Corneal GAG accumulation increased in severity with increasing age. Although low-dose ERT did not significantly reduce corneal stromal GAG accumulation in comparison with untreated animals, high-dose ERT did result in significantly less GAG accumulation compared with the untreated dogs (adjusted P = 0.0143) or the low-dose ERT group (adjusted P = 0.0031). Intrathecal treatments did not significantly affect GAG accumulation. Dogs that began ERT shortly after birth also had significantly less (P < 0.0001) GAG accumulation in the corneal stroma than dogs with a later onset of treatment. These data suggest that high-dose, intravenous ERT is effective at preventing and/or clearing corneal stromal GAG accumulation, particularly if initiated early after birth.

Cumulative or delayed nephrotoxicity after cisplatin (DDP) treatment.

PubMed

Pinnarò, P; Ruggeri, E M; Carlini, P; Giovannelli, M; Cognetti, F

1986-04-30

The present retrospective study reports data regarding renal toxicity in 115 patients (63 males, 52 females; median age, 56 years) who received cumulative doses of cisplatin (DDP) greater than or equal to 200 mg/m2. DDP was administered alone or in combination at a dose of 50-70 mg/m2 in 91 patients, and at a dose of 100 mg/m2 in 22 patients. Two patients after progression of ovarian carcinoma treated with conventional doses of DDP received 4 and 2 courses, respectively, of high-dose DDP (40 mg/m2 for 5 days) in hypertonic saline. The median number of DDP courses was 6 (range 2-14), and the median cumulative dose was 350 mg/m2 (range, 200-1200). Serum creatinine and urea nitrogen were determined before initiating the treatment and again 13-16 days after each administration. The incidence of azotemia (creatinina levels that exceeded 1.5 mg/dl) was similar before (7.8%) and after (6.1%) DDP doses of 200 mg/m2. Azotemia appears to be related to the association of DDP with other potentially nephrotoxic antineoplastic drugs (methotrexate) more than to the dose per course of DDP. Of 59 patients followed for 2 months or more after discontinuing the DDP treatment, 3 (5.1%) presented creatinine values higher than 1.5 mg/dl. The data deny that the incidence of nephrotoxicity is higher in patients receiving higher cumulative doses of DDP and confirm that increases in serum creatinine levels may occur some time after discontinuation of the drug.

Comparison of filgrastim and pegfilgrastim to prevent neutropenia and maintain dose intensity of adjuvant chemotherapy in patients with breast cancer.

PubMed

Kourlaba, Georgia; Dimopoulos, Meletios A; Pectasides, Dimitrios; Skarlos, Dimosthenis V; Gogas, Helen; Pentheroudakis, George; Koutras, Angelos; Fountzilas, George; Maniadakis, Nikos

2015-07-01

The aim of this study was to compare the effectiveness of prophylactic single fixed dose of pegfilgrastim and daily administration of filgrastim on febrile neutropenia (FN), severe neutropenia, treatment delay, and dose reduction in patients with breast cancer receiving dose-dense adjuvant chemotherapy. A retrospective cohort study with 1058 breast cancer patients matched by age and chemotherapy was conducted. The primary endpoints were FN, severe (grade 3, 4) neutropenia, dose reduction (>10 % reduction of the dose planned), and treatment delay (dose given more than 2 days later). Eighteen episodes of FN (3.4%) in the filgrastim group and 23 (4.3%) in the pegfilgrastim group (p = 0.500) were recorded. More than half of the total episodes (27/41) occurred during the first 4 cycles of treatment. Patients who received filgrastim were almost three times more likely to experience a severe neutropenia episode and were significantly more likely to experience a dose reduction (18.5%) compared to those who received pegfilgrastim (10.8%) (p < 0.001). The percentage of patients, who received their planned dose on time, was significantly lower in patients receiving filgrastim (58%) compared to those receiving pegfilgrastim (72.4%, p < 0.001). No significant difference was detected on FN rate between daily administration of filgrastim and single administration of pegfilgrastim. However, patients receiving pegfilgrastim had a significantly lower rate of severe neutropenia, as well as dose reduction and treatment delay, thus, achieving a higher dose density.

High-Risk Prescribing to Medicaid Enrollees Receiving Opioid Analgesics: Individual- and County-Level Factors.

PubMed

Heins, Sara E; Sorbero, Mark J; Jones, Christopher M; Dick, Andrew W; Stein, Bradley D

2018-01-05

Prescription opioid overdoses have increased dramatically in recent years, with the highest rates among Medicaid enrollees. High-risk prescribing includes practices associated with overdoses and a range of additional opioid-related problems. To identify individual- and county-level factors associated with high-risk prescribing among Medicaid enrollees receiving opioids. In a four-states, cross-sectional claims data study, Medicaid enrollees 18-64 years old with a new opioid analgesic treatment episode 2007-2009 were identified. Multivariate regression analyses were conducted to identify factors associated with high-risk prescribing, defined as high-dose opioid prescribing (morphine equivalent daily dose ≥100 mg for >6 days), opioid overlap, opioid-benzodiazepine overlap. High-risk prescribing occurred in 39.4% of episodes. Older age, rural county of residence, white race, and major depression diagnosis were associated with higher rates of all types of high-risk prescribing. Individuals with prior opioid, alcohol, and hypnotic/sedative use disorder diagnoses had lower odds of high-dose opioid prescribing but higher odds of opioid overlap and opioid-benzodiazepine overlap than individuals without such disorders. High-dose opioid prescribing in Massachusetts was less common than in California, Illinois, and New York, whereas the rate of benzodiazepine overlap in Massachusetts was more common than in other states. Conclusions/Importance: High-risk prescribing was common and associated with several important demographic, clinical, and community factors. Findings can be used to inform targeted interventions designed to reduce such prescribing, and given state variation observed, further research is needed to better understand the effects of state policies on high-risk prescribing.

Efficacy of a single dose of milbemycin oxime/praziquantel combination tablets, Milpro(®), against adult Echinococcus multilocularis in dogs and both adult and immature E. multilocularis in young cats.

PubMed

Cvejic, Dejan; Schneider, Claudia; Fourie, Josephus; de Vos, Christa; Bonneau, Stephane; Bernachon, Natalia; Hellmann, Klaus

2016-03-01

Two single-site, laboratory, negatively controlled, masked, randomised dose confirmation studies were performed: one in dogs, the other in cats. After a period of acclimatisation, both the dogs and cats were orally infected with Echinococcus multilocularis protoscoleces. In the dog study, 10 dogs received a single dose of Milpro® tablets at a minimum dose of 0.5 mg/kg milbemycin oxime and 5 mg/kg praziquantel 18 days post-infection and 10 dogs received no treatment. In the cat study, 10 cats received a single dose of Milpro® tablets at a minimum dose of 2 mg/kg milbemycin oxime and 5 mg/kg praziquantel 7 days post-infection, 10 cats received a single dose of the treatment 18 days post-infection and 10 cats remained untreated. In both studies, intestinal worm counts were performed 23 days post-infection at necropsy. No worms were retrieved from any of the 30 treated animals. Nine of 10 control dogs had multiple worms (geometric mean 91, arithmetic mean 304) and all 10 control cats had multiple worms (geometric mean 216, arithmetic mean 481). The difference in worm counts between all three treated groups and their controls was highly significant (ANOVA p values of log transformed data <0.0001). Efficacy of 100 % was demonstrated for the elimination of adult E. multilocularis in dogs and cats as well as for elimination of immature E. multilocularis in cats as evidenced by the effectiveness of treatment 7 days post-infection. The treatments were well accepted and tolerated, and there were no adverse drug reactions observed.

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

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.

SU-E-T-238: Monte Carlo Estimation of Cerenkov Dose for Photo-Dynamic Radiotherapy

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

Chibani, O; Price, R; Ma, C

Purpose: Estimation of Cerenkov dose from high-energy megavoltage photon and electron beams in tissue and its impact on the radiosensitization using Protoporphyrine IX (PpIX) for tumor targeting enhancement in radiotherapy. Methods: The GEPTS Monte Carlo code is used to generate dose distributions from 18MV Varian photon beam and generic high-energy (45-MV) photon and (45-MeV) electron beams in a voxel-based tissueequivalent phantom. In addition to calculating the ionization dose, the code scores Cerenkov energy released in the wavelength range 375–425 nm corresponding to the pick of the PpIX absorption spectrum (Fig. 1) using the Frank-Tamm formula. Results: The simulations shows thatmore » the produced Cerenkov dose suitable for activating PpIX is 4000 to 5500 times lower than the overall radiation dose for all considered beams (18MV, 45 MV and 45 MeV). These results were contradictory to the recent experimental studies by Axelsson et al. (Med. Phys. 38 (2011) p 4127), where Cerenkov dose was reported to be only two orders of magnitude lower than the radiation dose. Note that our simulation results can be corroborated by a simple model where the Frank and Tamm formula is applied for electrons with 2 MeV/cm stopping power generating Cerenkov photons in the 375–425 nm range and assuming these photons have less than 1mm penetration in tissue. Conclusion: The Cerenkov dose generated by high-energy photon and electron beams may produce minimal clinical effect in comparison with the photon fluence (or dose) commonly used for photo-dynamic therapy. At the present time, it is unclear whether Cerenkov radiation is a significant contributor to the recently observed tumor regression for patients receiving radiotherapy and PpIX versus patients receiving radiotherapy only. The ongoing study will include animal experimentation and investigation of dose rate effects on PpIX response.« less

Mepolizumab treatment in patients with severe eosinophilic asthma.

PubMed

Ortega, Hector G; Liu, Mark C; Pavord, Ian D; Brusselle, Guy G; FitzGerald, J Mark; Chetta, Alfredo; Humbert, Marc; Katz, Lynn E; Keene, Oliver N; Yancey, Steven W; Chanez, Pascal

2014-09-25

Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

Dose- dependent ameliorative effects of quercetin and l-Carnitine against atrazine- induced reproductive toxicity in adult male Albino rats.

PubMed

Abdel Aziz, Rabie L; Abdel-Wahab, Ahmed; Abo El-Ela, Fatma I; Hassan, Nour El-Houda Y; El-Nahass, El-Shaymaa; Ibrahim, Marwa A; Khalil, Abdel-Tawab A Y

2018-06-01

This study aimed to determine the protective effects of co-administration of Quercetin (QT) or l-Carnitine (LC) against the oxidative stress induced by Atrazine (ATZ) in the reproductive system of intact male Albino rats. 36 rats were divided equally into 6 groups. Rats in the control negative "CNT" group received 1.5 ml distilled water for 21 days. All rats in the other groups received ATZ (120 mg/kg bw) through gavage. Groups 3 and 4 were co-administered with either low or high dose of QT (10 "ATZLQT" and 50 "ATZHQT" mg/kg bw, respectively). Groups 5 and 6 were co-administered with either low or high dose of LC (200 "ATZLLC" and 400 "ATZHLC" mg/kg bw, respectively). At the end of the experiment, animals were sacrificed and all samples were collected. ATZ significantly increased serum level of malondialdehyde (MDA) and decreased total antioxidant capacity (TAC). Also, ATZ increased significantly the sperm cell abnormalities and reduced both testicular IgA and serum testosterone levels. Testicular DNA laddering % and CYP17A1 mRNA expression were significantly reduced in ATZ group. Interestingly, co-administration with low dose QT or different doses of LC succeeded to counteract the negative toxic effects of ATZ on serum oxidative stress indicators, serum testosterone levels, testicular IgA level and improved testicular CYP17A1 mRNA expression. In conclusion, QT in low dose and LC in both low and high doses exerted a significant protective action against the reproductive toxicity of ATZ, while higher dose of QT failed induce immune-stimulant effect against ATZ in adult male Albino rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Cardiovascular Morbidity and Pure Red Cell Aplasia Associated With Epoetin Theta Therapy in Patients With Chronic Kidney Disease: A Prospective, Noninterventional, Multicenter Cohort Study.

PubMed

Lammerich, Andreas; Balcke, Peter; Bias, Peter; Mangold, Simone; Wiesholzer, Martin

2016-02-01

The European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia. In this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) (cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7-11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62-125, and >125 IU/kg/wk for low, intermediate, and high). Data from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person-year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person-year. No cases of pure red cell aplasia were reported. The findings from the present study suggest that, for maintaining the optimal target Hb concentration (10-12 g/dL according to the current summary of product characteristics for epoetin theta; 10-11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

NASA Astrophysics Data System (ADS)

Said, M. A.; Ashhar, Z. N.; Suhaimi, N. E. F.; Zainon, R.

2016-01-01

In routine radiopharmaceutical Iodine-131 (131I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle 131I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the 131I. The new fabricated of low cost 131I dispenser was tested and the dose received by personnel were evaluated. The body of lead material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of 131 I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the 131I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of 131I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.

A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

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

Said, M. A.; Suhaimi, N. E. F.; Ashhar, Z. N., E-mail: aminhpj@gmail.com

In routine radiopharmaceutical Iodine-131 ({sup 131}I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle {sup 131}I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the {sup 131}I. The new fabricated of low cost {sup 131}I dispenser was tested and the dose received by personnel were evaluated. The body of leadmore » material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of {sup 131} I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the {sup 131}I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of {sup 131}I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.« less

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

PubMed

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

2017-01-01

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

High-dose tranexamic acid reduces intraoperative and postoperative blood loss in posterior lumbar interbody fusion.

PubMed

Kushioka, Junichi; Yamashita, Tomoya; Okuda, Shinya; Maeno, Takafumi; Matsumoto, Tomiya; Yamasaki, Ryoji; Iwasaki, Motoki

2017-03-01

OBJECTIVE Tranexamic acid (TXA), a synthetic antifibrinolytic drug, has been reported to reduce blood loss in orthopedic surgery, but there have been few reports of its use in spine surgery. Previous studies included limitations in terms of different TXA dose regimens, different levels and numbers of fused segments, and different surgical techniques. Therefore, the authors decided to strictly limit TXA dose regimens, surgical techniques, and fused segments in this study. There have been no reports of using TXA for prevention of intraoperative and postoperative blood loss in posterior lumbar interbody fusion (PLIF). The purpose of the study was to evaluate the efficacy of high-dose TXA in reducing blood loss and its safety during single-level PLIF. METHODS The study was a nonrandomized, case-controlled trial. Sixty consecutive patients underwent single-level PLIF at a single institution. The first 30 patients did not receive TXA. The next 30 patients received 2000 mg of intravenous TXA 15 minutes before the skin incision was performed and received the same dose again 16 hours after the surgery. Intra- and postoperative blood loss was compared between the groups. RESULTS There were no statistically significant differences in preoperative parameters of age, sex, body mass index, preoperative diagnosis, or operating time. The TXA group experienced significantly less intraoperative blood loss (mean 253 ml) compared with the control group (mean 415 ml; p < 0.01). The TXA group also had significantly less postoperative blood loss over 40 hours (mean 321 ml) compared with the control group (mean 668 ml; p < 0.01). Total blood loss in the TXA group (mean 574 ml) was significantly lower than in the control group (mean 1080 ml; p < 0.01). From 2 hours to 40 hours, postoperative blood loss in the TXA group was consistently significantly lower. There were no perioperative complications, including thromboembolic events. CONCLUSIONS High-dose TXA significantly reduced both intra- and postoperative blood loss without causing any complications during or after single-level PLIF.

Determining the behavioural dose-response relationship of marine mammals to air gun noise and source proximity.

PubMed

Dunlop, Rebecca A; Noad, Michael J; McCauley, Robert D; Scott-Hayward, Lindsay; Kniest, Eric; Slade, Robert; Paton, David; Cato, Douglas H

2017-08-15

The effect of various anthropogenic sources of noise (e.g. sonar, seismic surveys) on the behaviour of marine mammals is sometimes quantified as a dose-response relationship, where the probability of an animal behaviourally 'responding' (e.g. avoiding the source) increases with 'dose' (or received level of noise). To do this, however, requires a definition of a 'significant' response (avoidance), which can be difficult to quantify. There is also the potential that the animal 'avoids' not only the source of noise but also the vessel operating the source, complicating the relationship. The proximity of the source is an important variable to consider in the response, yet difficult to account for given that received level and proximity are highly correlated. This study used the behavioural response of humpback whales to noise from two different air gun arrays (20 and 140 cubic inch air gun array) to determine whether a dose-response relationship existed. To do this, a measure of avoidance of the source was developed, and the magnitude (rather than probability) of this response was tested against dose. The proximity to the source, and the vessel itself, was included within the one-analysis model. Humpback whales were more likely to avoid the air gun arrays (but not the controls) within 3 km of the source at levels over 140 re. 1 µPa 2  s -1 , meaning that both the proximity and the received level were important factors and the relationship between dose (received level) and response is not a simple one. © 2017. Published by The Company of Biologists Ltd.

Lipid metabolism abnormalities in alcohol-treated rabbits: a morphometric and haematologic study comparing high and low alcohol doses.

PubMed

Ikemura, Satoshi; Yamamoto, Takuaki; Motomura, Goro; Iwasaki, Kenyu; Yamaguchi, Ryosuke; Zhao, Garida; Iwamoto, Yukihide

2011-08-01

The pathogenesis of alcohol-induced osteonecrosis remains unclear. The purpose of the present study was to evaluate the morphological changes in bone marrow fat cells and the changes in the serum lipid levels in alcohol-treated rabbits. Fifteen rabbits were randomly assigned into three groups: Four rabbits intragastrically received low-dose alcohol (LDA) (15 ml/kg per day) containing 15% ethanol for 4 weeks, five rabbits received high-dose alcohol (HDA) (30 ml/kg per day) for 4 weeks and six rabbits received physiologic saline for 4 weeks as a control group. Six weeks after the initial alcohol administration, all rabbits were sacrificed. The mean size of the bone marrow fat cells in rabbits treated with HDA was significantly larger than that in the control group (P = 0.0001). Haematologically, the levels of triglycerides and free fatty acids in the rabbits treated with both low-dose and HDA were significantly higher than those in the control group (P = 0.001 for both comparisons). The results of this study are that there are lipid metabolism abnormalities, both morphologically and haematologically, after alcohol administration. Also these findings were more apparent in rabbits treated with HDA than those treated with LDA. © 2011 The Authors. International Journal of Experimental Pathology © 2011 International Journal of Experimental Pathology.

The Effect of Different Dosing Schedules of Intravitreal Sirolimus, a Mammalian Target of Rapamycin (mTOR) Inhibitor, in the Treatment of Non-Infectious Uveitis (An American Ophthalmological Society Thesis).

PubMed

Nguyen, Quan Dong; Sadiq, Mohammad Ali; Soliman, Mohamed Kamel; Agarwal, Aniruddha; Do, Diana V; Sepah, Yasir J

2016-08-01

To determine if two different doses of intravitreal sirolimus, an mTOR inhibitor, can decrease inflammation and is safe in eyes with non-infectious posterior, intermediate, or panuveitis in the Sirolimus as a Therapeutic Approach UVEitis: Protocol-2 (SAVE-2) Study. SAVE-2 is a prospective randomized, phase II, open-label interventional clinical trial conducted at 4 clinical centers in the United States. Eligible subjects were randomized into one of two treatments. Group 1 received 440µg of intravitreal sirolimus in study eyes on days 0, 30, 60, 90, 120, and 150; group 2 received 880µg of intravitreal sirolimus on days 0, 60, and 120. Fellow eyes were also eligible to receive sirolimus (of opposite dose to that of study eye). Primary endpoint of the study was at month 6 (M6). 24 subjects have been randomized in SAVE-2 and are included in the analysis. Vitreous haze decreased by ≥2 steps in 63.6% and 50% of patients in groups 1 and 2, respectively at M6 (p=0.695). Mean change in best-corrected visual acuity for subjects was +3.66 and -2.91 ETDRS letters in group 1 and 2, respectively. Among subjects with macular edema at baseline (n=13), the mean change in foveal thickness was -89.42µm in group 1 and +81.5µm in group 2 at M6. Both low and high doses of intravitreal sirolimus were found to decrease vitreous haze in eyes with non-infectious uveitis. Low dose (440µg) sirolimus administered monthly may be more efficacious in reducing uveitic macular edema than high dose (880µg) administered every 2 months.

The Effect of Different Dosing Schedules of Intravitreal Sirolimus, a Mammalian Target of Rapamycin (mTOR) Inhibitor, in the Treatment of Non-Infectious Uveitis (An American Ophthalmological Society Thesis)

PubMed Central

Nguyen, Quan Dong; Sadiq, Mohammad Ali; Soliman, Mohamed Kamel; Agarwal, Aniruddha; Do, Diana V.; Sepah, Yasir J.

2016-01-01

Purpose: To determine if two different doses of intravitreal sirolimus, an mTOR inhibitor, can decrease inflammation and is safe in eyes with non-infectious posterior, intermediate, or panuveitis in the Sirolimus as a Therapeutic Approach UVEitis: Protocol-2 (SAVE-2) Study. Methods: SAVE-2 is a prospective randomized, phase II, open-label interventional clinical trial conducted at 4 clinical centers in the United States. Eligible subjects were randomized into one of two treatments. Group 1 received 440µg of intravitreal sirolimus in study eyes on days 0, 30, 60, 90, 120, and 150; group 2 received 880µg of intravitreal sirolimus on days 0, 60, and 120. Fellow eyes were also eligible to receive sirolimus (of opposite dose to that of study eye). Primary endpoint of the study was at month 6 (M6). Results: 24 subjects have been randomized in SAVE-2 and are included in the analysis. Vitreous haze decreased by ≥2 steps in 63.6% and 50% of patients in groups 1 and 2, respectively at M6 (p=0.695). Mean change in best-corrected visual acuity for subjects was +3.66 and −2.91 ETDRS letters in group 1 and 2, respectively. Among subjects with macular edema at baseline (n=13), the mean change in foveal thickness was −89.42µm in group 1 and +81.5µm in group 2 at M6. Conclusions: Both low and high doses of intravitreal sirolimus were found to decrease vitreous haze in eyes with non-infectious uveitis. Low dose (440µg) sirolimus administered monthly may be more efficacious in reducing uveitic macular edema than high dose (880µg) administered every 2 months. PMID:27630374

Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive-compulsive disorder.

PubMed

Kontis, Dimitris; Boulougouris, Vasileios; Papakosta, Vasiliki Maria; Kalogerakou, Stamatina; Papadopoulos, Socrates; Poulopoulou, Cornelia; Papadimitriou, George N; Tsaltas, Eleftheria

2008-11-01

We have proposed rewarded T-maze alternation as a model of obsessive-compulsive disorder (OCD): the serotonin agonist m-chlorophenylpiperazine (mCPP) increments persistence therein, while chronic pretreatment with selective serotonin reuptake inhibitor (SSRI fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increase, counteracted by mCPP pretreatment. This study (a) further explores the cross-tolerance between fluoxetine and mCPP and (b) extends the model by investigating its sensitivity to dopaminergic manipulations (D2, 3 agonism--quinpirole). In both experiments, baseline and drug testing were carried out under daily T-maze alternation training. Exp. 1: Matched group (n = 8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration): (1) saline, (2) low-dose fluoxetine (2.5 mg/kg), (3) low-dose mCPP (0.5 mg/kg) or (4) combined fluoxetine + mCPP. One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10 mg/kg), the other with high-dose mCPP (2.5 mg/kg). Exp. 2: One group (n = 12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg). Exp. 1: Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine + mCPP pretreatment afforded full protection from either challenge. Exp. 2: Quinpirole significantly increased directional persistence after 13 administration days. These results establish the sensitivity of the rewarded alternation OCD model to D2, 3 receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial.

PubMed

Ladenstein, Ruth; Pötschger, Ulrike; Pearson, Andrew D J; Brock, Penelope; Luksch, Roberto; Castel, Victoria; Yaniv, Isaac; Papadakis, Vassilios; Laureys, Geneviève; Malis, Josef; Balwierz, Walentyna; Ruud, Ellen; Kogner, Per; Schroeder, Henrik; de Lacerda, Ana Forjaz; Beck-Popovic, Maja; Bician, Pavel; Garami, Miklós; Trahair, Toby; Canete, Adela; Ambros, Peter F; Holmes, Keith; Gaze, Mark; Schreier, Günter; Garaventa, Alberto; Vassal, Gilles; Michon, Jean; Valteau-Couanet, Dominique

2017-04-01

High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m 2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8-1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m 2 ) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m 2 per day for 4 days, and melphalan 70 mg/m 2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17. Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3-9·2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45-56) versus 38% (32-43; p=0·0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3-4 adverse events were general condition (74 [26%] of 281 in the busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1-3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Atorvastatin improves reflow after percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction by decreasing serum uric acid level].

PubMed

Yan, Ling; Ye, Lu; Wang, Kun; Zhou, Jie; Zhu, Chunjia

2016-05-25

Objective: To investigate the effect of atorvastatin on reflow in patients with acute ST-segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) and its relation to serum uric acid levels. Methods: One hundred and fourteen STEMI patients undergoing primary PCI were enrolled and randomly divided into two groups:55 cases received oral atorvastatin 20 mg before PCI (routine dose group) and 59 cases received oral atorvastatin 80 mg before PCI (high dose group). According to the initial serum uric acid level, patients in two groups were further divided into normal uric acid subgroup and hyperuricemia subgroup. The changes of uric acid level and coronary artery blood flow after PCI were observed. Correlations between the decrease of uric acid, the dose of atorvastatin and the blood flow of coronary artery after PCI were analyzed. Results: Serum uric acid levels were decreased after treatment in both groups (all P <0.05), and patients with hyperuricemia showed more significant decrease in serum uric acid level ( P <0.05). Compared with the routine dose group, serum uric acid level in patients with hyperuricemia decreased more significantly in the high dose group ( P <0.05), but no significant difference was observed between patients with normal serum uric acid levels in two groups ( P >0.05). Among 114 patients, there were 19 cases without reflow after PCI (16.7%). In the routine dose group, there were 12 patients without reflow, in which 3 had normal uric acid and 9 had high uric acid levels ( P <0.01). In the high dose group, there were 7 patients without reflow, in which 2 had normal uric acid and 5 had high uric acid ( P <0.05). Logistic regression analysis showed that hyperuricemia was one of independent risk factors for no-reflow after PCI ( OR =1.01, 95% CI :1.01-1.11, P <0.01). The incidence of no-flow after PCI in the routine dose group was 21.8% (12/55), and that in the high dose group was 11.9% (7/59) ( P <0.01). Conclusion: High dose atorvastatin can decrease serum uric acid levels and improve reflow after PCI in patients with STEMI.

Non-induction of radioadaptive response in zebrafish embryos by neutrons.

PubMed

Ng, Candy Y P; Kong, Eva Y; Kobayashi, Alisa; Suya, Noriyoshi; Uchihori, Yukio; Cheng, Shuk Han; Konishi, Teruaki; Yu, Kwan Ngok

2016-06-01

In vivo neutron-induced radioadaptive response (RAR) was studied using zebrafish (Danio rerio) embryos. The Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility at the National Institute of Radiological Sciences (NIRS), Japan, was employed to provide 2-MeV neutrons. Neutron doses of 0.6, 1, 25, 50 and 100 mGy were chosen as priming doses. An X-ray dose of 2 Gy was chosen as the challenging dose. Zebrafish embryos were dechorionated at 4 h post fertilization (hpf), irradiated with a chosen neutron dose at 5 hpf and the X-ray dose at 10 hpf. The responses of embryos were assessed at 25 hpf through the number of apoptotic signals. None of the neutron doses studied could induce RAR. Non-induction of RAR in embryos having received 0.6- and 1-mGy neutron doses was attributed to neutron-induced hormesis, which maintained the number of damaged cells at below the threshold for RAR induction. On the other hand, non-induction of RAR in embryos having received 25-, 50- and 100-mGy neutron doses was explained by gamma-ray hormesis, which mitigated neutron-induced damages through triggering high-fidelity DNA repair and removal of aberrant cells through apoptosis. Separate experimental results were obtained to verify that high-energy photons could disable RAR. Specifically, 5- or 10-mGy X-rays disabled the RAR induced by a priming dose of 0.88 mGy of alpha particles delivered to 5-hpf zebrafish embryos against a challenging dose of 2 Gy of X-rays delivered to the embryos at 10 hpf. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Method for microbeam radiation therapy

DOEpatents

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

1994-01-01

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

Real-life GH dosing patterns in children with GHD, TS or born SGA: a report from the NordiNet® International Outcome Study.

PubMed

Blankenstein, Oliver; Snajderova, Marta; Blair, Jo; Pournara, Effie; Pedersen, Birgitte Tønnes; Petit, Isabelle Oliver

2017-08-01

To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016. This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n  = 425/61/316/119), France ( n  = 1404/188/970/206), Germany ( n  = 2603/351/1387/411) and the UK ( n  = 259/60/87/35). GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications. In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown ( P  < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%). GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations. © 2017 The authors.

[Treatment outcome and prognosis of autologous hematopoietic stem cell transplantation combined with high dose radiotherapy/chemotherapy in 22 patients with nasal NK/T cell lymphoma].

PubMed

Cui, Xiu-Zhen; Wang, Hua-Qing; Liu, Xian-Ming; Zhang, Hui-Lai; Li, Wei

2007-09-01

To analyze the outcome and prognosis of autologous hematopoietic stem cell transplantation (AHSCT) combined with high dose radiotherapy/chemotherapy in 22 patients with nasal NK/T cell lymphoma. From July 1992 to December 2005, 22 patients with nasal NK/T cell lymphoma were diagnosed pathologically. Immunophenotyping was performed in 13 cases. The patients were classified by Ann Arbor staging system and international prognosis index (IPI). The patients received cycles of chemotherapy every other two weeks or combined with radiotherapy for remission induction, followed high dose radiotherapy/chemotherapy, combined with autologous peripheral blood stem cell transplantation (APBSCT), or autologous bone-marrow transplantation (ABMT). Patients were given complementary radiotherapy after transplantation if they did not have it before. Twelve patients of IPI 3 -4 received consolidation chemotherapy, and one of them received the second transplantation. The median follow-up duration was 64 (12 - 168) months. The 5 and 8-year overall survivals (OS) were 79.3% and 64.1%, and disease free survivals (DFS) were 36.4% and 27.3%, respectively. The 5-year OS were as follows: for stage I - II and III - IV disease were 90.0% and 70.0% (P = 0. 041); for patients without and with B symptom were 100.0% and 70.7% (P = 0.045); and for IPI 1 - 2 and 3 - 4 were 100.0% and 60.0% (P = 0.035), respectively. Multivariate analysis by COX regression revealed that disease stage, B symptom and IPI were independent prognostic factors. AHSCT combined with high dose radiotherapy/chemotherapy is an effective treatment for patients with poor prognosis nasal NK/T cell lymphoma.

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.

Acute Biological Effects of Simulating the Whole-Body Radiation Dose Distribution from a Solar Particle Event Using a Porcine Model

PubMed Central

Wilson, Jolaine M.; Sanzari, Jenine K.; Diffenderfer, Eric S.; Yee, Stephanie S.; Seykora, John T.; Maks, Casey; Ware, Jeffrey H.; Litt, Harold I.; Reetz, Jennifer A.; McDonough, James; Weissman, Drew; Kennedy, Ann R.; Cengel, Keith A.

2011-01-01

In a solar particle event (SPE), an unshielded astronaut would receive proton radiation with an energy profile that produces a highly inhomogeneous dose distribution (skin receiving a greater dose than internal organs). The novel concept of using megavoltage electron-beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation has been described previously. Here, Yucatan minipigs were used to determine the effects of a superficial, SPE-like proton dose distribution using megavoltage electrons. In these experiments, dose-dependent increases in skin pigmentation, ulceration, keratinocyte necrosis and pigment incontinence were observed. Five of 18 animals (one each exposed to 7.5 Gy and 12.5 Gy radiation and three exposed to 25 Gy radiation) developed symptomatic, radiation-associated pneumonopathy approximately 90 days postirradiation. The three animals from the highest dose group showed evidence of mycoplasmal pneumonia along with radiation pneumonitis. Moreover, delayed-type hypersensitivity was found to be altered, suggesting that superficial irradiation of the skin with ionizing radiation might cause immune dysfunction or dysregulation. In conclusion, using total doses, patterns of dose distribution, and dose rates that are compatible with potential astronaut exposure to SPE radiation, animals experienced significant toxicities that were qualitatively different from toxicities previously reported in pigs for homogeneously delivered radiation at similar doses. PMID:21859326

Temporal changes in physiology and haematology in response to high- and micro-doses of recombinant human erythropoietin.

PubMed

Clark, Brad; Woolford, Sarah M; Eastwood, Annette; Sharpe, Ken; Barnes, Peter G; Gore, Christopher J

2017-10-01

There is evidence to suggest athletes have adopted recombinant human erythropoietin (rHuEPO) dosing regimens that diminish the likelihood of being caught by direct detection techniques. However, the temporal response in physiology, performance, and Athlete Biological Passport (ABP) parameters to such regimens is not clearly understood. Participants were assigned to a high-dose only group (HIGH, n = 8, six rHuEPO doses of 250 IU/kg over two weeks), a combined high micro-dose group (COMB, n = 8, high-dose plus nine rHuEPO micro-doses over a further three weeks), or one of two placebo control groups who received saline in the same pattern as the HIGH (HIGH-PLACEBO, n = 4) or COMB (COMB-PLACEBO, n = 4) groups. Temporal changes in physiology and performance were tracked by graded exercise test (GXT) and haemoglobin mass assessment at baseline, after high dose, after micro-dose (COMB and COMB-PLACEBO only) and after a four-week washout. Venous blood samples were collected throughout the baseline, rHuEPO administration, and washout periods to determine the haematological and ABP response to each dosing regimen. Physiological adaptations induced by a two-week rHuEPO high-dose were maintained by rHuEPO micro-dosing for at least three weeks. However, all participants administered rHuEPO registered at least one suspicious ABP value during the administration or washout periods. These results indicate there is sufficient sensitivity in the ABP to detect use of high rHuEPO doping regimens in athletic populations and they provide important empirical examples for use by anti-doping experts. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Effect of high doses of 2-CdA on Schwann cells of mouse peripheral nerve.

PubMed

Djaldetti, R; Hart, J; Alexandrova, S; Cohen, S; Beilin, B; Djaldetti, M; Bessler, H

1996-07-01

The present study was undertaken to examine the effect of 2-CdA (Leustatin) on the Schwann cells of myelinated and unmyelinated fibers of peripheral mouse nerve. Two groups of mice were injected intravenously for seven days with 2-CdA: one group received daily doses of 1 mg/kg and the other 0.5 mg/kg. Both doses exceeded those accepted in clinical practice. Mice injected with saline served as controls. The sciatic nerve was then dissected and examined with a transmission electron microscope. The Schwann cells of both the myelinated and unmyelinated nerve fibers of the animals receiving the higher doses of 2-CdA showed nuclear and nucleolus damage, loss of heterochromatin, vacuolization and disorganization of the myelin sheaths. The mesaxons and the axons were also damaged. The Schwann cells of the animals treated with the lower doses appeared undamaged. The results indicate that in contrast to other anticancer drugs known to produce peripheral neuropathy, 2-CdA may cause damage to the Schwann cells only at doses exceeding the therapeutic ones.

UVER and UV index at high altitude in Northwestern Argentina.

PubMed

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

2016-10-01

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

Effects of supplementation with higher levels of manganese and magnesium on immune function.

PubMed

Son, Eun-Wha; Lee, Sung-Ryul; Choi, Hye-Sook; Koo, Hyun-Jung; Huh, Jung-Eun; Kim, Mi-Hyun; Pyo, Suhkneung

2007-06-01

The magnesium (Mg) and manganese (Mn) were evaluated for its effectiveness as an immunomodulator in rats. The treatments were as follows: Group 1, AIN-93M diet (0.05% Mg, 0.001% Mn); Group 2, high-dose Mg (0.1% Mg, 0.001% Mn); and Group 3, high dose Mn (0.05% Mg, 0.01% Mn) (n-12/group). After 12 weeks of supplementation, rats were sacrificed to assess the effect on a range of innate responses (tumoricidal activity, oxidative burst and nitric oxide) and the mitogen-stimulated lymphoproliferative response. Immune function was significantly affected in both the high dose Mg and the Mn group. Lymphocyte proliferative responses and NK cell activity were measured in pooled spleen from each group. The mitogen response of lymphocytes to LPS in the spleen was significantly reduced in high dose Mg-treated groups, whereas the response to ConA was not affected in both high dose minerals-treated groups. The reactive oxygen species level of macrophages was decreased in both groups. These effects were more pronounced in high dose Mg-treated group. Nitric oxide production was also decreased in high dose minerals-treated group. In addition, tumoricidal activities of splenic NK cell and peritoneal macrophage in mineral exposed rats were significantly increased. Moreover, percent death of macrophage was reduced in two groups receiving high dose mineral supplements. Taken together, the present data suggest that high dose trace min erals exert a differential effect on the function of immune cells.

Efficacy of short-term moderate or high-dose rosuvastatin in preventing contrast-induced nephropathy

PubMed Central

Liang, Min; Yang, Shicheng; Fu, Naikuan

2017-01-01

Abstract Background: The prophylactic efficacy of statin pretreatment for the prevention of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) remains controversial. The aim of the study was to perform a meta-analysis of randomized controlled trials (RCTs) to assess the effectiveness of short-term moderate or high-dose rosuvastatin pretreatment in preventing CIN. Methods: We included RCTs comparing short-term moderate or high-dose rosuvastatin treatment versus low-dose rosuvastatin treatment or placebo for preventing CIN. The primary endpoint was the incidence of CIN within 2 to 5 days after contrast administration, and related-parameters including serum creatinine (SCr), cystatin C (CysC), hypersensitive C-reactive protein (hs-CRP), urine microalbumin (mALB) were also extracted. Results: Fifteen RCTs with a total of 2673 patients were identified and analyzed. Patients who received moderate or high-dose rosuvastatin pretreatment had a 55% lower risk of CIN compared with low-dose rosuvastatin pretreatment or placebo group based on a fixed effect model (RR = 0.45, 95% CI 0.35–0.58, P < .0001). The benefit of moderate or high-dose rosuvastatin was consistent in both comparisons with low-dose rosuvastatin (RR = 0.40, 95% CI 0.27–0.59, P < .0001) or placebo (RR = 0.45, 95% CI 0.35–0.58, P < .0001). And moderate (20 mg) or high dose (≥40 mg) rosuvastatin significantly reduced the incidence of CIN compared with the control (RR = 0.39, 95% CI 0.29–0.54, P < .0001, RR = 0.56, 95% CI 0.37–0.85, P = .006, respectively). Subgroup analysis showed that moderate or high-dose rosuvastatin pretreatment could decrease the incidence of CIN in patients with chronic kidney disease (CKD) (RR = 0.53, 95% CI 0.30–0.93, P = .03) or diabetes mellitus (DM) (RR = 0.51, 95% CI 0.31–0.86, P = .01) or acute coronary syndrome (ACS) patients undergoing PCI (RR = 0.52, 95% CI 0.35–0.76, P = .0009) or in studies which received mean contrast volume ≥110 mL (RR = 0.43, 95% CI 0.32–0.58, P < .0001). The SCr, CysC, hs-CRP, and mALB after the operation in the moderate or high-dose rosuvastatin group were lower than those of low-dose rosuvastatin group. Conclusion: This meta-analysis demonstrated that moderate or high-dose rosuvastatin treatment could reduce the incidence of CIN in patients undergoing CAG or PCI. Moreover, moderate or high-dose rosuvastatin would be beneficial in high-risk patients with CKD or DM or undergoing PCI. PMID:28682890

Effective Dose Radon 222 of the Tap Water in Children and Adults People; Minab City, Iran.

PubMed

Fakhri, Yadolah; Kargosha, Morteza; Langarizadeh, Ghazaleh; Zandsalimi, Yahya; Rasouli Amirhajeloo, Leila; Moradi, Mahboobeh; Moradi, Bigard; Mirzaei, Maryam

2015-09-01

(222)Rn is a radioactive, odorless, and colorless element which has a half-life of 3.83 days. One of (222)Rn main resources are Groundwater (wells, springs, etc.). Hence, the use of groundwater with high concentration of (222)Rn can increase the risk of lung and stomach cancers. Concentration of (222)Rn in tap water of Minab city in two temperatures 5 and 15 ºC was measured by radon meter model RTM1668-2. The effective dose was calculated by equations proposed by UNSCEAR. Geometric mean concentration of (222)Rn in drinking water was found to be 0.78±0.06 and 0.46±0.04 Bq/l at 5 and 15 ̊C (p value<0.05), respectively. The effective doses were 0.006 and 0.003 mSv/y for adults, and 0.011 and 0.007 mSv/y for the children, respectively (p value<0.05). Besides, the effective dose for adult through inhaling (222)Rn at 5 and 15 ̊C were estimated 0.0021 and 0.0012mSv/y, respectively. Geometric mean concentration in (222)Rn drinking water and effective dose received from drinking water and inhalation of (222)Rn is lower than WHO and EPA standard limits. Increasing temperature of drinking water will decrease the effective dose received. Annual Effective dose received from inhalation and consumption of (222)Rn in drinking water in children is more than adults.

