Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Association between the skin microbiome and MHC class II diversity in an amphibian.

Microbiomes play an important role in determining the ecology and behaviour of their hosts. However, questions remain pertaining to how host genetics shape microbiomes, and how microbiome composition influences host fitness. We explored the effects of geography, evolutionary history and host genetics on the skin microbiome diversity and structure in a widespread amphibian. More specifically, we examined the association between bacterial diversity and composition and the major histocompatibility complex class II exon 2 diversity in 12 moor frog (Rana arvalis) populations belonging to two geographical clusters that show signatures of past and ongoing differential selection. We found that while bacterial alpha diversity did not differ between the two clusters, MHC alleles/supertypes and genetic diversity varied considerably depending on geography and evolutionary history. Bacterial alpha diversity was positively correlated with expected MHC heterozygosity and negatively with MHC nucleotide diversity. Furthermore, bacterial community composition showed significant variation between the two geographical clusters and between specific MHC alleles/supertypes. Our findings emphasize the importance of historical demographic events on hologenomic variation and provide new insights into how immunogenetic host variability and microbial diversity may jointly influence host fitness with consequences for disease susceptibility and population persistence.

The association between diabetes medication and weight change in a non-surgical weight management intervention: an intervention cohort study.

AIM: To compare weight change in a lifestyle-based weight management programme between participants taking weight-gaining, weight-neutral/loss and mixed diabetes medications. METHODS: Electronic health records for individuals (≥ 18 years) with Type 2 diabetes who had been referred to a non-surgical weight management programme between February 2008 and May 2014 were studied. Diabetes medications were classified into three categories based on their effect on body weight. In this intervention cohort study, weight change was calculated for participants attending two or more sessions. RESULTS: All 998 individuals who took oral diabetes medications and attended two or more sessions of weight management were included. Some 59.5% of participants were women, and participants had a mean BMI of 41.1 kg/m2 (women) and 40.2 kg/m2 (men). Of the diabetes medication combinations prescribed, 46.0% were weight-neutral/loss, 41.3% mixed and 12.7% weight-gaining. The mean weight change for participants on weight-gaining and weight-neutral/loss diabetes medications respectively was -2.5 kg [95% confidence interval (CI) -3.2 to -1.8) and -3.3 kg (95% CI -3.8 to -2.9) (P = 0.05) for those attending two or more sessions (n = 998). Compared with those prescribed weight-neutral medications, participants prescribed weight-gaining medication lost 0.86 kg less (95% CI 0.02 to 1.7; P = 0.045) in a model adjusted for age, sex, BMI and socio-economic status. CONCLUSIONS: Participants on weight-neutral/loss diabetes medications had a greater absolute weight loss within a weight management intervention compared with those on weight-gaining medications. Diabetes medications should be reviewed ahead of planned weight-loss interventions to help ensure maximal effectiveness of the intervention.

Effects of intentional weight loss in patients with obesity and heart failure: a systematic review.

OBJECTIVE: Obesity is an independent risk factor for the development of heart failure, and the two commonly co-exist. The European Society of Cardiology does not provide guidance regarding weight loss strategies in heart failure. The aim of this study was to systematically review the evidence for outcomes following intentional weight loss in patients with heart failure and obesity. METHOD: A systematic review of English articles was undertaken using databases PubMed, Embase and CENTRAL. Randomized controlled trials and observational studies reporting outcomes following intentional weight loss by lifestyle, surgical or pharmacotherapy intervention in patients with obesity and heart failure were included. RESULTS: Four randomized controlled trials and seven observational studies were identified. Two randomized controlled trials used diet and exercise as an intervention, one used diet alone and one used a pharmacological intervention (orlistat). All but one reported significant weight loss. Two reported improvement in exercise capacity and quality of life. One reported improvement in New York Heart Association functional class in heart failure with preserved ejection fraction. The observational studies, five of which reported on outcomes following bariatric surgery, despite being small, heterogeneous and high risk of bias, suggested a trend in improvement of left ventricular function, quality of life and exercise capacity following weight loss. CONCLUSION: Weight loss is achievable with lifestyle intervention in those with heart failure and obesity and may result in improvements in New York Heart Association classification, quality of life and exercise capacity.