Effective Dose Radon 222 of the Tap Water in Children and Adults People; Minab City, Iran

PubMed Central

Fakhri, Yadolah; Kargosha, Morteza; Langarizadeh, Ghazaleh; Zandsalimi, Yahya; Amirhajeloo, Leila Rasouli; Moradi, Mahboobeh; Moradi, Bigard; Mirzaei, Maryam

2016-01-01

222Rn is a radioactive, odorless, and colorless element which has a half-life of 3.83 days. One of 222Rn main resources are Groundwater (wells, springs, etc.). Hence, the use of groundwater with high concentration of 222Rn can increase the risk of lung and stomach cancers. Concentration of 222Rn in tap water of Minab city in two temperatures 5 and 15 ºC was measured by radon meter model RTM1668-2. The effective dose was calculated by equations proposed by UNSCEAR. Geometric mean concentration of 222Rn in drinking water was found to be 0.78±0.06 and 0.46±0.04 Bq/l at 5 and 15 °C (p value<0.05), respectively. The effective doses were 0.006 and 0.003 mSv/y for adults, and 0.011 and 0.007 mSv/y for the children, respectively (p value<0.05). Besides, the effective dose for adult through inhaling 222Rn at 5 and 15 °C were estimated 0.0021 and 0.0012mSv/y, respectively. Geometric mean concentration in 222Rn drinking water and effective dose received from drinking water and inhalation of 222Rn is lower than WHO and EPA standard limits. Increasing temperature of drinking water will decrease the effective dose received. Annual Effective dose received from inhalation and consumption of 222Rn in drinking water in children is more than adults. PMID:26573047

Teratogenic effects of retinoic acid on neurulation in mice embryos.

PubMed

Nobakht, M; Zirak, A; Mehdizadeh, M; Tabatabaeei, P

2006-02-21

Retinoic acids (RA) are natural chemicals that exert a hormone-like activity and a variety of biological effects on early development of mouse. In this study, the probable teratogenic effects of RA on CNS have been investigated in pregnant mice (n = 20) divided into four groups: (1) untreated controls, (2) controls which received a single dose of DMSO, (3) a group that received 40 mg/kg, and (4) a group that received 60 mg/kg of all-trans RA in DMSO, respectively on the eighth day of gestation. Embryos whose dams had received 40 and 60 mg/kg doses of RA, showed malformations and decreased size. At 40 mg/kg dosage level, 50% of the embryos had closed neural tubes while at 60 mg/kg dosage level the neural tube failed to close. The neuroblast mantle layers were disorganized in the 40 mg/kg and even more in the 60 mg/kg exposed group compared to the controls. In mitosis, the density of chromatin was increased in the 60 mg/kg dose group. Compared to controls the 40 and 60 mg/kg dose groups of RA treated dams decreases in the luminal longitudinal and internal measures were observed. Also the thickness of ventricular, mantle and marginal layers was smaller. Wide intercellular spaces due to the degenerated cells at high doses of RA as well as an accumulation of intercellular fluid were observed. Therefore, the wedge shape of neuroepithelium was abolished, preventing the elevation of the neural wall.

Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group.

PubMed

Lai, E C; Felice, K J; Festoff, B W; Gawel, M J; Gelinas, D F; Kratz, R; Murphy, M F; Natter, H M; Norris, F H; Rudnicki, S A

1997-12-01

The objective of this study was to investigate the safety and efficacy of recombinant human insulinlike growth factor-I (rhIGF-I) in the treatment of sporadic ALS. A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. Placebo or rhIGF-I (0.05 mg/kg/day or 0.10 mg/kg/day) was administered for 9 months. The primary outcome measure was disease symptom progression, assessed by the rate of change (per patient slope) in the Appel ALS rating scale total score. The Sickness Impact Profile (SIP), a patient-perceived, health-related quality of life assessment, was a secondary outcome variable. Progression of functional impairment in patients receiving high-dose (0.10 mg/kg/day) rhIGF-I was 26% slower than in patients receiving placebo (p = 0.01). The high-dose treatment group was less likely to terminate the study due to protocol-defined markers of disease symptom progression, and members in this group exhibited a slower decline in quality of life, as assessed by the SIP. Patients receiving 0.05 mg/kg/day of rhIGF-I exhibited trends similar to those associated with high-dose treatment, suggesting a dose-dependent response. The incidence of clinically significant adverse experiences was comparable among the three treatment groups. Recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects.

Protons and more: state of the art in radiotherapy.

PubMed

Hoskin, Peter J; Bhattacharya, Indrani S

2014-12-01

The purpose of modern radiotherapy is to deliver a precise high dose of radiation which will result in reproductive death of the cells. Radiation should transverse within the tumour volume whilst minimising damage to surrounding normal tissue. Overall 40% of cancers which are cured will have received radiotherapy. Current state of the art treatment will incorporate cross-sectional imaging and multiple high energy X-ray beams in processes called intensity modulated radiotherapy and image guided radiotherapy. Brachytherapy enables very high radiation doses to be delivered by the direct passage of a radiation source through or within the tumour volume and similar results can be achieved using rotational stereotactic X-ray beam techniques. Protons have the characteristics of particle beams which deposit their energy in a finite fixed peak at depth in tissue with no dose beyond this point - the Bragg peak. This has advantages in certain sites such as the spine adjacent to the spinal cord and particularly in children when the overall volume of tissue receiving radiation can be minimised. © 2014 Royal College of Physicians.

Five-year follow-up of survival and relapse in patients who received cryotherapy during high-dose chemotherapy for stem cell transplantation shows no safety concerns.

PubMed

Svanberg, A; Ohrn, K; Birgegård, G

2012-11-01

We have previously published a randomised controlled study of the efficacy of cryotherapy in preventing acute oral mucositis after high-dose chemotherapy for stem cell transplantation. The present study is a 5-year follow-up safety study of survival in these patients. In the previously published study oral cryotherapy (cooling of the oral cavity) during high-dose chemotherapy significantly reduced mucositis grade and opiate use in the treated group. All patients were followed up for at least 5 years with regard to relapse and death rates. Baseline data, transplant complications and mucositis data were compared. Significantly more patients (25/39) who received oral cryotherapy were alive after 5 years compared to 15/39 in the control group (P= 0.025). Relapse rates were similar. The only baseline difference was a lower proportion of patients in complete remission at transplantation in the control group (6 vs. 13, P= 0.047). This 5-year follow-up study gave no support for safety concerns with cryotherapy. © 2012 Blackwell Publishing Ltd.

A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia

PubMed Central

Qin, Yan; Han, Xiaohong; Wang, Lin; Du, Ping; Yao, Jiarui; Wu, Di; Song, Yuanyuan; Zhang, Shuxiang; Tang, Le; Shi, Yuankai

2017-01-01

Objective The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Methods Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. Results A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0–2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. Conclusions The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment. PMID:29142459

A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia.

PubMed

Qin, Yan; Han, Xiaohong; Wang, Lin; Du, Ping; Yao, Jiarui; Wu, Di; Song, Yuanyuan; Zhang, Shuxiang; Tang, Le; Shi, Yuankai

2017-10-01

The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0-2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment.

Memory immune response and safety of a booster dose of Japanese encephalitis chimeric virus vaccine (JE-CV) in JE-CV-primed children

PubMed Central

Feroldi, Emmanuel; Capeding, Maria Rosario; Boaz, Mark; Gailhardou, Sophia; Meric, Claude; Bouckenooghe, Alain

2013-01-01

Japanese encephalitis chimeric virus vaccine (JE-CV) is a licensed vaccine indicated in a single dose administration for primary immunization. This controlled phase III comparative trial enrolled children aged 36–42 mo in the Philippines. 345 children who had received one dose of JE-CV in a study two years earlier, received a JE-CV booster dose. 105 JE-vaccine-naïve children in general good health were randomized to receive JE-CV (JE-vaccine naïve group; 46 children) or varicella vaccine (safety control group; 59 children). JE neutralizing antibody titers were assessed using PRNT50. Immunological memory was observed in children who had received the primary dose of JE-CV before. Seven days after the JE-CV booster dose administration, 96.2% and 66.8% of children were seroprotected and had seroconverted, respectively, and the geometric mean titer (GMT) was 231 1/dil. Twenty-eight days after the JE-CV booster dose seroprotection and seroconversion were achieved in 100% and 95.3% of children, respectively, and the GMT was 2,242 1/dil. In contrast, only 15.4% of JE-CV-vaccine naïve children who had not received any prior JE vaccine were seroprotected seven days after they received JE-CV. One year after receiving the JE-CV booster dose, 99.4% of children remained seroprotected. We conclude that JE-CV is effective and safe, both as a single dose and when administrated as a booster dose. A booster dose increases the peak GMT above the peak level reached after primary immunization and the antibody persistence is maintained at least one year after the JE-CV booster dose administration. Five year follow up is ongoing. PMID:23442823

Memory immune response and safety of a booster dose of Japanese encephalitis chimeric virus vaccine (JE-CV) in JE-CV-primed children.

PubMed

Feroldi, Emmanuel; Capeding, Maria Rosario; Boaz, Mark; Gailhardou, Sophia; Meric, Claude; Bouckenooghe, Alain

2013-04-01

Japanese encephalitis chimeric virus vaccine (JE-CV) is a licensed vaccine indicated in a single dose administration for primary immunization. This controlled phase III comparative trial enrolled children aged 36-42 mo in the Philippines. 345 children who had received one dose of JE-CV in a study two years earlier, received a JE-CV booster dose. 105 JE-vaccine-naïve children in general good health were randomized to receive JE-CV (JE-vaccine naïve group; 46 children) or varicella vaccine (safety control group; 59 children). JE neutralizing antibody titers were assessed using PRNT50. Immunological memory was observed in children who had received the primary dose of JE-CV before. Seven days after the JE-CV booster dose administration, 96.2% and 66.8% of children were seroprotected and had seroconverted, respectively, and the geometric mean titer (GMT) was 231 1/dil. Twenty-eight days after the JE-CV booster dose seroprotection and seroconversion were achieved in 100% and 95.3% of children, respectively, and the GMT was 2,242 1/dil. In contrast, only 15.4% of JE-CV-vaccine naïve children who had not received any prior JE vaccine were seroprotected seven days after they received JE-CV. One year after receiving the JE-CV booster dose, 99.4% of children remained seroprotected. We conclude that JE-CV is effective and safe, both as a single dose and when administrated as a booster dose. A booster dose increases the peak GMT above the peak level reached after primary immunization and the antibody persistence is maintained at least one year after the JE-CV booster dose administration. Five year follow up is ongoing.

Timing of HPV vaccine intervals among United States teens with consideration to the current ACIP schedule and the WHO 2-dose schedule

PubMed Central

Cloessner, Emily A.; Stokley, Shannon; Yankey, David; Markowitz, Lauri E.

2016-01-01

Abstract The current recommendation for human papillomavirus (HPV) vaccination in the United States is for 3 doses to be administered over a 6 month period. In April 2014, the World Health Organization (WHO) recommended adoption of a 2-dose schedule, with doses spaced a minimum of 6 months apart, for teens who begin the series before age 15. We analyzed data from the 2013 National Immunization Survey-Teen to examine the timing of second and third dose receipt among US adolescents. All analyses were restricted to adolescents age 13–17 y who had adequate provider data. The Wilcoxon–Mann–Whitney test measured differences in time to receive vaccine doses among demographic and socioeconomic groups. Logistic regression identified socioeconomic characteristics associated with receiving the second dose of HPV vaccine at least 6 months after the first dose. The median time for teens to receive the second dose of HPV vaccine was 2.6 months after the first dose, and the median time to receive the third dose was 4.9 months after the second dose. Minority teens and teens living below the poverty level took significantly longer to receive doses. Among teens that initiated the HPV vaccine series before age 15 y, 28.6% received the second dose at least 6 months after the first dose. If these teens, who met the WHO criteria for up-to-date HPV vaccination, were classified as having completed the vaccination series, overall coverage in the US would increase 3.9 percentage points, with African American and Hispanic teens having the greatest increases in coverage. PMID:26587886

Timing of HPV vaccine intervals among United States teens with consideration to the current ACIP schedule and the WHO 2-dose schedule.

PubMed

Cloessner, Emily A; Stokley, Shannon; Yankey, David; Markowitz, Lauri E

2016-06-02

The current recommendation for human papillomavirus (HPV) vaccination in the United States is for 3 doses to be administered over a 6 month period. In April 2014, the World Health Organization (WHO) recommended adoption of a 2-dose schedule, with doses spaced a minimum of 6 months apart, for teens who begin the series before age 15. We analyzed data from the 2013 National Immunization Survey-Teen to examine the timing of second and third dose receipt among US adolescents. All analyses were restricted to adolescents age 13-17 y who had adequate provider data. The Wilcoxon-Mann-Whitney test measured differences in time to receive vaccine doses among demographic and socioeconomic groups. Logistic regression identified socioeconomic characteristics associated with receiving the second dose of HPV vaccine at least 6 months after the first dose. The median time for teens to receive the second dose of HPV vaccine was 2.6 months after the first dose, and the median time to receive the third dose was 4.9 months after the second dose. Minority teens and teens living below the poverty level took significantly longer to receive doses. Among teens that initiated the HPV vaccine series before age 15 y, 28.6% received the second dose at least 6 months after the first dose. If these teens, who met the WHO criteria for up-to-date HPV vaccination, were classified as having completed the vaccination series, overall coverage in the US would increase 3.9 percentage points, with African American and Hispanic teens having the greatest increases in coverage.

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

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

Baker, D.A.

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

Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age.

PubMed

Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

2016-01-01

The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. Delafloxacin Cmax and AUC0-∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses ≥1200 mg. Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg). Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Measures for curtailment of iatrogenic exposure. Guide to correct x-ray examinations (in Japanese)

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

Misonoo, K.

1973-08-01

Of the coposure dose for humans from various radiation sources, introgenic exposure amounts to 1/2 to twice the natural radiation source. Although the mechanism of induction of malignant tumor by radiation is not clanified, it is evident that it is induced after receiving a dose above 100 rads. However, the presence of a threshold, under which it does not develop, is unknown. Tabulated were ICRP's calculations on the degree of risk of injury and the estimated values of genetic injury due to 1 rad. In order to estimate the harmful effect of exposure in x-ray diagnosis, the dose in themore » critical tissue of the human body and the types and the frequency of radiation examinations are important. The judgment of genetic injury is expressed by the genetically significant dose, which is calculated from the dose in the genital gland received by individuals. The impcrtant criterion for the judgment of physical injury is the mean annual dose per person in the marrow (mean dose in the red marrow). The dose in the genital organ is important as the dose related to the evaluation of the degree of genetic risk. The characteristics of iatrogenic exposure are partial and acute exposure and a high dose rate. Tabulated individually were the frequency of x-ray examinations, the mean dose in the genital organ according urce. The radiation dose during x-ray pelvimetry to 51 patients was estimated, and the cytogenetic response of peripheral lymphocytes was determined in 25 of their newborn babies. The calculations resulted in an average midline fetal dose of 1,035 and 1,860 mrads for the patients receiving 2 projections and more than 2 projections, respectively. There was no evidence of radioinduced chromosomal darnage in the newborn infants following x-ray exposure in utero. (auth)« less

A Comparative Study on the Life-Saving Radioprotective Effects of Vitamins A, E, C and Over-the-Counter Multivitamins.

PubMed

Mortazavi, S M J; Rahimi, S; Mosleh-Shirazi, M A; Arjomandi, M; Soleimani, A; Koohi Hossein-Abadi, O; Haghani, M; Alavi, M

2015-06-01

Oral intake of vitamins which present antioxidant characteristics can protect living organisms against oxidative damage caused by exposure to ionizing radiation. It was previously reported that administration of high levels of vitamin C can lead to increased DNA damage through production of hydroxyl radicals from hydrogen peroxide by the Fenton reaction. However, our early experiments did not confirm this hypothesis. The main goal of this study was to determine if high doses of Vit C can show life-saving radioprotective effects. Phase I: Seventy two male Balb/c mice weighing 20-25g were randomly divided into six groups of 12 animals each. Group I; Vit E for five days, Groups II and III; Vit C and Vit A. Group 4; all three vitamins. Group V; an over-the-counter multivitamin. Group VI; none of the above. Phase II: 120 male BALB/c mice weighing 20-25g were randomly divided into 12 groups of 10 each. Group I; Vit A for five days. Groups II-IV; Vit C 200 mg/kg, 400 mg/kg, 800 mg/kg, respectively. Group V-VII; Vit E at daily doses of 200 iu/kg, 400 iu/kg, 800 iu/kg, respectively. Group VIII and IX; all three vitamins at low and high doses, respectively. Group X; an over-the-counter multivitamin. Group XI; controls group and Group XII; received pure olive oil. All animals (Phases I and II) were exposed to a lethal dose of gamma rays and the survival rates of the animals were monitored and recorded continuously for 16 days after exposure. Phase I: 14 days after irradiation the survival rate for control group was 33.33%, while the survival rates for the 1st to 5th groups were 45.45%, 81.81%, 50%, 57.14%, and 9.09% , respectively. Phase II: The survival rates in the control group and the group that only received pure olive oil, were 50% and 60%, respectively. Survival rate in the animals received Vit C at daily doses of 200 mg/kg, 400 mg/kg, 800 mg/kg, were 90%, 90% and 90%, respectively. Log rank (Mantel-Cox) test showed statistically significant differences between the survival rates in control irradiated mice (no vitamins) and mice received Vit C at daily doses of 200 mg/kg (P=0.042), 400 mg/kg (P=0.042) and 800 mg/kg (P=0.042). Altogether, findings of this study showed that even high doses of Vit C can show life-saving radioprotective effects. The significant radioprotective effect of Vit C at doses used in this study, opens new horizons in developing non-toxic, cost effective, easily available radioprotectors in life-threatening situations such as exposure to lethal doses of ionizing radiation.  The radioprotective effect of Vit A and Vit E seem to be less efficient compared to that of Vit C.

High-dose neutron detector project update

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

Menlove, Howard Olsen; Henzlova, Daniela

These are the slides for a progress review meeting by the sponsor. This is an update on the high-dose neutron detector project. In summary, improvements in both boron coating and signal amplification have been achieved; improved boron coating materials and procedures have increased efficiency by ~ 30-40% without the corresponding increase in the detector plate area; low dead-time via thin cell design (~ 4 mm gas gaps) and fast amplifiers; prototype PDT 8” pod has been received and testing is in progress; significant improvements in efficiency and stability have been verified; use commercial PDT 10B design and fabrication to obtainmore » a faster path from the research to practical high-dose neutron detector.« less

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

Mwidu, U; Devic, S; Shehadeh, M

Purpose: A retrospective comparison of dose distributions achievable by High dose rate brachytherapy (HDRBT), Helical TomoTherapy (TOMO), CyberKnife (CK) and RapidArc (RA) in locally advanced inoperable cervical cancer patients is presented. Methods: Five patients with advanced stage cervical carcinoma were selected for this study after a full course of external beam radiotherapy (EBRT), chemotherapy and HDR Brachytherapy. To highlight any significant similarities/differences in dose distributions, high-risk clinical target volume (HRCTV) coverage, organs at risk (OAR) sparing, and machine specific delivery limitations, we used D90 (dose received by 90% of the volume) as the parameter for HRCTV coverage as recommended bymore » the GEC-ESTRO Working Group. We also compared both integral and differential dose volume histograms (DVH) between different dose distributions treatment modalities for HRCTV and OAR. Results: TOMO and RA provided the most conformal dose distributions to HRCTV. Median doses (in Gy) to organs at risk were; for rectal wall: 1.7±0.6, 2.5±0.6,1.2±0.3, and 1.5±0.6, and for bladder wall: 1.6±0.1, 2.4±0.4, 0.8±0.6, and 1.5±0.5, for HDRBT, TOMO, CK, and RA, respectively. Conclusion: Contemporary EBRT modalities might be able to replace brachytherapy treatments for cervix cancer. While brachytherapy dose distributions feature high dose gradients, EBRT modalities provide highly conformal dose distributions to the target. However, it is still not clear whether a highly conformal dose or high gradient dose is more clinically relevant for the HRCTV in cervix cancer patients.« less

Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population.

PubMed

Stumpf, Janice L; Skyles, Amy J; Alaniz, Cesar; Erickson, Steven R

2007-01-01

To evaluate the knowledge of appropriate doses and potential toxicities of acetaminophen and assess the ability to recognize products containing acetaminophen in an adult outpatient setting. Cross-sectional, prospective study. University adult general internal medicine (AGIM) clinic. 104 adult patients presenting to the clinic over consecutive weekdays in December 2003. Three-page, written questionnaire. Ability of patients to identify maximum daily doses and potential toxicities of acetaminophen and recognize products that contain acetaminophen. A large percentage of participants (68.3%) reported pain on a daily or weekly basis, and 78.9% reported use of acetaminophen in the past 6 months. Only 2 patients correctly identified the maximum daily dose of regular acetaminophen, and just 3 correctly identified the maximum dose of extra-strength acetaminophen. Furthermore, 28 patients were unsure of the maximum dose of either product. Approximately 63% of participants either had not received or were unsure whether information on the possible danger of high doses of acetaminophen had been previously provided to them. When asked to identify potential problems associated with high doses of acetaminophen, 43.3% of patients noted the liver would be affected. The majority of the patients (71.2%) recognized Tylenol as containing acetaminophen, but fewer than 15% correctly identified Vicodin, Darvocet, Tylox, Percocet, and Lorcet as containing acetaminophen. Although nearly 80% of this AGIM population reported recent acetaminophen use, their knowledge of the maximum daily acetaminophen doses and potential toxicities associated with higher doses was poor and appeared to be independent of education level, age, and race. This indicates a need for educational efforts to all patients receiving acetaminophen-containing products, especially since the ability to recognize multi-ingredient products containing acetaminophen was likewise poor.

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

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

Baker, D.A.

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

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

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

Baker, D.A.

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

Preventive Effect of Cashew-Derived Protein Hydrolysate with High Fiber on Cerebral Ischemia

PubMed Central

Thukham-mee, Wipawee; Wannanon, Panakaporn; Tiamkao, Somsak

2017-01-01

This study aimed to determine the protective effect of cashew nut-derived protein hydrolysate with high dietary fiber (AO) in cerebral ischemic rats induced by the occlusion of right middle cerebral artery (Rt.MCAO). Acute toxicity was determined and data showed that LD50 of AO > 5000 mg/kg BW. To determine the cerebroprotective effect of AO, male Wistar rats were orally given AO at doses of 2, 10, and 50 mg/kg for 14 days and subjected to Rt.MCAO. Brain infarction volume, neurological score, spatial memory, serum lipid profiles, and C-reactive protein together with the brain oxidative stress status were assessed. All doses of AO significantly decreased brain infarction in cortex, hippocampus, and striatum together with the decreased oxidative stress status. The improvement of spatial memory and serum C-reactive protein were also observed in MCAO rats which received AO at all doses. In addition, the decreased serum cholesterol, TG, and LDL but increased HDL were observed in MCAO rats which received high dose of AO. Taken all together, AO is the potential protectant against cerebral ischemia. The improvement of oxidative stress, inflammation, and dyslipidemia might play roles in the actions. However, further researches are required to understand the precise underlying mechanism. PMID:29457029

SU-E-T-157: Evaluation and Comparison of Doses to Pelvic Lymph Nodes and to Point B with 3D Image Guided Treatment Planning for High Dose Brachytherapy for Treatment of Cervical Cancer

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

Bhandare, N.

2014-06-01

Purpose: To estimate and compare the doses received by the obturator, external and internal iliac lymph nodes and point Methods: CT-MR fused image sets of 15 patients obtained for each of 5 fractions of HDR brachytherapy using tandem and ring applicator, were used to generate treatment plans optimized to deliver a prescription dose to HRCTV-D90 and to minimize the doses to organs at risk (OARs). For each set of image, target volume (GTV, HRCTV) OARs (Bladder, Rectum, Sigmoid), and both left and right pelvic lymph nodes (obturator, external and internal iliac lymph nodes) were delineated. Dose-volume histograms (DVH) were generatedmore » for pelvic nodal groups (left and right obturator group, internal and external iliac chains) Per fraction DVH parameters used for dose comparison included dose to 100% volume (D100), and dose received by 2cc (D2cc), 1cc (D1cc) and 0.1 cc (D0.1cc) of nodal volume. Dose to point B was compared with each DVH parameter using 2 sided t-test. Pearson correlation were determined to examine relationship of point B dose with nodal DVH parameters. Results: FIGO clinical stage varied from 1B1 to IIIB. The median pretreatment tumor diameter measured on MRI was 4.5 cm (2.7– 6.4cm).The median dose to bilateral point B was 1.20 Gy ± 0.12 or 20% of the prescription dose. The correlation coefficients were all <0.60 for all nodal DVH parameters indicating low degree of correlation. Only 2 cc of obturator nodes was not significantly different from point B dose on t-test. Conclusion: Dose to point B does not adequately represent the dose to any specific pelvic nodal group. When using image guided 3D dose-volume optimized treatment nodal groups should be individually identified and delineated to obtain the doses received by pelvic nodes.« less

A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.

PubMed

Abbara, Ali; Clarke, Sophie; Islam, Rumana; Prague, Julia K; Comninos, Alexander N; Narayanaswamy, Shakunthala; Papadopoulou, Deborah; Roberts, Rachel; Izzi-Engbeaya, Chioma; Ratnasabapathy, Risheka; Nesbitt, Alexander; Vimalesvaran, Sunitha; Salim, Rehan; Lavery, Stuart A; Bloom, Stephen R; Huson, Les; Trew, Geoffrey H; Dhillo, Waljit S

2017-09-01

Can increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)? A second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS. Kisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12-14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS. Phase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation. Study participants: Sixty-two women aged 18-34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence. A second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2-50%, P = 0.042). Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial 'rescue' LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%). Further studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation. Triggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS. The study was designed, conducted, analysed and reported entirely by the authors. The Medical Research Council (MRC), Wellcome Trust & National Institute of Health Research (NIHR) provided research funding to carry out the studies. There are no competing interests to declare. Clinicaltrial.gov identifier NCT01667406. 8 August 2012. 10 August 2015. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial.

PubMed

Zhu, Feng-Cai; Wurie, Alie H; Hou, Li-Hua; Liang, Qi; Li, Yu-Hua; Russell, James B W; Wu, Shi-Po; Li, Jing-Xin; Hu, Yue-Mei; Guo, Qiang; Xu, Wen-Bo; Wurie, Abdul R; Wang, Wen-Juan; Zhang, Zhe; Yin, Wen-Jiao; Ghazzawi, Manal; Zhang, Xu; Duan, Lei; Wang, Jun-Zhi; Chen, Wei

2017-02-11

A recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant showed good safety and immunogenicity in a phase 1 trial of healthy Chinese adults. We aimed to assess the safety and immunogenicity of this vaccine in healthy adults in Sierra Leone and to determine the optimal dose. We did a single-centre, randomised, double-blind, placebo-controlled, phase 2 clinical trial at Sierra Leone-China Friendship Hospital, Freetown, Sierra Leone. We recruited healthy adults aged 18-50 years who were HIV negative, had no history of Ebola virus infection, and had no previous immunisation with other Ebola vaccine candidates. Participants were sequentially enrolled and randomly assigned (2:1:1), by computer-generated block randomisation (block size of eight), to receive the high-dose vaccine (1·6 × 10 11 viral particles), low-dose vaccine (8·0 × 10 10 viral particles), or placebo (containing only vaccine excipients, with no viral particles). Participants, investigators, and study staff (except two study pharmacists) were masked from treatment allocation. The primary safety outcome was occurrence of solicited adverse reactions within 7 days of vaccination, analysed by intention to treat. The primary immunogenicity outcome was glycoprotein-specific antibody responses at days 14, 28, and 168 after vaccination, analysed in all vaccinated participants who had blood samples drawn for antibody tests. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201509001259869, and is completed. During Oct 10-28, 2015, 500 participants were enrolled and randomly assigned to receive the high-dose vaccine (n=250), low-dose vaccine (n=125), or placebo (n=125). 132 (53%) participants in the high-dose group, 60 (48%) in the low-dose group, and 54 (43%) in the placebo group reported at least one solicited adverse reaction within 7 days of vaccination. Most adverse reactions were mild and self-limiting. Solicited injection-site adverse reactions were significantly more frequent in vaccine recipients (65 [26%] in high-dose group and 31 [25%] in low-dose group) than in those receiving placebo (17 [14%]; p=0·0169). Glycoprotein-specific antibody responses were detected from day 14 onwards (geometric mean titre 1251·0 [95% CI 976·6-1602·5] in low-dose group and 1728·4 [1459·4-2047·0] in high-dose group) and peaked at day 28 (1471·8 [1151·0-1881·8] and 2043·1 [1762·4-2368·4]), but declined quickly in the following months (223·3 [148·2-336·4] and 254·2 [185·0-349·5] at day 168). Geometric mean titres in the placebo group remained around 6·0-6·8 throughout the study period. Three serious adverse events (malaria, gastroenteritis, and one fatal asthma episode) were reported in the high-dose vaccine group, but none was deemed related to the vaccine. The recombinant adenovirus type-5 vector-based Ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8·0 × 10 10 viral particles was the optimal dose. Chinese Ministry of Science and Technology and the National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparative pharmacokinetic study of high-dose etoposide and etoposide phosphate in patients with lymphoid malignancy receiving autologous stem cell transplantation.

PubMed

Dorr, R T; Briggs, A; Kintzel, P; Meyers, R; Chow, H-H S; List, A

2003-04-01

The pharmacokinetics of two etoposide (E) formulations were evaluated in patients with refractory hematologic malignancies receiving high-dose conditioning with autologous stem cell transplantation. Patients were randomized to either E at 800 mg/m(2) (containing polysorbate 80 and polyethylene glycol) or etoposide phosphate (EP) at 910 mg/m(2) on days -7 and -5, prior to melphalan, 80 mg/m(2) on day -5. On day -3, EP was repeated. Plasma E was analyzed after each formulation on days -7 and -5 to compare intrapatient pharmacokinetics. In total, 10 patients were treated: four each with multiple myeloma or Hodgkin's disease and two with non-Hodgkin's lymphoma. Mucositis was the major toxicity with seven patients. EP first produced grade 3 mucositis. There was no procedure-related mortality and eight patients remained alive 1 year post-transplant. Cumulative etoposide exposure (AUC) was slightly greater with EP (P=0.056). Conversely, the volume of distribution was slightly, 33%, larger (P=0.052) and clearance was increased with the E infusion (P=0.14). As none of the differences reached statistical significance, both E formulations appear to be pharmacokinetically equivalent in the high-dose transplant setting. The combination of high-dose EP with melphalan is an active preparative regimen prior to ABMT for hematologic malignancies.

G-CSF plus preemptive plerixafor vs hyperfractionated CY plus G-CSF for autologous stem cell mobilization in multiple myeloma: effectiveness, safety and cost analysis.

PubMed

Antar, A; Otrock, Z K; Kharfan-Dabaja, M A; Ghaddara, H A; Kreidieh, N; Mahfouz, R; Bazarbachi, A

2015-06-01

The optimal stem cell mobilization regimen for patients with multiple myeloma (MM) remains undefined. We retrospectively compared our experience in hematopoietic cell mobilization in 83 MM patients using fractionated high-dose CY and G-CSF with G-CSF plus preemptive plerixafor. All patients in the CY group (n=56) received fractionated high-dose CY (5 g/m(2) divided into five doses of 1 g/m(2) every 3 h) with G-CSF. All patients in the plerixafor group (n=27) received G-CSF and plerixafor preemptively based on an established algorithm. Compared with plerixafor, CY use was associated with higher total CD34+ cell yield (7.5 × 10(6) vs 15.5 × 10(6) cells/kg, P=0.005). All patients in both groups yielded ⩾4 × 10(6) CD34+ cells/kg. Conversely, CY use was associated with high frequency of febrile neutropenia, blood and platelet transfusions need and hospitalizations. The average total cost of mobilization in Lebanon was slightly higher in the plerixafor group ($7886 vs $7536; P=0.16). Our data indicate robust stem cell mobilization in MM patients with either fractionated high-dose CY and G-CSF or G-CSF alone with preemptive plerixafor. The chemo-mobilization approach was associated with twofold stem cell yield, slightly lower cost but significantly increased toxicity.

Diazepam dose-dependently increases or decreases implicit priming of alcohol associations in problem drinkers.

PubMed

Zack, Martin; Poulos, Constantine X; Woodford, Tracy M

2006-01-01

Words denoting negative affect (NEG) have been found to prime alcohol-related words (ALC) on semantic priming tasks, and this effect is tied to severity of addiction. Previous research suggested that high doses of benzodiazepines may dampen NEG-ALC priming. The present study tested this possibility and the role of motivation for alcohol in this process. A placebo-controlled, double blind, between-within, counterbalanced design was employed. Two groups of male problem drinkers (n = 6/group) received a high (15-mg) or low (5-mg) dose of diazepam versus placebo on two identical test sessions. A lexical decision task assessed priming. Under placebo, significant NEG-->ALC priming emerged in each group. High-dose diazepam selectively reversed this effect, while low-dose selectively enhanced it. Correlations between NEG-->ALC priming and desire for alcohol provided further support that semantic priming of ALC concepts reflects a motivational process. The bi-directional effects found here parallel the effects of high- versus low-dose benzodiazepines on alcohol self-administration in animals. High-dose diazepam reduces prime-induced activation of ALC concepts in problem drinkers. Low-dose diazepam facilitates this process, and cross-priming of motivation for alcohol appears to explain this effect. Neurochemical modulation of the alcohol memory network may contribute to the motivational effects of benzodiazepines in problem drinkers.

Thyroid Adenomas After Solid Cancer in Childhood

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

Haddy, Nadia; El-Fayech, Chiraz; Guibout, Catherine

Purpose: Very few childhood cancer survivor studies have been devoted to thyroid adenomas. We assessed the role of chemotherapy and the radiation dose to the thyroid in the risk of thyroid adenoma after childhood cancer. Methods and Materials: A cohort of 3254 2-year survivors of a solid childhood cancer treated in 5 French centers before 1986 was established. The dose received by the isthmus and the 2 lobes of the thyroid gland during each course of radiation therapy was estimated after reconstruction of the actual radiation therapy conditions in which each child was treated as well as the dose receivedmore » at other anatomical sites of interest. Results: After a median follow-up of 25 years, 71 patients had developed a thyroid adenoma. The risk strongly increased with the radiation dose to the thyroid up to a few Gray, plateaued, and declined for high doses. Chemotherapy slightly increased the risk when administered alone but also lowered the slope of the dose-response curve for the radiation dose to the thyroid. Overall, for doses up to a few Gray, the excess relative risk of thyroid adenoma per Gray was 2.8 (90% CI: 1.2-6.9), but it was 5.5 (90% CI: 1.9-25.9) in patients who had not received chemotherapy or who had received only 1 drug, and 1.1 (90% CI: 0.4-3.4) in the children who had received more than 1 drug (P=.06, for the difference). The excess relative risk per Gray was also higher for younger children at the time of radiation therapy than for their older counterparts and was higher before attaining 40 years of age than subsequently. Conclusions: The overall pattern of thyroid adenoma after radiation therapy for a childhood cancer appears to be similar to that observed for thyroid carcinoma.« less

Limited Margin Radiation Therapy for Children and Young Adults With Ewing Sarcoma Achieves High Rates of Local Tumor Control

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

Talleur, Aimee C.; Navid, Fariba; Spunt, Sheri L.

Purpose: To determine the rate of local failure using focal conformal, limited margin radiation therapy (RT) and dose escalation for tumors ≥8 cm (greatest dimension at diagnosis) in children and young adults with Ewing sarcoma (EWS). Methods and Materials: Eligible patients with EWS were treated on a phase 2 institutional trial of focal conformal, limited margin RT using conformal or intensity modulated techniques. The treatment volume incorporated a 1-cm constrained margin around the gross tumor. Unresected tumors, <8 cm at diagnosis, received a standard dose of 55.8 Gy and tumors ≥8 cm, an escalated dose to 64.8 Gy. Patients with microscopic residual disease after resectionmore » received adjuvant RT to 50.4 Gy. Adjuvant brachytherapy was permitted in selected patients. Results: Forty-five patients were enrolled: 26 with localized and 19 with metastatic disease. Median (range) age, tumor size, and follow-up were 13.0 years (2.9-24.7 years), 9.0 cm (2.4-17.0 cm), and 54.5 months (1.9-122.2 months), respectively. All patients received systemic chemotherapy. The median (range) RT dose for all patients was 56.1 Gy (45-65.5 Gy). Seventeen patients received adjuvant, 16 standard-dose, and 12 escalated-dose RT. Failures included 1 local, 10 distant, and 1 local/distant. The estimated 10-year cumulative incidence of local failure was 4.4% ± 3.1%, with no statistical difference seen between RT treatment groups and no local failures in the escalated-dose RT treatment group. Conclusions: Treatment with focal conformal, limited margin RT, including dose escalation for larger tumors, provides favorable local tumor control in EWS.« less

Extensive antibiotic prescription rate among hospitalized patients in Uganda: but with frequent missed-dose days

PubMed Central

Kiguba, Ronald; Karamagi, Charles; Bird, Sheila M.

2016-01-01

Objectives To describe the patterns of systemic antibiotic use and missed-dose days and detail the prescription, dispensing and administration of frequently used hospital-initiated antibiotics among Ugandan inpatients. Methods This was a prospective cohort of consented adult inpatients admitted on the medical and gynaecological wards of the 1790 bed Mulago National Referral Hospital. Results Overall, 79% (603/762; 95% CI: 76%–82%) of inpatients received at least one antibiotic during hospitalization while 39% (300/762; 95% CI: 36%–43%) had used at least one antibiotic in the 4 weeks pre-admission; 1985 antibiotic DDDs, half administered parenterally, were consumed in 3741 inpatient-days. Two-fifths of inpatients who received at least one of the five frequently used hospital-initiated antibiotics (ceftriaxone, metronidazole, ciprofloxacin, amoxicillin and azithromycin) missed at least one antibiotic dose-day (44%, 243/558). The per-day risk of missed antibiotic administration was greatest on day 1: ceftriaxone (36%, 143/398), metronidazole (27%, 67/245), ciprofloxacin (34%, 39/114) and all inpatients who missed at least one dose-day of prescribed amoxicillin and azithromycin. Most patients received fewer doses than were prescribed: ceftriaxone (74%, 273/371), ciprofloxacin (90%, 94/105) and metronidazole (97%, 222/230). Of prescribed doses, only 62% of ceftriaxone doses (1178/1895), 35% of ciprofloxacin doses (396/1130) and 27% of metronidazole doses (1043/3862) were administered. Seven percent (13/188) of patients on intravenous metronidazole and 6% (5/87) on intravenous ciprofloxacin switched to oral route. Conclusions High rates of antibiotic use both pre-admission and during hospitalization were observed, with low parenteral/oral switch of hospital-initiated antibiotics. Underadministration of prescribed antibiotics was common, especially on the day of prescription, risking loss of efficacy and antibiotic resistance. PMID:26945712

Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine.

PubMed

Kreimer, Aimée R; Rodriguez, Ana Cecilia; Hildesheim, Allan; Herrero, Rolando; Porras, Carolina; Schiffman, Mark; González, Paula; Solomon, Diane; Jiménez, Silvia; Schiller, John T; Lowy, Douglas R; Quint, Wim; Sherman, Mark E; Schussler, John; Wacholder, Sholom

2011-10-05

Three-dose regimens for human papillomavirus (HPV) vaccines are expensive and difficult to complete, especially in settings where the need for cervical cancer prevention is greatest. We evaluated the vaccine efficacy of fewer than three doses of the HPV16/18 vaccine Cervarix in our Costa Rica Vaccine Trial. Women were randomly assigned to receive three doses of the HPV16/18 vaccine or to a control vaccine and were followed for incident HPV16 or HPV18 infection that persisted in visits that were 10 or more months apart (median follow-up 4.2 years). After excluding women who had no follow-up or who were HPV16 and HPV18 DNA positive at enrollment, 5967 women received three vaccine doses (2957 HPV vaccine vs 3010 control vaccine), 802 received two doses (422 HPV vs. 380 control), and 384 received one dose (196 HPV vs. 188 control). Reasons for receiving fewer doses and other pre- and post-randomization characteristics were balanced within each dosage group between women receiving the HPV and control vaccines. Incident HPV16 or HPV18 infections that persisted for 1 year were unrelated to dosage of the control vaccine. Vaccine efficacy was 80.9% for three doses of the HPV vaccine (95% confidence interval [CI] = 71.1% to 87.7%; 25 and 133 events in the HPV and control arms, respectively), 84.1% for two doses (95% CI = 50.2% to 96.3%; 3 and 17 events), and 100% for one dose (95% CI = 66.5% to 100%; 0 and 10 events). Four years after vaccination of women who appeared to be uninfected, this nonrandomized analysis suggests that two doses of the HPV16/18 vaccine, and maybe even one dose, are as protective as three doses.

High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study.

PubMed

Osunkwo, Ifeyinwa; Ziegler, Thomas R; Alvarez, Jessica; McCracken, Courtney; Cherry, Korin; Osunkwo, Chinyere E; Ofori-Acquah, Solomon F; Ghosh, Samit; Ogunbobode, Adeolu; Rhodes, Jim; Eckman, James R; Dampier, Carlton; Tangpricha, Vin

2012-10-01

We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were given a 6-week course of oral high-dose cholecalciferol (4000-100 000 IU per week) or placebo and monitored prospectively for a period of six months. Vitamin D insufficiency and deficiency was present at baseline in 82·5% and 52·5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects. © 2012 Blackwell Publishing Ltd.

Compliance with birth dose of Hepatitis B vaccine in high endemic and hard to reach areas in the Colombian amazon: results from a vaccination survey.

PubMed

Choconta-Piraquive, Luz Angela; De la Hoz-Restrepo, Fernando; Sarmiento-Limas, Carlos Arturo

2016-07-21

Hepatitis B vaccination was introduced into the Expanded Program of Immunization in Colombia in 1992, in response to WHO recommendations on hepatitis B immunization. Colombia is a low endemic country for Hepatitis B virus infection (HBV) but it has several high endemic areas like the Amazon basin where more than 70 % of adults had been infected. A cross- sectional study was carried out in three rural areas of the Colombian Amazon to evaluate compliance with the recommended schedule for hepatitis B vaccine in Colombian children (one monovalent dose given in the first 24 h after birth + 3 doses of a pentavalent containing Hepatitis B. (DPT + Hib + Hep B). A household survey was conducted in order to collect vaccination data from children aged from 6 months to <8 years. Vaccination status was related to sociodemographic data obtained from children caretakers. Among 938 children above 6 months and < 8 years old studied, 79 % received a monovalent dose of hepatitis B vaccine, but only 30.7 % were vaccinated in the first 24 h after birth. This proportion did not increase by age or subsequent birth cohorts. Coverage with three doses of a DTP-Hib-HepB vaccine was 98 %, but most children did not receive them according to the recommended schedule. Being born in a health facility was the strongest predictor of receiving a timely birth dose. This study suggests that more focused strategies on improving compliance with hepatitis B birth dose should be implemented in rural areas of the Amazon, if elimination of perinatal transmission of HBV is to be achieved. Increasing the proportion of newborns delivered at health facilities should be one of the priorities to reach that goal.

High dose radiation with chemotherapy followed by salvage esophagectomy among patients with locally advanced esophageal squamous cell carcinoma.

PubMed

Lertbutsayanukul, Chawalit; Tharavej, Chadin; Klaikeaw, Naruemon; Prayongrat, Anussara; Lowanitchai, Chutinan; Sriuranpong, Virote

2017-05-01

Locoregional failure is a major problem associated with chemoradiation treatment for squamous cell esophageal carcinoma. The aim of this study was to assess the feasibility, efficacy, and toxicity of preoperative radiation (dose > 50 Gy) with platinum-based chemotherapy followed by esophagectomy in locally advanced squamous cell carcinoma. Data of patients with cT2-cT4 or node positive squamous cell carcinoma of the esophagus who received trimodality treatment between February 2006 and June 2015 were reviewed. Forty-four patients were treated with intensity-modulated radiation therapy, volumetric-modulated arc therapy or three-dimensional radiation therapy. The median radiation dose was 60 Gy. The average volume of the lungs receiving 10 Gy was 48.1%, 20 Gy was 24.5%, and the average mean lung dose was 14 Gy. After chemoradiation, R0 resection was achieved in 31 patients (71%). Patients who received >60 Gy had a higher pathologic complete remission rate than those in the lower dose group (59.1% vs. 36.4%). R0 resection and radiation dose >60 Gy were associated with better overall survival in Cox proportional hazards regression analysis. The median follow-up duration was 22.4 months and median survival was 25.6 months. Two-year overall, progression-free survival and locoregional control rates were 55.9%, 28.6%, and 56%, respectively. The most common grade 3-4 toxicities were esophagitis (63.6%) and neutropenia (25%). Grade 3-4 postoperative morbidities included surgical wound infection (2.3%), acute renal failure (2.3%), and anastomosis stricture (2.3%). Trimodality treatment with a high preoperative radiation dose and chemotherapy yielded a good pathologic complete response rate, and long-term survival with low toxicities. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

IMRT delivers lower radiation doses to dental structures than 3DRT in head and neck cancer patients.

PubMed

Fregnani, Eduardo Rodrigues; Parahyba, Cláudia Joffily; Morais-Faria, Karina; Fonseca, Felipe Paiva; Ramos, Pedro Augusto Mendes; de Moraes, Fábio Yone; da Conceição Vasconcelos, Karina Gondim Moutinho; Menegussi, Gisela; Santos-Silva, Alan Roger; Brandão, Thais B

2016-09-07

Radiotherapy (RT) is frequently used in the treatment of head and neck cancer, but different side-effects are frequently reported, including a higher frequency of radiation-related caries, what may be consequence of direct radiation to dental tissue. The intensity-modulated radiotherapy (IMRT) was developed to improve tumor control and decrease patient's morbidity by delivering radiation beams only to tumor shapes and sparing normal tissue. However, teeth are usually not included in IMRT plannings and the real efficacy of IMRT in the dental context has not been addressed. Therefore, the aim of this study is to assess whether IMRT delivers lower radiation doses to dental structures than conformal 3D radiotherapy (3DRT). Radiation dose delivery to dental structures of 80 patients treated for head and neck cancers (oral cavity, tongue, nasopharynx and oropharynx) with IMRT (40 patients) and 3DRT (40 patients) were assessed by individually contouring tooth crowns on patients' treatment plans. Clinicopathological data were retrieved from patients' medical files. The average dose of radiation to teeth delivered by IMRT was significantly lower than with 3DRT (p = 0.007); however, only patients affected by nasopharynx and oral cavity cancers demonstrated significantly lower doses with IMRT (p = 0.012 and p = 0.011, respectively). Molars received more radiation with both 3DRT and IMRT, but the latter delivered significantly lower radiation in this group of teeth (p < 0.001), whereas no significant difference was found for the other dental groups. Maxillary teeth received lower doses than mandibular teeth, but only IMRT delivered significantly lower doses (p = 0.011 and p = 0.003). Ipsilateral teeth received higher doses than contralateral teeth with both techniques and IMRT delivered significantly lower radiation than 3DRT for contralateral dental structures (p < 0.001). IMRT delivered lower radiation doses to teeth than 3DRT, but only for some groups of patients and teeth, suggesting that this decrease was more likely due to the protection of other high risk organs, and was not enough to remove teeth from the zone of high risk for radiogenic disturbance (>30Gy).

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

PubMed

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

2011-01-01

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

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

PubMed Central

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

2013-01-01

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

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

PubMed Central

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

2013-01-01

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

PHASE II STUDY OF HIGH DOSE PHOTON/PROTON RADIOTHERAPY IN THE MANAGEMENT OF SPINE SARCOMAS

PubMed Central

DeLaney, Thomas F.; Liebsch, Norbert J.; Pedlow, Francis X.; Adams, Judith; Dean, Susan; Yeap, Beow Y.; McManus, Patricia; Rosenberg, Andrew E.; Nielsen, G. Petur; Harmon, David C.; Spiro, Ira J.; Raskin, Kevin A.; Suit, Herman D.; Yoon, Sam S.; Hornicek, Francis J.

2009-01-01

Purpose Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of ≥ 66 Gy are recommended. A Phase II clinical trial evaluated high dose photon/proton XRT for spine sarcomas. Materials/Methods Eligible patients had non-metastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or post-op photon/proton XRT +/- radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (GyRBE) to subclinical disease, 70.2 GyRBE to microscopic disease in the tumor bed, and 77.4 GyRBE to gross disease at 1.8 GyRBE q.d. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 GyRBE to surface/center. Intra-operative boost doses of 7.5-10 Gy could be given by dural plaque. Results 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n=25) or subtotal (n=12) resection or biopsy (n=13). With 48 month median follow-up, five-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence, p<0.001. Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared following 77.12-77.4 GyRBE. Conclusions Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 GyRBE are at risk for late toxicity. PMID:19095372

Tumor Control Outcomes After Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases From Renal Cell Carcinoma

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

Zelefsky, Michael J., E-mail: zelefskm@mskcc.org; Greco, Carlo; Motzer, Robert

2012-04-01

Purpose: To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Patients and Methods: Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48). Results: The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a highmore » single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). Conclusion: High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking.« less

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.

Pregnancy outcomes in women with different doses of corticosteroid supplementation during labor and delivery.

PubMed

Owa, Takao; Mimura, Kazuya; Kakigano, Aiko; Matsuzaki, Shinya; Kumasawa, Keiichi; Endo, Masayuki; Tomimatsu, Takuji; Kimura, Tadashi

2017-07-01

The aim of this study was to report the pregnancy outcomes of women who received different doses of corticosteroid supplementation during labor and delivery. We conducted a retrospective review of 102 pregnant women who received oral corticosteroid therapy, delivered at Osaka University Hospital, and were administered intravenous corticosteroid supplementation during labor and delivery. From January 2008 to May 2012, 47 women were administered a high dose of corticosteroids (HD group). From June 2012 to December 2016, 55 women were given a low dose of corticosteroids (LD group). There were no significant differences in the patient characteristics between the two groups. The most frequent disease was systemic lupus erythematosus (30/102; 29.4%). Most women used prednisolone for more than 1 year (91/102; 89.2%) and at a dose of more than 5 mg/day (88/102; 86.3%). The total intravenous dose of hydrocortisone during labor and delivery ± standard deviation was 233.5 ± 129.4 mg (HD group) and 143.4 ± 38.1 mg (LD group), exhibiting a significantly larger dose in the HD group. No patients suffered an adrenal deficiency and there were no significant differences in the hemodynamics. There were three cases of puerperal endometritis, two patients with hyperglycemia, and one wound infection in the HD group, whereas one case of puerperal endometritis in the LD group. There were no significant differences in the neonatal outcomes. Pregnancy outcomes did not differ between the high and low doses of corticosteroid supplementation during labor and delivery. © 2017 Japan Society of Obstetrics and Gynecology.

Effects of dietary calcium fructoborate supplementation on joint comfort and flexibility and serum inflammatory markers in dogs with osteoarthritis.

PubMed

Price, A K; de Godoy, M R C; Harper, T A; Knap, K E; Joslyn, S; Pietrzkowski, Z; Cross, B K; Detweiler, K B; Swanson, K S

2017-07-01

Our objective was to evaluate the short-term effects of calcium fructoborate (CFB) on gait, joint range of motion, serum inflammatory markers, and owner perception of pain in client-owned dogs. We used 59 osteoarthritic dogs with impairment, with dogs being randomly assigned to 4 treatments: placebo (60 mg fructose; = 15), low dose (69 mg CFB; = 14), high dose (127 mg CFB; = 14), or combination (69 mg CFB, 500 mg glucosamine hydrochloride and 200 mg chondroitin sulfate; = 16). Dogs up to 22.9 kg received 1 capsule/d, while dogs weighing 23 to 50 kg received 2 capsules/d. A physical examination, radiographs, goniometry measurements, gait analysis, blood sample collection, and a canine brief pain inventory questionnaire were performed on d 0 and 28. Change from baseline values were statistically analyzed among groups. After 28 d, dogs fed the low and high doses had an improved ( < 0.05) ability to rise from a lying position compared to placebo. Dogs fed the high dose also had a greater ( = 0.05) increase in soluble receptor for advanced glycation end products concentration than dogs fed the placebo. Sub-analysis of only large dogs (> 23 kg) showed that dogs fed the low dose had decreased ( < 0.05) pain severity score and pain at its worst compared to dogs fed the placebo. Large dogs fed the low dose also were shown to improve ( < 0.05) in their ability to rise from a lying position compared to dogs fed the placebo. Overall, CFB supplementation was well-tolerated and may aid in mitigating joint discomfort in dogs.

Pharmacokinetics of terbinafine in little brown myotis (Myotis lucifugus) infected with Pseudogymnoascus destructans.

PubMed

Court, Michael H; Robbins, Alison H; Whitford, Anne M; Beck, Erika V; Tseng, Flo S; Reeder, DeeAnn M

2017-01-01

OBJECTIVE To determine the pharmacokinetics of terbinafine in little brown myotis (Myotis lucifugus) infected with Pseudogymnoascus destructans. ANIMALS 123 bats from a P destructans-infected hibernation site in Virginia. PROCEDURES 3 bats were euthanized and necropsied to confirm the presence of P destructans within the population. The remaining 120 bats were systematically assigned to 6 groups (20 bats/group). Bats in each of 3 groups received 6, 20, or 60 mg of terbinafine/kg, SC, once daily for 10 days. Bats in another group received 200 mg of terbinafine/kg, SC, once daily for 5 days. Bats in 1 group received the terbinafine vehicle solution (0.1 mL/kg, SC, once daily for 10 days). Bats in the remaining group did not receive any treatment. Following the treatment period (days 1 through 10), bats were housed in a hibernation chamber and monitored daily until euthanasia on day 42, 75, or 109. Tissue specimens were collected from all bats as soon as possible after death or euthanasia to determine terbinafine concentration. Within each group and tissue type, terbinafine concentration data were pooled, and pharmacokinetic parameters were calculated by noncompartmental methods. RESULTS Adverse neurologic effects and a high mortality rate before day 10 were observed in bats that received the highest terbinafine dose (200 mg/kg) but not those that received lower doses. Presumed therapeutic terbinafine concentrations (≥ 2 μg/g) were maintained in skin and wing for at least 30 and 6 days in bats that received the 60 and 20 mg/kg doses, respectively, but were not achieved in most bats that received the 6 mg/kg dose. Tissue terminal half-life ranged from 14 to 22 days. Terbinafine concentration in hair was positively correlated with that in skin and wing. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated terbinafine doses > 6 but < 200 mg/kg should be further evaluated for the treatment of P destructans-infected bats. Collection of serial hair specimens may represent a noninvasive method for monitoring terbinafine concentration in treated bats.

A randomized, double-blinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy.

PubMed

Davis, Ian D; Kiers, Lynette; MacGregor, Lachlan; Quinn, Michael; Arezzo, Joseph; Green, Michael; Rosenthal, Mark; Chia, Michael; Michael, Michael; Bartley, Peter; Harrison, Leonie; Daly, Michael

2005-03-01

To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy (CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m(2) over 3 hours). Randomized double-blind placebo-controlled phase II clinical trial. Eligible patients had solid tumors for which treatment with carboplatin/paclitaxel was appropriate. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocities and amplitudes, measured at baseline and after four cycles of chemotherapy. Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 microg/kg), high-dose rhuLIF (4 microg/kg), or placebo. Patients (n = 117) were randomized across seven neurology test centers. Thirty-six patients received low dose rhuLIF (2 microg/kg), 39 received high dose rhuLIF (4 microg/kg) and 42 received placebo. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed between baseline and cycle 4 or by the secondary efficacy variables. rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel. CPNE is a reliable and valid tool that was sensitive to the onset and progression of CIPN.

High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy.

PubMed

Depositario-Cabacar, Dewi T; Peters, Jurriaan M; Pong, Amanda W; Roth, Julie; Rotenberg, Alexander; Riviello, James J; Takeoka, Masanori

2010-07-01

We review our experience with high-dose intravenous levetiracetam (IV-LEV) for acute seizure exacerbations in nine children with medically intractable epilepsy. All children had acute repetitive seizures-while on chronic antiepileptic drugs-that either led to hospitalization (eight) or occurred during hospitalization (one), and received doses of IV-LEV of 150 mg/kg/day or greater, with a mean dose of 228 +/- 48 mg/kg/day. Eight of nine children had resolution of the acute repetitive seizures. Seizure frequency was reduced to less than baseline in seven children (seizure-free in two, >/=80% reduction in four, and 50% reduction in one). Except for one child with increased seizures, IV-LEV was well tolerated in all children without complications.

Angiotensin II for the Treatment of Vasodilatory Shock.

PubMed

Khanna, Ashish; English, Shane W; Wang, Xueyuan S; Ham, Kealy; Tumlin, James; Szerlip, Harold; Busse, Laurence W; Altaweel, Laith; Albertson, Timothy E; Mackey, Caleb; McCurdy, Michael T; Boldt, David W; Chock, Stefan; Young, Paul J; Krell, Kenneth; Wunderink, Richard G; Ostermann, Marlies; Murugan, Raghavan; Gong, Michelle N; Panwar, Rakshit; Hästbacka, Johanna; Favory, Raphael; Venkatesh, Balasubramanian; Thompson, B Taylor; Bellomo, Rinaldo; Jensen, Jeffrey; Kroll, Stew; Chawla, Lakhmir S; Tidmarsh, George F; Deane, Adam M

2017-08-03

Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).

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

Pirlepesov, F.; Shin, J.; Moskvin, V. P.

Purpose: Dose weighted Linear Energy Transfer (LETd) analysis of critical structures may be useful in understanding the side effects of the proton therapy. The objective is to analyze the differences between LETd and dose distributions in brain tumor patients receiving double scattering proton therapy, to quantify LETd variation in critical organs, and to identify beam arrangements contributing to high LETd in critical organs. Methods: Monte Carlo simulations of 9 pediatric brain tumor patients were performed. The treatment plans were reconstructed with the TOPAS Monte Carlo code to calculate LETd and dose. The beam data were reconstructed proximal to the aperturemore » of the double scattering nozzle. The dose and LETd to target and critical organs including brain stem, optic chiasm, lens, optic nerve, pituitary gland, and hypothalamus were computed for each beam. Results: Greater variability in LETd compared to dose was observed in the brainstem for patients with a variety of tumor types including 5 patients with tumors located in the posterior fossa. Approximately 20%–44% brainstem volume received LETd of 5kev/µm or greater from beams within gantry angles 180°±30° for 5 patients treated with a 3 beam arrangement. Critical organs received higher LETd when located in the vicinity of the beam distal edge. Conclusion: This study presents a novel strategy in the evaluation of the proton treatment impact on critical organs. While the dose to critical organs is confined below the required limits, the LETd may have significant variation. Critical organs in the vicinity of beam distal edge receive higher LETd and depended on beam arrangement, e.g. in posterior fossa tumor treatment, brainstem receive higher LETd from posterior-anterior beams. This study shows importance of the LETd analysis of the radiation impact on the critical organs in proton therapy and may be used to explain clinical imaging observations after therapy.« less

Favorable toxicity and biochemical control using real-time inverse optimization technique for prostate brachytherapy.

PubMed

Raben, Adam; Rusthoven, Kyle E; Sarkar, Abrihup; Glick, Andrew; Benge, Bruce; Jacobs, Dayee; Raben, David

2009-01-01

Favorable dosimetric results have been reported using intraoperative inverse optimization (IO) for permanent prostate brachytherapy. The clinical implications of these improvements in dosimetry are unclear. We review toxicity and early biochemical outcomes for patients implanted using IO technique. Between 2001 and 2007, 165 patients received permanent prostate implants using real-time IO and had >/=3 months of followup. Dose constraints for inverse planning were: the prostate volume receiving 100% of the prescription dose [prostate V(100)] was >95%; the dose received by 90% of the gland [prostate D(90)] was within the 140-180 by dose range; the volume of urethra receiving 150% of the prescription dose [urethra V(150)] was <30%; and the volume of rectal wall receiving 110% of the prescription dose [rectal V(110)] was <1.0 cc. Toxicity was prospectively scored using the Radiation Therapy Oncology Group toxicity scale and the International Prostate Symptom Score questionnaire. Biochemical control was determined using the nadir + 2 ng/mL definition. Mean followup was 30 months (range, 6-63 months). Risk classification was low risk in 89% and intermediate risk in 11%. Iodine-125 sources were used for 161 implants and palladium-103 sources for four implants. The median number of seeds and total activity implanted were 61 and 999 MBq, respectively, for a median prostate volume of 33.6 cc. Late GU and GI morbidity was uncommon. Among patients with at least 24 months followup, 16% had persistent Grade 2-3 urinary morbidity. Grade 2 rectal bleeding occurred in 1 patient (0.6%). Biochemical failure has occurred in only 4 patients at last followup. IO technique for prostate brachytherapy is associated with low rates of late morbidity and excellent early biochemical control. Additionally, the number of seeds and total implanted activity required to achieve a high-quality implant are lower compared with historical controls.

Palmar-plantar erythrodysesthesia syndrome following treatment with high-dose methotrexate or high-dose cytarabine.

PubMed

Karol, Seth E; Yang, Wenjian; Smith, Colton; Cheng, Cheng; Stewart, Clinton F; Baker, Sharyn D; Sandlund, John T; Rubnitz, Jeffrey E; Bishop, Michael W; Pappo, Alberto S; Jeha, Sima; Pui, Ching-Hon; Relling, Mary V

2017-09-15

Palmar-plantar erythrodysesthesia syndrome (PPES) is an uncommon side effect of high-dose cytarabine or methotrexate. Prior case reports of PPES have been limited, and the predisposing factors for the development of PPES remain unknown. A review of databases identified 22 patients (1.3%) who developed 39 episodes of PPES among 1720 patients after treatment with high-dose cytarabine or methotrexate. Symptoms lasted a mean of 6.4 days. Hands and feet were both involved in 68% of the initial episodes. Parenteral opioids were required for pain control by 27% of the patients. In comparison with the 1698 children treated with similar therapy, the children who developed PPES were older (mean age at diagnosis, 14.3 vs 7.7 years; P = 7.5 × 10 -7 ). The frequency of PPES was less common in patients receiving methotrexate alone (7 of 946 or 0.7%) versus cytarabine (7 of 205 or 3.4%; P = .005) but was not different for those receiving both high-dose methotrexate and cytarabine (8 of 569 or 1.4%; P = .32). Prolonged infusions of methotrexate were associated with less frequent PPES in comparison with rapid infusions (P = 1.5 × 10 -5 ), as was the co-administration of dexamethasone with cytarabine (P = 2.5 × 10 -6 ). Self-described race and sex were not associated with PPES. In a multivariate analysis, older age and high-dose cytarabine administration without dexamethasone remained associated with PPES (P = 1.1 × 10 -4 and P = .038, respectively). A genome-wide association study did not identify any associations with PPES meeting the genome-wide significance threshold, but top variants were enriched for skin expression quantitative trait loci, including rs11764092 in AUTS2 (P = 6.45 × 10 -5 ). These data provide new insight into the incidence of PPES as well as its risk factors. Cancer 2017;123:3602-8. © 2017 American Cancer Society. © 2017 American Cancer Society.

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

MDMA modifies active avoidance learning and recall in mice.

PubMed

Trigo, José Manuel; Cabrero-Castel, Araceli; Berrendero, Fernando; Maldonado, Rafael; Robledo, Patricia

2008-04-01

Several studies have suggested the existence of cognitive deficits after repeated or high doses of 3,4-methylenedioxymethamphetamine (MDMA) in humans and experimental animals. However, the extent of the impairments observed in learning or memory tasks remains unclear. The objective of this study was to evaluate the effects of different dosing regimens of MDMA on the ability of mice to learn and recall an active avoidance task. Animals were treated with MDMA (0, 1, 3, 10 and 30 mg/kg) under four different experimental conditions, and active avoidance acquisition and recall were evaluated. In experiments 1 and 2, MDMA was administered 1 h before different active avoidance training sessions. In experiments 3 and 4, mice received a repeated treatment with MDMA before or after active avoidance training, respectively. Changes in presynaptic striatal dopamine transporter (DAT) binding sites were evaluated at two different time points in animals receiving a high dose of MDMA (30 mg/kg) or saline twice a day over 4 days. MDMA administered before the active avoidance sessions interfered with the acquisition and the execution of a previously learned task. A repeated treatment with high doses of MDMA administered before training reduced acquisition of active avoidance in mice, while pre-treatment with both high and low doses of MDMA impaired recall of this task. A reduction in DAT binding was observed 4 days but not 23 days after the last MDMA administration. Acute MDMA modifies the acquisition and execution of active avoidance in mice, while repeated pre-treatment with MDMA impairs acquisition and recall of this task.

[G-CSF administration following autologous peripheral blood stem cell transplantation--the effect of G-CSF level on neutrophil recovery].

PubMed

Saigo, K; Sugimoto, T; Matsuo, M; Narita, H; Ryo, R; Kumagai, S

2000-03-01

We studied the usefulness of rhG-CSF (filgrastim) administration in patients who received autologous peripheral blood stem cell transplantation (PBSCT) combined with super-high dose chemotherapy. Twenty patients received 0-8.3 micrograms/kg/day filgrastim after PBSCT. There was a significant relationship between G-CSF dose and the neutrophil recovery rate, and the highest levels of serum G-CSF tended to correlate with neutrophil recovery rate. The highest G-CSF level after 75 micrograms injection in normal volunteers is reported to be 1,500 pg/ml. On the other hand, as one patient in our series exhibited extremely high endogenous G-CSF of 11,500 pg/ml, measurements of G-CSF might reduce the over-administration of rhG-CSF.

Evaluation of genotype-guided acenocoumarol dosing algorithms in Russian patients.

PubMed

Sychev, Dmitriy Alexeyevich; Rozhkov, Aleksandr Vladimirovich; Ananichuk, Anna Viktorovna; Kazakov, Ruslan Evgenyevich

2017-05-24

Acenocoumarol dose is normally determined via step-by-step adjustment process based on International Normalized Ratio (INR) measurements. During this time, the risk of adverse reactions is especially high. Several genotype-based acenocoumarol dosing algorithms have been created to predict ideal doses at the start of anticoagulant therapy. Nine dosing algorithms were selected through a literature search. These were evaluated using a cohort of 63 patients with atrial fibrillation receiving acenocoumarol therapy. None of the existing algorithms could predict the ideal acenocoumarol dose in 50% of Russian patients. The Wolkanin-Bartnik algorithtm based on European population was the best-performing one with the highest correlation values (r=0.397), mean absolute error (MAE) 0.82 (±0.61). EU-PACT also managed to give an estimate within the ideal range in 43% of the cases. The two least accurate results were yielded by the Indian population-based algorithms. Among patients receiving amiodarone, algorithms by Schie and Tong proved to be the most effective with the MAE of 0.48±0.42 mg/day and 0.56±0.31 mg/day, respectively. Patient ethnicity and amiodarone intake are factors that must be considered when building future algorithms. Further research is required to find the perfect dosing formula of acenocoumarol maintenance doses in Russian patients.

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

PubMed

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

2014-12-01

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

Proton irradiation of stem cells: Radiation damage and chemical radioprotection

NASA Technical Reports Server (NTRS)

Riley, R. C.; Montour, J. L.; Gurney, C. W.

1972-01-01

Effects of high energy protons on erythropoietic stem cells and radioprotection by chemicals were investigated in NASA Space Radiation Effects Laboratory. The effects of a parallel beam of 600 MeV protons. The fluence, when converted to dose, were referenced to the synchrocyclotron beam monitors which were then used to administer radiation exposures. Mice were given graded doses to 300 rads to determine dose-response curve. Other mice received saline, AET, or 5-hydroxytryptamine 10 to 15 minutes before exposure.

High rate of long-term survival for high-risk lymphoma patients treated with hematopoietic stem cell transplantation as consolidation or salvage therapy.

PubMed

Espigado, I; Ríos, E; Marín-Niebla, A; Carmona, M; Parody, R; Pérez-Hurtado, J M; Márquez, F J; Urbano-Ispizua, A

2008-11-01

Patients with high-relapse-risk lymphomas or those relapsing after initial therapy have a limited probability of cure with conventional treatment. There is recent inconclusive evidence that, in such cases, intensification or salvage treatment with high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT) increases the response rate and may improve survival. Nevertheless, published data on long-term follow-up of high-risk lymphoma patients treated with HSCT are scarce. We analyzed 101 consecutive patients receiving high-dose chemotherapy followed by HSCT after induction with standard chemotherapy. The median age was 38 years (range, 12-63 years). The diagnoses were Hodgkin's disease (n = 32), follicular lymphoma (n = 33), diffuse large B-cell lymphoma (n = 12), mantle cell lymphoma (n = 7), T-cell lymphoma (n = 14), and others (n = 3). Patients received either an autologous graft (n = 72) in first complete remission (1CR; n = 23) or in advanced stages (AS; n = 49), or an allogeneic graft (n = 29) in 1CR (n = 7) or in AS (n = 22). We concluded that transplant-related mortality was 2.7% for patients receiving an autologous HSCT and 27% for patients receiving an allogeneic HSCT. The main etiologies were graft-versus-host disease and infection in the allogeneic setting, and infection in the autologous setting. The probability of long-term (12-year) overall survival was 71%, higher than that described for high-relapse-risk lymphoma patients treated without HSCT and significantly better (P < .05) for patients who received the transplant in 1CR (89%) than in AS (65%). Finally, the probability of long-term survival was significantly better for patients treated with HSCT during the period from 2000-2007 (85%) compared with the period from 1989-1999 (72%).

Diagnostic radiation exposure in pediatric trauma patients.

PubMed

Brunetti, Marissa A; Mahesh, Mahadevappa; Nabaweesi, Rosemary; Locke, Paul; Ziegfeld, Susan; Brown, Robert

2011-02-01

The amount of imaging studies performed for disease diagnosis has been rapidly increasing. We examined the amount of radiation exposure that pediatric trauma patients receive because they are an at-risk population. Our hypothesis was that pediatric trauma patients are exposed to high levels of radiation during a single hospital visit. Retrospective review of children who presented to Johns Hopkins Pediatric Trauma Center from July 1, 2004, to June 30, 2005. Radiographic studies were recorded for each patient and doses were calculated to give a total effective dose of radiation. All radiographic studies that each child received during evaluation, including any associated hospital admission, were included. A total of 945 children were evaluated during the study year. A total of 719 children were included in the analysis. Mean age was 7.8 (±4.6) years. Four thousand six hundred three radiographic studies were performed; 1,457 were computed tomography (CT) studies (31.7%). Average radiation dose was 12.8 (±12) mSv. We found that while CT accounted for only 31.7% of the radiologic studies performed, it accounted for 91% of the total radiation dose. Mean dose for admitted children was 17.9 (±13.8) mSv. Mean dose for discharged children was 8.4 (±7.8) mSv (p<0.0001). Burn injuries had the lowest radiation dose [1.2 (±2.6) mSv], whereas motor vehicle collision victims had the highest dose [18.8 (±14.7) mSv]. When the use of radiologic imaging is considered essential, cumulative radiation exposure can be high. In young children with relatively long life spans, the benefit of each imaging study and the cumulative radiation dose should be weighed against the long-term risks of increased exposure.

Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group.

PubMed

Fleischmann, R; Mease, P J; Schwartzman, S; Hwang, L-J; Soma, K; Connell, C A; Takiya, L; Bananis, E

2017-01-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (≤12.5 mg/week), moderate (>12.5 to <17.5 mg/week), or high (≥17.5 mg/week) stable background MTX. Efficacy endpoints (at months 3 and 6) included American College of Rheumatology (ACR) 20/50/70 response rates, and mean change from baseline in Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints (DAS28)-4(erythrocyte sedimentation rate [ESR]), Health Assessment Questionnaire-Disability Index (HAQ-DI), and modified Total Sharp score. 797 patients were treated with tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28-4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.

Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion?

PubMed

Vigen, Rebecca; Weideman, Rick A; Reilly, Robert F

2011-09-01

In the 1980s a change occurred in hydrochlorothiazide prescribing practices for hypertension from high-dose (50 mg/day) to low-dose (12.5-25 mg/day) therapy. However, randomized controlled trials (RCT) for prevention of calcium-containing kidney stones (CCKS) employed only high doses (≥ 50 mg/day). We hypothesized that these practices have resulted in underdosing of hydrochlorothiazide for prevention of CCKS. Patients with a filled prescription for thiazide diuretics that underwent a 24-h urine stone risk factor analysis were eligible. Those with evidence that thiazide was prescribed for CCKS were further analyzed. Of 107 patients, 102 were treated with hydrochlorothiazide, 4 with indapamide, and one with chlorthalidone. Only 35% of hydrochlorothiazide-treated patients received 50 mg/day; a dose previously shown to reduce stone recurrence. Fifty-two percent were prescribed 25 mg and 13% 12.5 mg daily, doses that were not studied in RCT. Evidence-based hydrochlorothiazide use was suboptimal regardless of where the patient received care (Nephrology or Endocrinology clinic). In a small subset of patients (n = 6) with 24-h urinary calcium excretion measured at baseline and after 2 hydrochlorothiazide doses (25 and ≥ 50 mg), there was a trend toward decreased urinary calcium excretion as the dose was increased from 25 to ≥ 50 mg/day (p = 0.051). Low-dose hydrochlorothiazide was often used for prevention of CCKS despite the fact that there is no evidence that it is effective in this setting. This may have resulted from a practice pattern of using lower doses for hypertension therapy or a lack of knowledge of RCT results in treatment of CCKS.

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study.

PubMed

Hunt, Hazel; Donaldson, Kirsteen; Strem, Mark; Zann, Vanessa; Leung, Pui; Sweet, Suzanne; Connor, Alyson; Combs, Dan; Belanoff, Joseph

2018-05-01

CORT125134 is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first-in-human study was conducted to evaluate the dose-related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty-one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high-fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half-life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone. © 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study

PubMed Central

Shepshelovich, Daniel; Edel, Yonatan; Goldvaser, Hadar; Dujovny, Tal; Wolach, Ofir; Raanani, Pia

2015-01-01

AIMS Cytarabine is a pyrimidine analogue used to treat a variety of haematological malignancies. There are few data regarding the pharmacodynamics of cytarabine. The only publications regarding this issue cite a biphasic pattern of decline in white blood cell (WBC) counts following low and intermediate doses, in patients with various malignancies, most of them non-haematological. Our purpose was to establish the pharmacodynamics of cytarabine induced leucopenia in acute myeloid leukaemia (AML) patients treated with contemporary cytarabine containing protocols. METHODS We conducted a retrospective cohort study, including 56 patients with AML in complete remission who had received 89 cycles of intermediate or high dose cytarabine. Daily counts for WBCs and neutrophils (ANC) were collected during the first 15 days after the initiation of cytarabine administration and pharmacodynamics were analyzed. Further analysis was carried out to correlate between WBC and ANC pharmacodynamics and different cytarabine protocols [high dose cytarabine (HiDAC) vs. intermediate dose cytarabine (IDAC)]. RESULTS Analysis of blood counts demonstrated a monophasic decline of WBCs and ANCs, unlike a previous depiction of a biphasic pattern. HiDAC was associated with a significantly sharper decline of WBCs than IDAC. CONCLUSIONS Our data support a monophasic decline pattern of WBCs and ANCs following contemporary cytarabine protocols. The decline rate is steeper for patients receiving HiDAC than for those receiving IDAC. These results might help form evidence based guidelines regarding patient monitoring intensity, timing of prophylactic antibacterial and antifungal treatment as well as growth factors' support following cytarabine based consolidation for AML. PMID:25303309

Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study.

PubMed

Shepshelovich, Daniel; Edel, Yonatan; Goldvaser, Hadar; Dujovny, Tal; Wolach, Ofir; Raanani, Pia

2015-04-01

Cytarabine is a pyrimidine analogue used to treat a variety of haematological malignancies. There are few data regarding the pharmacodynamics of cytarabine. The only publications regarding this issue cite a biphasic pattern of decline in white blood cell (WBC) counts following low and intermediate doses, in patients with various malignancies, most of them non-haematological. Our purpose was to establish the pharmacodynamics of cytarabine induced leucopenia in acute myeloid leukaemia (AML) patients treated with contemporary cytarabine containing protocols. We conducted a retrospective cohort study, including 56 patients with AML in complete remission who had received 89 cycles of intermediate or high dose cytarabine. Daily counts for WBCs and neutrophils (ANC) were collected during the first 15 days after the initiation of cytarabine administration and pharmacodynamics were analyzed. Further analysis was carried out to correlate between WBC and ANC pharmacodynamics and different cytarabine protocols [high dose cytarabine (HiDAC) vs. intermediate dose cytarabine (IDAC)]. Analysis of blood counts demonstrated a monophasic decline of WBCs and ANCs, unlike a previous depiction of a biphasic pattern. HiDAC was associated with a significantly sharper decline of WBCs than IDAC. Our data support a monophasic decline pattern of WBCs and ANCs following contemporary cytarabine protocols. The decline rate is steeper for patients receiving HiDAC than for those receiving IDAC. These results might help form evidence based guidelines regarding patient monitoring intensity, timing of prophylactic antibacterial and antifungal treatment as well as growth factors' support following cytarabine based consolidation for AML. © 2014 The British Pharmacological Society.

Human papilloma virus vaccination in Nepal: an initial experience in Nepal.

PubMed

Singh, Yogendra; Shah, Aarti; Singh, Meeta; Verma, Sheela; Shrestha, Bhakta Man; Vaidya, Prabhu; Nakarmi, Radha Pyari; Shrestha, Surendra Bb

2010-01-01

Cervical cancer is the most common cancer among women in Nepal. Human papilloma virus (HPV) infection, a recognized cause of cervical cancer, is very common in sexually active women and HPV vaccination has been recommended as a prophylactic therapy. If HPV infection is prevented by the HPV vaccination to the adolescent girls, cervical cancer is also prevented. We received 3,300 vials of quadrivalent human papilloma virus (types 6, 11, 16, 18) recombinant vaccine (Gardasil; Merck and Co.) as a gift from the Australian Cervical Cancer Foundation (ACCF) which has a mission to provide life-saving HPV cervical cancer vaccines for women in developing countries, who cannot otherwise afford vaccination. HPV vaccine was offered to 1,096 of 10 to 26 year aged girls attending 17 secondary schools. In total, 1,091 (99.5%) received the second dose and 1,089 (99.3%) received the third dose of the vaccine. The remaining 5 girls at second dose and 2 girls at third dose remained unvaccinated. No serious vaccine related adverse events were reported except mild pain at the injection site in 7.8% of the vaccine recipients. High cost and low public awareness are the key barriers for successful implementation of the vaccination program in resource limited developing countries. In conclusion, HPV vaccine is safe with high acceptability in Nepalese school girls. However a large population study for longer follow up is warranted to validate the findings of this vaccination program.

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

PubMed Central

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

1998-01-01

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

Implementation of a hepatitis A/B vaccination program using an accelerated schedule among high-risk inmates, Los Angeles County Jail, 2007-2010.

PubMed

Costumbrado, John; Stirland, Ali; Cox, Garrett; El-Amin, Alvin Nelson; Miranda, Armidia; Carter, Ann; Malek, Mark

2012-11-06

The Centers for Disease Control and Prevention recommend vaccination for men who have sex with men (MSM) and injection drug users against hepatitis A and B. This study is the first report of a hepatitis vaccination program in a United States jail with a combined vaccine using an accelerated schedule. Los Angeles County has the largest jail system in the nation and Men's Central Jail (MCJ) is the largest facility within that system. MCJ includes a unit for self-identified MSM, where approximately 2700 inmates are housed per year. Starting in August 2007, a combined hepatitis A and B vaccine was offered to all inmates housed in this special unit. Using an accelerated schedule (0-, 7-, 21-30 days, 12-month booster), a total of 3931 doses were administered to 1633 inmates as of June 2010. Of those, 77% received 2 doses, 58% received 3 doses, and 11% received the booster dose. Inmates who screened positive for a sexually transmitted infection in this unit were 1.3 times more likely to be vaccinated (95% CI 1.2-1.4) compared to others in the same housing unit who screened negative. Hepatitis vaccination initiatives can be successfully implemented in an urban jail among an extremely high-risk population using the accelerated, combined hepatitis A/B vaccine. Ours may be a useful model for other programs to vaccinate incarcerated populations. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

Johnson, D.W.; Safai, C.; Goffinet, D.R.

Eleven patients with obstructive jaundice from unresectable cholangiocarcinoma, metastatic porta hepatis adenopathy, or direct compression from a pancreatic malignancy were treated at the Stanford University Medical Center from 1978-1983 with an external drainage procedure followed by high-dose external-beam radiotherapy and by an intracavitary boost to the site of obstruction with Iridium/sup 192/ (Ir/sup 192/). A median dose of 5000 cGy was delivered with 4-6 Mv photons to the tumor bed and regional lymphatics in 9 patients, 1 patient received 2100 cGy to the liver in accelerated fractions because of extensive intrahepatic disease, and 1 patient received 7000 equivalent cGy tomore » his pancreatic tumor bed and regional lymphatics with neon heavy particles. An Ir/sup 192/ wire source later delivered a 3100-10,647 cGy boost to the site of biliary obstruction in each patient, for a mean combined dose of 10,202 cGy to a point 5 mm from the line source. Few acute complications were noted, but 3/11 patients (27%) subsequently developed upper gastrointestinal bleeding from duodenitis or frank duodenal ulceration 4 weeks, 4 months, and 7.5 months following treatment. Eight patients died - 5 with local recurrence +/- distant metastasis, 2 with sepsis, and 1 with widespread systemic metastasis. Autopsies revealed no evidence of biliary tree obstruction in 3/3 patients. Evolution of radiation treatment technqiues for biliary obstruction in the literature is reviewed. High-dose external-beam therapy followed by high-dose Ir/sup 192/ intracavitary boost is well tolerated and provides significant palliation.« less

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

PubMed

Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-07-01

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Reactogenicity of tetanus, diphtheria, 5-component acellular pertussis vaccine administered as a sixth consecutive acellular pertussis vaccine dose to adolescents.

PubMed

Liese, Johannes G; Rieber, Nikolaus; Malzer, Thomas; Ocak, Marion; Johnson, David R; Decker, Michael D

2010-12-01

Safety of a sixth consecutive dose of acellular pertussis vaccine in adolescents was assessed in a 2-armed, randomized study. Adolescents who had received 5 doses of acellular pertussis vaccine combined with diphtheria and tetanus toxoids (6-dose group) received 1 dose of reduced 5-component acellular pertussis vaccine combined with tetanus toxoid and reduced diphtheria toxoid (Tdap). Adolescents who had received a primary series of 3 doses of whole-cell pertussis and 1 acellular or whole-cell pertussis booster received 1 dose of Tdap vaccine (5-dose group). Of 214 participants, 176 (82%) reported an injection-site reaction with pain (80%), erythema (22%), and swelling (19%) most frequently reported. A systemic reaction was reported by 169 of 214 (79%) with myalgia (66%), headache (42%), malaise (39%), and fever (9%) most frequently reported. The overall rate of solicited reactions was lower in the 6-dose group than in the 5-dose group (for injection-site reactions: 76.1% vs. 89.7%; for systemic reactions 72.6% vs. 86.6%). Significant differences were observed for injection-site pain, erythema, and for grade 1 or grade 2 increases in arm circumference. Fever, myalgia, and headache were reported at a significantly lower rate in the 6-dose group. Swelling >10 cm was observed in 5 patients (2%), 4 in the 5-dose group. Tdap vaccine was safe when given to adolescents who had received 5 prior doses of acellular pertussis vaccine.

Randomized clinical trial comparing high versus standard dose of ribavirin plus peginterferon alfa-2a in hepatitis C genotype 3 and high viral load. Dargen-3 study.