Quantifying fine particle emission events from time-resolved measurements: Method description and application to 18 California low-income apartments.

PM2.5 exposure is associated with significant health risk. Exposures in homes derive from both outdoor and indoor sources, with emissions occurring primarily in discrete events. Data on emission event magnitudes and schedules are needed to support simulation-based studies of exposures and mitigations. This study applied an identification and characterization algorithm to quantify time-resolved PM2.5 emission events from data collected during 224 days of monitoring in 18 California apartments with low-income residents. We identified and characterized 836 distinct events with median and mean values of 12 and 30 mg emitted mass, 16 and 23 minutes emission duration, 37 and 103 mg/h emission rates, and pseudo-first-order decay rates of 1.3 and 2.0/h. Mean event-averaged concentrations calculated using the determined event characteristics agreed to within 6% of measured values for 14 of the apartments. There were variations in event schedules and emitted mass across homes, with few events overnight and most emissions occurring during late afternoons and evenings. Event characteristics were similar during weekdays and weekends. Emitted mass was positively correlated with number of residents (Spearman coefficient, ρ=.10), bedrooms (ρ=.08), house volume (ρ=.29), and indoor-outdoor CO2 difference (ρ=.27). The event schedules can be used in probabilistic modeling of PM2.5 in low-income apartments.

Attrition and weight loss outcomes for patients with complex obesity, anxiety and depression attending a weight management programme with targeted psychological treatment.

The objective of the study is to investigate the effect of baseline anxiety and depression, using different definitions for caseness, on attrition and weight outcomes following a multidisciplinary weight management programme. The study design is a prospective observational study. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression with 'caseness' scoring ≥11 and severity ≥14. The participants were all patients who began a weight management programme between 1 October 2008 and 30 September 2009 (n = 1838). The setting was the Glasgow and Clyde Weight Management Service (GCWMS), a specialist multidisciplinary service, which aims to achieve a minimum of ≥5 kg weight loss. The results were as follows: patients with HADS score ≥14 were referred to the integrated psychology service for psychological assessment or intervention. Patients with caseness (HADS ≥11) for anxiety (33%) and depression (27%) were significantly younger, heavier, more socio-economically deprived and a higher proportion was female. There was a significant positive correlation between HADS anxiety and depression scores and increasing body mass index (r(2) = 0.094, P < 0.001 and r(2) = 0.175, P < 0.001, respectively). Attendance and completion was lower throughout follow-up amongst patients with anxiety or depression. More patients with HADS score ≥11 achieved ≥5 kg or ≥5% weight loss and by 12 months those with anxiety had a significantly higher mean weight loss (P = 0.032). Participants who scored for severe anxiety (HADS ≥14) achieved similar weight loss to those without, whilst participants who scored for severe depression achieved significantly greater weight loss than non-cases at 3, 6 and 12 months of follow-up (P < 0.01). Despite a less favourable case-mix of risk-factors for poor weight loss, patients who scored caseness for severe anxiety or depression and were offered additional psychological input achieved similar or better weight loss outcomes.

Variations in weight management services in Scotland: a national survey of weight management provision.