PubMed

Fernández-Rodríguez, Conrado M; Morillas, Rosa María; Masnou, Helena; Navarro, José María; Bárcena, Rafael; González, José Manuel; Martín-Martín, Leticia; Poyato, Antonio; Miquel-Planas, Mireia; Jorquera, Francisco; Casanovas, Teresa; Salmerón, Javier; Calleja, José Luis; Solà, Ricard; Alonso, Sonia; Planas, Ramón; Romero-Gomez, Manuel

2014-01-01

Less than half of patients with chronic hepatitis C genotype 3 (G3) and high viral load (HVL) without a rapid virological response (RVR) achieve a sustained virological response (SVR) when treated with peginterferon plus ribavirin (RBV). To assess the impact of high doses of RBV on SVR in patients with G3 and HVL. Ninety-seven patients were randomized to receive peginterferon α-2a+RBV 800 mg/day (A; n=42) or peginterferon α-2a+RBV 1600 mg/day+epoetin β 400 IU/kg/week SC (B; n=55). Patients allocated to group B who achieved RVR continued on RBV (800mg/day) for a further 20 weeks (B1; n=42) while non-RVR patients received a higher dose of RBV (1600 mg/day)+epoetin β (B2; n=13). RVR was observed in 64.3% of patients in A and in 76.4% in B (p=0.259). Intention-to-treat (ITT) analysis showed SVR rates of 64.3% (A) and 61.8% (B), with a reduction of -2.5% (-21.8% to 16.9%) (p=0.835). The SVR rate was 61.9% in arm B1 and 61.5% in arm B2. No serious adverse events were reported, and the rate of moderate adverse events was < 5%. G3 patients with high viral load without RVR did not obtain a benefit from a higher dose of RBV. Higher doses of RBV plus epoetin β were safe and well tolerated (Clin Trials Gov NCT00830609). Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

Exogenous surfactant preserves lung function and reduces alveolar Evans blue dye influx in a rat model of ventilation-induced lung injury.

PubMed

Verbrugge, S J; Vazquez de Anda, G; Gommers, D; Neggers, S J; Sorm, V; Böhm, S H; Lachmann, B

1998-08-01

Changes in pulmonary edema infiltration and surfactant after intermittent positive pressure ventilation with high peak inspiratory lung volumes have been well described. To further elucidate the role of surfactant changes, the authors tested the effect of different doses of exogenous surfactant preceding high peak inspiratory lung volumes on lung function and lung permeability. Five groups of Sprague-Dawley rats (n = 6 per group) were subjected to 20 min of high peak inspiratory lung volumes. Before high peak inspiratory lung volumes, four of these groups received intratracheal administration of saline or 50, 100, or 200 mg/kg body weight surfactant; one group received no intratracheal administration. Gas exchange was measured during mechanical ventilation. A sixth group served as nontreated, nonventilated controls. After death, all lungs were excised, and static pressure-volume curves and total lung volume at a transpulmonary pressure of 5 cm H2O were recorded. The Gruenwald index and the steepest part of the compliance curve (Cmax) were calculated. A bronchoalveolar lavage was performed; surfactant small and large aggregate total phosphorus and minimal surface tension were measured. In a second experiment in five groups of rats (n = 6 per group), lung permeability for Evans blue dye was measured. Before 20 min of high peak inspiratory lung volumes, three groups received intratracheal administration of 100, 200, or 400 mg/ kg body weight surfactant; one group received no intratracheal administration. A fifth group served as nontreated, nonventilated controls. Exogenous surfactant at a dose of 200 mg/kg preserved total lung volume at a pressure of 5 cm H2O, maximum compliance, the Gruenwald Index, and oxygenation after 20 min of mechanical ventilation. The most active surfactant was recovered in the group that received 200 mg/kg surfactant, and this dose reduced minimal surface tension of bronchoalveolar lavage to control values. Alveolar influx of Evans blue dye was reduced in the groups that received 200 and 400 mg/kg exogenous surfactant. Exogenous surfactant preceding high peak inspiratory lung volumes prevents impairment of oxygenation, lung mechanics, and minimal surface tension of bronchoalveolar lavage fluid and reduces alveolar influx of Evans blue dye. These data indicate that surfactant has a beneficial effect on ventilation-induced lung injury.

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

PubMed

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

2018-04-01

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

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

PubMed Central

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

2018-01-01

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

The relationship between ovarian function and ovarian limited dose in radiotherapy postoperation of ovarian transposition in young patients with cervical cancer.

PubMed

Du, Zhenhua; Qu, Hui

2017-03-01

In this study, the relationship between ovarian function and ovarian limited dose in radiotherapy was evaluated in young patients with cervical cancer who underwent ovarian transposition (Fig1B). Moreover, the novel ovarian dose limit for a better preservation of ovarian function in intensity-modulated radiation therapy (IMRT) was determined. We retrospectively analyzed data from 86 patients with cervical cancer who received radical hysterectomy and ovarian transposition from January 2013 to June 2015. In agreement with the National Comprehensive Cancer Network Guidelines (NCCN) for Cervical Cancer Version 2.2015, 65 patients with pathological high-risk factors were administered adjuvant radiotherapy-20 of them received three-dimensional conformal radiotherapy (Observation Group A), 24 patients received IMRT with no limitation on radiation dose to ovaries (Observation Group B), and 21 patients underwent IMRT with limited radiation dose(V 10 <20%) to ovaries (Observation Group C). Twenty-one patients without any predetermined high-risk factors did not received radiation therapy (Control Group D). Patients from all four groups were followed up, and sex hormone levels (E 2 , P, follicle-stimulating hormone [FSH], LH) before radiation, postradiation, 3 month, and 6 month after the radiation therapy were measured by electrochemiluminescence immunoassay. Subsequently, changes in sex hormone levels in all four groups of patients at various time points were analyzed. The levels of sexual hormones (E 2 , P, FSH, LH) before radiation, postradiation, 3 month, and 6 month after the radiation therapy in patients from all three observation groups were significantly lower than those in patients of the control group (P < 0.05). There was no statistically significant difference in the levels of sex hormones in patients of the control group at different time points (P > 0.05). Within each observation group, there was a statistically significant difference in the sex hormone levels in patients before the radiation and after the radiation (P < 0.05); however, when data from all three observation groups were compared, only the difference in the levels of FSH and LH between the patients from Group A and Group C was statistically significant (P < 0.05). The results of receiver-operating characteristic (ROC) curve analysis suggested that limiting ovarian radiation dose to V 7.5  < 26% in IMRT prevents the disruption of ovarian function (area under ROC curve was 0.740, confidence interval [CI] = 0.606-0.874). In young patients with cervical cancer who underwent radical hysterectomy and ovarian transposition without receiving adjuvant radiotherapy, ovarian endocrine function was well preserved. In patients who received any type of postoperative radiotherapy, ovarian function was affected, suggesting that the standard ovarian limited dose used in IMRT disrupted ovarian function. The results of the ROC curve analysis suggested that the new optimal dose limit of V 7.5  < 26% should be used in IMRT to preserve ovarian function (P = 0.003). © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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

Detection of erythropoietin misuse by the Athlete Biological Passport combined with reticulocyte percentage.

PubMed

Bejder, Jacob; Aachmann-Andersen, Niels Jacob; Bonne, Thomas Christian; Olsen, Niels Vidiendal; Nordsborg, Nikolai Baastrup

2016-10-01

The sensitivity of the adaptive model of the Athlete Biological Passport (ABP) and reticulocyte percentage (ret%) in detection of recombinant human erythropoietin (rHuEPO) misuse was evaluated using both a long-term normal dose and a brief high dose treatment regime. Sixteen subjects received either 65 IU rHuEPO × kg -1 every second day for two weeks (normal-dose), 390 IU rHuEPO × kg -1 on three consecutive days (high-dose), or frequent placebo treatment for 13 days in a randomized, placebo-controlled, double-blind crossover design. Blood variables were measured 4, 11, and 25 days following treatment initiation. The ABP based on haemoglobin concentration ([Hb]) and OFF-hr score ([Hb] - 60 × √ret%) yielded atypical profiles following both normal-dose and high-dose treatment (0 %, 31 %, 13 % vs. 21 %, 33 %, 20 % at days 4, 11, and 25 after normal and high dose, respectively). Including ret% as a stand-alone marker for atypical blood profiles increased (P < 0.05) the sensitivity of the adaptive model at day 11 to 63 % and 67 % for normal-dose and high-dose rHuEPO administration, respectively. In conclusion, ~30 % of subjects injecting a normal-dose rHuEPO for two weeks or a high-dose rHuEPO for three days will present an atypical ABP profile. Including ret% as a stand-alone parameter improves the sensitivity two-fold. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial.

PubMed

Bakhshi, Sameer; Batra, Atul; Biswas, Bivas; Dhawan, Deepa; Paul, Reeja; Sreenivas, Vishnubhatla

2015-11-01

Aprepitant, a neurokinin-1 receptor antagonist, in combination with 5 HT-3 antagonist and dexamethasone is recommended in adults receiving moderately and highly emetogenic chemotherapy to reduce chemotherapy-induced vomiting (CIV). Data for use of aprepitant in children is limited and hence aprepitant is not recommended by Pediatric Oncology Group of Ontario guidelines for prevention of CIV in children <12 years. A randomized, double-blind, placebo-controlled trial was conducted at a single center in chemotherapy naïve children (5-18 years) receiving highly emetogenic chemotherapy. All patients received intravenous ondansetron (0.15 mg/kg) and dexamethasone (0.15 mg/kg) prior to chemotherapy followed by oral ondansetron and dexamethasone. Patients randomly assigned to aprepitant arm received oral aprepitant (15-40 kg = days 1-3, 80 mg; 41-65 kg = day 1, 125 mg and days 2-3, 80 mg) 1 h before chemotherapy. Control group received placebo as add-on therapy. Primary outcome measure was the incidence of acute moderate to severe vomiting, which was defined as more than two vomiting episodes within 24 h after the administration of the first chemotherapy dose until 24 h after the last chemotherapy dose in the block. Complete response (CR) was defined as absence of vomiting and retching during the specified phase. Of the 96 randomized patients, three were excluded from analysis; 93 patients were analyzed (50 in aprepitant arm and 43 in placebo arm). Acute moderate and severe vomiting was reported in 72 % patients receiving placebo and 38 % patients receiving aprepitant (p = 0.001). Complete response rates during acute phase were significantly higher in aprepitant arm (48 vs. 12 %, p < 0.001). No major adverse effects were reported by patients/guardians. This double-blind, randomized, placebo-controlled trial shows that aprepitant significantly decreases the incidence of CIV during acute phase when used as an add-on drug with ondansetron and dexamethasone in children receiving highly emetogenic chemotherapy.

Predictors of Local Control After Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases

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

Greco, Carlo; Zelefsky, Michael J., E-mail: zelefskm@mskcc.or; Lovelock, Michael

2011-03-15

Purpose: To report tumor local control after treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) to extracranial metastatic sites. Methods and Materials: A total of 126 metastases in 103 patients were treated with SD-IGRT to prescription doses of 18-24 Gy (median, 24 Gy) between 2004 and 2007. Results: The overall actuarial local relapse-free survival (LRFS) rate was 64% at a median follow-up of 18 months (range, 2-45 months). The median time to failure was 9.6 months (range, 1-23 months). On univariate analysis, LRFS was significantly correlated with prescription dose (p = 0.029). Stratification by dose into high (23 to 24 Gy),more » intermediate (21 to 22 Gy), and low (18 to 20 Gy) dose levels revealed highly significant differences in LRFS between high (82%) and low doses (25%) (p < 0.0001). Overall, histology had no significant effect on LRFS (p = 0.16). Renal cell histology displayed a profound dose-response effect, with 80% LRFS at the high dose level (23 to 24 Gy) vs. 37% with low doses ({<=}22 Gy) (p = 0.04). However, for patients who received the high dose level, histology was not a statistically significant predictor of LRFS (p = 0.90). Target organ (bone vs. lymph node vs. soft tissues) (p = 0.5) and planning target volume size (p = 0.55) were not found to be associated with long-term LRFS probability. Multivariate Cox regression analysis confirmed prescription dose to be a significant predictor of LRFS (p = 0.003). Conclusion: High-dose SD-IGRT is a noninvasive procedure resulting in high probability of local tumor control. Single-dose IGRT may be effectively used to locally control metastatic deposits regardless of histology and target organ, provided sufficiently high doses (> 22 Gy) of radiation are delivered.« less

Bladder accumulated dose in image-guided high-dose-rate brachytherapy for locally advanced cervical cancer and its relation to urinary toxicity

NASA Astrophysics Data System (ADS)

Zakariaee, Roja; Hamarneh, Ghassan; Brown, Colin J.; Gaudet, Marc; Aquino-Parsons, Christina; Spadinger, Ingrid

2016-12-01

The purpose of this study was to estimate locally accumulated dose to the bladder in multi-fraction high-dose-date (HDR) image-guided intracavitary brachytherapy (IG-ICBT) for cervical cancer, and study the locally-accumulated dose parameters as predictors of late urinary toxicity. A retrospective study of 60 cervical cancer patients who received five HDR IG-ICBT sessions was performed. The bladder outer and inner surfaces were segmented for all sessions and a bladder-wall contour point-set was created in MATLAB. The bladder-wall point-sets for each patient were registered using a deformable point-set registration toolbox called coherent point drift (CPD), and the fraction doses were accumulated. Various dosimetric and volumetric parameters were calculated using the registered doses, including r{{\\text{D}}n \\text{c{{\\text{m}}\\text{3}}}} (minimum dose to the most exposed n-cm3 volume of bladder wall), r V n Gy (wall volume receiving at least m Gy), and r\\text{EQD}{{2}n \\text{c{{\\text{m}}\\text{3}}}} (minimum equivalent biologically weighted dose to the most exposed n-cm3 of bladder wall), where n  =  1/2/5/10 and m  =  3/5/10. Minimum dose to contiguous 1 and 2 cm3 hot-spot volumes was also calculated. The unregistered dose volume histogram (DVH)-summed equivalent of r{{\\text{D}}n \\text{c{{\\text{m}}3}}} and r\\text{EQD}{{2}n \\text{c{{\\text{m}}3}}} parameters (i.e. s{{\\text{D}}n \\text{c{{\\text{m}}\\text{3}}}} and s\\text{EQD}{{2}n \\text{c{{\\text{m}}3}}} ) were determined for comparison. Late urinary toxicity was assessed using the LENT-SOMA scale, with toxicity Grade 0-1 categorized as Controls and Grade 2-4 as Cases. A two-sample t-test was used to identify the differences between the means of Control and Case groups for all parameters. A binomial logistic regression was also performed between the registered dose parameters and toxicity grouping. Seventeen patients were in the Case and 43 patients in the Control group. Contiguous values were on average 16 and 18% smaller than parameters for 1 and 2 cm3 volumes, respectively. Contiguous values were on average 26 and 27% smaller than parameters. The only statistically significant finding for Case versus Control based on both methods of analysis was observed for r V3 Gy (p  =  0.01). DVH-summed parameters based on unregistered structure volumes overestimated the bladder dose in our patients, particularly when contiguous high dose volumes were considered. The bladder-wall volume receiving at least 3 Gy of accumulated dose may be a parameter of interest in further investigations of Grade 2+  urinary toxicity.

A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

PubMed

Bell, D; Duffin, A; Jacobs, A; Pediconi, C; Gruss, H J

2014-03-01

The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

Maternal Tetanus Toxoid Vaccination and Neonatal Mortality in Rural North India

PubMed Central

Singh, Abhishek; Pallikadavath, Saseendran; Ogollah, Reuben; Stones, William

2012-01-01

Objectives Preventable neonatal mortality due to tetanus infection remains common. We aimed to examine antenatal vaccination impact in a context of continuing high neonatal mortality in rural northern India. Methods and Findings Using the third round of the Indian National Family Health Survey (NFHS) 2005–06, mortality of most recent singleton births was analysed in discrete-time logistic model with maternal tetanus vaccination, together with antenatal care utilisation and supplementation with iron and folic acid. 59% of mothers reported receiving antenatal care, 48% reported receiving iron and folic acid supplementation and 68% reported receiving two or more doses of tetanus toxoid (TT) vaccination. The odds of all-cause neonatal death were reduced following one or more antenatal dose of TT with odds ratios (OR) of 0.46 (95% CI 0.26 to 0.78) after one dose and 0.45 (95% CI 0.31 to 0.66) after two or more doses. Reported utilisation of antenatal care and iron-folic acid supplementation did not influence neonatal mortality. In the statistical model, 16% (95% CI 5% to 27%) of neonatal deaths could be attributed to a lack of at least two doses of TT vaccination during pregnancy, representing an estimated 78,632 neonatal deaths in absolute terms. Conclusions Substantial gains in newborn survival could be achieved in rural North India through increased coverage of antenatal TT vaccination. The apparent substantial protective effect of a single antenatal dose of TT requires further study. It may reflect greater population vaccination coverage and indicates that health programming should prioritise universal antenatal coverage with at least one dose. PMID:23152814

Maternal tetanus toxoid vaccination and neonatal mortality in rural north India.

PubMed

Singh, Abhishek; Pallikadavath, Saseendran; Ogollah, Reuben; Stones, William

2012-01-01

Preventable neonatal mortality due to tetanus infection remains common. We aimed to examine antenatal vaccination impact in a context of continuing high neonatal mortality in rural northern India. Using the third round of the Indian National Family Health Survey (NFHS) 2005-06, mortality of most recent singleton births was analysed in discrete-time logistic model with maternal tetanus vaccination, together with antenatal care utilisation and supplementation with iron and folic acid. 59% of mothers reported receiving antenatal care, 48% reported receiving iron and folic acid supplementation and 68% reported receiving two or more doses of tetanus toxoid (TT) vaccination. The odds of all-cause neonatal death were reduced following one or more antenatal dose of TT with odds ratios (OR) of 0.46 (95% CI 0.26 to 0.78) after one dose and 0.45 (95% CI 0.31 to 0.66) after two or more doses. Reported utilisation of antenatal care and iron-folic acid supplementation did not influence neonatal mortality. In the statistical model, 16% (95% CI 5% to 27%) of neonatal deaths could be attributed to a lack of at least two doses of TT vaccination during pregnancy, representing an estimated 78,632 neonatal deaths in absolute terms. Substantial gains in newborn survival could be achieved in rural North India through increased coverage of antenatal TT vaccination. The apparent substantial protective effect of a single antenatal dose of TT requires further study. It may reflect greater population vaccination coverage and indicates that health programming should prioritise universal antenatal coverage with at least one dose.

Quality indicators for prostate radiotherapy: are patients disadvantaged by receiving treatment in a 'generalist' centre?

PubMed

Freeman, Amanda R; Roos, Daniel E; Kim, Laurence

2015-04-01

The purpose of this retrospective review was to evaluate concordance with evidence-based quality indicator guidelines for prostate cancer patients treated radically in a 'generalist' (as distinct from 'sub-specialist') centre. We were concerned that the quality of treatment may be lower in a generalist centre. If so, the findings could have relevance for many radiotherapy departments that treat prostate cancer. Two hundred fifteen consecutive patients received external beam radiotherapy (EBRT) and/or brachytherapy between 1.10.11 and 30.9.12. Treatment was deemed to be in line with evidence-based guidelines if the dose was: (i) 73.8-81 Gy at 1.8-2.0 Gy/fraction for EBRT alone (eviQ guidelines); (ii) 40-50 Gy (EBRT) for EBRT plus high-dose rate (HDR) brachytherapy boost (National Comprehensive Cancer Network (NCCN) guidelines); and (iii) 145 Gy for low dose rate (LDR) I-125 monotherapy (NCCN). Additionally, EBRT beam energy should be ≥6 MV using three-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT), and high-risk patients should receive neo-adjuvant androgen-deprivation therapy (ADT) (eviQ/NCCN). Treatment of pelvic nodes was also assessed. One hundred four high-risk, 84 intermediate-risk and 27 low-risk patients (NCCN criteria) were managed by eight of nine radiation oncologists. Concordance with guideline doses was confirmed in: (i) 125 of 136 patients (92%) treated with EBRT alone; (ii) 32 of 34 patients (94%) treated with EBRT + HDR BRT boost; and (iii) 45 of 45 patients (100%) treated with LDR BRT alone. All EBRT patients were treated with ≥6 MV beams using 3D-CRT (78%) or IMRT (22%). 84%, 21% and 0% of high-risk, intermediate-risk and low-risk patients received ADT, respectively. Overall treatment modality choice (including ADT use and duration where assessable) was concordant with guidelines for 176/207 (85%) of patients. The vast majority of patients were treated concordant with evidence-based guidelines suggesting that, within the limits of the selected criteria, prostate cancer patients are unlikely to be disadvantaged by receiving radiotherapy in this 'generalist' centre. © 2014 The Royal Australian and New Zealand College of Radiologists.

The effect of high-dose vitamin D supplementation on muscular function and quality of life in postmenopausal women-A randomized controlled trial.

PubMed

Grimnes, G; Emaus, N; Cashman, K D; Jorde, R

2017-07-01

Observational studies have suggested positive associations between serum 25-hydroxyvitamin D (25(OH)D) levels and muscular strength, balance and quality of life. Our aim was to examine whether high-dose vitamin D supplementation would improve these measures as compared to standard-dose vitamin D, as well as the possible muscular effects of single nucleotide polymorphisms (SNPs) in genes encoding vitamin D-related enzymes. A 12-month randomized, double-blind, controlled trial where the participants received daily elemental calcium (1000 mg) plus vitamin D 3 (800 IU). In addition, the participants were randomized to receive either capsules with vitamin D 3 (20 000 IU) or matching placebos to be taken twice a week. A total of 297 postmenopausal women with osteopenia or osteoporosis. Muscle strength (handgrip and knee extensor strength), balance (tandem test) and quality of life (EQ-5D) were measured at baseline and after 12 months. The subjects were genotyped for SNPs related to vitamin D metabolism. Of the 297 included women, 275 completed the study. Mean serum 25(OH)D levels dramatically increased in the high-dose group (from 64.7 to 164.1 nmol/L; P<.01), while a more moderate increased was observed in the standard-dose group (from 64.1 to 81.8 nmol/L; P<.01). There was no significant difference between the groups in change in muscular strength, balance or quality of life over the intervention period. Polymorphisms in rs3829251 (located in the 7-dehydrocholesterol reductase gene) were associated with muscle strength and treatment effects. One-year treatment with high-dose vitamin D had no effect on muscular strength, balance or quality of life in postmenopausal women with osteopenia or osteoporosis as compared to standard dose. The association between rs3829251 and muscle strength needs confirmation in other populations. © 2017 John Wiley & Sons Ltd.

How does exercise dose affect patients with long-term osteoarthritis of the knee? A study protocol of a randomised controlled trial in Sweden and Norway: the SWENOR Study

PubMed Central

Grooten, Wilhelmus J A; Østerås, Håvard; Heijne, Annette; Harms-Ringdahl, Karin; Äng, Björn Olov

2018-01-01

Introduction Osteoarthritis (OA) of the knee is characterised by knee pain, disability and degenerative changes, and places a burden on societies all over the world. Exercise therapy is an often-used modality, but there is little evidence of what type of exercise dose is the most effective, indicating a need for controlled studies of the effect of different dosages. Thus, the aim of the study described in this protocol is to evaluate the effects of high-dose versus low-dose medical exercise therapy (MET) in patients with knee OA. Methods and analysis This is a multicentre prospective randomised two-arm trial with blinded assessment and data analysis. We are planning to include 200 patients aged 45–85 years with symptomatic (pain and decreased functioning) and X-ray verified diagnosis of knee OA. Those eligible for participation will be randomly allocated to either high-dose (n=100) or low-dose (n=100) MET. All patients receive three supervised treatments each week for 12 weeks, giving a total of 36 MET sessions. The high-dose group exercises for 70–90 min compared with 20–30 min for the low-dose group. The high-dose group exercises for a longer time, and receives a greater number of exercises with more repetitions and sets. Background and outcome variables are recorded at inclusion, and outcome measures are collected after every sixth treatment, at the end of treatment, and at 6-month and 12-month follow-ups. Primary outcome is self-rated knee functioning and pain using the Knee Injury and Osteoarthritis Outcome Score (KOOS). The primary end point is at the end of treatment after 3 months, and secondary end points are at 6 months and 12 months after the end of treatment. Ethics and dissemination This project has been approved by the Regional Research Ethics Committees in Stockholm, Sweden, and in Norway. Our results will be submitted to peer-reviewed journals and presented at national and international conferences. Trial registration number NCT02024126; Pre-results. PMID:29730615

Evaluation of rotigotine transdermal patch for the treatment of apathy and motor symptoms in Parkinson's disease.

PubMed

Hauser, Robert A; Slawek, Jaroslaw; Barone, Paolo; Dohin, Elisabeth; Surmann, Erwin; Asgharnejad, Mahnaz; Bauer, Lars

2016-06-07

This multicenter, double-blind, placebo-controlled study assessed the efficacy of rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson's disease (PD). Patients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to "low-dose" rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), "high-dose" rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory. Of 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose rotigotine, n = 30/41 [73.2 %]; high-dose rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [-2.42, 2.50], p =0.977; high-dose, -0.22 [-2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, -7.29 [-12.30, -2.28], p = 0.005; high-dose, -6.06 [-10.90, -1.21], p = 0.015), and the "mood/apathy" domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in rotigotine-treated patients were application site reactions, somnolence, and nausea. Rotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living. ClinicalTrials.gov identifier NCT01782222 . Trial registration date: January 30, 2013.

Anti-radiation damage effect of polyethylenimine as a toll-like receptor 5 targeted agonist

PubMed Central

Hu, Zhiqiang; Xing, Yaling; Qian, Yuanyu; Chen, Xiaojuan; Tu, Jian; Ren, Lening; Wang, Kai; Chen, Zhongbin

2013-01-01

A number of agents are now available for use in protecting against ionizing radiation. These radiation-protective agents, however, have many adverse effects. Efforts have been made to develop new radiation-protective agents for medical application. Here, we investigated whether a compound, polyethylenimine (PEI), which activates Toll-like receptor 5 (TLR5)-mediated NF-kB signaling pathways, could have an anti-radiation effect on a mouse model. First, a cell-based screening model for an agonist of TLR5-mediated NF-kB pathway was established and then validated by activation of TLR5-mediated NF-kB luciferase reporter activity with a known TLR5 agonist, flagellin. We found that PEI induced dose-dependent activation of the TLR5-mediated NF-kB pathway, indicating that PEI is indeed a TLR5 agonist. Furthermore, the anti-radiation effect of polyethylenimine was assessed using a γ-ray total body irradiation (TBI) mouse model. Compared with the irradiation control, both survival time and survival rate were significantly improved in mice that received either a low dose of polyethylenimine (P= 0.019) or a high dose of polyethylenimine (P< 0.001). We also observed a positive correlation between animal body weight and survival time in mice that received a low dose of polyethylenimine, a high dose of polyethylenimine and amifostine, over a period of 30 days, r= 0.42 (P< 0.02), 0.72 (P< 0.0001) and 0.95 (P< 0.0001), respectively, while a negative correlation between animal body weight and survival time was observed in the irradiation control (r= –0.89; P< 0.0001). These results indicate that polyethylenimine is a new TLR5 agonist with potential application in offering protection for patients receiving radiotherapy or in radiation-related accidents. PMID:23104900

Anti-radiation damage effect of polyethylenimine as a toll-like receptor 5 targeted agonist.

PubMed

Hu, Zhiqiang; Xing, Yaling; Qian, Yuanyu; Chen, Xiaojuan; Tu, Jian; Ren, Lening; Wang, Kai; Chen, Zhongbin

2013-03-01

A number of agents are now available for use in protecting against ionizing radiation. These radiation-protective agents, however, have many adverse effects. Efforts have been made to develop new radiation-protective agents for medical application. Here, we investigated whether a compound, polyethylenimine (PEI), which activates Toll-like receptor 5 (TLR5)-mediated NF-kB signaling pathways, could have an anti-radiation effect on a mouse model. First, a cell-based screening model for an agonist of TLR5-mediated NF-kB pathway was established and then validated by activation of TLR5-mediated NF-kB luciferase reporter activity with a known TLR5 agonist, flagellin. We found that PEI induced dose-dependent activation of the TLR5-mediated NF-kB pathway, indicating that PEI is indeed a TLR5 agonist. Furthermore, the anti-radiation effect of polyethylenimine was assessed using a γ-ray total body irradiation (TBI) mouse model. Compared with the irradiation control, both survival time and survival rate were significantly improved in mice that received either a low dose of polyethylenimine (P= 0.019) or a high dose of polyethylenimine (P< 0.001). We also observed a positive correlation between animal body weight and survival time in mice that received a low dose of polyethylenimine, a high dose of polyethylenimine and amifostine, over a period of 30 days, r= 0.42 (P< 0.02), 0.72 (P< 0.0001) and 0.95 (P< 0.0001), respectively, while a negative correlation between animal body weight and survival time was observed in the irradiation control (r= -0.89; P< 0.0001). These results indicate that polyethylenimine is a new TLR5 agonist with potential application in offering protection for patients receiving radiotherapy or in radiation-related accidents.

[Disseminated intravascular coagulation induced by endotoxin in rabbits: effect of treatment with t-PA and urokinase].

PubMed

Paloma, M J; Páramo, J A; Rifón, J; Rocha, E

1992-12-01

To assess the therapeutic efficacy of agents capable of stimulating the fibrinolytic system, such as tissue plasminogen activator (t-PA) and urokinase (UK) on endotoxin-induced disseminated intravascular coagulation (DIC) in the rabbit. DIC was induced by intravenous administration of endotoxin, 20 micrograms/kg/hr during 6 hr. Four different groups were established: a) control group, receiving only saline solution; b) t-PA group receiving 0.2 mg/kg; c) t-PA group receiving 0.7 mg/kg, and d) UK group, which was given 3,000 IU/kg/hr for 6 hr. Blood samples were drawn before and after 2 hr and 6 hr of endotoxin administration. Platelet count, and fibrinogen, factor XII and antithrombin III concentrations, were assessed in each sample. Mean, standard deviation and percentage of increase or decrease with respect to the basal value, this considered 100%, were used to evaluate the findings. For comparison of values, Student's t and Mann Whitney's U were used; the Fisher test was used for mortality studies. No statistical differences appeared for any of the values in the rabbits under basal conditions. The rabbits in the control group developed DIC. No doses of t-PA modified the changes appearing in blood coagulation. UK reduced the fibrinogen and factor XII consumption induced by endotoxin. The mortality rate in the control group reached 70%. High-dose t-PA decreased such figure to 50%, while low-dose t-PA or UK failed to reduce mortality. High-dose t-PA has beneficial effects on endotoxin-induced DIC in rabbits. UK failed to achieve such effect at the doses given in this experimental DIC model.

[Evaluation of an Experimental Production Wireless Dose Monitoring System for Radiation Exposure Management of Medical Staff].

PubMed

Fujibuchi, Toshioh; Murazaki, Hiroo; Kuramoto, Taku; Umedzu, Yoshiyuki; Ishigaki, Yung

2015-08-01

Because of the more advanced and more complex procedures in interventional radiology, longer treatment times have become necessary. Therefore, it is important to determine the exposure doses received by operators and patients. The aim of our study was to evaluate an experimental production wireless dose monitoring system for pulse radiation in diagnostic X-ray. The energy, dose rate, and pulse fluoroscopy dependence were evaluated as the basic characteristics of this system for diagnostic X-ray using a fully digital fluoroscopy system. The error of 1 cm dose equivalent rate was less than 15% from 35.1 keV to 43.2 keV with energy correction using metal filter. It was possible to accurately measure the dose rate dependence of this system, which was highly linear until 100 μSv/h. This system showed a constant response to the pulse fluoroscopy. This system will become useful wireless dosimeter for the individual exposure management by improving the high dose rate and the energy characteristics.

High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns.

PubMed

Avasiloaiei, Andreea; Dimitriu, Cristina; Moscalu, Mihaela; Paduraru, Luminita; Stamatin, Maria

2013-10-01

The aim of this study was to compare two neuroprotective strategies to supportive care in the treatment of perinatal asphyxia. A total of 67 term newborns with perinatal asphyxia were included and randomized into three groups: one group received supportive treatment; another group received a single dose of 40 mg/kg phenobarbital; and the third received three daily doses of 1000 IU/kg erythropoietin. The following parameters were analyzed: gestational age, birthweight, Apgar scores, cord blood pH, total serum antioxidant status (TAS), superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). The newborns were included in the follow-up program and examined up to 18 months of age. TAS was higher in the erythropoietin group than in the other groups. SOD and GPx were lower for infants treated with phenobarbital or erythropoietin compared to control infants. MDA was lower in the erythropoietin group compared to the other groups, although the difference was not statistically significant (P > 0.05). The mortality rate was lower in the phenobarbital and erythropoietin groups (both 4.6%) than in the control group (17.4%). Long-term neurologic follow up showed a high incidence of sequelae in the control group compared to the phenobarbital and erythropoietin groups. Follow-up results were better in the phenobarbital group than in the erythropoietin group for motor and cognitive function at 3 and 6 months and worse for expressive language. At 18 months, however, the differences between these two groups were not significant. High-dose phenobarbital or erythropoietin along with supportive treatment has a positive influence on the outcome of newborns with perinatal asphyxia. Phenobarbital has the advantage of low cost and simplicity. © 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.

Dosimetric comparison of normal structures associated with accelerated partial breast irradiation and whole breast irradiation delivered by intensity modulated radiotherapy for early breast cancer after breast conserving surgery.

PubMed

Wu, S; He, Z; Guo, J; Li, F; Lin, Q; Guan, X

2014-01-01

To assess the heart and lung dosimetry results associated with accelerated partial breast irradiation intensity-modulated radiotherapy (APBI-IMRT) and whole breast field-in-field intensity-modulated radiotherapy (WBI-FIF-IMRT). A total of 29 patients with early-stage breast cancer after lumpectomy were included in this study. APBI-IMRT and WBI-FIF-IMRT plans were generated for each patient. The dosimetric parameters of ipsilateral lung and heart in both plans were then compared with and without radiobiological correction. With and without radiobiological correction, the volume of ipsilateral lung showed a substantially lower radiation exposure in APBI-IMRT with moderate to high doses (P < 0.05) but non-significant increases in volume of ipsilateral lung in 2.5 Gy than WBI-FIF-IMRT (P > 0.905).There was no significant difference in volume of ipsilateral lung receiving 1, 2.5, and 5 Gy between APBI-IMRT and WBI (P > 0.05) in patients with medial tumor location, although APBI-IMRT exposed more lung to 2.5 and 5 Gy. APBI-IMRT significantly decreases the volume of heart receiving low to high doses in left-sided breast cancer (P < 0.05). APBI-IMRT can significantly spare the volume of heart and ipsilateral lung receiving moderate and high dose. Non-significant increases in volume of the ipsilateral lung exposed to low doses of radiation were observed for APBI-IMRT in comparison to WBI-FIF-IMRT, particularly in patients with medial tumor location. With the increasing interest in APBI-IMRT, our data may help clinicians individualize patient treatment decisions.

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.

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.

Oral bioavailability of DN101, a concentrated formulation of calcitriol, in tumor-bearing dogs.

PubMed

Rassnick, Kenneth M; Muindi, Josephia R; Johnson, Candace S; Bailey, Dennis B; Trump, Donald L

2011-01-01

High-dose calcitriol (1,25-dihydroxyvitamin D(3)) has antineoplastic activity against a range of tumors and potentiates chemotherapeutic agents. In an earlier canine study, the MTD of intravenous (i.v.) calcitriol was 3.75 μg/kg, but polysorbate-associated hypersensitivity reactions were common. Use of commercially available oral calcitriol is limited by the absence of a formulation of suitable strength to allow administration of a reasonable number of caplets. This study evaluated the bioavailability of DN101, a concentrated oral calcitriol formulation specifically developed for anticancer applications. An open-label, single-dose, 2-way crossover study was conducted. Dogs randomly received a single 3.75 μg/kg dose of calcitriol either i.v. or oral (as DN101), followed by cisplatin (60 mg/m(2)). Three weeks later, the alternate form of calcitriol was given prior to another dose of cisplatin. Dogs received antihistamines and corticosteroids prior to both treatments. Food was withheld for 12 h before and after therapy. Serum calcitriol concentrations were measured by radioimmunoassay. Ten tumor-bearing dogs received both i.v. and oral calcitriol. Six dogs experienced hypersensitivity reactions during i.v. calcitriol. Sequence of calcitriol administration (day-1 vs. day-21) by either i.v. or oral routes had no effect on the major calcitriol pharmacokinetic parameters. Oral calcitriol resulted in significantly lower values for AUC (P = 0.05) and prolonged T (1/2) (P = 0.003) when compared to i.v. Calcitriol oral bioavailability was highly variable among dogs (mean ± SEM, 71 ± 12.6%). This study demonstrates that a high-dose formulation of calcitriol has a moderate bioavailability in dogs, but inter-individual variability in PK parameters is similar to that observed in people. With this bioavailability, serum concentrations of calcitriol that exhibit antitumor activity in a preclinical murine model were achieved in some dogs. Exploration of methods to minimize variation in calcitriol systemic exposure is warranted.

A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients: A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study.

PubMed

Amalraj, Augustine; Varma, Karthik; Jacob, Joby; Divya, Chandradhara; Kunnumakkara, Ajaikumar B; Stohs, Sidney J; Gopi, Sreeraj

2017-10-01

Rheumatoid arthritis (RA) is an autoimmune, chronic systemic inflammatory disorder. The long-term use of currently available drugs for the treatment of RA has many potential side effects. Natural phytonutrients may serve as alternative strategies for the safe and effective treatment of RA, and curcuminoids have been used in Ayurvedic medicine for the treatment of inflammatory conditions for centuries. In this study, a novel, highly bioavailable form of curcumin in a completely natural turmeric matrix was evaluated for its ability to improve the clinical symptoms of RA. A randomized, double-blind, placebo-controlled, three-arm, parallel-group study was conducted to evaluate the comparative efficacy of two different doses of curcumin with that of a placebo in active RA patients. Twelve patients in each group received placebo, 250 or 500 mg of the curcumin product twice daily for 90 days. The responses of the patients were assessed using the American College of Rheumatology (ACR) response, visual analog scale (VAS), C-reactive protein (CRP), Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) values. RA patients who received the curcumin product at both low and high doses reported statistically significant changes in their clinical symptoms at the end of the study. These observations were confirmed by significant changes in ESR, CPR, and RF values in patients receiving the study product compared to baseline and placebo. The results indicate that this novel curcumin in a turmeric matrix acts as an analgesic and anti-inflammatory agent for the management of RA at a dose as low as 250 mg twice daily as evidenced by significant improvement in the ESR, CRP, VAS, RF, DAS28, and ACR responses compared to placebo. Both doses of the study product were well tolerated and without side effects.

Dosimetric benefit of adaptive re-planning in pancreatic cancer stereotactic body radiotherapy

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

Li, Yongbao; Center for Advanced Radiotherapy Technologies University of California San Diego, La Jolla, CA; Department of Radiation Oncology, University of California San Diego, La Jolla, CA

Stereotactic body radiotherapy (SBRT) shows promise in unresectable pancreatic cancer, though this treatment modality has high rates of normal tissue toxicity. This study explores the dosimetric utility of daily adaptive re-planning with pancreas SBRT. We used a previously developed supercomputing online re-planning environment (SCORE) to re-plan 10 patients with pancreas SBRT. Tumor and normal tissue contours were deformed from treatment planning computed tomographies (CTs) and transferred to daily cone-beam CT (CBCT) scans before re-optimizing each daily treatment plan. We compared the intended radiation dose, the actual radiation dose, and the optimized radiation dose for the pancreas tumor planning target volumemore » (PTV) and the duodenum. Treatment re-optimization improved coverage of the PTV and reduced dose to the duodenum. Within the PTV, the actual hot spot (volume receiving 110% of the prescription dose) decreased from 4.5% to 0.5% after daily adaptive re-planning. Within the duodenum, the volume receiving the prescription dose decreased from 0.9% to 0.3% after re-planning. It is noteworthy that variation in the amount of air within a patient's stomach substantially changed dose to the PTV. Adaptive re-planning with pancreas SBRT has the ability to improve dose to the tumor and decrease dose to the nearby duodenum, thereby reducing the risk of toxicity.« less

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.

Evaluation of entrance surface air kerma in pediatric chest radiography

NASA Astrophysics Data System (ADS)

Porto, L.; Lunelli, N.; Paschuk, S.; Oliveira, A.; Ferreira, J. L.; Schelin, H.; Miguel, C.; Denyak, V.; Kmiecik, C.; Tilly, J.; Khoury, H.

2014-11-01

The objective of this study was to evaluate the entrance surface air kerma in pediatric chest radiography. An evaluation of 301 radiographical examinations in anterior-posterior (AP) and posterior-anterior (PA) (166 examinations) and lateral (LAT) (135 examinations) projections was performed. The analyses were performed on patients grouped by age; the groups included ages 0-1 y, 1-5 y, 5-10 y, and 10-15 y. The entrance surface air kerma was determined with DoseCal software (Radiological Protection Center of Saint George's Hospital, London) and thermoluminescent dosimeters. Two different exposure techniques were compared. The doses received by patients who had undergone LAT examinations were 40% higher, on average, those in AP/PA examinations because of the difference in tube voltage. A large high-dose “tail” was observed for children up to 5 y old. An increase in tube potential and corresponding decrease in current lead to a significant dose reduction. The difference between the average dose values for different age ranges was not practically observed, implying that the exposure techniques are still not optimal. Exposure doses received using the higher tube voltage and lower current-time product correspond to the international diagnostic reference levels.

Effects of Radiation Exposure From Cardiac Imaging: How Good Are the Data?

PubMed Central

Einstein, Andrew J.

2012-01-01

Concerns about medical exposure to ionizing radiation have become heightened in recent years due to rapid growth in procedure volumes and the high radiation doses incurred from some procedures. This article summarizes the evidence base undergirding concerns about radiation exposure in cardiac imaging. After classifying radiation effects, explaining terminology used to quantify the radiation received by patients, and describing typical doses from cardiac imaging procedures, I address the major epidemiological studies having bearing on radiation effects at doses comparable to those received by patients undergoing cardiac imaging. These include studies of atomic bomb survivors, nuclear industry workers, and children exposed in utero to x-rays, all of which have evidenced increased cancer risks at low doses. Additional higher dose epidemiological studies of cohorts exposed to radiation in the context of medical treatment are described and found to be generally compatible with these cardiac-dose-level studies, albeit with exceptions. Using risk projection models developed by the US National Academies that incorporate these data and reflect several evidence-based assumptions, cancer risk from cardiac imaging can be estimated and compared to benefits from imaging. Several ongoing epidemiological studies will provide better understanding of radiation-associated cancer risks. PMID:22300689

Assessment of physician and patient (child and adult) equivalent doses during renal angiography by Monte Carlo method.

PubMed

Karimian, A; Nikparvar, B; Jabbari, I

2014-11-01

Renal angiography is one of the medical imaging methods in which patient and physician receive high equivalent doses due to long duration of fluoroscopy. In this research, equivalent doses of some radiosensitive tissues of patient (adult and child) and physician during renal angiography have been calculated by using adult and child Oak Ridge National Laboratory phantoms and Monte Carlo method (MCNPX). The results showed, in angiography of right kidney in a child and adult patient, that gall bladder with the amounts of 2.32 and 0.35 mSv, respectively, has received the most equivalent dose. About the physician, left hand, left eye and thymus absorbed the most amounts of doses, means 0.020 mSv. In addition, equivalent doses of the physician's lens eye, thyroid and knees were 0.023, 0.007 and 7.9E-4 mSv, respectively. Although these values are less than the reported thresholds by ICRP 103, it should be noted that these amounts are related to one examination. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Dosimetric and radiobiologic comparison of 3D conformal versus intensity modulated planning techniques for prostate bed radiotherapy.

PubMed

Koontz, Bridget F; Das, Shiva; Temple, Kathy; Bynum, Sigrun; Catalano, Suzanne; Koontz, Jason I; Montana, Gustavo S; Oleson, James R

2009-01-01

Adjuvant radiotherapy for locally advanced prostate cancer improves biochemical and clinical disease-free survival. While comparisons in intact prostate cancer show a benefit for intensity modulated radiation therapy (IMRT) over 3D conformal planning, this has not been studied for post-prostatectomy radiotherapy (RT). This study compares normal tissue and target dosimetry and radiobiological modeling of IMRT vs. 3D conformal planning in the postoperative setting. 3D conformal plans were designed for 15 patients who had been treated with IMRT planning for salvage post-prostatectomy RT. The same computed tomography (CT) and target/normal structure contours, as well as prescription dose, was used for both IMRT and 3D plans. Normal tissue complication probabilities (NTCPs) were calculated based on the dose given to the bladder and rectum by both plans. Dose-volume histogram and NTCP data were compared by paired t-test. Bladder and rectal sparing were improved with IMRT planning compared to 3D conformal planning. The volume of the bladder receiving at least 75% (V75) and 50% (V50) of the dose was significantly reduced by 28% and 17%, respectively (p = 0.002 and 0.037). Rectal dose was similarly reduced, V75 by 33% and V50 by 17% (p = 0.001 and 0.004). While there was no difference in the volume of rectum receiving at least 65 Gy (V65), IMRT planning significant reduced the volume receiving 40 Gy or more (V40, p = 0.009). Bladder V40 and V65 were not significantly different between planning modalities. Despite these dosimetric differences, there was no significant difference in the NTCP for either bladder or rectal injury. IMRT planning reduces the volume of bladder and rectum receiving high doses during post-prostatectomy RT. Because of relatively low doses given to the bladder and rectum, there was no statistically significant improvement in NTCP between the 3D conformal and IMRT plans.

Biology of high single doses of IORT: RBE, 5 R's, and other biological aspects.

PubMed

Herskind, Carsten; Ma, Lin; Liu, Qi; Zhang, Bo; Schneider, Frank; Veldwijk, Marlon R; Wenz, Frederik

2017-01-19

Intraoperative radiotherapy differs from conventional, fractionated radiotherapy in several aspects that may influence its biological effect. The radiation quality influences the relative biologic effectiveness (RBE), and the role of the five R's of radiotherapy (reassortment, repair, reoxygenation, repopulation, radiosensitivity) is different. Furthermore, putative special biological effects and the small volume receiving a high single dose may be important. The present review focuses on RBE, repair, and repopulation, and gives an overview of the other factors that potentially contribute to the efficacy. The increased RBE should be taken into account for low-energy X-rays while evidence of RBE < 1 for high-energy electrons at higher doses is presented. Various evidence supports a hypothesis that saturation of the primary DNA double-strand break (DSB) repair mechanisms leads to increasing use of an error-prone backup repair system leading to genomic instability that may contribute to inactivate tumour cells at high single doses. Furthermore, the elimination of repopulation of residual tumour cells in the tumour bed implies that some patients are likely to have very few residual tumour cells which may be cured even by low doses to the tumour bed. The highly localised dose distribution of IORT has the potential to inactivate tumour cells while sparing normal tissue by minimising the volume exposed to high doses. Whether special effects of high single doses also contribute to the efficacy will require further experimental and clinical studies.

Determination of cytokine protein levels in oral secretions in patients undergoing radiotherapy for head and neck malignancies

PubMed Central

2012-01-01

Background Cytokines may be elevated in tumor and normal tissues following irradiation. Cytokine expression in these tissues may predict for toxicity or tumor control. The purpose of this pilot study was to determine the feasibility of measuring local salivary cytokine levels using buccal sponges in patients receiving chemo-radiation for head and neck malignancies. Patients and methods 11 patients with epithelial malignancies of the head and neck were recruiting to this study. All patients received radiotherapy to the head and neck region with doses ranging between 60 – 67.5 Gy. Chemotherapy was delivered concurrently with radiation in all patients. Salivary samples were obtained from high dose and low dose regions prior to treatment and at three intervals during treatment for assessment of cytokine levels (IL-4, IL-6, IL-8, IL-10, EGF, MCP-1, TNF-α, and VEGF). Results Cytokine levels were detectable in the salivary samples. Salivary cytokine levels of IL-4, IL-6, IL-8, EGF, MCP-1, TNF- α , and VEGF were higher in the high dose region compared to the low dose region at all time points (p < 0.05). A trend toward an increase in cytokine levels as radiation dose increased was observed for IL-6, IL-8, MCP-1, and TNF-α. Conclusion Assessment of salivary cytokine levels may provide a novel method to follow local cytokine levels during radiotherapy and may provide a mechanism to study cytokine levels in a regional manner. PMID:22537315

Evaluation of optimum room entry times for radiation therapists after high energy whole pelvic photon treatments.

PubMed

Ho, Lavine; White, Peter; Chan, Edward; Chan, Kim; Ng, Janet; Tam, Timothy

2012-01-01

Linear accelerators operating at or above 10 MV produce neutrons by photonuclear reactions and induce activation in machine components, which are a source of potential exposure for radiation therapists. This study estimated gamma dose contributions to radiation therapists during high energy, whole pelvic, photon beam treatments and determined the optimum room entry times, in terms of safety of radiation therapists. Two types of technique (anterior-posterior opposing and 3-field technique) were studied. An Elekta Precise treatment system, operating up to 18 MV, was investigated. Measurements with an area monitoring device (a Mini 900R radiation monitor) were performed, to calculate gamma dose rates around the radiotherapy facility. Measurements inside the treatment room were performed when the linear accelerator was in use. The doses received by radiation therapists were estimated, and optimum room entry times were determined. The highest gamma dose rates were approximately 7 μSv/h inside the treatment room, while the doses in the control room were close to background (~0 μSv/h) for all techniques. The highest personal dose received by radiation therapists was estimated at 5 mSv/yr. To optimize protection, radiation therapists should wait for up to11 min after beam-off prior to room entry. The potential risks to radiation therapists with standard safety procedures were well below internationally recommended values, but risks could be further decreased by delaying room entry times. Dependent on the technique used, optimum entry times ranged between 7 to 11 min. A balance between moderate treatment times versus reduction in measured equivalent doses should be considered.

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.

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.

Radiation exposure to nuclear medicine staffs during 18F-FDG PET/CT procedures at Ramathibodi Hospital

NASA Astrophysics Data System (ADS)

Donmoon, T.; Chamroonrat, W.; Tuntawiroon, M.

2016-03-01

The aim of this study is to estimate the whole body and finger radiation doses per study received by nuclear medicine staff involved in dispensing, administration of 18F-FDG and interacting with radioactive patients during PET/CT imaging procedures in a PET/CT facility. The whole-body doses received by radiopharmacists, technologists and nurses were measured by electronic dosimeter and the finger doses by ring dosimeter during a period of 4 months. In 70 PET/CT studies, the mean whole-body dose per study to radiopharmacist, technologist, and nurse were 1.07±0.09, 1.77±0.46, μSv, and not detectable respectively. The mean finger doses per study received by radiopharmacist, technologist, and nurse were 265.65±107.55, 4.84±1.08 and 19.22±2.59 μSv, respectively. The average time in contact with 18F-FDG was 5.88±0.03, 39.06±1.89 and 1.21±0.02 minutes per study for radiopharmacist, technologist and nurse respectively. Technologists received highest mean effective whole- body dose per study and radiopharmacist received the highest finger dose per study. When compared with the ICRP dose limit, each individual worker can work with many more 18F- FDG PET/CT studies for a whole year without exceeding the occupational dose limits. This study confirmed that low levels of radiation does are received by our medical personnel involved in 18F-FDG PET/CT procedures.

Management of relapsed and refractory classical Hodgkin lymphoma in children and adolescents.

PubMed

Daw, Stephen; Wynn, Rob; Wallace, Hamish

2011-02-01

There are a number of options for salvage treatment in children and adolescents with relapsed and refractory classical Hodgkin Lymphoma. These include salvage with standard dose chemotherapy, high dose chemotherapy with autologous stem cell transplant, allogeneic stem cell transplant or other novel approach. Radiotherapy has an important role in the salvage of some patients as part of a combined modality approach. This review outlines these salvage approaches and discusses whether the evidence from paediatric studies justifies a risk-adapted approach to salvage for individual patients or whether all patients should receive consolidation with high dose chemotherapy and autologous stem cell transplantation, which is often described as standard salvage management in adults. The important prognostic factors and how these may be used to allocate patients to standard versus high dose chemotherapy regimens are discussed. The role of allogeneic transplantation, novel agents and late effects will also be discussed. © 2010 Blackwell Publishing Ltd.

High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naïve lymphocytes and prevents TTV reactivation.

PubMed

Iovino, Lorenzo; Mazziotta, Francesco; Carulli, Giovanni; Guerrini, Francesca; Morganti, Riccardo; Mazzotti, Valentina; Maggi, Fabrizio; Macera, Lisa; Orciuolo, Enrico; Buda, Gabriele; Benedetti, Edoardo; Caracciolo, Francesco; Galimberti, Sara; Pistello, Mauro; Petrini, Mario

2018-05-02

Zinc plays an important role in thymic function and immune homeostasis. We performed a prospective clinical trial using a high-dose zinc oral supplementation to improve the immune reconstitution after hematopoietic stem cell transplant (HSCT). We enrolled 18 patients undergoing autologous HSCT for multiple myeloma. Nine patients were randomized to receive only a standard antimicrobial prophylaxis; whereas, nine patients received in addition 150 mg/day of zinc from day +5 to day +100 after transplant. CD4+ naïve lymphocytes and TRECs showed a significant increase from day +30 until day +100 only in the zinc-treated group. Moreover, the load of Torquetenovirus, a harmless virus that replicates in course of immunedepression, increased at day +100 only in the control group. No severe adverse events were reported during the zinc consumption. First data from the ZENITH trial suggest that high-dose zinc supplementation is safe and may enhance the thymic reconstitution after HSCT. Registered: http://Clinicaltrials.gov (NCT03159845); and EUDRACT: 2014-28 004499-47. Copyright © 2018 Elsevier Ltd. All rights reserved.

Efficacy of topotecan treatment on antioxidant enzymes and TBA-RS levels in submandibular glands of rabbits: an experimental study.

PubMed

Muluk, Nuray Bayar; Kisa, Uçler; Kaçmaz, Murat; Apan, Alpaslan; Koç, Can

2005-01-01

The aim of this study was to investigate the effects of topotecan (Hycamtin), a topoisomerase I inhibiting anticancer agent, on antioxidant enzymes (SOD, CAT, and GSH-Px) and TBA-RS values of the submandibular glands of the rabbits. The study was conveyed in two groups (Group I, II) and control with a total of 24 rabbits. Eight rabbits in group I received intravenous (i.v.) topotecan (0.25 mg/kg once daily) for 3 days. Eight rabbits in group II received i.v. topotecan (0.5 mg/kg once daily) for 3 days. On the 15th day after administration of topotecan, submandibular glands were removed and levels of the SOD, CAT, and GSH-Px and the TBA-RS in the submandibular glands of the rabbits were examined. SOD, CAT, and GSH-Px values were significantly higher in high-dose topotecan group compared to control group (P < 0.05). SOD and TBA-RS values were significantly higher in high-dose topotecan group compared to low-dose topotecan group (P < 0.05). It was concluded that, to prevent the hazardous effects of oxygen free radicals due to topotecan, antioxidant enzymes SOD, CAT, and GSH-Px were increased. The higher levels of the TBA-RS values in group II showed that permanent damage was present because of high-dose topotecan administration in the submandibular glands of the rabbits.

RadioImmunotherapy for adenoid cystic carcinoma: a single-institution series of combined treatment with cetuximab

PubMed Central

2010-01-01

Background Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent. However, some clinical situations do not allow application of tumouricidal doses (i.e. re-irradiation) hence radiation sensitization by exploitation of high endothelial growth factor receptor (EGFR)-expression in ACC seems beneficial. This is a single-institution experience of combined radioimmunotherapy (RIT) with the EGFR-inhibitor cetuximab. Methods Between 2006 and 2010, 9 pts received RIT for advanced/recurrent ACC, 5/9 pts as re-irradiation. Baseline characteristics as well as treatment parameters were retrieved to evaluate efficacy and toxicity of the combination regimen were evaluated. Control rates (local/distant) and overall survival were calculated using Kaplan-Meier estimation. Results Median dose was 65 Gy, pts received a median of 6 cycles cetuximab. RIT was tolerated well with only one °III mucositis/dysphagia. Overall response/remission rates were high (77,8%); 2-year estimate of local control was 80% hence reaching local control levels comparable to high-dose RT. Progression-free survival (PFS) at 2 years and median overall survival were only 62,5% and 22,2 mo respectively. Conclusion While local control and treatment response in RIT seems promising, PFS and overall survival are still hampered by distant failure. The potential benefit of RIT with cetuximab warrants exploration in a prospective controlled clinical trial. PMID:21047402

Delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen: a case report.

PubMed

Sokolova, Alexandra; Chan, Onyee; Ullah, Waqas; Hamdani, Auon Abbas; Anwer, Faiz

2017-04-11

High-dose chemotherapy with autologous stem cell rescue is commonly used for the treatment of relapsed germ cell tumors. We report the first case of delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen. We report a case of a 21-year-old African-American man diagnosed with relapsed non-seminomatous germ cell tumor who received high-dose chemotherapy with carboplatin and etoposide following TIGER trial arm B off-protocol. His course was complicated by muscle pain and rhabdomyolysis after cycle 4 on day +12 after infusion of autologous stem cells. To the best of our knowledge, this complication has not been reported with this regimen. A differential diagnosis of sepsis and neutropenic fever along with side effects of high-dose chemotherapy were considered, but based on the timing of events, it was concluded that the etiology of rhabdomyolysis is high-dose chemotherapy. Rhabdomyolysis was successfully treated with hydration and did not recur during subsequent cycle 5. Delayed rhabdomyolysis after high-dose chemotherapy with paclitaxel, ifosfamide, carboplatin, and etoposide regimen has not been previously reported and needs to be considered for preventive strategy and prompt diagnosis and treatment to avoid renal complications. Physicians should have a low threshold to check creatine kinase enzymes in patients with unexplained muscle pain or renal insufficiency after high-dose chemotherapy.

Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence.

PubMed

Milman, Garry; Bergamaschi, Mateus M; Lee, Dayong; Mendu, Damodara R; Barnes, Allan J; Vandrey, Ryan; Huestis, Marilyn A

2014-04-01

Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic, daily cannabis smokers who received high-dose oral THC pharmacotherapy and later a smoked cannabis challenge. Eleven daily cannabis smokers received 0, 30, 60, or 120 mg/d THC for four 5-day medication sessions, each separated by 9 days of ad libitum cannabis smoking. On the fifth day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the first and fifth days was quantified by two-dimensional gas chromatography mass spectrometer for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5-100 for THC, 1-50 for 11-OH-THC, and 0.5-200 for THCCOOH. During placebo dosing, THC, 11-OH-THC, and THCCOOH concentrations consistently decreased, whereas all cannabinoids increased dose dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during the 60- and 120-mg/d doses, and THCCOOH increased significantly only during the 120-mg/d dose. THC, 11-OH-THC, and THCCOOH concentrations peaked within 0.25 hours after cannabis smoking, except after 120 mg/d THC when THCCOOH peaked 0.5 hours before smoking. The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 hour, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 hours after overnight oral dronabinol abstinence but cannot distinguish oral THC dosing from the smoked cannabis intake.

Plasma Cannabinoid Concentrations during Dronabinol Pharmacotherapy for Cannabis Dependence

PubMed Central

Milman, Garry; Bergamaschi, Mateus M.; Lee, Dayong; Mendu, Damodara R.; Barnes, Allan J.; Vandrey, Ryan; Huestis, Marilyn A.

2013-01-01

Background Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic daily cannabis smokers who received high-dose oral THC pharmacotherapy and later, a smoked cannabis challenge. Methods 11 daily cannabis smokers received 0, 30, 60, or 120 mg/day THC for four 5-day medication sessions, each separated by 9-days of ad-libitum cannabis smoking. On the 5th day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the 1st and 5th days was quantified by GC-GC-MS for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5–100 for THC, 1–50 11-OH-THC, and 0.5–200 THCCOOH. Results During placebo dosing, THC, 11-OH-THC and THCCOOH concentrations consistently decreased, while all cannabinoids increased dose-dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during 60 and 120 mg/day doses, and THCCOOH increased significantly only during the 120 mg/day dose. THC and 11-OH-THC, and THCCOOH concentrations peaked within 0.25 h after cannabis smoking, except after 120 mg/day THC when THCCOOH peaked 0.5 h before smoking. Conclusions The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 h, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 h after overnight oral dronabinol abstinence, but cannot distinguish oral THC dosing from smoked cannabis intake. PMID:24067260

[Analysis of the cumulative solar ultraviolet radiation in Mexico].

PubMed

Castanedo-Cázares, Juan Pablo; Torres-Álvarez, Bertha; Portales-González, Bárbara; Martínez-Rosales, Karla; Hernández-Blanco, Diana

2016-01-01

The incidence of skin cancer has increased in Mexico in recent years. Ultraviolet radiation is the main risk factor associated. Due to the need to develop strategies to prevent skin cancer, the aim of the study was to estimate the UV intensity in several representative regions of Mexico, the average annual UV dose of these populations, and the potential benefit of applying sunscreen at different ages. The intensity of UV radiation was quantified by remote and terrestrial radiometry. The dose of UV exposure was measured in minimal erythema doses using validated models for face and arms. The benefit of using a sunscreen was calculated with the use of a sunscreen with SPF 15 from birth to age 70. The UV radiation is lower in December and greater in the period from May to July. The region with a lower annual dose is Tijuana; and the higher annual dose is in the Mexico City area. The annual difference between these regions was 58 %. Through life, a low SPF sunscreen can reduce up to 66 % of the received UV dose. The geographical location is a risk factor for accumulation of UV radiation in Mexico. Since childhood, people receive high amounts of it; however, most of this dose can be reduced using any commercially available sunscreen, if applied strategically.

[Comparative study on the tolerance and efficacy of high doses of metoclopramide and clebopride in vomiting induced by cisplatin].

PubMed

Martín, M; Díaz-Rubio, E

1989-06-10

Forty-one patients treated with cisplatin (100-120 mg/m2), alone or associated with vindesine (3 mg/m2), were included in a randomized crossover pilot study which compared 3 different doses of intravenous clebopride with intravenous metoclopramide. The patients were randomly assigned to receive clebopride in the first chemotherapy course in one of the three dose levels used (0.5 mg/kg, 21 patients; 0.75 mg/kg, 11 patients; 1 mg/kg, 10 patients) or metoclopramide (10 mg/kg). In the second course of the same chemotherapy the patients received the alternative antiemetic, and thus each patient was his own control. The total dose of both antiemetic drugs was infused in 5 intravenous fractions given every 2 hours. The antiemetic activity of clebopride was moderately lower to that of metoclopramide with the first two tested doses (overall doses of 0.5 and 0.75 mg/kg) and similar with the last dose (1 mg/kg). Clebopride was reasonably well tolerated at the used dosages, inducing sedation in 20% of cases (versus 24% with metoclopramide) and diarrhea in 37% (versus 20% with metoclopramide). Extrapyramidal reactions developed in 17% of the courses which included metoclopramide and in none including clebopride. This difference was statistically significant.

Doxycycline shows dose-dependent changes in hernia repair strength after mesh repair.

PubMed

Tharappel, Job C; Harris, Jennifer W; Zwischenberger, Brittany A; Levy, Salomon M; Puleo, David A; Roth, J Scott

2016-05-01

Ventral hernia is a commonly occurring surgical problem. Our earlier studies have shown that a 30 mg/kg dose of doxycycline can significantly impact the strength of polypropylene (PP) mesh in a rat hernia repair model at 6 and 12 weeks. The objective of the present study was to investigate the dose dependence of doxycycline treatment on hernia repair strengths in rats. Fifty-six Sprague-Dawley rats underwent hernia repair with either PP mesh (n = 28) or sutures only (primary; n = 28); both groups were further divided into four doxycycline groups of seven animals each: control (0 mg/kg), low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg). One day before hernia repair surgery, animals received doxycycline doses by gavage and continued receiving daily until euthanasia. After 8 weeks, rats were euthanized and tissue samples from hernia repaired area were collected and analyzed for tensile strength using a tensiometer (Instron, Canton, MA, USA), while MMPs 2, 3, and 9, and collagen type 1 and 3 were analyzed by western blotting. In mesh-repaired animals, medium and high doxycycline dose repaired mesh fascia interface (MFI) showed significant increase in tensile strength when compared to control. In the primary repaired animals, there was no significant difference in MFI tensile strength in any dose group. In medium-dose MFI, there was a significant reduction in MMPs 2, 3, and 9. In this animal group, MFI showed significant increase in collagen 1 and significant reduction in collagen type 3 when compared to control. It is possible to improve the strength of mesh-repaired tissue by administering a significantly lower dose of the drug, which has implications for translation of the findings.

Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3.

PubMed

Harris, Ruth B S; Desai, Bhavna N

2016-12-01

Previous studies have shown that very low-dose infusions of leptin into the third or the fourth ventricle alone have little effect on energy balance, but simultaneous low-dose infusions cause rapid weight loss and increased phosphorylation of STAT3 (p-STAT3) in hypothalamic sites that express leptin receptors. Other studies show that injecting high doses of leptin into the fourth ventricle inhibits food intake and weight gain. Therefore, we tested whether fourth-ventricle leptin infusions that cause weight loss are associated with increased leptin signaling in the hypothalamus. In a dose response study 14-day infusions of increasing doses of leptin showed significant hypophagia, weight loss, and increased hypothalamic p-STAT3 in rats receiving at least 0.9 μg leptin/day. In a second study 0.6 μg leptin/day transiently inhibited food intake and reduced carcass fat, but had no significant effect on energy expenditure. In a final study, we identified the localization of STAT3 activation in the hypothalamus of rats receiving 0, 0.3, or 1.2 μg leptin/day. The high dose of leptin, which caused weight loss in the first experiment, increased p-STAT3 in the ventromedial, dorsomedial, and arcuate nuclei of the hypothalamus. The low dose that increased brown fat UCP1 but did not affect body composition in the first experiment had little effect on hypothalamic p-STAT3. We propose that hindbrain leptin increases the precision of control of energy balance by lowering the threshold for leptin signaling in the forebrain. Further studies are needed to directly test this hypothesis. Copyright © 2016 the American Physiological Society.

High-dose and extended-field intensity modulated radiation therapy for early-stage NK/T-cell lymphoma of Waldeyer's ring: dosimetric analysis and clinical outcome.

PubMed

Bi, Xi-Wen; Li, Ye-Xiong; Fang, Hui; Jin, Jing; Wang, Wei-Hu; Wang, Shu-Lian; Liu, Yue-Ping; Song, Yong-Wen; Ren, Hua; Dai, Jian-Rong

2013-12-01

To assess the dosimetric benefit, treatment outcome, and toxicity of high-dose and extended-field intensity modulated radiation therapy (IMRT) in patients with early-stage NK/T-cell lymphoma of Waldeyer's ring (WR-NKTCL). Thirty patients with early-stage WR-NKTCL who received extended-field IMRT were retrospectively reviewed. The prescribed dose was 50 Gy to the primary involved regions and positive cervical lymph nodes (planning target volume requiring radical irradiation [PTV50]) and 40 Gy to the negative cervical nodes (PTV40). Dosimetric parameters for the target volume and critical normal structures were evaluated. Locoregional control (LRC), overall survival (OS), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The median mean doses to the PTV50 and PTV40 were 53.2 Gy and 43.0 Gy, respectively. Only 1.4% of the PTV50 and 0.9% of the PTV40 received less than 95% of the prescribed dose, indicating excellent target coverage. The average mean doses to the left and right parotid glands were 27.7 and 28.4 Gy, respectively. The 2-year OS, PFS, and LRC rates were 71.2%, 57.4%, and 87.8%. Most acute toxicities were grade 1 to 2, except for grade ≥3 dysphagia and mucositis. The most common late toxicity was grade 1-2 xerostomia, and no patient developed any ≥grade 3 late toxicities. A correlation between the mean dose to the parotid glands and the degree of late xerostomia was observed. IMRT achieves excellent target coverage and dose conformity, as well as favorable survival and locoregional control rates with acceptable toxicities in patients with WR-NKTCL. Copyright © 2013 Elsevier Inc. All rights reserved.

What is the optimal radiation dose for non-operable esophageal cancer? Dissecting the evidence in a meta-analysis.

PubMed

Chen, Yong; Zhu, Hui-Ping; Wang, Tao; Sun, Chang-Jiang; Ge, Xiao-Lin; Min, Ling-Feng; Zhang, Xian-Wen; Jia, Qing-Qing; Yu, Jie; Yang, Jian-Qi; Allgayer, Heike; Abba, Mohammed L; Zhang, Xi-Zhi; Sun, Xin-Chen

2017-10-24

The standard radiation dose 50.4 Gy with concurrent chemotherapy for localized inoperable esophageal cancer as supported by INT-0123 trail is now being challenged since a radiation dose above 50 Gy has been successfully administered with an observable dose-response relationship and insignificant untoward effects. Therefore, to ascertain the treatment benefits of different radiation doses, we performed a meta-analysis with 18 relative publications. According to our findings, a dose between 50 and 70 Gy appears optimal and patients who received ≥ 60 Gy radiation had a significantly better prognosis (pooled HR = 0.78, P = 0.004) as compared with < 60 Gy, especially in Asian countries (pooled HR = 0.75, P = 0.003). However, contradictory results of treatment benefit for ≥ 60 Gy were observed in two studies from Western countries, and the pooled treatment benefit of ≥ 60 Gy radiation was inconclusive (pooled HR = 0.86, P = 0.64). There was a marginal benefit in locoregional control in those treated with high dose (> 50.4/51 Gy) radiation when compared with those treated with low dose (≤ 50.4/51 Gy) radiation (pooled OR = 0.71, P = 0.06). Patients that received ≥ 60 Gy radiation had better locoregional control (OR = 0.29, P = 0.001), and for distant metastasis control, neither the > 50.4 Gy nor the ≥ 60 Gy treated group had any treatment benefit as compared to the groups that received ≤ 50.4 Gy and < 60 Gy group respectively. Taken together, a dose range of 50 to 70 Gy radiation with CCRT is recommended for non-operable EC patients. A dose of ≥ 60 Gy appears to be better in improving overall survival and locoregional control, especially in Asian countries, while the benefit of ≥ 60 Gy radiation in Western countries still remains controversial.

Evaluation of Emergency Department Management of Opioid-Tolerant Cancer Patients With Acute Pain.

PubMed

Patel, Pina M; Goodman, Lauren F; Knepel, Sheri A; Miller, Charles C; Azimi, Asma; Phillips, Gary; Gustin, Jillian L; Hartman, Amber

2017-10-01

There are no previously published studies examining opioid doses administered to opioid-tolerant cancer patients during emergency department (ED) encounters. To determine if opioid-tolerant cancer patients presenting with acute pain exacerbations receive adequate initial doses of as needed (PRN) opioids during ED encounters based on home oral morphine equivalent (OME) use. We performed a retrospective cohort study of opioid-tolerant cancer patients who received opioids in our ED over a two-year period. The percentage of patients who received an adequate initial dose of PRN opioid (defined as ≥10% of total 24-hour ambulatory OME) was evaluated. Logistic regression was used to establish the relationship between 24-hour ambulatory OME and initial ED OME to assess whether higher home usage was associated with higher likelihood of being undertreated. Out of 216 patients, 61.1% of patients received an adequate initial PRN dose of opioids in the ED. Of patients taking <200 OMEs per day at home, 77.4% received an adequate initial dose; however, only 3.2% of patients taking >400 OMEs per day at home received an adequate dose. Patients with ambulatory 24-hour OME greater than 400 had 99% lower odds of receiving an adequate initial dose of PRN opioid in the ED compared to patients with ambulatory 24-hour OME less than 100 (OR <0.01, CI 0.00-0.02, P < 0.001). Patients with daily home use less than 200 OMEs generally received adequate initial PRN opioid doses during their ED visit. However, patients with higher home opioid usage were at increased likelihood of being undertreated. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Long-term recurrence-free survival after an unplanned reduction in radiotherapy for HPV-positive oropharyngeal SCC: Two cases and a review of the literature.

PubMed

Liu, Jason; Goldenberg, David; Almokadem, Salah; Crist, Henry; Mackley, Heath B

2017-07-01

There is currently no clear distinction between the treatment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC). HPV-positive OPSCC has been demonstrated to be more radiosensitive than its HPV-negative counterpart. Despite this, patients with HPV-positive OPSCC continue to receive a full dose of radiation (70 Gy) outside clinical trials. However, this high dose comes with considerable morbidities, including severe mucositis, dysphagia, and xerostomia. We describe the cases of 2 patients with HPV-positive OPSCC who received two cycles of high-dose cisplatin at 100 mg/m 2 on 3 separate days, along with concurrent radiotherapy at 50 Gy in 25 fractions for one and 46 Gy in 23 fractions for the other. During treatment, both patients experienced significant acute-phase toxicities-including grade 3 mucositis, grade 3 nausea, and grade 2 dermatitis-and their treatment regimen was stopped before its planned completion. Nevertheless, after a follow-up of 75 and 78 months, respectively, neither patient exhibited any evidence of disease. Late toxicities included grade 1 xerostomia, grade 1 pharyngeal-phase dysphagia, and grade 1 dysgeusia with some foods. We conclude that de-escalating the dose of radiation for HPV-positive patients by 30% and identifying which patients can safely be treated with this level of dose reduction warrants further study.

Patients with Acute Coronary Syndrome are at High Risk Prior to the Event and Lipid Management is Underachieved Pre- and Post- Hospitalization.

PubMed

Vlachopoulos, C; Andrikopoulos, G; Terentes-Printzios, D; Tzeis, S; Iliodromitis, E K; Richter, D; Mantas, I; Kartalis, A; Vasilikos, V; Stakos, D; Patsilinakos, S; Lampropoulos, S; Symeonidis, D; Kyrpizidis, C; Marinakis, N; Nikas, N; Lekakis, J; Tousoulis, D; Vardas, P

2018-01-01

Current European Guidelines suggest the use of cardiovascular risk categories and also recommend using high-intensity statins for patients with acute coronary syndromes (ACS). We examined the risk of ACS patients prior to the event, as well as the overall use and intensity of statins. We enrolled 687 ACS patients (mean age 63 years, 78% males). Low-density lipoprotein cholesterol (LDL-C) levels upon admission were used to assess attainment of LDL-C targets. Patients were categorized as very high, high, moderate and low risk based on their prior to admission cardiovascular (CV) risk. We examined statin use and dosage intensity among patients discharged from the hospital. Patients were followed for a median period of 189 days. The majority of the patients (n=371, 54%) were at very high CV risk prior to admission, while 101 patients were at high risk (15%), 147 (21%) moderate risk and 68 (10%) low risk. Interestingly, LDL-C target attainment decreased as the risk increased (p<0.001). The majority (96%) of patients received statins at discharge; however, most of them (60.4%) received low/moderate intensity statins and just 35.9% received the suggested by the Guidelines high-intensity dose of statins. At follow-up, the rate of patients at high-intensity dose of statins remained similar (34.8%); 6% received no statins at all at follow-up. According to our study, the majority of ACS patients are already at high risk prior to their admission. Further, LDL-C targets are underachieved prior to the event and high-intensity statins are underutilized in ACS patients at, and post-discharge. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Phase I/II trial of single-fraction high-dose-rate brachytherapy-boosted hypofractionated intensity-modulated radiation therapy for localized adenocarcinoma of the prostate.

PubMed

Myers, Michael A; Hagan, Michael P; Todor, Dorin; Gilbert, Lynn; Mukhopadhyay, Nitai; Randolf, Jessica; Heimiller, Jeffrey; Anscher, Mitchell S

2012-01-01

A Phase I/II protocol was conducted to examine the toxicity and efficacy of the combination of intensity-modulated radiation therapy (IMRT) with a single-fraction high-dose-rate (HDR) brachytherapy implant. From 2001 through 2006, 26 consecutive patients were treated on the trial. The primary objective was to demonstrate a high rate of completion without experiencing a treatment-limiting toxicity. Eligibility was limited to patients with T stage ≤2b, prostate-specific antigen (PSA) ≤20, and Gleason score ≤7. Treatment began with a single HDR fraction of 6Gy to the entire prostate and 9Gy to the peripheral zone, followed by IMRT optimized to deliver in 28 fractions with a normalized total dose of 70Gy. Patients received 50.4Gy to the pelvic lymph node. The prostate dose (IMRT and HDR) resulted in an average biologic equivalent dose >128Gy (α/β=3). Patients whose pretreatment PSA was ≥10ng/mL, Gleason score 7, or stage ≥T2b received short-term androgen ablation. Median followup was 53 months (9-68 months). There were no biochemical failures by either the American Society of Therapeutic Radiology and Oncology or the Phoenix definitions. The median nadir PSA was 0.32ng/mL. All the 26 patients completed the treatment as prescribed. The rate of Grade 3 late genitourinary toxicity was 3.8% consisting of a urethral stricture. There was no other Grade 3 or 4 genitourinary or gastrointestinal toxicities. Single-fraction HDR-boosted IMRT is a safe effective method of dose escalation for localized prostate cancer. Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Free fatty acid suppositories are as effective as docusate sodium and sorbitol enemas in treating constipation in children.

PubMed

Ormarsson, Orri Thor; Asgrimsdottir, Gudrun Marta; Loftsson, Thorsteinn; Stefansson, Einar; Lund, Sigrun Helga; Bjornsson, Einar Stefan

2016-06-01

A well-documented, clinically proven per rectum treatment for childhood constipation is needed. This phase two clinical trial evaluated the efficacy of suppositories containing free fatty acids (FFA) compared with Klyx docusate sodium and sorbitol enemas. A randomised, controlled, single-blind study was undertaken on 77 children aged between one and 17 who presented to an emergency department in Iceland and were diagnosed with constipation. In stage one, 23 patients were randomised to receive lower dose FFA suppositories or Klyx (n = 33). In stage two, 21 different patients were randomised to receive higher dose suppositories and compared with the same Klyx control subjects. The suppositories were effective at bowel emptying in 39% of the group who received the lower FFA doses and 81% of the group receiving higher doses, compared with 88% in the Klyx control group. Symptom relief was obtained in 30% of the group receiving the lower doses and 71% of the group receiving the higher doses, compared with 73% in the control group. The higher dose FFA suppositories were as effective as the Klyx enemas with regard to bowel emptying and symptom relief and might provide an important and less invasive alternative for childhood constipation. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

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.

In-flight measured and predicted ambient dose equivalent and latitude differences on effective dose estimates.

PubMed

Saez Vergara, J C; Romero Gutiérrez, A M; Rodriguez Jiménez, R; Dominguez-Mompell Román, R

2004-01-01

The results from 2 years (2001-2002) of experimental measurements of in-board radiation doses received at IBERIA commercial flights are presented. The routes studied cover the most significant destinations and provide a good estimate of the route doses as required by the new Spanish regulations on air crew radiation protection. Details on the experimental procedures and calibration methods are given. The experimental measurements from the different instruments (Tissue Equivalent Proportional Counter and the combination of a high pressure ion chamber and a high-energy neutron compensated rem-counter) and their comparison with the predictions from some route-dose codes (CARI-6, EPCARD 3.2) are discussed. In contrast with the already published data, which are mainly focused on North latitudes over parallel 50, many of the data presented in this work have been obtained for routes from Spain to Central and South America.

10 CFR 20.1301 - Dose limits for individual members of the public.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Section 20.1301 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation..., exclusive of the dose contributions from background radiation, from any medical administration the....75, to receive a radiation dose greater than 0.1 rem (1 mSv) if— (1) The radiation dose received does...

10 CFR 20.1301 - Dose limits for individual members of the public.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Section 20.1301 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation..., exclusive of the dose contributions from background radiation, from any medical administration the....75, to receive a radiation dose greater than 0.1 rem (1 mSv) if— (1) The radiation dose received does...

10 CFR 20.1301 - Dose limits for individual members of the public.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Section 20.1301 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation..., exclusive of the dose contributions from background radiation, from any medical administration the....75, to receive a radiation dose greater than 0.1 rem (1 mSv) if— (1) The radiation dose received does...

10 CFR 20.1301 - Dose limits for individual members of the public.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Section 20.1301 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation..., exclusive of the dose contributions from background radiation, from any medical administration the....75, to receive a radiation dose greater than 0.1 rem (1 mSv) if— (1) The radiation dose received does...

10 CFR 20.1301 - Dose limits for individual members of the public.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Section 20.1301 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation..., exclusive of the dose contributions from background radiation, from any medical administration the....75, to receive a radiation dose greater than 0.1 rem (1 mSv) if— (1) The radiation dose received does...

Effective and safe mannitol administration in patients undergoing supratentorial tumor surgery: A prospective, randomized and double blind study.

PubMed

Akcil, Eren Fatma; Dilmen, Ozlem Korkmaz; Karabulut, Esra Sultan; Koksal, Serdar Selcuk; Altindas, Fatis; Tunali, Yusuf

2017-08-01

Although osmotic diuresis with mannitol is commonly used to provide brain relaxation, there is no consensus regarding its optimal dose and combination with loop diuretics. The aim of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity in patients undergoing supratentorial tumor surgery. This prospective, randomized, double blind, placebo-controlled study included 51 patients (ASA I-III) scheduled for elective supratentorial craniotomy. Different doses and combinations of diuretics were administered after the bone flap removal. The Group 1 received mannitol at 0.5gkg -1 and furosemide at 0.5mgkg -1 , the Group 2 received mannitol at 1gkg -1 and furosemide at 0.5mgkg -1 , and the Group 3 received mannitol at 0.5gkg -1 and placebo. The primary end-point of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and the secondary end-points are to evaluate their effects on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity. This study shows that mannitol alone (0.5gkg -1 ), and the combinations of furosemide (0.5mgkg -1 ) with different doses of mannitol (0.5gkg -1 -1gkg -1 ) provides adequate brain relaxation. However, administration of furosemide with low or high doses of mannitol may cause reduction in the sodium and chloride levels as well as rise in the lactate level. Moreover it may cause high urine output and negative intra-operative fluid balance. Administration of 0.5gkg -1 mannitol provides adequate brain relaxation without causing systemic side effects in patients undergoing supratentorial tumor surgery. This study is registered to clinical trials (Clinical Trials.gov identifier NCT02712476). Copyright © 2017 Elsevier B.V. All rights reserved.

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease.

PubMed

Sands, B E; Bank, S; Sninsky, C A; Robinson, M; Katz, S; Singleton, J W; Miner, P B; Safdi, M A; Galandiuk, S; Hanauer, S B; Varilek, G W; Buchman, A L; Rodgers, V D; Salzberg, B; Cai, B; Loewy, J; DeBruin, M F; Rogge, H; Shapiro, M; Schwertschlag, U S

1999-07-01

Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohn's disease and to explore the effects of dose and schedule on platelet count and Crohn's disease activity. A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohn's disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. Short-term treatment with rhIL-11 is well tolerated in patients with active Crohn's disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohn's disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Effects of oral electrolyte supplementation on endurance horses competing in 80 km rides.