BACKGROUND: Despite National guidance recommending their use, there is uncertainty regarding the best way to deliver weight management services across the UK and worldwide. METHODS: To ascertain access, provision and interventions used in lifestyle Tier 2 and specialist Tier 3 weight management services in Scotland, a survey was distributed to all mainland health boards covering pathways for referral, eligibility criteria, intervention format and definitions of attendance completion and adherence. RESULTS: Nine Health boards provided information on their weight management services. The provision of services was low. Only four health boards offered services for those with a BMI 25-30 kg/m2. Lifestyle Tier 2 services were mainly weekly or fortnightly group sessions for 8-12 weeks delivered by dietitians or community workers. Specialist Tier 3 services were largely similar to lifestyle Tier 2 services. The provision of specialist interventions including pharmacotherapy, cognitive behavioural therapy sessions and low-calorie prescribed diets was low. CONCLUSIONS: This national survey has illustrated large disparities in the provision of weight management across Scotland, a likely consequence of uncertainty regarding best practice. There is a clear requirement for the evaluation of existing services to identify those that lead to the largest improvements in health outcomes and are cost-effective.

Contributions of maternal and paternal adiposity and smoking to adult offspring adiposity and cardiovascular risk: the Midspan Family Study.

OBJECTIVE: Obesity has some genetic basis but requires interaction with environmental factors for phenotypic expression. We examined contributions of gender-specific parental adiposity and smoking to adiposity and related cardiovascular risk in adult offspring. DESIGN: Cross-sectional general population survey. SETTING: Scotland. PARTICIPANTS: 1456 of the 1477 first generation families in the Midspan Family Study: 2912 parents (aged 45-64 years surveyed between 1972 and 1976) who had 1025 sons and 1283 daughters, aged 30-59 years surveyed in 1996. MAIN MEASURES: Offspring body mass index (BMI), waist circumference (WC), cardiometabolic risk (lipids, blood pressure and glucose) and cardiovascular disease as outcome measures, and parental BMI and smoking as determinants. All analyses adjusted for age, socioeconomic status and family clustering and offspring birth weight. RESULTS: Regression coefficients for BMI associations between father-son (0.30) and mother-daughter (0.33) were greater than father-daughter (0.23) or mother-son (0.22). Regression coefficient for the non-genetic, shared-environment or assortative-mating relationship between BMIs of fathers and mothers was 0.19. Heritability estimates for BMI were greatest among women with mothers who had BMI either <25 or ≥30 kg/m(2). Compared with offspring without obese parents, offspring with two obese parents had adjusted OR of 10.25 (95% CI 6.56 to 13.93) for having WC ≥102 cm for men, ≥88 cm women, 2.46 (95% CI 1.33 to 4.57) for metabolic syndrome and 3.03 (95% CI 1.55 to 5.91) for angina and/or myocardial infarct (p<0.001). Neither parental adiposity nor smoking history determined adjusted offspring individual cardiometabolic risk factors, diabetes or stroke. Maternal, but not paternal, smoking had significant effects on WC in sons (OR=1.50; 95% CI 1.13 to 2.01) and daughters (OR=1.42; 95% CI 1.10 to 1.84) and metabolic syndrome OR=1.68; 95% CI 1.17 to 2.40) in sons. CONCLUSIONS: There are modest genetic/epigenetic influences on the environmental factors behind adverse adiposity. Maternal smoking appears a specific hazard on obesity and metabolic syndrome. A possible epigenetic mechanism linking maternal smoking to obesity and metabolic syndrome in offspring is proposed. Individuals with family histories of obesity should be targeted from an early age to prevent obesity and complications.

Effect of orlistat on glycaemic control in overweight and obese patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