PubMed

Sampieri, F; Schott, H C; Hinchcliff, K W; Geor, R J; Jose-Cunilleras, E

2006-08-01

There is no evidence that use of oral electrolyte pastes enhances performance in competing endurance horses. To ascertain whether oral administration of a high dose (HD) of sodium chloride (NaCl) and potassium chloride (KCl) to endurance horses would differentially increase water intake, attenuate bodyweight (bwt) loss and improve performance when compared to a low dose (LD). A randomised, blinded, crossover study was conducted on 8 horses participating in two 80 km rides (same course, 28 days apart). Thirty minutes before and at 40 km of the first ride 4, horses received orally 02 g NaCl/kg bwt and 0.07 g KCl/kg bwt. The other 4 received 0.07 g NaCl/kg bwt and 0.02 g KCl/kg bwt. Horses received the alternate treatment in the second ride. Data were analysed with 2-way ANOVA for repeated measures (P<0.05). Estimated water intake was significantly greater with HD both at the 40 km mark and as total water intake; however, differences in bwt loss and speed between HD and LD were not found. Treatment significantly affected serum Na+, Cl-, HCO3, pH and water intake, but not serum K+ or bwt. Serum Na+ and Cl- were significantly higher at 80 km when horses received HD, but no differences were found in early recovery. Venous HCO3- and pH were significantly lower throughout the ride and in early recovery when horses received HD. Other than enhancing water intake, supplementing endurance horses with high doses of NaCI and KCl did not provide any detectable competitive advantage in 80 km rides. Further, the elevated serum electrolyte concentrations induced with HD might not be appropriate for endurance horses.

Reproductive toxicity assessment of chronic dietary exposure to soy isoflavones in male rats.

PubMed

Faqi, Ali S; Johnson, William D; Morrissey, Robert L; McCormick, David L

2004-06-01

Epidemiologic and experimental data suggest that consumption of diets that are rich in isoflavones may decrease cancer risk in the breast, prostate, and other tissues. Isoflavones such as genistein and daidzein are structurally similar to endogenous estrogens, and demonstrate both estrogenic and weak anti-estrogenic activities; these activities may underlie the impaired fertility and reproductive tract disorders reported in animals exposed to high doses of isoflavones. To identify possible effects of isoflavones on male fertility, we evaluated reproductive parameters in Wistar-Unilever rats receiving dietary exposure to PTI G-2535, a characterized mixture of soy-derived isoflavones containing 45% genistein, 23% daidzein, and 4% glycitein. Beginning at 10 weeks of age, rats received chronic dietary exposure to the soy isoflavone mixture (200 or 2000 mg/kg diet) for a minimum of 12 months. Controls received unsupplemented chow diet only for the same period. Dietary exposure to isoflavones induced no gross toxicity or alterations in body weight gain. Absolute and relative weights of the testis and epididymis in groups receiving high or low doses of isoflavones were comparable to those of controls, and histopathologic evaluations demonstrated that testicular morphology was similar in all study groups. Isoflavone exposure had no significant effects on spermatid count, sperm production, or sperm morphology in any group. These data suggest that the reproductive system of adult male rats is relatively insensitive to isoflavone toxicity at dose levels that demonstrate significant activity in cancer chemoprevention, and that male reproductive function is unlikely to be affected by long-term administration of isoflavones for cancer prevention or other purposes. The results of this study conducted in adult male rats differ from the significant alterations in reproductive parameters that have been reported in female rats receiving prenatal or juvenile exposure to isoflavones.

High-doses of proton pump inhibitors in refractory gastro-intestinal cancer: A case series and the state of art.

PubMed

Falcone, Rosa; Roberto, Michela; D'Antonio, Chiara; Romiti, Adriana; Milano, Annalisa; Onesti, Concetta Elisa; Marchetti, Paolo; Fais, Stefano

2016-12-01

In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumour microenvironment acidification thus restoring chemotherapeutic sensitivity. Moreover, several clinical data supports the role of cytotoxic drugs at low-dose continuously delivered as anticancer therapy. Clinical records of three patients affected with gastrointestinal cancer refractory to standard treatments, who had received a combination of high-dose rabeprazole and metronomic chemotherapy were reviewed. The first case, a 78-year-old man was treated for lung metastasis from colon adenocarcinoma. The second case, a 73-year-old man was treated for metastatic rectal cancer to the liver. The third one, a 68-year-old man, underwent the combination regimen for colon cancer with lung, liver and peritoneal metastases. Despite the failure of previous standard chemotherapy for metastatic disease, good clinical outcome was shown in these patients treated with an unconventional association of high-dose PPIs and metronomic chemotherapy. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial.

PubMed

Dobson, Simon R M; McNeil, Shelly; Dionne, Marc; Dawar, Meena; Ogilvie, Gina; Krajden, Mel; Sauvageau, Chantal; Scheifele, David W; Kollmann, Tobias R; Halperin, Scott A; Langley, Joanne M; Bettinger, Julie A; Singer, Joel; Money, Deborah; Miller, Dianne; Naus, Monika; Marra, Fawziah; Young, Eric

2013-05-01

Global use of human papillomavirus (HPV) vaccines to prevent cervical cancer is impeded by cost. A 2-dose schedule for girls may be possible. To determine whether mean antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses was noninferior to women receiving 3 doses. Randomized, phase 3, postlicensure, multicenter, age-stratified, noninferiority immunogenicity study of 830 Canadian females from August 2007 through February 2011. Follow-up blood samples were provided by 675 participants (81%). Girls (9-13 years) were randomized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0, 2, and 6 months (n = 261) or 2 doses at 0 and 6 months (n = 259). Young women (16-26 years) received 3 doses at 0, 2, and 6 months (n = 310). Antibody levels were measured at 0, 7, 18, 24, and 36 months. Primary outcome was noninferiority (95% CI, lower bound >0.5) of geometric mean titer (GMT) ratios for HPV-16 and HPV-18 for girls (2 doses) compared with young women (3 doses) 1 month after last dose. Secondary outcomes were noninferiority of GMT ratios of girls receiving 2 vs 3 doses of vaccine; and durability of noninferiority to 36 months. The GMT ratios were noninferior for girls (2 doses) to women (3 doses): 2.07 (95% CI, 1.62-2.65) for HPV-16 and 1.76 (95% CI, 1.41-2.19) for HPV-18. Girls (3 doses) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL (mMU/mL) (95% CI, 6651-8999) and HPV-18 of 1730 mMU/mL (95% CI, 1512-1980). The GMT ratios were noninferior for girls (2 doses) to girls (3 doses): 0.95 (95% CI, 0.73-1.23) for HPV-16 and 0.68 (95% CI, 0.54-0.85) for HPV-18. The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36. Among girls who received 2 doses of HPV vaccine 6 months apart, responses to HPV-16 and HPV-18 one month after the last dose were noninferior to those among young women who received 3 doses of the vaccine within 6 months. Because of the loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses, more data on the duration of protection are needed before reduced-dose schedules can be recommended. clinicaltrials.gov Identifier: NCT00501137.

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling.

PubMed

Mori, Takehiko; Koh, Hideo; Onishi, Yasushi; Kako, Shinichi; Onizuka, Makoto; Kanamori, Heiwa; Ozawa, Yukiyasu; Kato, Chiaki; Iida, Hiroatsu; Suzuki, Ritsuro; Ichinohe, Tatsuo; Kanda, Yoshinobu; Maeda, Tetsuo; Nakao, Shinji; Yamazaki, Hirohito

2016-04-01

The standard conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia from a human leukocyte antigen (HLA)-identical sibling has been high-dose cyclophosphamide (CY 200 mg/kg). In the present study, results for 203 patients with aplastic anemia aged 16 years or older who underwent allogeneic HSCT from HLA-identical siblings were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. Conditioning regimens were defined as a (1) high-dose CY (200 mg/kg or greater)-based (n = 117); (2) reduced-dose CY (100 mg/kg or greater, but less than 200 mg/kg)-based (n = 38); and (3) low-dose CY (less than 100 mg/kg)-based (n = 48) regimen. Patient age and the proportion of patients receiving fludarabine were significantly higher in the reduced- and low-dose CY groups than the high-dose CY group. Engraftment was comparable among the groups. Five-year overall survival (OS) tended to be higher in the low-dose CY group [93.0 % (95 % CI 85.1-100.0 %)] than the high-dose CY [84.2 % (95 % CI 77.1-91.3 %)] or reduced-dose CY groups [83.8 % (95 % CI 71.8-95.8 %); P = 0.214]. Age-adjusted OS was higher in the low-dose CY group than the high- and reduced-dose CY groups with borderline significance (P = 0.067). These results suggest that CY dose can safely be reduced without increasing graft rejection by adding fludarabine in allogeneic HSCT for aplastic anemia from an HLA-identical sibling.

Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial.

PubMed

Zhu, Feng-Cai; Hou, Li-Hua; Li, Jing-Xin; Wu, Shi-Po; Liu, Pei; Zhang, Gui-Rong; Hu, Yue-Mei; Meng, Fan-Yue; Xu, Jun-Jie; Tang, Rong; Zhang, Jin-Long; Wang, Wen-Juan; Duan, Lei; Chu, Kai; Liang, Qi; Hu, Jia-Lei; Luo, Li; Zhu, Tao; Wang, Jun-Zhi; Chen, Wei

2015-06-06

Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18-60 years) were sequentially enrolled and randomly assigned (2:1), by computer-generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T-cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT02326194. Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high-dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0·0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (p<0·0001). We recorded no statistical differences in other adverse reactions and laboratory tests across groups. Glycoprotein-specific antibody titres were significantly increased in participants in the low-dose and high-dose vaccine groups at both day 14 (geometric mean titre 421·4 [95% CI 249·7-711·3] and 820·5 [598·9-1124·0], respectively; p<0·0001) and day 28 (682·7 [424·3-1098·5] and 1305·7 [970·1-1757·2], respectively; p<0·0001). T-cell responses peaked at day 14 at a median of 465·0 spot-forming cells (IQR 180·0-1202·5) in participants in the low-dose group and 765·0 cells (400·0-1460·0) in those in the high-dose group. 21 (18%) participants had mild fever (n=9 in the placebo group, n=6 in the low-dose group, and n=6 in the high-dose group). No serious adverse events were recorded. Our findings show that the high-dose vaccine is safe and robustly immunogenic. One shot of the high-dose vaccine could mount glycoprotein-specific humoral and T-cell response against Ebola virus in 14 days. China National Science and Technology, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Recovery from severe dysphagia in systemic sclerosis - myositis overlap: a case report.

PubMed

Chinniah, Keith J; Mody, Girish M

2017-06-01

Dysphagia is common in inflammatory myopathies and usually responds to corticosteroids. Severe dysphagia requiring feeding by percutaneous endoscopic gastrostomy is associated with significant morbidity and high mortality. A 56-year old African Black woman initially presented with systemic sclerosis (SSC) - myositis overlap and interstitial lung disease. She responded to high dose corticosteroids and cyclophosphamide followed by azathioprine, with improvement in her lung function and regression of the skin changes. Six years later she had a myositis flare with severe dysphagia. Her myositis improved after high doses of corticosteroids, azathioprine and two doses of intravenous immunoglobulin (IVIG). As her dysphagia persisted, she was fed via a percutaneous endoscopic gastrostomy (PEG) tube and given a course of rituximab. Her dysphagia gradually resolved and the PEG tube was removed within two months. She received another dose of rituximab six months later and continued low dose prednisone and azathioprine. Her muscle power improved, weight returned to normal and she remained well 20 months after hospital discharge. Our patient with SSC-myositis overlap and severe dysphagia requiring PEG feeding, improved with high dose corticosteroids, azathioprine, two courses of IVIG and rituximab, and remained in remission 20 months after hospital discharge.

Predicting astronaut radiation doses from major solar particle events using artificial intelligence

NASA Astrophysics Data System (ADS)

Tehrani, Nazila H.

1998-06-01

Space radiation is an important issue for manned space flight. For long missions outside of the Earth's magnetosphere, there are two major sources of exposure. Large Solar Particle Events (SPEs) consisting of numerous energetic protons and other heavy ions emitted by the Sun, and the Galactic Cosmic Rays (GCRs) that constitute an isotropic radiation field of low flux and high energy. In deep-space missions both SPEs and GCRs can be hazardous to the space crew. SPEs can provide an acute dose, which is a large dose over a short period of time. The acute doses from a large SPE that could be received by an astronaut with shielding as thick as a spacesuit maybe as large as 500 cGy. GCRs will not provide acute doses, but may increase the lifetime risk of cancer from prolonged exposures in a range of 40-50 cSv/yr. In this research, we are using artificial intelligence to model the dose-time profiles during a major solar particle event. Artificial neural networks are reliable approximators for nonlinear functions. In this study we design a dynamic network. This network has the ability to update its dose predictions as new input dose data is received while the event is occurring. To accomplish this temporal behavior of the system we use an innovative Sliding Time-Delay Neural Network (STDNN). By using a STDNN one can predict doses received from large SPEs while the event is happening. The parametric fits and actual calculated doses for the skin, eye and bone marrow are used. The parametric data set obtained by fitting the Weibull functional forms to the calculated dose points has been divided into two subsets. The STDNN has been trained using some of these parametric events. The other subset of parametric data and the actual doses are used for testing with the resulting weights and biases of the first set. This is done to show that the network can generalize. Results of this testing indicate that the STDNN is capable of predicting doses from events that it has not seen before.

Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial.

PubMed

Frye, R E; Slattery, J; Delhey, L; Furgerson, B; Strickland, T; Tippett, M; Sailey, A; Wynne, R; Rose, S; Melnyk, S; Jill James, S; Sequeira, J M; Quadros, E V

2018-02-01

We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4  months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg -1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.

Evaluation of clinical hypothyroidism risk due to irradiation of thyroid and pituitary glands in radiotherapy of nasopharyngeal cancer patients.

PubMed

Lin, Zhixiong; Wang, Xiaoyan; Xie, Wenjia; Yang, Zhining; Che, Kaijun; Wu, Vincent W C

2013-12-01

Radiation-induced thyroid dysfunction after radiotherapy for nasopharyngeal cancer (NPC) has been reported. This study investigated the radiation effects of the thyroid and pituitary glands on thyroid function after radiotherapy for NPC. Sixty-five NPC patients treated with radiotherapy were recruited. Baseline thyroid hormone levels comprising free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) were taken before treatment and at 3, 6, 12 and 18 months. A seven-beam intensity-modulated radiotherapy plan was generated for each patient. Thyroid and pituitary gland dose volume histograms were generated, dividing the patients into four groups: high (>50 Gy) thyroid and pituitary doses (HTHP group); high thyroid and low pituitary doses (HTLP group); low thyroid and high pituitary doses; and low thyroid and pituitary doses. Incidence of hypothyroidism was analysed. Twenty-two (34%) and 17 patients (26%) received high mean thyroid and pituitary doses, respectively. At 18 months, 23.1% of patients manifested various types of hypothyroidism. The HTHP group showed the highest incidence (83.3%) of hypothyroidism, followed by the HTLP group (50%). NPC patients with high thyroid and pituitary gland doses carried the highest risk of abnormal thyroid physiology. The dose to the thyroid was more influential than the pituitary dose at 18 months after radiotherapy, and therefore more attention should be given to the thyroid gland in radiotherapy planning. © 2013 The Royal Australian and New Zealand College of Radiologists.

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

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

Parenica, H; Ford, J; Mavroidis, P

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

Dosimetry during intramedullary nailing of the tibia.

PubMed

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

2009-10-01

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

Myeloablative therapy against high risk Ewing's sarcoma: A single institution experience and literature review

PubMed Central

Lopez, Jose Luis; Pérez, Concepcion; Marquez, Catalina; Cabrera, Patricia; Perez, Jose Maria; Ramirez, Gema Lucia; Ordoñez, Rafael; Praena-Fernandez, Juan Manuel; Ortiz, Maria Jose

2011-01-01

Background Attempts to improve survival outcomes of patients with high risk Ewing's sarcoma (ES) have focused on chemotherapy dose intensification strategies. Aim The objective of this study is to retrospectively evaluate clinical characteristics and outcome of pediatric patients with high risk ES treated at a single institution. Materials and methods From 1995 to 2008, seventeen patients (male:female, 14:3) were treated with dose-intensive therapy in our institution. Median age at diagnosis was 10 years (range: 2–15). Seven patients had metastases at diagnosis (lung in 6 cases and bone in one case). Eleven patients presented with unresectable disease. Fifteen (88.2%) received the Spanish Society of Pediatric Oncology protocol which includes six cycles of vincristine, doxorubicin, ifosfamide and etoposide. Two out of the six cases that were resectable received postoperative radiation. In addition, eleven patients received definitive radiation therapy. Finally, twelve (70.5%) out of 17 patients received myeloablative therapy with melphalan/etoposide. The rest of patients (N = 5) received busulfan/melphalan. Results Median follow-up was 78 months (range: 15–155 months). Initial responses were complete in all patients, but 9 of them developed progression disease. Seven patients became long-term event-free survivors. No patient died of toxicity after transplantation. The 2- and 5-year overall survival rates for all patients were 93% and 73%, respectively. Event-free survival rates were 74% and 54% at 2 and 5 years, respectively. Conclusion This single-institution experience suggests that myeloablative therapy against high risk ES is effective and safe. PMID:24376974

A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer.

PubMed

Flaig, Thomas W; Glodé, Michael; Gustafson, Daniel; van Bokhoven, Adrie; Tao, Yuzhen; Wilson, Shandra; Su, Lih-Jen; Li, Yuan; Harrison, Gail; Agarwal, Rajesh; Crawford, E David; Lucia, M Scott; Pollak, Michael

2010-06-01

Silibinin is a polyphenolic flavonolignan derived from milk thistle (Silybum marianium) with anti-oxidant properties. The purpose of the current trial was to determine the tissue and blood effects of high-dose silybin-phytosome in prostate cancer patients. Subjects with localized prostate cancer planning for a prostatectomy were eligible to enroll. Six patients received 13 g of silybin-phytosome daily with six additional participants serving as control subjects. Patients in the treatment arm received silybin-phytosome for 14-31 days (mean was 20 days) prior to surgery. Silibinin blood levels were measured 1 hr after the first silybin-phytosome dose with a mean value of 19.7 microM. Trough silibinin levels were assessed at the end of the trial with an average concentration of 1.2 microM. In contrast to the high peak levels of silibinin observed in blood, the highest silibinin level observed in the harvested prostate tissue was 496.6 pmol/g. There were no significant differences noted in baseline and post-treatment blood levels of IGF-I and IGFBP-3. One of the treated patients developed a grade 4 post-operative thromboembolic event. The other observed toxicities in the treatment group were mild: four subjects had diarrhea and one had asymptomatic grade 2 hyperbilirubinemia which was transient. High-dose oral silybin-phytosome achieves high blood concentrations transiently, but low levels of silibinin are seen in prostate tissue. Silibinin's lack of tissue penetration may be explained by its short half-life, the brief duration of therapy in this study or an active process removing silibinin from the prostate.

Ultra-low dose naltrexone enhances cannabinoid-induced antinociception.

PubMed

Paquette, Jay; Olmstead, Mary C; Olmstead, Mary

2005-12-01

Both opioids and cannabinoids have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to Gi/o-proteins. Surprisingly, the analgesic effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist, naltrexone. As opioid and cannabinoid systems interact, this study investigated whether ultra-low dose naltrexone also influences cannabinoid-induced antinociception. Separate groups of Long-Evans rats were tested for antinociception following an injection of vehicle, a sub-maximal dose of the cannabinoid agonist WIN 55 212-2, naltrexone (an ultra-low or a high dose) or a combination of WIN 55 212-2 and naltrexone doses. Tail-flick latencies were recorded for 3 h, at 10-min intervals for the first hour, and at 15-min intervals thereafter. Ultra-low dose naltrexone elevated WIN 55 212-2-induced tail flick thresholds without extending its duration of action. This enhancement was replicated in animals receiving intraperitoneal or intravenous injections. A high dose of naltrexone had no effect on WIN 55 212-2-induced tail flick latencies, but a high dose of the cannabinoid 1 receptor antagonist SR 141716 blocked the elevated tail-flick thresholds produced by WIN 55 212-2+ultra-low dose naltrexone. These data suggest a mechanism of cannabinoid-opioid interaction whereby activated opioid receptors that couple to Gs-proteins may attenuate cannabinoid-induced antinociception and/or motor functioning.

Effect of High-Dose vs Standard-Dose Wintertime Vitamin D Supplementation on Viral Upper Respiratory Tract Infections in Young Healthy Children

PubMed Central

Aglipay, Mary; Birken, Catherine S.; Parkin, Patricia C.; Loeb, Mark B.; Thorpe, Kevin; Chen, Yang; Laupacis, Andreas; Mamdani, Muhammad; Macarthur, Colin; Hoch, Jeffrey S.; Mazzulli, Tony

2017-01-01

Importance Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown. Objective To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children. Design, Setting, and Participants A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice–based research network in Toronto, Ontario, Canada. Interventions Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May. Main Outcome Measures The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination. Results Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, −0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02-5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66-4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88-1.16). At study termination, serum 25-hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9-50.5 ng/mL) in the high-dose group and 36.8 ng/mL (95% CI, 35.4-38.2 ng/mL) in the standard-dose group. Conclusions and Relevance Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections. Trial Registration clinicaltrials.gov Identifier: NCT01419262 PMID:28719693

Effect of High-Dose vs Standard-Dose Wintertime Vitamin D Supplementation on Viral Upper Respiratory Tract Infections in Young Healthy Children.

PubMed

Aglipay, Mary; Birken, Catherine S; Parkin, Patricia C; Loeb, Mark B; Thorpe, Kevin; Chen, Yang; Laupacis, Andreas; Mamdani, Muhammad; Macarthur, Colin; Hoch, Jeffrey S; Mazzulli, Tony; Maguire, Jonathon L

2017-07-18

Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown. To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children. A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice-based research network in Toronto, Ontario, Canada. Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May. The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination. Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, -0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02-5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66-4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88-1.16). At study termination, serum 25-hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9-50.5 ng/mL) in the high-dose group and 36.8 ng/mL (95% CI, 35.4-38.2 ng/mL) in the standard-dose group. Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections. clinicaltrials.gov Identifier: NCT01419262.

Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials.

PubMed

Kreimer, Aimée R; Struyf, Frank; Del Rosario-Raymundo, Maria Rowena; Hildesheim, Allan; Skinner, S Rachel; Wacholder, Sholom; Garland, Suzanne M; Herrero, Rolando; David, Marie-Pierre; Wheeler, Cosette M; González, Paula; Jiménez, Silvia; Lowy, Douglas R; Pinto, Ligia A; Porras, Caroline; Rodriguez, Ana Cecilia; Safaeian, Mahboobeh; Schiffman, Mark; Schiller, John T; Schussler, John; Sherman, Mark E; Bosch, F Xavier; Castellsague, Xavier; Chatterjee, Archana; Chow, Song-Nan; Descamps, Dominique; Diaz-Mitoma, Francisco; Dubin, Gary; Germar, Maria Julieta; Harper, Diane M; Lewis, David J M; Limson, Genara; Naud, Paulo; Peters, Klaus; Poppe, Willy A J; Ramjattan, Brian; Romanowski, Barbara; Salmeron, Jorge; Schwarz, Tino F; Teixeira, Julio C; Tjalma, Wiebren A A

2015-07-01

There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received. Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase. We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7-79·1), two doses was 76·0% (62·0-85·3), and one dose was 85·7% (70·7-93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0-63·0), two doses was 37·7% (12·4-55·9), and one dose was 36·6% (-5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2-87·5) and 82·6% (42·3-96·1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68·1%, 27·0-87·0; CVT data only), but not those receiving it at one month (10·1%, -42·0 to 43·3), was similar to the three-dose group. 4 years after vaccination of women aged 15-25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine. US National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA). Copyright © 2015 Elsevier Ltd. All rights reserved.

Improved long-term survival after intra-operative single high-dose ATG-Fresenius induction in renal transplantation: a single centre experience.

PubMed

Kaden, Jürgen; May, Gottfried; Völp, Andreas; Wesslau, Claus

2009-01-01

In organ grafts donor-specific sensitization is initiated immediately after revascularization. Therefore, in 1990 we introduced the intra-operative single high-dose ATG-Fresenius (ATG-F) induction in addition to standard triple drug therapy (TDT) consisting of steroids, azathioprine and cyclosporin. A total of 778 first renal transplantations from deceased donors, performed between 1987 and 1998, were included in this evaluation. This retrospective analysis of clinic records and electronic databases presents data of all recipients of first kidney grafts who received two different ATG-F inductions (1(st) group: 9 mg/kg body weight as single high-dose intra-operatively, n=484; 2(nd) group: 3 mg/kg body weight on 7 or 8 consecutive days as multiple-dose starting also intra-operatively, n=78) and standard TDT alone (3(rd) group: TDT alone, n=216). The 10-year patient survival rates were 72.6+/-2.6% (TDT + ATG-F single high-dose), 79.5+/-5.1% (TDT + ATG-F multiple-dose) and 67.2+/-3.7%% (TDT alone; Kaplan-Meier estimates with standard errors; ATG-F vs TDT alone, p=0.001). The 10-year graft survival rates with censoring of patients that died with a functioning graft were 73.8+/-2.4%, 57.7+/-5.8% and 58.4+/-3.6% (Kaplan-Meier estimates with standard errors; 1(st) vs 2(nd )and 3(rd) group, respectively, p<0.001) and the 10-year graft survival rates with patient death counted as graft failure were 58.3+/-2.7%, 55.7+/-5.8% and 48.2+/-3.5% (Kaplan-Meier estimates with standard errors; ATG-F single high-dose vs TDT, p=0.023). In pre-sensitized recipients there were also significant differences in favour of ATG-F, more notably in the single high-dose ATG-F induction. A total of 69% of the patients in the two cohorts receiving ATG-F did not experience any transplant rejections compared to 56% in patients undergoing TDT alone (p=0.018). The incidence of infectious complications was comparable across all groups. According to evidence obtained from the routine documentation of 778 renal transplantations, ATG-F induction therapy administered as a part of immunosuppressive therapy significantly improves patient survival and reduces the risk of graft failure and transplant rejections.

The protons of space and brain tumors: I. Clinical and dosimetric considerations

NASA Astrophysics Data System (ADS)

Dalrymple, G. V.; Nagle, W. A.; Moss, A. J.; Cavin, L. A.; Broadwater, J. R.; McGuire, E. L.; Eason, C. S.; Mitchell, J. C.; Hardy, K. A.; Wood, D. H.; Salmon, Y. A.; Yochmowitz, M. G.

1989-05-01

Almost 25 years ago a large group of Rhesus monkeys were irradiated with protons (32-2300 MeV). The experiments were designed: 1) To estimate the RBE of protons, per se, and 2) To provide some estimate of the hazards of the radiation environment of space. The initial results showed the RBE to be about 1.0 for acute radiation effects (mortality, hematologic changes, etc). The colony has been maintained at Brooks AFB, TX since irradiation. The survivors of 55 MeV proton irradiation have developed a very high incidence of Glioblastoma multiforme, a highly malignant primary brain tumor. These tumors appeared 1-20 yrs after surface doses of 400-800 rads. Reconstruction of the dosimetry suggests that some areas within the brain may have received doses of 1500-2500 rads. More than 30 radiation induced Glioblastomas have been reported in human patients who had received therapeutic head irradiation. The radiation doses required to induce Glioblastoma were of the same order of magnitude as required to induce Glioblastoma in the Rhesus monkey.

An Improved Model for Predicting Radiation Pneumonitis Incorporating Clinical and Dosimetric Variables;Lung cancer; Radiation pneumonitis; Dose-volume histogram; Angiotensin converting enzyme inhibitor

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

Jenkins, Peter, E-mail: peter.jenkins@glos.nhs.uk; Watts, Joanne

2011-07-15

Purpose: Single dose-volume metrics are of limited value for the prediction of radiation pneumonitis (RP) in day-to-day clinical practice. We investigated whether multiparametric models that incorporate clinical and physiologic factors might have improved accuracy. Methods and Materials: The records of 160 patients who received radiation therapy for non-small-cell lung cancer were reviewed. All patients were treated to the same dose and with an identical technique. Dosimetric, pulmonary function, and clinical parameters were analyzed to determine their ability to predict for the subsequent development of RP. Results: Twenty-seven patients (17%) developed RP. On univariate analysis, the following factors were significantly correlatedmore » with the risk of pneumonitis: fractional volume of lung receiving >5-20 Gy, absolute volume of lung spared from receiving >5-15 Gy, mean lung dose, craniocaudal position of the isocenter, transfer coefficient for carbon monoxide (KCOc), total lung capacity, coadministration of angiotensin converting enzyme inhibitors, and coadministration of angiotensin receptor antagonists. By combining the absolute volume of lung spared from receiving >5 Gy with the KCOc, we defined a new parameter termed Transfer Factor Spared from receiving >5 Gy (TFS{sub 5}). The area under the receiver operator characteristic curve for TFS{sub 5} was 0.778, increasing to 0.846 if patients receiving modulators of the renin-angiotensin system were excluded from the analysis. Patients with a TFS{sub 5} <2.17 mmol/min/kPa had a risk of RP of 30% compared with 5% for the group with a TFS{sub 5} {>=}2.17. Conclusions: TFS{sub 5} represents a simple parameter that can be used in routine clinical practice to more accurately segregate patients into high- and low-risk groups for developing RP.« less

Predictive factors of head and neck squamous cell carcinoma patient tolerance to high-dose cisplatin in concurrent chemoradiotherapy

PubMed Central

NAKANO, KENJI; SATO, YASUYOSHI; TOSHIYASU, TAKASHI; SATO, YUKIKO; INAGAKI, LINA; TOMOMATSU, JUNICHI; SASAKI, TORU; SHIMBASHI, WATARU; FUKUSHIMA, HIROFUMI; YONEKAWA, HIROYUKI; MITANI, HIROKI; KAWABATA, KAZUYOSHI; TAKAHASHI, SHUNJI

2016-01-01

Although high-dose cisplatin is the standard regimen of concurrent chemoradiotherapy (CCRT) for locally advanced head and neck squamous cell carcinoma (HNSCC), varying levels of patient tolerance towards cisplatin have been reported, and the predictive factors of cisplatin tolerance remain to be elucidated. The present study retrospectively reviewed newly diagnosed HNSCC patients who received CCRT. Cisplatin (80 mg/m2) was administered every 3 weeks. The proportion of high-dose cisplatin-tolerant patients (cumulative cisplatin dose, ≥200 mg/m2) was determined, and the predictive factors of cisplatin tolerance were analyzed in a logistic regression analysis. Between June 2006 and March 2013, a total of 159 patients were treated with CCRT. The median follow-up time was 36.7 months. A total of 73 patients (46%) tolerated a cumulative cisplatin dose ≥200 mg/m2; male gender [odds ratio (OR), 25.00; P=0.005] and high body surface area (BSA) (>1.80 m2; OR, 2.21; P=0.032) were significantly predictive of high-dose cisplatin tolerance. The high-dose cisplatin-tolerant patients had a significantly higher complete response (CR) rate (82 vs. 67%, P=0.045); however, there were no significant between-group differences in the 3-year OS (79.5 vs. 81.2%, P=0.59) or PFS (70.4 vs. 44.6%, P=0.076) by cisplatin tolerance. In clinical practice, approximately one-half of the patients tolerated high-dose cisplatin in CCRT. Male gender and high BSA could be predictive of cisplatin tolerance. PMID:26893880

Occupational radiation doses during interventional procedures

NASA Astrophysics Data System (ADS)

Nuraeni, N.; Hiswara, E.; Kartikasari, D.; Waris, A.; Haryanto, F.

2016-03-01

Digital subtraction angiography (DSA) is a type of fluoroscopy technique used in interventional radiology to clearly visualize blood vessels in a bony or dense soft tissue environment. The use of DSA procedures has been increased quite significantly in the Radiology departments in various cities in Indonesia. Various reports showed that both patients and medical staff received a noticeable radiation dose during the course of this procedure. A study had been carried out to measure these doses among interventionalist, nurse and radiographer. The results show that the interventionalist and the nurse, who stood quite close to the X-ray beams compared with the radiographer, received radiation higher than the others. The results also showed that the radiation dose received by medical staff were var depending upon the duration and their position against the X-ray beams. Compared tothe dose limits, however, the radiation dose received by all these three medical staff were still lower than the limits.

Mean esophageal radiation dose is predictive of the grade of acute esophagitis in lung cancer patients treated with concurrent radiotherapy and chemotherapy.

PubMed

Ozgen, Aytul; Hayran, Mutlu; Kahraman, Fatih

2012-11-01

The intention of this research was to define the predictive factors for acute esophagitis (AE) in lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy. The data for 72 lung cancer patients treated with concurrent chemoradiotherapy between 2008 and 2010 were prospectively evaluated. Mean lung dose, mean dose of esophagus, volume of esophagus irradiated and percentage of esophagus volume treated were analysed according to esophagitis grades. The mean esophageal dose was associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P < 0.001). However, the mean lung dose and the volume of esophagus irradiated were not associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P = 0.50 and P = 0.41, respectively). The mean radiation dose received by the esophagus was found to be highly correlated with the duration of Grade 2 esophagitis (Spearman test, r = 0.82, P < 0.001). The mean dose of esophagus ≥28 Gy showed statistical significance with respect to AE Grade 2 or worse (receiver operating characteristic curve analysis, 95% CI, 0.929-1.014). In conclusion, the mean esophageal dose was significantly associated with a risk of esophageal toxicity in patients with lung cancer treated with concurrent radiotherapy and chemotherapy.

Mean esophageal radiation dose is predictive of the grade of acute esophagitis in lung cancer patients treated with concurrent radiotherapy and chemotherapy

PubMed Central

Ozgen, Aytul; Hayran, Mutlu; Kahraman, Fatih

2012-01-01

The intention of this research was to define the predictive factors for acute esophagitis (AE) in lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy. The data for 72 lung cancer patients treated with concurrent chemoradiotherapy between 2008 and 2010 were prospectively evaluated. Mean lung dose, mean dose of esophagus, volume of esophagus irradiated and percentage of esophagus volume treated were analysed according to esophagitis grades. The mean esophageal dose was associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P < 0.001). However, the mean lung dose and the volume of esophagus irradiated were not associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P = 0.50 and P = 0.41, respectively). The mean radiation dose received by the esophagus was found to be highly correlated with the duration of Grade 2 esophagitis (Spearman test, r = 0.82, P < 0.001). The mean dose of esophagus ≥28 Gy showed statistical significance with respect to AE Grade 2 or worse (receiver operating characteristic curve analysis, 95% CI, 0.929–1.014). In conclusion, the mean esophageal dose was significantly associated with a risk of esophageal toxicity in patients with lung cancer treated with concurrent radiotherapy and chemotherapy. PMID:22915782

NTP Toxicology and Carcinogenesis Studies of 1,4-Dichlorobenzene (CAS No. 106-46-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

PubMed

1987-01-01

1,4-Dichlorobenzene is commonly used as a space deodorant in toilets and for moth control. Because of its extensive production and use and the absence of carcinogenicity data, carcinogenesis studies were conducted by administering 1,4-dichlorobenzene (greater than 99% pure) in corn oil by gavage (5 days per week) to male F344/N rats at doses of 0, 150, or 300 mg/kg and to female F344/N rats and male and female B6C3F1 mice at doses of 0, 300, or 600 mg/kg per day for 2 years (50 animals per group). Fourteen-day and 13-week studies were performed to characterize the toxicity, identify affected sites, and set doses for the 2-year studies. Clinical chemistry and hematologic studies were performed during the 13-week studies to assess the effects of 1,4-dichlorobenzene on the liver, kidney, and hematopoietic system and to assess whether the compound produced hepatic porphyria. Two 13-week studies were performed in rats. In the first study, rats were dosed with 300-1,500 mg/kg 1,4-dichlorobenzene. Because histologic changes were observed in the kidney of male rats at all doses, a second 13-week study was performed at doses of 38-600 mg/kg. In the 13-week studies, survival was decreased in groups of male rats given 1,200 or 1,500 mg/kg and in female rats given 1,500 mg/kg. Weight gain was decreased in male rats receiving doses of 300 mg/kg or more and in female rats given doses of 1,200 or 1,500 mg/kg. Doses of 1,200 or 1,500 mg/kg produced degeneration and necrosis of hepatocytes, hypoplasia of the bone marrow, lymphoid depletion of the spleen and thymus, and epithelial necrosis of the nasal turbinates in male and female rats. Renal tubular cell degeneration was observed in male rats receiving 300 mg/kg or more in the first study, but only slight changes were seen at 300 mg/kg in the second study. Liver weight to brain weight ratios were increased at 900 mg/kg or more for both male and female rats. The kidney weight to brain weight ratio was increased in male rats receiving doses of 600 mg/kg or more. Administration of 1,4-dichlorobenzene to rats for 13 weeks produced slight but statistically significant decreases in the hematocrit, red blood cell count, and hemoglobin level in all males receiving doses of 300-1,200 mg/kg. No clear hematologic changes were observed in female rats. 1,4-Dichlorobenzene produced minimal changes in clinical chemistry parameters in the 13-week studies. Serum cholesterol levels were increased by doses of 600 mg/kg or more in male rats and 900 mg/kg or more in female rats. Serum triglycerides were reduced by doses of 300 mg/kg or more in male rats. The blood urea nitrogen level was increased slightly in male rats dosed with 900 mg/kg or more. Urinary porphyrins were increased slightly in male rats administered 1,200 or 1,500 mg/kg and female rats receiving 1,200 mg/kg. However, these increases were modest and indicative of a mild porphyrinuria rather than hepatic porphyria. Liver porphyrins were not increased at any dose. Two 13-week studies were performed in mice. The doses selected for the first study were 600-1,800 mg/kg. Survival was decreased in male and female mice receiving doses of 1,500 mg/kg or more, and body weight gain was decreased at all doses. Hepatocellular degeneration was observed in both sexes at all doses, and the liver weight to brain weight ratio was increased at doses of 900 mg/kg or more. Serum cholesterol levels were increased in male mice at doses of 900 mg/kg or more, whereas serum protein and triglycerides were increased at doses of 1,500 mg/kg or more. These relatively modest clinical chemistry changes probably reflect the hepatic effects of this compound. The white blood cell count was reduced significantly in male mice receiving doses of 600 mg/kg or more and female mice receiving 1,000 mg/kg or more, but this effect was not dramatic. Hepatic porphyria was not found in mice at any dose in the 13-week study. Because hepatic effects were seen in all dose groups in the first study, a second 13-week study was performed at doses of 85-900 mg/kg. In this study, hepatocellularellular cytomegaly was observed im male and female mice at doses of 675 mg/kg or more but not at 338 mg/kg. Renal damage was not observed in mice in either 13-week study. Based on the histopathologic findings in the kidney of male rats and in the liver of both sexes of rats and mice in the 13-week studies, the doses selected for the 2-year studies were 150 and 300 mg/kg for male rats and 300 and 600 mg/kg for female rats and male and female mice. In the 2-year studies, survival of female rats and of both sexes of mice was comparable to that of the vehicle controls; survival of high dose male rats was significantly lower than that of the vehicle controls (vehicle control, 32/50; low dose, 31/50; high dose, 20/50). Mean body weights of high dose male rats were 5%-8% lower than those of vehicle controls after week 38, and those of high dose female rats were 5%-7% lower than those of vehicle controls after week 55. Mean body weights of mice dosed with 1,4-dichlorobenzene were comparable to those of vehicle controls throughout the studies. Administration of 1,4-dichlorobenzene to male rats increased the average seveity of nephropathy and caused epithelial hyperplasia of the renal pelvis (1/50; 30/50; 31/50), mineralization of the collecting tubules in the renal medulla (4/50; 46/50; 47/50), and focal hyperplasia of renal tubular epithelium (0/50; 1/50; 9/50). There were increased incidences of nephropathy in both low and high dose female rats compared with vehicle controls (21/49; 32/50; 41/49). 1,4-Dichlorobenzene produced a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats (1/50; 3/50; 7/50); one tubular cell adenoma was observed in a high dose male rat. These malignant tumors are uncommon in male F344/N rats. They have been diagnosed in only 4/1,098 (0.4%) corn oil gavage controls in previous NTP studies. There were no tubular cell tumors in dosed or vehicle control female rats. There was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats compared with that in vehicle controls (5/50; 7/50; 11/50). 1,4-Dichlorobenzene increased the incidences of nonneoplastic liver lesions in male and female mice, including alteration in cell size (cytomegaly and karyomegaly), hepatocellular degeneration, and individual cell necrosis. 1,4-Dichlorobenzene also increased the incidences of nephropathy in male mice and renal tubular regeneration in female mice. 1,4-Dichlorobenzene increased the incidences of hepatocellular carcinomas in high dose male (14/50; 11/49; 32/50) and female (5/50; 5/48; 19/50) mice and hepatocellular adenomas in dosed male (5/50; 13/49; 16/50) and high dose female (10/50; 6/48; 21/50) mice. Hepatoblastomas were observed in four high dose male mice but not in vehicle controls. This rare tumor has not occurred in 1,091 male vehicle control mice in NTP studies. An increase in thyroid gland follicular cell hyperplasia was observed in dosed male mice (1/47; 4/48; 10/47), and there was a marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland in female mice (0/48; 0/45; 3/46). Pheochromocytomas (benign or malignant, combined) of the adrenal gland occurred with a positive trend in dosed male mice, and the incidence in the high dose group was significantly greater than in vehicle controls (0/47; 2/48; 4/49). The incidence of adrenal gland medullary hyperplasia in male mice was 2/47; 4/48; and 4/49. Focal hyperplasia of the adrenal gland capsule was also observed in dosed male mice (11/47;21/48; 28/49). 1,4-Dichlorobenzene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when tested according to a preincubational protocol at concentrations up to 100 ug/plate. 1,4-Dichlorobenzene did not induce forward mutations in the mouse lymphoma L5178Y/TK± assay in the absence of exogenous metabolic activation; however, the results were equivocal in this system in the presence of metabolic activation. 1,4-Dichlorobenzene did not produce an increase in sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in culture with or without exogenous metabolic activation. No increase in micronucleated cells was seen in erythrocytes of mice from the first 13-week studies. An audit of the experimental data was conducted for the 2-year studies of 1,4-dichlorobenzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, 1,4-dichlorobenzene produced clear evidence of carcinogenicity for male F344/N rats, as shown by an increased incidence of renal tubular cell adenocarcinomas. There was no evidence of carcinogenicity for female F344/N rats receiving doses of 300 or 600 mg/kg. There was clear evidence of carcinogenicity for both male and female B6C3F1 mice, as shown by increased incidences of hepatocellular carcinomas and hepatocellular adenomas. Marginal increases were observed in the incidences of pheochromocytomas of the adrenal gland in male mice. Nonneoplastic effects in the kidney of male and female rats, in the liver of male and female mice, and in the thyroid gland and adrenal gland of male mice were also associated with the administration of 1,4-dichlorobenzene. Synonyms: p-dichlorobenzene; para-dichlorobenzene; para-chlorophenyl chloride

Implant breast reconstruction followed by radiotherapy: Can helical tomotherapy become a standard irradiation treatment?