Orlistat is an effective adjunctive treatment to lifestyle modifications in the treatment of obesity. While the majority of current evidence is on the effect of orlistat in obese patients without diabetes, some studies suggest that patients who are obese and have diabetes mellitus lose more weight and have greater improvements in diabetic outcomes when treated with orlistat plus a lifestyle intervention than when treated by lifestyle interventions alone. The aim of this study was to review the evidence of the effects of orlistat on glycaemic control in overweight and obese patients with type 2 diabetes. A systematic review of randomized controlled trials of orlistat in people with type 2 diabetes reporting diabetes outcomes in studies published between January 1990 and September 2013 was conducted. We searched for articles published in English in MEDLINE and EMBASE. Inclusion criteria included all randomized controlled trials of orlistat carried out on adult participants with a body mass index of 25 kg m(-2) or over diagnosed with type 2 diabetes, which reported weight change and at least one diabetic outcome. A total of 765 articles were identified out of which 12 fulfilled the inclusion criteria. The overall mean weight reduction (3, 6 and 12 months) in the orlistat group was -4.25 kg (95% CI: -4.5 to -3.9 kg). The mean weight difference between treatment and control groups was -2.10 kg (95% CI: -2.3 to -1.8 kg, P < 0.001), the mean HbA1c difference was -6.12 mmol mol(-1) (95% CI: -10.3 to -1.9 mmol mol(-1) , P < 0.004) and the mean fasting blood glucose difference was -1.16 mmol L(-1) (95% CI: -1.4 to -0.8 mmol L(-1) , P < 0.001). Treatment with orlistat plus lifestyle intervention resulted in significantly greater weight loss and improved glycaemic control in overweight and obese patients with type 2 diabetes compared with lifestyle intervention alone.

Patient-reported outcomes and health-related quality of life in prostate cancer treated with a single fraction of high dose rate brachytherapy combined with hypofractionated external beam radiotherapy.

AIMS: High dose rate (HDR) brachytherapy offers a highly conformal approach to radiotherapy delivery, enabling dose escalation. We report our experience using a combined HDR boost and external beam radiotherapy (EBRT) approach and its associated toxicity and effect on quality of life. MATERIALS AND METHODS: Patients with intermediate- or high-risk prostate cancer were treated with a single fraction HDR boost and EBRT between July 2008 and March 2010. Patient-reported toxicity data were collected at baseline and regular intervals after radiotherapy using International Prostate Symptom Score and Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales (LENT-SOMA) questionnaires; health-related quality of life data were captured by the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: Ninety-five patients received an HDR boost of 12.5 Gy followed by EBRT delivered as 37.5 Gy in 15 fractions over 3 weeks. The International Prostate Symptom Score peaked 6 weeks after radiotherapy (median value: 9). The LENT-SOMA bladder/urethra mean baseline score was 0.35 and peaked 6 weeks after radiotherapy (mean = 0.59). Difficulties with urinary flow and frequency were the most common reported symptoms. LENT-SOMA rectum/bowel mean scores at baseline were 0.24 and peaked after 6 months (mean = 0.37). Bowel urgency was the most common reported toxicity. EPIC urinary scores returned to baseline values at 6 months and bowel median scores recovered after 24 months. There were no statistically significant associations between patient or dosimetric parameters and patient-reported outcomes. CONCLUSION: A combined HDR boost and hypofractionated EBRT regimen offers a well-tolerated method of dose escalation with acceptable levels of patient-reported toxicity.

Updated and expanded study of polycythemia vera and other myeloproliferative neoplasms in the tri-county area.

INTRODUCTION: The results of a 2001-2005 polycythemia vera (PV) investigation in Eastern Pennsylvania revealed a disease cluster plus underreporting and false reporting to the Pennsylvania Cancer Registry (PCR). PURPOSE: The objectives of this study were 1) to assess PV reporting to the PCR in 2006-2009, 2) to determine whether a cancer cluster persisted, and 3) to determine whether other myeloproliferative neoplasms (MPNs), including essential thrombocytopenia (ET), were subject to similar reporting problems. METHODS: Cases were identified from: 1) PCR records from the Tri-County, 2) reviewing billing records at Tri-County hematologist/oncologist offices, and 3) self-identification. An expert panel of physicians reviewed medical records and determined "true," "false," or "indeterminate" cases reported to the PCR. The analyses were conducted to determine sensitivity and positive predictive value (PPV) of case reporting to the PCR, estimate cancer incidence rates, and evaluate the presence of cancer clusters. RESULTS: Of 290 cases identified, 90% were from the original PCR, 9% from billing records, and 1% from self-report. Fifty-five cases consented to participate, and medical records were obtained for 44. The expert panel determined that 45% were true cases, 32% were false cases, and 23% were indeterminate. PV had 100% (95% CI, 59-100) sensitivity, but only 47% PPV (95% CI, 20-70): ET had 78% (95% CI, 47-99) sensitivity and 100% PPV (95% CI, 59-100). Low participation and chart review rates led to rates with wide confidence intervals. We did not identify any PV cancer clusters, but we did identify a cluster of 9 ET cases in the Wilkes-Barre, Pennsylvania area. CONCLUSION: The current study was limited by the low response rate (22%) from MPN patients in the Tri-County area. This study identified 47% PPV for PV reporting and 100% PPV for ET.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Do men develop type 2 diabetes at lower body mass indices than women?