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

Massabeau, Carole, E-mail: cmassabeau@hotmail.com; Fournier-Bidoz, Nathalie; Wakil, Georges

2012-01-01

To evaluate the benefits and limitations of helical tomotherapy (HT) for loco-regional irradiation of patients after a mastectomy and immediate implant-based reconstruction. Ten breast cancer patients with retropectoral implants were randomly selected for this comparative study. Planning target volumes (PTVs) 1 (the volume between the skin and the implant, plus margin) and 2 (supraclavicular, infraclavicular, and internal mammary nodes, plus margin) were 50 Gy in 25 fractions using a standard technique and HT. The extracted dosimetric data were compared using a 2-tailed Wilcoxon matched-pair signed-rank test. Doses for PTV1 and PTV2 were significantly higher with HT (V95 of 98.91 andmore » 97.91%, respectively) compared with the standard technique (77.46 and 72.91%, respectively). Similarly, the indexes of homogeneity were significantly greater with HT (p = 0.002). HT reduced ipsilateral lung volume that received {>=}20 Gy (16.7 vs. 35%), and bilateral lungs (p = 0.01) and neighboring organs received doses that remained well below tolerance levels. The heart volume, which received 25 Gy, was negligible with both techniques. HT can achieve full target coverage while decreasing high doses to the heart and ipsilateral lung. However, the low doses to normal tissue volumes need to be reduced in future studies.« less

Accuracy of Reduced-Dose Computed Tomography for Ureteral Stones in Emergency Department Patients

PubMed Central

Moore, Christopher L.; Daniels, Brock; Ghita, Monica; Gunabushanam, Gowthaman; Luty, Seth; Molinaro, Annette M.; Singh, Dinesh; Gross, Cary P.

2016-01-01

Study objective Reduced-dose computed tomography (CT) scans have been recommended for diagnosis of kidney stone but are rarely used in the emergency department (ED) setting. Test characteristics are incompletely characterized, particularly in obese patients. Our primary outcome is to determine the sensitivity and specificity of a reduced-dose CT protocol for symptomatic ureteral stones, particularly those large enough to require intervention, using a protocol stratified by patient size. Methods This was a prospective, blinded observational study of 201 patients at an academic medical center. Consenting subjects underwent both regular- and reduced-dose CT, stratified into a high and low body mass index (BMI) protocol based on effective abdominal diameter. Reduced-dose CT scans were interpreted by radiologists blinded to regular-dose interpretations. Follow-up for outcome and intervention was performed at 90 days. Results CT scans with both regular and reduced doses were conducted for 201 patients, with 63% receiving the high BMI reduced-dose protocol. Ureteral stone was identified in 102 patients (50.7%) of those receiving regular-dose CT, with a ureteral stone greater than 5 mm identified in 26 subjects (12.9%). Sensitivity of the reduced-dose CT for any ureteral stone was 90.2% (95% confidence interval [CI] 82.3% to 95.0%), with a specificity of 99.0% (95% CI 93.7% to 100.0%). For stones greater than 5 mm, sensitivity was 100% (95% CI 85.0% to 100.0%). Reduced-dose CT identified 96% of patients who required intervention for ureteral stone within 90 days. Mean reduction in size-specific dose estimate was 18.6 milligray (mGy), from 21.7 mGy (SD 9.7) to 3.4 mGy (SD 0.9). Conclusion CT with substantial dose reduction was 90.2% (95% CI 82.3% to 95.0%) sensitive and 98.9% (95% CI 85.0% to 100.0%) specific for ureteral stones in ED patients with a wide range of BMIs. Reduced-dose CT was 96.0% (95% CI 80.5% to 99.3%) sensitive for ureteral stones requiring intervention within 90 days. PMID:25441242

Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients

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

Pan, Charlie C.; Eisbruch, Avraham; Lee, Julia S.

Purpose: To determine the relationship between the radiation dose to the inner ear and long-term hearing loss. Methods and Materials: Eligible patients included those receiving curative radiotherapy (RT) for head-and-neck cancer. After enrollment, patients underwent three-dimensional conformal RT planning and delivery (180-200 cGy/fraction) appropriate for their disease site and stage. The inner ear was contoured on axial CT planning images. Dose-volume histograms, as well as the mean and maximal dose for each structure, were calculated. Patients underwent pure tone audiometry at baseline (before treatment) and 1, 6, 12, 24, and 36 months after RT. The threshold level (the greater themore » value, the more hearing loss) in decibels was recorded for 250, 500, 1000, 2000, 4000, and 8000 Hz. For patients receiving predominantly unilateral RT, the contralateral ear served as the de facto control. The differences in threshold level between the ipsilateral and contralateral ears were calculated, and the temporal pattern and dose-response relation of hearing loss were analyzed using statistical methods that take into account the correlation between two ears in the same subject and repeated, sequential measurements of each subject. Results: Of the 40 patients enrolled in this study, 35 qualified for analysis. Four patients who received concurrent chemotherapy and RT were analyzed separately. The 31 unilaterally treated patients received a median dose of 47.4 Gy (range, 14.1-68.8 Gy) to the ipsilateral inner ear and 4.2 Gy (range, 0.5-31.3 Gy) to the contralateral inner ear. Hearing loss was associated with the radiation dose received by the inner ear (loss of 210dB was observed in ears receiving {>=}45 Gy) and was most appreciable in the higher frequencies ({>=}2000 Hz). For a 60-year-old patient with no previous hearing loss in either ear, after receiving 45 Gy, the ipsilateral ear, according to our clinical model, would have a 19.3-dB (95% confidence interval [CI], 15.5-23.0) and 5.4-dB (95% CI, 3.5-7.5) hearing decrement compared with the contralateral ear for 8000 Hz and 1000 Hz, respectively. Age and an initial hearing difference within an ear pair also affected hearing loss. The baseline hearing threshold was inversely related to radiation-induced hearing loss. The degree of hearing loss was dependent on the frequency tested, age, baseline hearing, and baseline difference in hearing between a patient's two ears. Conclusion: High-frequency ({>=}2000 Hz) hearing acuity worsens significantly after RT in a dose-dependent fashion. A larger number of patients needs to be studied to validate these results. This knowledge can be applied to create guidelines regarding future dose limits to the auditory apparatus for patients undergoing head-and-neck RT.« less

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.

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 .).

Modelling the effects of booster dose vaccination schedules and recommendations for public health immunization programs: the case of Haemophilus influenzae serotype b.

PubMed

Charania, Nadia A; Moghadas, Seyed M

2017-09-13

Haemophilus influenzae serotype b (Hib) has yet to be eliminated despite the implementation of routine infant immunization programs. There is no consensus regarding the number of primary vaccine doses and an optimal schedule for the booster dose. We sought to evaluate the effect of a booster dose after receiving the primary series on the long-term disease incidence. A stochastic model of Hib transmission dynamics was constructed to compare the long-term impact of a booster vaccination and different booster schedules after receiving the primary series on the incidence of carriage and symptomatic disease. We parameterized the model with available estimates for the efficacy of Hib conjugate vaccine and durations of both vaccine-induced and naturally acquired immunity. We found that administering a booster dose substantially reduced the population burden of Hib disease compared to the scenario of only receiving the primary series. Comparing the schedules, the incidence of carriage for a 2-year delay (on average) in booster vaccination was comparable or lower than that observed for the scenario of booster dose within 1 year after primary series. The temporal reduction of symptomatic disease was similar in the two booster schedules, suggesting no superiority of one schedule over the other in terms of reducing the incidence of symptomatic disease. The findings underscore the importance of a booster vaccination for continued decline of Hib incidence. When the primary series provides a high level of protection temporarily, delaying the booster dose (still within the average duration of protection conferred by the primary series) may be beneficial to maintain longer-term protection levels and decelerate the decline of herd immunity in the population.

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

Breastfeeding Problems Following Anesthetic Administration

PubMed Central

Howie, William O.; McMullen, Patricia C.

2006-01-01

Research literature supports the notion that maternal comfort should be considered a priority and that mothers should receive adequate information regarding any drug prior to receiving that drug. Some studies indicate that difficulties with breastfeeding may be related to the amount of the anesthetic or analgesic that is administered to the mother. Thus, it seems wise to administer the lowest possible dose to the mother in order to minimize the amount of drug (or metabolite) exposure to the nursing infant. Infant exposure can be further reduced if breastfeeding is avoided during the times when the mother receives high doses of anesthetics and analgesics. However, because relatively small amounts of the drug are excreted into the breast milk, some mothers may opt to continue nursing after weighing the benefits of breastfeeding against the potential risk to the infant. Others may choose to “pump and dump” breast milk while they receive anesthetic or analgesic agents. Any concerns in this regard should be discussed with the anesthesia provider, preferably prior to labor or to any surgeries while breastfeeding. PMID:17541461

Breastfeeding problems following anesthetic administration.

PubMed

Howie, William O; McMullen, Patricia C

2006-01-01

Research literature supports the notion that maternal comfort should be considered a priority and that mothers should receive adequate information regarding any drug prior to receiving that drug. Some studies indicate that difficulties with breastfeeding may be related to the amount of the anesthetic or analgesic that is administered to the mother. Thus, it seems wise to administer the lowest possible dose to the mother in order to minimize the amount of drug (or metabolite) exposure to the nursing infant. Infant exposure can be further reduced if breastfeeding is avoided during the times when the mother receives high doses of anesthetics and analgesics. However, because relatively small amounts of the drug are excreted into the breast milk, some mothers may opt to continue nursing after weighing the benefits of breastfeeding against the potential risk to the infant. Others may choose to "pump and dump" breast milk while they receive anesthetic or analgesic agents. Any concerns in this regard should be discussed with the anesthesia provider, preferably prior to labor or to any surgeries while breastfeeding.

SU-E-T-580: Comparison of Cervical Carcinoma IMRT Plans From Four Commercial Treatment Planning Systems (TPS)

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

Cao, Y; Li, R; Chi, Z

2014-06-01

Purpose: Different treatment planning systems (TPS) use different treatment optimization and leaf sequencing algorithms. This work compares cervical carcinoma IMRT plans optimized with four commercial TPSs to investigate the plan quality in terms of target conformity and delivery efficiency. Methods: Five cervical carcinoma cases were planned with the Corvus, Monaco, Pinnacle and Xio TPSs by experienced planners using appropriate optimization parameters and dose constraints to meet the clinical acceptance criteria. Plans were normalized for at least 95% of PTV to receive the prescription dose (Dp). Dose-volume histograms and isodose distributions were compared. Other quantities such as Dmin(the minimum dose receivedmore » by 99% of GTV/PTV), Dmax(the maximum dose received by 1% of GTV/PTV), D100, D95, D90, V110%, V105%, V100% (the volume of GTV/PTV receiving 110%, 105%, 100% of Dp), conformity index(CI), homogeneity index (HI), the volume of receiving 40Gy and 50 Gy to rectum (V40,V50) ; the volume of receiving 30Gy and 50 Gy to bladder (V30,V50) were evaluated. Total segments and MUs were also compared. Results: While all plans meet target dose specifications and normal tissue constraints, the maximum GTVCI of Pinnacle plans was up to 0.74 and the minimum of Corvus plans was only 0.21, these four TPSs PTVCI had significant difference. The GTVHI and PTVHI of Pinnacle plans are all very low and show a very good dose distribution. Corvus plans received the higer dose of normal tissue. The Monaco plans require significantly less segments and MUs to deliver than the other plans. Conclusion: To deliver on a Varian linear-accelerator, the Pinnacle plans show a very good dose distribution. Corvus plans received the higer dose of normal tissue. The Monaco plans have faster beam delivery.« less

Application of the Extended Health Control Belief Model to Predict Hepatitis A and B Vaccinations.

PubMed

Reynolds, Grace L; Nguyen, Hannah H; Singh-Carlson, Savitri; Fisher, Dennis G; Odell, Anne; Xandre, Pamela

2016-09-01

Adult vaccination compliance rates vary according to sample and type of vaccine administered (influenza, pneumococcal). This study looked at vaccination of a community sample of low-income, minority adults. Nurses offered free vaccination for hepatitis A and B in the form of the combined Twinrix vaccine to adults on a walk-in basis. In addition to dosing information, participants completed the Risk Behavior Assessment, the Coping Strategies Indicator and the Cardiovascular Risk Assessment. Skaff's extended Health Belief Model was used as the theoretical framework. Count regression was used to model receipt of one, two, or three doses. The majority of participants were male with a mean age of 40 years. The distribution of doses was: 173 individuals (27.6%) received one dose only, 261 (41.7%) received two doses, and 191 (30.5%) received three doses of vaccine. The multivariate count regression model including being male, having previously been told by a health care provider that one has syphilis, having severe negative emotions, and perceived social support were associated with participants' receiving fewer doses of hepatitis vaccine. A greater problem-solving score was associated with a higher number of vaccine doses received. Despite free vaccinations offered in an easily accessible community setting, the majority of participants failed to complete the hepatitis vaccine series. More effort is needed to get adult men to participate in hepatitis vaccination clinics. Additional research is necessary to understand barriers other than cost to adults receiving vaccination. © 2016 Wiley Periodicals, Inc.

Identification of Trends into Dose Calculations for Astronauts through Performing Sensitivity Analysis on Calculational Models Used by the Radiation Health Office

NASA Technical Reports Server (NTRS)

Adams, Thomas; VanBaalen, Mary

2009-01-01

The Radiation Health Office (RHO) determines each astronaut s cancer risk by using models to associate the amount of radiation dose that astronauts receive from spaceflight missions. The baryon transport codes (BRYNTRN), high charge (Z) and energy transport codes (HZETRN), and computer risk models are used to determine the effective dose received by astronauts in Low Earth orbit (LEO). This code uses an approximation of the Boltzman transport formula. The purpose of the project is to run this code for various International Space Station (ISS) flight parameters in order to gain a better understanding of how this code responds to different scenarios. The project will determine how variations in one set of parameters such as, the point of the solar cycle and altitude can affect the radiation exposure of astronauts during ISS missions. This project will benefit NASA by improving mission dosimetry.

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

Donovan, Ellen M., E-mail: ellen.donovan@icr.ac.u; Ciurlionis, Laura; Fairfoul, Jamie

Purpose: To establish planning solutions for a concomitant three-level radiation dose distribution to the breast using linear accelerator- or tomotherapy-based intensity-modulated radiotherapy (IMRT), for the U.K. Intensity Modulated and Partial Organ (IMPORT) High trial. Methods and Materials: Computed tomography data sets for 9 patients undergoing breast conservation surgery with implanted tumor bed gold markers were used to prepare three-level dose distributions encompassing the whole breast (36 Gy), partial breast (40 Gy), and tumor bed boost (48 or 53 Gy) treated concomitantly in 15 fractions within 3 weeks. Forward and inverse planned IMRT and tomotherapy were investigated as solutions. A standardmore » electron field was compared with a photon field arrangement encompassing the tumor bed boost volume. The out-of-field doses were measured for all methods. Results: Dose-volume constraints of volume >90% receiving 32.4 Gy and volume >95% receiving 50.4 Gy for the whole breast and tumor bed were achieved. The constraint of volume >90% receiving 36 Gy for the partial breast was fulfilled in the inverse IMRT and tomotherapy plans and in 7 of 9 cases of a forward planned IMRT distribution. An electron boost to the tumor bed was inadequate in 8 of 9 cases. The IMRT methods delivered a greater whole body dose than the standard breast tangents. A contralateral lung volume >2.5 Gy was increased in the inverse IMRT and tomotherapy plans, although it did not exceed the constraint. Conclusion: We have demonstrated a set of widely applicable solutions that fulfilled the stringent clinical trial requirements for the delivery of a concomitant three-level dose distribution to the breast.« less

Methotrexate in the treatment of penile carcinoma.

PubMed

Sklaroff, R B; Yagoda, A

1980-01-15

Eight patients with epidermoid carcinoma of the penis received methotrexate, five with high-dose methotrexate, 250--1500 mg/m2 with citrovorum rescue Q 2--4 weeks, and three with low-dose methotrexate, 0.5--3.0 mg/kg weekly. Three (38%) patients achieved a complete or partial remission which persisted for 11, 3 and 2 months, respectively. Methotrexate appears to be an active agent in the treatment of advanced penile cancer.

Lessons Learned From the Introduction of Inactivated Poliovirus Vaccine in Bangladesh.

PubMed

Estivariz, Concepcion F; Snider, Cynthia J; Anand, Abhijeet; Hampton, Lee M; Bari, Tajul I; Billah, Mallick M; Chai, Shua J; Wassilak, Steven G; Heffelfinger, James D; Zaman, K

2017-07-01

We assessed programmatic adaptations and infants' uptake of inactivated poliovirus vaccine (IPV) after its introduction into the routine immunization schedule in Bangladesh. Using convenience and probability sampling, we selected 23 health facilities, 36 vaccinators, and 336 caregivers, within 5 districts and 3 city corporations. We collected data during August-October 2015 by conducting interviews, reviewing vaccination records, and observing activities. Knowledge about IPV was high among vaccinators (94%). No problems with IPV storage, transport, or waste disposal were detected, but shortages were reported in 20 health facilities (87%). Wastage per 5-dose vaccine vial was above the recommended 30% in 20 health facilities (87%); all were related to providing <5 doses per open vial. Among eligible infants, 87% and 86% received the third dose of pentavalent and oral poliovirus vaccine, respectively, but only 65% received IPV at the same visit. Among 73 infants not vaccinated with IPV, 58% of caregivers reported that vaccine was unavailable. Bangladesh successfully introduced IPV, but shortages related to insufficient global supply and high vaccine wastage in small outreach immunization sessions might reduce its impact on population immunity. Minimizing wastage and use of a 2-dose fractional-IPV schedule could extend IPV immunization to more children. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Quantifying Unnecessary Normal Tissue Complication Risks due to Suboptimal Planning: A Secondary Study of RTOG 0126.

PubMed

Moore, Kevin L; Schmidt, Rachel; Moiseenko, Vitali; Olsen, Lindsey A; Tan, Jun; Xiao, Ying; Galvin, James; Pugh, Stephanie; Seider, Michael J; Dicker, Adam P; Bosch, Walter; Michalski, Jeff; Mutic, Sasa

2015-06-01

The purpose of this study was to quantify the frequency and clinical severity of quality deficiencies in intensity modulated radiation therapy (IMRT) planning in the Radiation Therapy Oncology Group 0126 protocol. A total of 219 IMRT patients from the high-dose arm (79.2 Gy) of RTOG 0126 were analyzed. To quantify plan quality, we used established knowledge-based methods for patient-specific dose-volume histogram (DVH) prediction of organs at risk and a Lyman-Kutcher-Burman (LKB) model for grade ≥2 rectal complications to convert DVHs into normal tissue complication probabilities (NTCPs). The LKB model was validated by fitting dose-response parameters relative to observed toxicities. The 90th percentile (22 of 219) of plans with the lowest excess risk (difference between clinical and model-predicted NTCP) were used to create a model for the presumed best practices in the protocol (pDVH0126,top10%). Applying the resultant model to the entire sample enabled comparisons between DVHs that patients could have received to DVHs they actually received. Excess risk quantified the clinical impact of suboptimal planning. Accuracy of pDVH predictions was validated by replanning 30 of 219 patients (13.7%), including equal numbers of presumed "high-quality," "low-quality," and randomly sampled plans. NTCP-predicted toxicities were compared to adverse events on protocol. Existing models showed that bladder-sparing variations were less prevalent than rectum quality variations and that increased rectal sparing was not correlated with target metrics (dose received by 98% and 2% of the PTV, respectively). Observed toxicities were consistent with current LKB parameters. Converting DVH and pDVH0126,top10% to rectal NTCPs, we observed 94 of 219 patients (42.9%) with ≥5% excess risk, 20 of 219 patients (9.1%) with ≥10% excess risk, and 2 of 219 patients (0.9%) with ≥15% excess risk. Replanning demonstrated the predicted NTCP reductions while maintaining the volume of the PTV receiving prescription dose. An equivalent sample of high-quality plans showed fewer toxicities than low-quality plans, 6 of 73 versus 10 of 73 respectively, although these differences were not significant (P=.21) due to insufficient statistical power in this retrospective study. Plan quality deficiencies in RTOG 0126 exposed patients to substantial excess risk for rectal complications. Copyright © 2015 Elsevier Inc. All rights reserved.

Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation

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

Krishnan, Sunil, E-mail: skrishnan@mdanderson.org; Chadha, Awalpreet S.; Suh, Yelin

2016-03-15

Purpose: To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. Methods and Materials: A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume wasmore » treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. Results: Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P=.03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local-regional RFS (10.2 vs 6.2 months, P=.05) as compared with those receiving BED ≤70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. Conclusion: Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS.« less

Switch from epoetin to darbepoetin alfa in hemodialysis: dose equivalence and hemoglobin stability.

PubMed

Arrieta, Javier; Moina, Iñigo; Molina, José; Gallardo, Isabel; Muñiz, María Luisa; Robledo, Carmen; García, Oscar; Vidaur, Fernando; Muñoz, Rosa Inés; Iribar, Izaskun; Aguirre, Román; Maza, Antonio

2014-01-01

The objective of the study reported here was to describe dose equivalence and hemoglobin (Hb) stability in a cohort of unselected hemodialysis patients who were switched simultaneously from epoetin alfa to darbepoetin alfa. This was a multicenter, observational, retrospective study in patients aged ≥18 years who switched from intravenous (IV) epoetin alfa to IV darbepoetin alfa in October 2007 (Month 0) and continued on hemodialysis for at least 24 months. The dose was adjusted to maintain Hb within 1.0 g/dL of baseline. We included 125 patients (59.7% male, mean [standard deviation (SD)] age 70.4 [13.4] years). No significant changes were observed in Hb levels (mean [SD] 11.9 [1.3] g/dL, 12.0 [1.5], 12.0 [1.5], and 12.0 [1.7] at Months -12, 0, 12 and 24, respectively, P=0.409). After conversion, the erythropoiesis-stimulating agent (ESA) dose decreased significantly (P<0.0001), with an annual mean of 174.7 (88.7) international units (IU)/kg/week for epoetin versus 95.7 (43.4) (first year) and 91.4 (42.7) IU/kg/week (second year) for darbepoetin (65% and 64% reduction, respectively). The ESA resistance index decreased from 15.1 (8.5) IU/kg/week/g/dL with epoetin to 8.1 (3.9) (first year) and 7.9 (4.0) (second year) with darbepoetin (P<0.0001). The conversion rate was 354:1 in patients requiring high (>200 IU/kg/week) doses of epoetin and 291:1 in patients requiring low doses. In patients on hemodialysis receiving ESAs, conversion from epoetin alfa to darbepoetin alfa was associated with an approximate and persistent reduction of 65% of the required dose. To maintain Hb stability, a conversion rate of 300:1 seems to be appropriate for most patients receiving low doses of epoetin alfa (≤200 IU/kg/week), while 350:1 would be better for patients receiving higher doses.

Intermittent preventive treatment of malaria in pregnancy: a cross-sectional survey to assess uptake of the new sulfadoxine-pyrimethamine five dose policy in Ghana.

PubMed

Owusu-Boateng, Ivy; Anto, Francis

2017-08-10

Malaria in pregnancy poses a great risk to both mother and fetus. In Ghana, malaria accounts for 3.4% of deaths and 16.8% of all hospital admissions in pregnant women. In 2014, Ghana updated her policy on intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) to reflect the updated policy of the WHO. This study determined the level of uptake of sulfadoxine pyrimethamine (SP) to serve as baseline for monitoring progress and also reviewed stock levels of SP, a key factor in the programme implementation. A cross-sectional hospital-based study was carried out among nursing mothers who had delivered within 12 weeks and were seeking postnatal care at Osu Government Maternity Home in Accra. Antenatal record books of the mothers were reviewed and data collected on number of visits and receipt of IPTp-SP. Mothers were interviewed and data collected on their background characteristics and obstetric history. Data on SP stock levels for the past 6 months were also reviewed. Logistic regression analysis was carried out to determine antenatal indicators on uptake of IPTp-SP using Stata version 12. The proportion of uptake of three-five doses of SP were: IPT3 (87.5%), IPT4 (55.7%) and IPT5 (14.5%). The proportion of women who received the first dose of SP at 16 weeks of gestation was 21.3%. Women who made ≥4 visits were more likely to receive ≥3 doses of SP than those who made <4 visits (AOR = 4.57, 95% CI 1.15-18.16, p < 0.05). Women receiving the first dose of SP in the third trimester were less likely to receive ≥3 doses of SP than those who received the drug in the second trimester (AOR = 0.04, 95% CI 0.01-0.16, p < 0.05). Stock levels of SP were adequate to meet the demands by the pregnant women at the Maternity Home for the period under review. The uptake of ≥3 doses of SP was high in the study area. Frequent visits to the antenatal clinic and early uptake of the first dose of SP by pregnant women are necessary to achieve the new target of five or more doses of SP.

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis.

PubMed

Xue, Hong-Xia; Fu, Wen-Yi; Cui, Hua-Dong; Yang, Li-Li; Zhang, Ning; Zhao, Li-Juan

2015-05-01

Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide.

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis

PubMed Central

Xue, Hong-xia; Fu, Wen-yi; Cui, Hua-dong; Yang, Li-li; Zhang, Ning; Zhao, Li-juan

2015-01-01

Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide. PMID:26109960

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.

Incidence of Hyponatremia with High-Dose Trimethoprim-Sulfamethoxazole Exposure.

PubMed

Tsapepas, Demetra; Chiles, Mariana; Babayev, Revekka; Rao, Maya K; Jaitly, Manasvi; Salerno, David; Mohan, Sumit

2016-12-01

Trimethoprim-sulfamethoxazole (TMP-SMX) is a commonly prescribed antibiotic used at high doses for treatment of pneumocystis pneumonia and other infections. Trimethoprim is structurally related to the potassium-sparing diuretic amiloride and has been associated with hyperkalemia and hyponatremia through blocking of epithelial sodium channels in the distal nephron. The incidence of hyponatremia in hospitalized patients treated with high-dose TMP-SMX is unknown. We performed a single-center retrospective chart review of all hospitalized patients who received high-dose TMP-SMX (n = 235) from January 2012 to July 2014. Patients with congestive heart failure, cirrhosis, estimated glomerular filtration rate <30 mL/min/1.73 m 2 , baseline hyponatremia, and those on other medications associated with hyponatremia were excluded. Hyponatremia was defined as a serum sodium level <136 mEq/L. Analysis was restricted to 76 unique patients who received more than 8 mg/kg/d of TMP for ≥3 days. Mean starting serum sodium at time of TMP-SMX initiation was 138.4 ± 2.1 mEq/L. Fifty-five patients (72.3%) developed hyponatremia while on therapy, of which 43.6% (n = 24) were cases of serum sodium <130 mEq/L. Mean sodium at the time of nadir was 131.6 ± 5.1 mEq/L. Hyponatremia was noted, on average, 5.5 days after initiation of therapy, with more severe hyponatremia development among African American patients. Urine sodium concentrations were available for 40.0% (22/55) of incident hyponatremia cases, with mean urinary sodium of 104.8 ± 55.9 mEq/L. Hyponatremia often resolved within 3 weeks of drug discontinuation. There is a high incidence (72.3%) of hyponatremia associated with the use of high-dose TMP-SMX among hospitalized patients. This is an overlooked and potentially reversible cause of hyponatremia. Copyright © 2016 Elsevier Inc. 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.

Partial palivizumab prophylaxis and increased risk of hospitalization due to respiratory syncytial virus in a Medicaid population: a retrospective cohort analysis.

PubMed

Krilov, Leonard R; Masaquel, Anthony S; Weiner, Leonard B; Smith, David M; Wade, Sally W; Mahadevia, Parthiv J

2014-10-13

Infection with respiratory syncytial virus (RSV) is common among young children insured through Medicaid in the United States. Complete and timely dosing with palivizumab is associated with lower risk of RSV-related hospitalizations, but up to 60% of infants who receive palivizumab in Medicaid population do not receive full prophylaxis. The purpose of this study was to evaluate the association of partial palivizumab prophylaxis with the risk of RSV hospitalization among high-risk Medicaid-insured infants. Claims data from 12 states during 6 RSV seasons (October 1st to April 30th in the first year of life in 2003-2009) were analyzed. Inclusion criteria were birth hospital discharge before October 1st, continuous insurance eligibility from birth through April 30th, ≥ one palivizumab administration from August 1st to end of season, and high-risk status (≤34 weeks gestational age or chronic lung disease of prematurity [CLDP] or hemodynamically significant congenital heart disease [CHD]). Fully prophylaxed infants received the first palivizumab dose by November 30th with no gaps >35 days up to the first RSV-related hospitalization or end of follow-up. All other infants were categorized as partially prophylaxed. Of the 8,443 high-risk infants evaluated, 67% (5,615) received partial prophylaxis. Partially prophylaxed infants were more likely to have RSV-related hospitalization than fully prophylaxed infants (11.7% versus 7.9%, p< 0.001). RSV-related hospitalization rates ranged from 8.5% to 24.8% in premature, CHD, and CLDP infants with partial prophylaxis. After adjusting for potential confounders, logistic regression showed that partially prophylaxed infants had a 21% greater odds of hospitalization compared with fully prophylaxed infants (odds ratio 1.21, 95% confidence interval 1.09-1.34). RSV-related hospitalization rates were significantly higher in high-risk Medicaid infants with partial palivizumab prophylaxis compared with fully prophylaxed infants. These findings suggest that reduced and/or delayed dosing is less effective.

Determination of the adequate dosage of rebamipide, a gastric mucoprotective drug, to prevent low-dose aspirin-induced gastrointestinal mucosal injury.

PubMed

Ota, Kazuhiro; Takeuchi, Toshihisa; Nouda, Sadaharu; Ozaki, Haruhiko; Kawaguchi, Shinpei; Takahashi, Yoshiaki; Harada, Satoshi; Edogawa, Shoko; Kojima, Yuichi; Kuramoto, Takanori; Higuchi, Kazuhide

2016-11-01

Small intestinal mucosal injury caused by low-dose aspirin is a common cause of obscure gastrointestinal bleeding. We aimed to investigate the protective effects and optimal dose of rebamipide for low-dose aspirin-induced gastrointestinal mucosal injury. In this prospective randomized trial, 45 healthy volunteers (aged 20-65 years) were included and divided into three groups. The groups received enteric-coated aspirin 100 mg (low-dose aspirin) plus omeprazole 10 mg (Group A: proton pump inhibitor group), low-dose aspirin plus rebamipide 300 mg (Group B: standard-dose group), or low-dose aspirin plus rebamipide 900 mg (Group C: high-dose group). Esophagogastroduodenoscopy and video capsule endoscopy were performed, and the fecal occult blood reaction and fecal calprotectin levels were measured before and two weeks after drug administration. Although the fecal calprotectin levels increased significantly in Group A, they did not increase in Groups B and C. The esophagogastroduodenoscopic and video capsule endoscopic findings and the fecal occult blood test findings did not differ significantly among the three groups. In conclusion, standard-dose rebamipide is sufficient for preventing mucosal injury of the small intestine induced by low-dose aspirin, indicating that high-dose rebamipide is not necessary.

Efficacy and Safety of Escalation of Adalimumab Therapy to Weekly Dosing in Pediatric Patients with Crohn's Disease.

PubMed

Dubinsky, Marla C; Rosh, Joel; Faubion, William A; Kierkus, Jaroslaw; Ruemmele, Frank; Hyams, Jeffrey S; Eichner, Samantha; Li, Yao; Huang, Bidan; Mostafa, Nael M; Lazar, Andreas; Thakkar, Roopal B

2016-04-01

The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; ≥40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing. Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab. Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing.

Vaccination coverage and factors influencing routine vaccination status in 12 high risk health zones in the Province of Kinshasa City, Democratic Republic of Congo (DRC), 2015.

PubMed

Mwamba, Guillaume Ngoie; Yoloyolo, Norbert; Masembe, Yolande; Nsambu, Muriel Nzazi; Nzuzi, Cathy; Tshekoya, Patrice; Dah, Barthelemy; Kaya, Guylain

2017-01-01

Vaccination coverage of the first dose of diphtheria-tetanus-pertussis-hepatitis B- Haemophilus influenza type b (pentavalent) vaccine for the City-Province of Kinshasain the years 2012 - 2014 wasbelow the national objective of 92%, with coverage less than 80% reported in 12 of the 35 health zones (HZ). The purpose of this study was to discern potential contributing factors to low vaccination coverage in Kinshasa. We conducted a multi-stage cluster household study of children 6 - 11 months in households residing in their current neighborhood for at least 3 months in the 12 high risk HZ in Kinshasa. Additional information on vaccination status of the children was collected at the health facility. Of the 1,513 households with a child 6-11 months old, 81% were eligible and participated. Among the 1224 children surveyed, 96% had received the first dose of pentavalent vaccine; 84% had received the third dose; and 71% had received all recommended vaccines for their age. Longer travel time to get to health facility (p=0.04) and shorter length of residence in the neighborhood (p=0.04) showed significant differences in relation to incomplete vaccination. Forty percent of children received their most recent vaccination in a facility outside of their HZ of residence. This survey found vaccination coverage in 12 HZs in Kinshasa was higher than estimates derived from administrative reports. The large percentage of children vaccinated outside of their HZ of residence demonstrates the challenge to use of the Reaching Every District strategy in urban areas.

Efficacy of transfusion with granulocytes from G-CSF/dexamethasone–treated donors in neutropenic patients with infection

PubMed Central

Boeckh, Michael; Harrison, Ryan W.; McCullough, Jeffrey; Ness, Paul M.; Strauss, Ronald G.; Nichols, W. Garrett; Hamza, Taye H.; Cushing, Melissa M.; King, Karen E.; Young, Jo-Anne H.; Williams, Eliot; McFarland, Janice; Holter Chakrabarty, Jennifer; Sloan, Steven R.; Friedman, David; Parekh, Samir; Sachais, Bruce S.; Kiss, Joseph E.; Assmann, Susan F.

2015-01-01

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/μL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 109 granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 109 granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393. PMID:26333778

The histomorphological findings of kidneys after application of high dose and high-energy shock wave lithotripsy.

PubMed

Demir, Aslan; Türker, Polat; Bozkurt, Suheyla Uyar; İlker, Yalcin Nazmi

2015-01-01

In this animal study, we reviewed the histomorphological findings in rabbit kidneys after a high number of high-energy shock wave applications and observed if there were any cumulative effects after repeated sessions. We formed 2 groups, each consisting of 8 rabbits. Group 1 received 1 session and group 2 received 3 sessions of ESWL with a 7 day interval between sessions, consisting of 3500 beats to the left kidney and 5500 beats to the right kidney per session. The specimens of kidneys were examined histomorphologically after bilateral nephrectomy was performed. For statistical analysis, 4 groups of specimens were formed. The first and second groups received 1 session, 3500 and 5500 beats, respectively. The third and fourth groups received 3 sessions, at 3500 and 5500 beats per each session, respectively. The sections were evaluated under a light microscope to determine subcapsular thickening; subcapsular, intratubular and parenchymal hemorrhage; subcapsular, intersitital, perivascular and proximal ureteral fibrosis; paranchymal necrosis; tubular epithelial vacuolization; tubular atrophy; glomerular destruction and calcification. In histopathological examinations capsular thickening, subcapsular hematoma, tubuloepithelial vacuolisation, glomerular destruction, parenchymal hemorrhage, interstitial fibrosis, and perivascular fibrosis were observed in all groups. In statistical analysis, on the basis of perivascular fibrosis and tubular atrophy, there was a beats per session dependent increase of both. The detrimental effects from ESWL are dose dependent but not cumulative for up to 3 sessions. Histopathological experimental animal studies will aid in understanding local and maybe, by means of these local effects, systemic effects.

Analysis of dose heterogeneity using a subvolume-DVH

NASA Astrophysics Data System (ADS)

Said, M.; Nilsson, P.; Ceberg, C.

2017-11-01

The dose-volume histogram (DVH) is universally used in radiation therapy for its highly efficient way of summarizing three-dimensional dose distributions. An apparent limitation that is inherent to standard histograms is the loss of spatial information, e.g. it is no longer possible to tell where low- and high-dose regions are, and whether they are connected or disjoint. Two methods for overcoming the spatial fragmentation of low- and high-dose regions are presented, both based on the gray-level size zone matrix, which is a two-dimensional histogram describing the frequencies of connected regions of similar intensities. The first approach is a quantitative metric which can be likened to a homogeneity index. The large cold spot metric (LCS) is here defined to emphasize large contiguous regions receiving too low a dose; emphasis is put on both size, and deviation from the prescribed dose. In contrast, the subvolume-DVH (sDVH) is an extension to the standard DVH and allows for a qualitative evaluation of the degree of dose heterogeneity. The information retained from the two-dimensional histogram is overlaid on top of the DVH and the two are presented simultaneously. Both methods gauge the underlying heterogeneity in ways that the DVH alone cannot, and both have their own merits—the sDVH being more intuitive and the LCS being quantitative.

[Pretreatment doses of antithymocyte globubin-fresenius for allogeneic hematopoietic stem cell transplantation for beta-thalassemia major].

PubMed

Li, Chunfu; Wang, Yanhua; Wu, Xuedong; Pei, Fuyu; He, Yuelin; Feng, Xiaoqin; Liu, Huaying

2012-05-01

To investigate the effects of different doses of antithymocyte globubin-fresenius (ATG-F) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with beta-thalassemia Major. Sixty-four children with beta-thalassemia major undergoing allo-HSCT were divided into two equal groups to receive ATG-F pretreatments at high (30 mg/kg) or low (15 mg/kg) doses as part of the conditioning regimen including mainly cyclophosphamide, busulfan, fludarabine, and thiotepa. The outcomes of the patients were compared between the two groups. No obvious difference were noted in the time to leukocyte and platelet engraftment between the two groups. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) appeared to be higher in the low-dose group than in the high-dose group (12.5% vs 9.4%). The incidence of grade III-IV aGVHD was also higher in the low dose group (12.5% vs 6.3%), but the difference was not statistically significant. Application of high-dose ATG-F was associated with a higher rate of probable and possible fungal infection (P<0.05). The two doses of ATG-F is feasible as a part of the conditioning regimen for allo-HSCT in children with beta-thalassemia major.

The effect of sulforaphane on oxidative stress and inflammation in rats with toxic hepatitis induced by acetaminophene.

PubMed

Dokumacioglu, E; Iskender, H; Aktas, M S; Hanedan, B; Dokumacioglu, A; Sen, T M; Musmul, A

2017-01-01

The aim of the present study was to reveal the possible effect of sulforaphane on oxidative stress and inflammation in rats liver with toxic hepatitis induced by acetaminophene. Sulforaphane is a compound with high antioxidant properties. Acetaminophen, which is a para-aminophenol derivative, can lead to fatal hepatic necrosis with direct hepatotoxic effects at high doses. Thirty six male Sprague-Dawley rats were randomly divided into four groups. Control group (n = 9) was fed with standard rat chow and water for 3 days. Group APAP (n = 9) received a single dose acetaminophen 1 g/kg by oral gavage in addition to standard chow and water. Group SFN (n = 9) received sulforaphane 500 μg/kg by oral gavage in addition to standard chow and water for 3 days. Group APAP+SFN (n = 9) received sulforaphane 500 μg/kg and a single dose acetaminophen 1 g/kg by oral gavage in addition to standard chow and water. Acetaminophen was administered three hours after SFN administration. Neopterin, MDA, AST, ALT and CRP levels of group APAP were significantly increased compared to control group. GSH level of group APAP was significantly lower than in the control group. Sulforaphane is a protective agent against acetaminophen-induced liver damage and it can be added in the treatment protocol (Tab. 1, Fig. 5, Ref. 51).

The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial.

PubMed

Yu, Zhaocai; Liu, Wenchao; Wang, Ling; Liang, Houjie; Huang, Ying; Si, Xiaoming; Zhang, Helong; Liu, Duhu; Zhang, Hongmei

2009-01-01

This clinical trial was conducted to evaluate the efficacy and safety of Palonosetron in preventing chemotherapy-induced vomiting (CIV) among the Chinese cancer patients. Two hundred and forty patients were scheduled to be enrolled and randomized to receive a single intravenous dose of palonosetron 0.25 mg, or granisetron 3 mg, 30 min before receiving highly emetogenic chemotherapy. The primary efficacy endpoint was the complete response (CR) rate for acute CIV (during the 0-24-h interval after chemotherapy). Secondary endpoints included the CR rates for delayed CIV (more than 24 h after chemotherapy). Two hundred and eight patients were accrued and received study medication. CR rates for acute CIV were 82.69% for palonosetron and 72.12% for granisetron, which demonstrated that palonosetron was not inferior to granisetron in preventing acute CIV. Comparisons of CR rates for delayed CIV yielded no statistical difference between palonosetron and granisetron groups and did not reveal non-inferiority of palonosetron to granisetron. Adverse events were mostly mild to moderate, with quite low rates among the two groups. A single dose (0.25 mg) of palonosetron is not inferior to a single dose (3 mg) of granisetron in preventing CIV and possesses an acceptable safety profile in the Chinese population.

Paraquat detoxication with multiple emulsions.

PubMed

Frasca, S; Couvreur, P; Seiller, M; Pareau, D; Lacour, B; Stambouli, M; Grossiord, J L

2009-10-01

In this study, we show that detoxifying W/O/W multiple emulsions, prepared with an appropriate extractant/trapping couple, represent a promising technology for quick and safe poisoning treatments, with application to the highly toxic herbicide Paraquat, responsible of poisonings from low-dose exposure leading to several deaths every year. In vitro tests led to the choice of an appropriate extractant/trapping couple system with significant detoxication performance. In vivo tests showed (i) that rats receiving high doses of Paraquat, then a detoxifying emulsion, presented an increase from 50% to 100% of the MST (median survival time) and (ii) that no mortality was observed during 30 days with rats dosed with emulsions initially loaded with Paraquat at a concentration much higher than the lethal dose, proving the stability and the inocuity of the detoxifying multiple emulsion in the gastrointestinal tract.

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

Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis.

PubMed

Cakici, Cagri; Yigitbasi, Turkan; Ayla, Sule; Karimkhani, Hadi; Bayramoglu, Feyza; Yigit, Pakize; Kilic, Ertugrul; Emekli, Nesrin

2018-02-08

Background The purpose of this study is to examine the dose-dependent effects of vitamin 1,25(OH)2D3 on apoptosis and oxidative stress. Methods In this study, 50 male Balb/c mice were used as control and experiment groups. The mice were divided into 5 groups each consisting of 10 mice. Calcitriol was intraperitoneally administered as low dose, medium dose, medium-high dose and high dose vitamin D groups (at 0.5, 1, 5 and 10 μg/kg, respectively), for three times a week during 14 days. At the end of the study, annexin V was measured by enzyme-linked immunosorbent assay method, and total antioxidant capacity and total oxidant status values were measured by colorimetric method in serum. Hematoxylin eosin staining was performed in liver tissues and periodic acid schiff staining was performed in kidney tissues. Results While comparing the results of medium-high dose (5 μg/kg) and high dose (10 μg/kg) vitamin D administration to that of the control group, it was observed that serum antioxidant status and annexin V levels decreased and glomerular mesenchial matrix ratio increased in kidney (p<0.05). In addition to these findings, in the group receiving high dose vitamin D (10 μg/kg), it was observed that the damage to the liver increased together with the the oxidative stress index values (p<0.05). Conclusions As a result, this study was the first in the literature to report that use of high-dose vitamin D (10 μg/kg) results in oxidant effect, rather than being an antioxidant, and causes severe histopathological toxicity in the liver and kidney.

High- and low-dose oral delayed-release mesalamine in children with mild-to-moderately active ulcerative colitis.

PubMed

Winter, Harland S; Krzeski, Piotr; Heyman, Melvin B; Ibarguen-Secchia, Eduardo; Iwanczak, Barbara; Kaczmarski, Maciej; Kierkus, Jaroslaw; Kolaček, Sanja; Osuntokun, Bankole; Quiros, J Antonio; Shah, Manoj; Yacyshyn, Bruce; Dunnmon, Preston M

2014-12-01

The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis. Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of ≥ 10 to ≤ 55 and a truncated Mayo Score of ≥ 1 for both rectal bleeding and stool frequency, were enrolled. They received body weight-dependent doses of oral, delayed-release mesalamine for 6 weeks in a low- (27-71 mg · g(-1) · day(-1)) or high-dose group (53-118 mg · g(-1) · day(-1)). The primary endpoint was treatment success, defined as the proportion of patients who achieved remission (PUCAI score <10) or partial response (PUCAI score ≥ 10 with a decrease from baseline by ≥ 20 points). Secondary endpoints included truncated Mayo Score and global assessment of change of disease activity. The modified intent-to-treat population included 81 of 83 patients enrolled. Treatment success by PUCAI was achieved by 23 of 41 (56%) and 22 of 40 (55%) patients in the mesalamine low- and high-dose groups, respectively (P = 0.924). Truncated Mayo Score (low-dose 30 [73%] and high-dose 28 [70%] patients) and other efficacy results did not differ between the groups. The type and severity of adverse events were consistent with those reported in previous studies of adults with ulcerative colitis and did not differ between groups. Both low- and high-dose oral, delayed-release mesalamine doses were equally effective as short-term treatment of mild-to-moderately active ulcerative colitis in children, without a specific benefit or risk to using either dose.

Combination Antifungal Therapy for Cryptococcal Meningitis

PubMed Central

Day, Jeremy N.; Chau, Tran T.H.; Wolbers, Marcel; Mai, Pham P.; Dung, Nguyen T.; Mai, Nguyen H.; Phu, Nguyen H.; Nghia, Ho D.; Phong, Nguyen D.; Thai, Cao Q.; Thai, Le H.; Chuong, Ly V.; Sinh, Dinh X.; Duong, Van A.; Hoang, Thu N.; Diep, Pham T.; Campbell, James I.; Sieu, Tran P.M.; Baker, Stephen G.; Chau, Nguyen V.V.; Hien, Tran T.

2014-01-01

BACKGROUND Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P = 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P = 0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P = 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P = 0.13). amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.) PMID:23550668

Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation.

PubMed

Nava-Mesa, Mauricio O; Lamprea, Marisol R; Múnera, Alejandro

2013-11-01

Acute stress induces short-term object recognition memory impairment and elicits endogenous opioid system activation. The aim of this study was thus to evaluate whether opiate system activation mediates the acute stress-induced object recognition memory changes. Adult male Wistar rats were trained in an object recognition task designed to test both short- and long-term memory. Subjects were randomly assigned to receive an intraperitoneal injection of saline, 1 mg/kg naltrexone or 3 mg/kg naltrexone, four and a half hours before the sample trial. Five minutes after the injection, half the subjects were submitted to movement restraint during four hours while the other half remained in their home cages. Non-stressed subjects receiving saline (control) performed adequately during the short-term memory test, while stressed subjects receiving saline displayed impaired performance. Naltrexone prevented such deleterious effect, in spite of the fact that it had no intrinsic effect on short-term object recognition memory. Stressed subjects receiving saline and non-stressed subjects receiving naltrexone performed adequately during the long-term memory test; however, control subjects as well as stressed subjects receiving a high dose of naltrexone performed poorly. Control subjects' dissociated performance during both memory tests suggests that the short-term memory test induced a retroactive interference effect mediated through light opioid system activation; such effect was prevented either by low dose naltrexone administration or by strongly activating the opioid system through acute stress. Both short-term memory retrieval impairment and long-term memory improvement observed in stressed subjects may have been mediated through strong opioid system activation, since they were prevented by high dose naltrexone administration. Therefore, the activation of the opioid system plays a dual modulating role in object recognition memory. Copyright © 2013 Elsevier Inc. All rights reserved.

The dose-effect relationship of baclofen in alcohol dependence: A 1-year cohort study.

PubMed

Pignon, Baptiste; Labreuche, Julien; Auffret, Marine; Gautier, Sophie; Deheul, Sylvie; Simioni, Nicolas; Cottencin, Olivier; Bordet, Régis; Duhamel, Alain; Rolland, Benjamin

2017-07-01

Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence. Two hundred two patients with alcohol dependence, who received baclofen treatment for drinking reduction, were followed up for 1 year. For each patient-month of treatment, the maximum daily dose of baclofen (DDB) and average weekly alcohol consumption (AWAC) were calculated. We defined a favorable drinking outcome as an AWAC under 200 g/w for at least 2 consecutive months. We divided the DDB of each patient-month into 3 categories (low dose: <90 mg/d, medium dose: 90-150 mg/d, and high dose: >150 mg/d) and investigated the relationship between reaching a favorable outcome and the concurrent DDB category in a time-varying Cox regression analysis. Hazard ratios (HRs) were adjusted based on age, sex, and initial AWAC. One hundred forty subjects were followed during at least 1 month. Of these patients, 58 (41%) had a favorable drinking outcome. In comparison to low dose, medium dose was associated with a decreased rate of favorable drinking outcome (HR = 0.42; 95% CI [0.20, 0.88]), whereas no difference was found with high dose (HR = 1.31; 95% CI [0.65, 2.64]). The relationship between dose of baclofen and favorable drinking outcome was U-shaped, that is, was increased at low and high doses compared to medium doses. Copyright © 2017 John Wiley & Sons, Ltd.

Nonaqueous, mini-dose glucagon for treatment of mild hypoglycemia in adults with type 1 diabetes: A dose-seeking study

USDA-ARS?s Scientific Manuscript database

To evaluate mini-dose glucagon in adults with type 1 diabetes using a stable, liquid, ready-to-use preparation, twelve adults with type 1 diabetes receiving treatment with insulin pumps received subcutaneous doses of 75, 150, and 300 ug of nonaqueous glucagon. Plasma glucose, glucagon, and insulin c...

42 CFR 82.5 - Definition of terms used in this part.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Illness Compensation Program Act of 2000, 42 U.S.C. 7384-7385 [1994, supp. 2001]. (i) Equivalent dose is... equivalent dose that is received from radiation sources outside of the body. (k) Internal dose means that portion of the equivalent dose that is received from radioactive materials taken into the body. (l) NIOSH...

A multicenter, randomized, double-blind, placebo-controlled trial of high-dose rebamipide treatment for low-dose aspirin-induced moderate-to-severe small intestinal damage.

PubMed

Watanabe, Toshio; Takeuchi, Toshihisa; Handa, Osamu; Sakata, Yasuhisa; Tanigawa, Tetsuya; Shiba, Masatsugu; Naito, Yuji; Higuchi, Kazuhide; Fujimoto, Kazuma; Yoshikawa, Toshikazu; Arakawa, Tetsuo

2015-01-01

Low-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy. We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity) from baseline to 8 weeks. The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13). After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did not. The triple dose of rebamipide was well tolerated. High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy. UMIN Clinical Trials Registry UMIN000003463.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of High-Dose Rebamipide Treatment for Low-Dose Aspirin-Induced Moderate-to-Severe Small Intestinal Damage

PubMed Central

Watanabe, Toshio; Takeuchi, Toshihisa; Handa, Osamu; Sakata, Yasuhisa; Tanigawa, Tetsuya; Shiba, Masatsugu; Naito, Yuji; Higuchi, Kazuhide; Fujimoto, Kazuma; Yoshikawa, Toshikazu; Arakawa, Tetsuo

2015-01-01

Background Low-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant. Aim We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy. Methods We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity) from baseline to 8 weeks. Results The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13). After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did not. The triple dose of rebamipide was well tolerated. Conclusions High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy. Trial Registration UMIN Clinical Trials Registry UMIN000003463 PMID:25874951

Dosimetry around metallic ports in tissue expanders in patients receiving postmastectomy radiation therapy: an ex vivo evaluation.

PubMed

Moni, Janaki; Graves-Ditman, Maria; Cederna, Paul; Griffith, Kent; Krueger, Editha A; Fraass, Benedick A; Pierce, Lori J

2004-01-01

Postmastectomy breast reconstruction can be accomplished utilizing tissue expanders and implants. However, in patients who require postoperative radiotherapy, the complication rate with tissue expander/implant reconstruction can exceed 50%. One potential cause of this high complication rate may be the metallic port in the tissue expander producing altered dosimetry in the region of the metallic device. The purpose of this study was to quantify the radiation dose distribution in the vicinity of the metallic port and determine its potential contribution to this extremely high complication rate. The absolute dosimetric effect of the tissue expander's metallic port was quantified using film and thermoluminescent dosimetry (TLD) studies with a single beam incident on a metallic port extracted from an expander. TLD measurements were performed at 11 reproducible positions on an intact expander irradiated with tangential fields. A computed tomography (CT)-based treatment plan without inhomogeneity corrections was used to derive expected doses for all TLD positions. Multiple irradiation experiments were performed for all TLD data. Confidence intervals for the dose at TLD sites with the metallic port in place were compared to the expected dose at the site without the metallic port. Film studies did not reveal a significant component of scatter around the metallic port. TLD studies of the extracted metallic port revealed highest doses within the casing of the metallic port and no consistent increased dose at the surface of the expander. No excess dose due to the metallic port in the expander was noted with the phantom TLD data. Based upon these results, it does not appear that the metallic port in tissue expanders significantly contributes to the high complication rate experienced in patients undergoing tissue expander breast reconstruction and receiving radiation therapy. Strategies designed to reduce the breast reconstruction complication rate in this clinical setting will need to focus on factors other than adjusting the dosimetry around the tissue expander metallic port.

Evaluation of Radiation Exposure to Staff and Environment Dose from [18F]-FDG in PET/CT and Cyclotron Center using Thermoluminescent Dosimetry

PubMed Central

Zargan, S.; Ghafarian, P.; Shabestani Monfared, A.; Sharafi, A.A.; Bakhshayeshkaram, M.; Ay, M.R.

2017-01-01

Background: PET/CT imaging using [18F]-FDG is utilized in clinical oncology for tumor detecting, staging and responding to therapy procedures. Essential consideration must be taken for radiation staff due to high gamma radiation in PET/CT and cyclotron center. The aim of this study was to assess the staff exposure regarding whole body and organ dose and to evaluate environment dose in PET/CT and cyclotron center. Materials and Methods: 80 patients participated in this study. Thermoluminescence, electronic personal dosimeter and Geiger-Muller dosimeter were also utilized for measurement purpose. Results: The mean annual equivalent organ dose for scanning operator with regard to lens of eyes, thyroid, breast and finger according to mean±SD value, were 0.262±0.044, 0.256±0.046, 0.257±0.040 and 0.316±0.118, respectively. The maximum and minimum estimated annual whole body doses were observed for injector and the chemist group with values of (3.98±0.021) mSv/yr and (1.64±0.014) mSv/yr, respectively. The observed dose rates were 5.67 µSv/h in uptake room at the distance of 0.5 meter from the patient whereas the value 4.94 and 3.08 µSv/h were recorded close to patient’s head in PET/CT room and 3.5 meter from the reception desk. Conclusion: In this study, the injector staff and scanning operator received the first high level and second high level of radiation. This study confirmed that low levels of radiation dose were received by all radiation staff during PET/CT procedure using 18F-FDG due to efficient shielding and using trained radiation staff in PET/CT and cyclotron center of Masih Daneshvari hospital. PMID:28451574

Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas

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

DeLaney, Thomas F.; Liebsch, Norbert J.; Pedlow, Francis X.

Purpose: Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of {>=}66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. Methods and Materials: Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to grossmore » disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. Results: A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. Conclusions: Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.« less

Outcomes of peptic ulcer bleeding following treatment with proton pump inhibitors in routine clinical practice: 935 patients with high- or low-risk stigmata.

PubMed

Lanas, Angel; Carrera-Lasfuentes, Patricia; García-Rodríguez, Luis A; García, Santiago; Arroyo-Villarino, María Teresa; Ponce, Julio; Bujanda, Luis; Calleja, José L; Polo-Tomas, Mónica; Calvet, Xavier; Feu, Faust; Perez-Aisa, Angeles

2014-10-01

To assess rates of further bleeding, surgery and mortality in patients hospitalized owing to peptic ulcer bleeding. Consecutive patients hospitalized for peptic ulcer bleeding and treated with a proton pump inhibitor (PPI) (esomeprazole or pantoprazole) were identified retrospectively in 12 centers in Spain. Patients were included if they had high-risk stigmata (Forrest class Ia-IIb, underwent therapeutic endoscopy and received intravenous PPI ≥120 mg/day for ≥24 h) or low-risk stigmata (Forrest class IIc-III, underwent no therapeutic endoscopy and received intravenous or oral PPI [any dose]). Of 935 identified patients, 58.3% had high-risk stigmata and 41.7% had low-risk stigmata. After endoscopy, 88.3% of high-risk patients and 22.1% of low-risk patients received intravenous PPI therapy at doses of at least 160 mg/day. Further bleeding within 72 h occurred in 9.4% and 2.1% of high- and low-risk patients, respectively (p < 0.001). Surgery to stop bleeding was required within 30 days in 3.5% and 0.8% of high- and low-risk patients, respectively (p = 0.007). Mortality at 30 days was similar in both groups (3.3% in high-risk and 2.3% in low-risk patients). Among patients hospitalized owing to peptic ulcer bleeding and treated with PPIs, patients with high-risk stigmata have a higher risk of further bleeding and surgery, but not of death, than those with low-risk stigmata.

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.

Colistin-associated Acute Kidney Injury in Severely Ill Patients: A Step Toward a Better Renal Care? A Prospective Cohort Study.

PubMed

Dalfino, Lidia; Puntillo, Filomena; Ondok, Maria Josephine Mura; Mosca, Adriana; Monno, Rosa; Coppolecchia, Sara; Spada, Maria Luigia; Bruno, Francesco; Brienza, Nicola

2015-12-15

Critically ill patients with severe sepsis or septic shock may need relatively high colistin daily doses for efficacy against multidrug-resistant and extensively drug-resistant gram-negative rods. However, acute kidney injury (AKI) may represent a major dose-limiting adverse effect of colistin. We sought to determine AKI occurrence and to identify factors influencing AKI risk in severely ill patients receiving colistin according to a recently proposed dosing strategy. A prospective, observational, cohort study involving patients with severe sepsis or septic shock who received colistin was performed. AKI was defined according to Acute Kidney Injury Network criteria. Colistin administration was driven by a modified pharmacokinetics-pharmacodynamics (PK/PD)-based dosing approach. Of 70 patients who received colistin at a median daily dose of 9 million IU (MIU; interquartile range, 5.87-11.1 MIU), 31 (44%) developed AKI. In univariate analysis, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA), score and baseline renal impairment were significantly associated with AKI. Moreover, patients with AKI were less frequently treated with adjuvant ascorbic acid (P = .003). In multivariate analysis, independent predictors of AKI were baseline renal impairment (adjusted hazard ratio, 4.15; 95% confidence interval, 1.9-9.2; P < .001) and age (1.03; 1.0-1.05; P = .028), whereas a strong independent renal-protective role emerged for ascorbic acid (0.27; .12-.57; P < .001). In severely ill patients receiving colistin according to a PK/PD-driven dosing approach, baseline renal impairment and older age strongly predict AKI occurrence, but concomitant administration of ascorbic acid markedly reduces AKI risk, allowing safer use of colistin. © The Author 2015. 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 methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance.

PubMed

Joannon, Pilar; Oviedo, Iris; Campbell, Myriam; Tordecilla, Juan

2004-07-01

The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable. Copyright 2004 Wiley-Liss, Inc.

Effect of vitamin C on male fertility in rats subjected to forced swimming stress.

PubMed

Vijayprasad, Sanghishetti; Bb, Ghongane; Bb, Nayak

2014-07-01

Stress is defined as a general body response to initially threatening external or internal demands, involving the mobilization of physiological and psychological resources to deal with them. Recently, oxidative stress has become the focus of interest as a potential cause of male infertility. Normally, equilibrium exists between reactive oxygen species (ROS) production and antioxidant scavenging activities in the male reproductive organs. The ascorbic acid is a known antioxidant present in the testis with the precise role of protecting the latter from the oxidative damage. It also contributes to the support of spermatogensis at least in part through its capacity to maintain antioxidant in an active state. Group1: Normal Control animal received Distilled water, Group 2: Positive control (Only Stress), Group 3: Normal rats received an intermediate dose of Vitamin C (20mg/kg/day), Group 4: Stress + Low dose Vitamin C (10mg/kg/day), Group 5: Stress+ Intermediate dose Vitamin C (20mg/kg/day), Group 6: High dose Vitamin C (30mg/kg/day). On 16(th) day effect of stress on body weight, Reproductive organ weight, sperm parameters, and hormonal assay was studied. In the present context, in stress group the sperm count, motility, testicular weight declined significantly. The intermediate dose and high dose of vitamin C showed significantly increased effect on the sperm count and motility. Various physiological changes produced force swimming indicates that swimming is an effective model for producing stress in albino rats. The results suggest that Vitamin C supplementation improves the stress induced reproductive infertility due to both their testosterone increase effect and their antioxidant effect.

Testosterone influences spatial strategy preferences among adult male rats

PubMed Central

Spritzer, Mark D.; Fox, Elliott C.; Larsen, Gregory D.; Batson, Christopher G.; Wagner, Benjamin A.; Maher, Jack

2013-01-01

Males outperform females on some spatial tasks, and this may be partially due to the effects of sex steroids on spatial strategy preferences. Previous work with rodents indicates that low estradiol levels bias females toward a striatum-dependent response strategy, whereas high estradiol levels bias them toward a hippocampus-dependent place strategy. We tested whether testosterone influenced the strategy preferences in male rats. All subjects were castrated and assigned to one of three daily injection doses of testosterone (0.125, 0.250, or 0.500 mg/rat) or a control group that received daily injections of the drug vehicle. Three different maze protocols were used to determine rats’ strategy preferences. A low dose of testosterone (0.125 mg) biased males toward a motor-response strategy on a T-maze task. In a water maze task in which the platform itself could be used intermittently as a visual cue, a low testosterone dose (0.125 mg) caused a significant increase in the use of a cued-response strategy relative to control males. Results from this second experiment also indicated that males receiving a high dose of testosterone (0.500 mg) were biased toward a place strategy. A third experiment indicated that testosterone dose did not have a strong influence on the ability of rats to use a nearby visual cue (floating ball) in the water maze. For this experiment, all groups seemed to use a combination of place and cued-response strategies. Overall, the results indicate that the effects of testosterone on spatial strategy preference are dose dependent and task dependent. PMID:23597827

Testosterone influences spatial strategy preferences among adult male rats.

PubMed

Spritzer, Mark D; Fox, Elliott C; Larsen, Gregory D; Batson, Christopher G; Wagner, Benjamin A; Maher, Jack

2013-05-01

Males outperform females on some spatial tasks, and this may be partially due to the effects of sex steroids on spatial strategy preferences. Previous work with rodents indicates that low estradiol levels bias females toward a striatum-dependent response strategy, whereas high estradiol levels bias them toward a hippocampus-dependent place strategy. We tested whether testosterone influenced the strategy preferences in male rats. All subjects were castrated and assigned to one of three daily injection doses of testosterone (0.125, 0.250, or 0.500 mg/rat) or a control group that received daily injections of the drug vehicle. Three different maze protocols were used to determine rats' strategy preferences. A low dose of testosterone (0.125 mg) biased males toward a motor-response strategy on a T-maze task. In a water maze task in which the platform itself could be used intermittently as a visual cue, a low testosterone dose (0.125 mg) caused a significant increase in the use of a cued-response strategy relative to control males. Results from this second experiment also indicated that males receiving a high dose of testosterone (0.500 mg) were biased toward a place strategy. A third experiment indicated that testosterone dose did not have a strong influence on the ability of rats to use a nearby visual cue (floating ball) in the water maze. For this experiment, all groups seemed to use a combination of place and cued-response strategies. Overall, the results indicate that the effects of testosterone on spatial strategy preference are dose dependent and task dependent. Copyright © 2013 Elsevier Inc. All rights reserved.

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

Effects of radiation exposure from cardiac imaging: how good are the data?

PubMed

Einstein, Andrew J

2012-02-07

Concerns about medical exposure to ionizing radiation have become heightened in recent years as a result of rapid growth in procedure volumes and the high radiation doses incurred from some procedures. This paper summarizes the evidence base undergirding concerns about radiation exposure in cardiac imaging. After classifying radiation effects, explaining terminology used to quantify the radiation received by patients, and describing typical doses from cardiac imaging procedures, this paper will address the major epidemiological studies having bearing on radiation effects at doses comparable to those received by patients undergoing cardiac imaging. These include studies of atomic bomb survivors, nuclear industry workers, and children exposed in utero to x-rays, all of which have evidenced increased cancer risks at low doses. Additional higher-dose epidemiological studies of cohorts exposed to radiation in the context of medical treatment are described and found to be generally compatible with these cardiac dose-level studies, albeit with exceptions. Using risk projection models developed by the U.S. National Academies that incorporate these data and reflect several evidence-based assumptions, cancer risk from cardiac imaging can be estimated and compared with the benefits from imaging. Several ongoing epidemiological studies will provide better understanding of radiation-associated cancer risks. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.

PubMed

Weber, Catherine; Kasberg, Heather; Copelan, Edward

2012-01-01

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Heterogeneity of Rotavirus Vaccine Efficacy Among Infants in Developing Countries.

PubMed

Gruber, Joann F; Hille, Darcy A; Liu, G Frank; Kaplan, Susan S; Nelson, Micki; Goveia, Michelle G; Mast, T Christopher

2017-01-01

Rotavirus is the leading cause of severe diarrhea worldwide in young children. Although rotavirus vaccine efficacy is high in developed countries, efficacy is lower in developing countries. Here, we investigated heterogeneity of rotavirus vaccine efficacy by infant characteristics in developing countries. An exploratory, post hoc analysis was conducted using randomized controlled trial data of the pentavalent rotavirus vaccine (RV5) conducted in Africa and Asia (NCT00362648). Infants received either 3 doses of vaccine/placebo and were followed for up to 2 years. Within subgroups, vaccine efficacies and 95% confidence intervals (CIs) against rotavirus gastroenteritis (RVGE) were estimated using Poisson regression. We assessed heterogeneity of efficacy by age at first dose, gender, breastfeeding status and nutrition status. African children receiving the first dose at <8 weeks had lower efficacy (23.7%; 95% CI: -8.2%-46.3%) than those vaccinated at ≥8 weeks (59.1%; 95% CI: 34.0%-74.6%). Marginally statistically significant differences were observed by age at first dose, gender and underweight status in Ghana and gender in Asian countries. Heterogeneity of efficacy was observed for age at first dose in African countries. This was an exploratory analysis; additional studies are needed to validate these results.

Y-box-binding protein YB-1 identifies high-risk patients with primary breast cancer benefiting from rapidly cycled tandem high-dose adjuvant chemotherapy.

PubMed

Gluz, Oleg; Mengele, Karin; Schmitt, Manfred; Kates, Ronald; Diallo-Danebrock, Raihana; Neff, Frauke; Royer, Hans-Dieter; Eckstein, Niels; Mohrmann, Svjetlana; Ting, Evelyn; Kiechle, Marion; Poremba, Christopher; Nitz, Ulrike; Harbeck, Nadia

2009-12-20

To investigate the potential of Y-box-binding protein YB-1, a multifunctional protein linked to tumor aggressiveness and multidrug resistance, to identify patients with breast cancer likely to benefit from dose-intensified chemotherapy regimens. YB-1 was immunohistochemically determined in 211 primary tumors from the prospective, randomized West German Study Group WSG-AM-01 trial in high-risk (> or = 10 involved lymph-nodes) breast cancer (HRBC). Predictive impact of YB-1 was assessed by multivariate survival analysis, including time-varying factor-therapy interactions. At median follow-up of 61.7 months, patients receiving rapidly cycled tandem high-dose therapy (HD; two cycles [2x] epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) every 14 days, followed by 2x epirubicin 90 mg/m(2), cyclophosphamide 3,000 mg/m(2), and thiotepa 400 mg/m(2) every 21 days) had better disease-free survival (DFS; hazard ratio [HR] = 0.62; 95% CI, 0.44 to 0.89) and overall survival (OS; HR = 0.59; 95% CI, 0.4 to 0.89) than those receiving conventional dose-dense chemotherapy (DD; 4x epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), followed by 3x cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) every 14 days). High YB-1 was associated with aggressive tumor phenotype (negative steroid hormone receptor status, positive human epidermal growth factor receptor 2 and p53 status, high MIB-1, unfavorable tumor grade) and poor OS (median 78 v 97 months; P = .01). In patients with high YB-1, HD yielded a 63-month median DFS (P = .001) and a 46-month median OS advantage (P = .002) versus DD. In multivariate models, patients with high B-1 receiving HD (v DD) had one third the hazard rate after 20 months for DFS and one sixth after 40 months for OS. In a randomized prospective cancer therapy trial, for the first time, a strong predictive impact of YB-1 on survival has been demonstrated: enhanced benefit from HD (v DD) therapy occurs in HRBC with high YB-1. Future trials could therefore address optimal chemotherapeutic strategies,taking YB-1 into account.

Bacteremia due to viridans streptococcus in neutropenic patients with cancer: clinical spectrum and risk factors.

PubMed

Bochud, P Y; Eggiman, P; Calandra, T; Van Melle, G; Saghafi, L; Francioli, P

1994-01-01

Between 1988 and 1991, 26 episodes of bacteremia due to viridans streptococci occurred in 25 neutropenic patients undergoing intensive chemotherapy for hematologic malignancies. Complications related to the bacteremia were observed in 10 episodes: unilateral pulmonary infiltrates (4), acute respiratory distress syndrome (ARDS) (4), hypotension (3), and endocarditis (2). All patients with ARDS had received high doses of cytosine arabinoside and had bacteremia due to Streptococcus mitis. Death occurred in three patients (12%) but was possibly related to bacteremia in only one case. Case patients who had received prophylaxis with quinolones were compared with matched control patients who received similar prophylaxis but who did not have bacteremia due to viridans streptococci. Multivariate analysis of predisposing factors showed that high doses of cytosine arabinoside (P = .01), the presence of mucositis (P = .02), and the absence of previous therapy with parenteral antibiotics (P = .01) were independent risk factors for the development of viridans streptococcal bacteremia. Of 259 patients who had received quinolone prophylaxis during the study period, 22 (8.5%) developed an episode of viridans streptococcal bacteremia as compared with three episodes (3.7%) in 82 patients who had received a quinolone and penicillin (P = .07). However, the latter three episodes were caused by strains with decreased susceptibility to penicillin, thus suggesting that resistance to penicillin might limit the use of this antibiotic as a prophylactic agent in the future.

The effect of low dose ionizing radiation on homeostasis and functional integrity in an organotypic human skin model

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

von Neubeck, Claere; Geniza, Matthew; Kauer, Paula M.

Outside the protection of earth’s atmosphere, astronauts are exposed to low doses of high linear energy transfer (LET) radiation. Future NASA plans for deep space missions or a permanent settlement on the moon are limited by the health risks associated with space radiation exposures. There is a paucity of direct epidemiological data for low dose exposures to space radiation-relevant high LET ions. Health risk models are used to estimate the risk for such exposures, though these models are based on high dose experiments. There is increasing evidence, however, that low and high dose exposures result in different signaling events atmore » the molecular level, and may involve different response mechanisms. Further, despite their low abundance, high LET particles have been identified as the major contributor to health risk during manned space flight. The human skin is exposed in every external radiation scenario, making it an ideal epithelial tissue model in which to study radiation induced effects. Here, we exposed an in vitro three dimensional (3-D) human organotypic skin tissue model to low doses of high LET oxygen (O), silicon (Si) and iron (Fe) ions. We measured proliferation and differentiation profiles in the skin tissue and examined the integrity of the skin’s barrier function. We discuss the role of secondary particles in changing the proportion of cells receiving a radiation dose, emphasizing the possible impact on radiation-induced health issues in astronauts.« less

A randomized controlled study comparing omeprazole and cimetidine for the prophylaxis of stress-related upper gastrointestinal bleeding in patients with intracerebral hemorrhage.

PubMed

Liu, Bo-lin; Li, Bing; Zhang, Xiang; Fei, Zhou; Hu, Shi-jie; Lin, Wei; Gao, Da-kuan; Zhang, Li

2013-01-01

Patients with intracerebral hemorrhage (ICH) are at high risk for severe stress-related upper gastrointestinal (UGI) bleeding, which is predictive of higher mortality. The aim of this study was to evaluate the effectiveness of omeprazole and cimetidine compared with a placebo in the prevention and management of stress-related UGI bleeding in patients with ICH. In a single-center, randomized, placebo-controlled study, 184 surgically treated patients with CT-proven ICH within 72 hours of ictus and negative results for gastric occult blood testing were included. Of these patients, 165 who were qualified upon further evaluation were randomized into 3 groups: 58 patients received 40 mg intravenous omeprazole every 12 hours, 54 patients received 300 mg intravenous cimetidine every 6 hours, and 53 patients received a placebo. Patients whose gastric occult blood tests were positive at admission (n = 70) and during/after the prophylaxis procedure (n = 48) were treated with high-dose omeprazole at 80 mg bolus plus 8 mg/hr infusion for 3 days, followed by 40 mg intravenous omeprazole every 12 hours for 7 days. Of the 165 assessable patients, stress-related UGI bleeding occurred in 9 (15.5%) in the omeprazole group compared with 15 patients (27.8%) in the cimetidine group and 24 patients (45.3%) in the placebo group (p = 0.003). The occurrence of UGI bleeding was significantly related to death (p = 0.022). Nosocomial pneumonia occurred in 14 patients (24.1%) receiving omeprazole, 12 (22.2%) receiving cimetidine, and 8 (15.1%) receiving placebo (p > 0.05). In patients with UGI bleeding in which high-dose omeprazole was initiated, UGI bleeding arrested within the first 3 days in 103 patients (87.3%). Omeprazole significantly reduced the morbidity of stress-related UGI bleeding in patients with ICH due to its effective prophylactic effect without increasing the risk of nosocomial pneumonia, but it did not reduce the 1-month mortality or ICU stay. Further evaluation of high-dose omeprazole as the drug of choice for patients presenting with UGI bleeding is warranted. Clinical trial registration no.: ChiCTR-TRC-12001871, registered at the Chinese clinical trial registry (http://www.chictr.org/en/proj/show.aspx?proj=2384).

Botulinum Toxin Dosing Trends in Spasmodic Dysphonia Over a 20-year Period.

PubMed

Namin, Arya W; Christopher, Kara M; Eisenbeis, John F

2017-01-01

The study aims to (1) identify the botulinum toxin (BTX) dosing trend in a cohort of patients who received at least 20 injections for the treatment of adductor spasmodic dysphonia (ADSD), (2) describe two distinct BTX dosing trends in treating ADSD (a "classic" dosing trend that initially decreases before stabilizing, and a "fluctuating" dosing trend), and (3) determine if patients with the "classic" dosing trend differed in age or in dosing intervals from those with the "fluctuating" dosing trend. This is a retrospective case series. Of 149 patients who received a total of 2484 BTX injections for the treatment of spasmodic dysphonia in 1993-2013, 49 patients received at least 20 injections. The BTX dose and the interval between doses were recorded. The mean dose of injections 1-20 was determined. The age at initial injection, initial dose, and interval in days between treatments were compared for the "fluctuating" and "classic" groups. The cohort exhibits a significant decrease in dose during the first 10-15 injections. The "fluctuating" group had a significantly shorter interval between injections (mean interval = 97.09 days, SD = 29.41; mean interval = 136.90 days, SD = 43.76, P = 0.002). The mean age at initial dose was not significantly different between the "classic" and "fluctuating" groups. The average BTX dose of patients with ADSD who receive long-term injections significantly decreases during the initial 10-15 injections before stabilizing. Patients who exhibit the "fluctuating" dosing pattern have a significantly shorter interval between injections than those with the "classic" dosing pattern. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

PubMed

Dean, J A; Welsh, L C; Wong, K H; Aleksic, A; Dunne, E; Islam, M R; Patel, A; Patel, P; Petkar, I; Phillips, I; Sham, J; Schick, U; Newbold, K L; Bhide, S A; Harrington, K J; Nutting, C M; Gulliford, S L

2017-04-01

A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Clinical Toxicities and Dosimetric Parameters After Whole-Pelvis Versus Prostate-Only Intensity-Modulated Radiation Therapy for Prostate Cancer

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

Deville, Curtiland, E-mail: deville@uphs.upenn.ed; Both, Stefan; Hwang, Wei-Ting

2010-11-01

Purpose: To assess whether whole-pelvis (WP) intensity-modulated radiation therapy (IMRT) is associated with increased toxicity compared with prostate-only (PO) IMRT. Methods and Materials: We retrospectively analyzed all patients with prostate cancer undergoing definitive IMRT to 79.2 Gy with concurrent androgen deprivation at our institution from November 2005 to May 2007 with a minimum follow-up of 12 months. Thirty patients received initial WP IMRT to 45 Gy in 1.8-Gy fractions, and thirty patients received PO IMRT. Study patients underwent computed tomography simulation and treatment planning by use of predefined dose constraints. Bladder and rectal dose-volume histograms, maximum genitourinary (GU) and gastrointestinalmore » (GI) Radiation Therapy Oncology Group toxicity grade, and late Grade 2 or greater toxicity-free survival curves were compared between the two groups by use of the Student t test, Fisher exact test, and Kaplan-Meier curve, respectively. Results: Bladder minimum dose, mean dose, median dose, volume receiving 5 Gy, volume receiving 20 Gy, volume receiving 40 Gy, and volume receiving 45 Gy and rectal minimum dose, median dose, and volume receiving 20 Gy were significantly increased in the WP group (all p values < 0.01). Maximum acute GI toxicity was limited to Grade 2 and was significantly increased in the WP group at 50% vs. 13% the PO group (p = 0.006). With a median follow-up of 24 months (range, 12-35 months), there was no difference in late GI toxicity (p = 0.884) or in acute or late GU toxicity. Conclusions: Despite dosimetric differences in the volume of bowel, bladder, and rectum irradiated in the low-dose and median-dose regions, WP IMRT results only in a clinically significant increase in acute GI toxicity, in comparison to PO IMRT, with no difference in GU or late GI toxicity.« less

Dosimetry during intramedullary nailing of the tibia

PubMed Central

2009-01-01

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

Relationships between iron dose, hospitalizations and mortality in incident haemodialysis patients: a propensity-score matched approach.

PubMed

Varas, Javier; Ramos, Rosa; Aljama, Pedro; Pérez-García, Rafael; Moreso, Francesc; Pinedo, Miguel; Ignacio Merello, José; Stuard, Stefano; Canaud, Bernard; Martín-Malo, Alejandro

2018-01-01

Intravenous iron management is common in the haemodialysis population. However, the safest dosing strategy remains uncertain, in terms of the risk of hospitalization and mortality. We aimed to determine the effects of cumulative monthly iron doses on mortality and hospitalization. This multicentre observational retrospective propensity-matched score study included 1679 incident haemodialysis patients. We measured baseline demographic variables, haemodialysis clinical parameters and laboratory analytical values. We compared outcomes among quartiles of cumulative iron dose (mg/kg/month). We implemented propensity-score matching (PSM) to reduce confounding due to indication. In the PSM cohort (330 patients), we compared outcomes between groups that received cumulative iron doses above and below 5.66 mg/kg/month. Kaplan-Meier analyses showed that the high iron dose group had significantly worse survival than the low iron dose group. A univariate analysis indicated that the monthly iron dose could significantly predict mortality. However, a multivariate regression did not confirm that finding. The multivariate regression analysis revealed that iron doses  >5.58 mg/kg/month were not associated with elevated mortality risk, but they were associated with elevated risks of all-cause and cardiovascular-related hospitalizations. These results were ratified in the PSM population. Intravenous iron administration is advisable for maintaining haemoglobin levels in patients that receive haemodialysis. Our data suggested that large monthly iron doses, adjusted for body weight, were associated with more hospitalizations, but not with mortality or infection-related hospitalizations. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Current Status of Treatment of Radiation Injury in the United States

DTIC Science & Technology

2005-01-01

radiation accident victims receiving CSFs, and c) improved sur- vival in irradiated canines and nonhuman primates treated with CSFs. Colony-stimulating...more: Adults over 40 (to prevent hypothyroidism ) The FDA revised the KI dosing and action levels in part as a result of case control study evidence of...and hypothyroidism may occur but generally require chronic high doses of KI. Individuals, usually adults, with multinodular goiter, Grave’s disease

Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus.

PubMed

Lujan-Zilbermann, Jorge; Warshaw, Meredith G; Williams, Paige L; Spector, Stephen A; Decker, Michael D; Abzug, Mark J; Heckman, Barb; Manzella, Adam; Kabat, Bill; Jean-Philippe, Patrick; Nachman, Sharon; Siberry, George K

2012-10-01

To compare the immunogenicity of 1 vs 2 doses of meningococcal polysaccharide conjugate vaccine (MCV4) in youth infected with human immunodeficiency virus (HIV). P1065 was a phase I/II immunogenicity and safety trial of MCV4 in 324 youth infected with HIV performed at 27 sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network in the US. At entry subjects received 1 dose of MCV4. At 24 weeks, those with screening cluster of differentiation 4 (CD4)% ≥ 15 were randomized to receive a second dose or not, and all with screening CD4% <15 received a second dose. Immunogenicity was evaluated as the proportion of subjects with a ≥ 4-fold rise from entry in serum bactericidal antibody against each meningococcal serogroup (SG) at weeks 28 and 72. Logistic regression models adjusting for HIV disease severity were used to evaluate the effect of 1 vs 2 MCV4 doses among those with screening CD4% ≥ 15. Subjects randomized to receive 2 vs 1 MCV4 dose had significantly higher response rates to all SGs at week 28 and to all except Neisseria meningitidis SG Y at week 72, with adjusted ORs of 2.5-5.6. In 31 subjects with screening CD4% <15 who received 2 MCV4 doses, response rates ranged from 22%-55% at week 28 and 6%-28% at week 72. In youth infected with HIV with a CD4% ≥ 15, a second dose of MCV4 given 6 months after the initial dose significantly improves response rates at 28 and 72 weeks. Subjects with CD4% <15 at entry had lower response rates despite 2 doses of MCV4. Copyright © 2012 Mosby, Inc. All rights reserved.