AIMS/HYPOTHESIS: To describe the associations between age, sex and BMI at diagnosis of type 2 diabetes, and test the hypothesis that men are diagnosed with diabetes at lower average BMI than women of similar age. METHODS: Linear regression was used to estimate and compare the relationship between age and BMI at diagnosis among 51,920 men and 43,137 women included in a population-based diabetes register in Scotland for whom an index BMI measurement was taken within 1 year of diabetes diagnosis. We also examined HbA(1c) values by sex within the same timescale. RESULTS: Mean BMI closest to date of diagnosis of type 2 diabetes mellitus was 31.83 kg/m(2) (SD 5.13) in men and 33.69 kg/m(2) (SD 6.43) in women. The inverse relationship between age and BMI at diagnosis of type 2 diabetes mellitus was significantly steeper in women than in men (slope estimate in men -0.12 kg/m(2) per year [95% CI -0.13, -0.12] women -0.18 kg/m(2) per year [95% CI -0.18, -0.17], p < 0.0001 for formal test of interaction). Mean BMI difference was most marked at younger ages and narrowed with advancing age. However, HbA(1c) levels within 1 year of diagnoses were broadly similar in men and women. CONCLUSIONS/INTERPRETATION: Men are diagnosed with type 2 diabetes at lower BMI than women across the age range. This observation may help explain why type 2 diabetes is more common among middle-aged men in populations of European extraction. Whether the same pattern is also observed in other ethnic groups requires confirmation.

Comparison of dynamic contrast-enhanced MRI and dynamic contrast-enhanced CT biomarkers in bladder cancer.

Dynamic contrast-enhanced MRI (DCE-MRI) is frequently used to provide response biomarkers in clinical trials of novel cancer therapeutics but assessment of their physiological accuracy is difficult. DCE-CT provides an independent probe of similar pharmacokinetic processes and may be modeled in the same way as DCE-MRI to provide purportedly equivalent physiological parameters. In this study, DCE-MRI and DCE-CT were directly compared in subjects with primary bladder cancer to assess the degree to which the model parameters report modeled physiology rather than artefacts of the measurement technique and to determine the interchangeability of the techniques in a clinical trial setting. The biomarker K(trans) obtained by fitting an extended version of the Kety model voxelwise to both DCE-MRI and DCE-CT data was in excellent agreement (mean across subjects was 0.085 ± 0.030 min(-1) for DCE-MRI and 0.087 ± 0.033 min(-1) for DCE-CT, intermodality coefficient of variation 9%). The parameter v(p) derived from DCE-CT was significantly greater than that derived from DCE-MRI (0.018 ± 0.006 compared to 0.009 ± 0.008, P = 0.0007) and v(e) was in reasonable agreement only for low values. The study provides evidence that the biomarker K(trans) is a robust parameter indicative of the underlying physiology and relatively independent of the method of measurement.

Hazard assessment of chemical air contaminants measured in residences.

UNLABELLED: Identifying air pollutants that pose a potential hazard indoors can facilitate exposure mitigation. In this study, we compiled summary results from 77 published studies reporting measurements of chemical pollutants in residences in the United States and in countries with similar lifestyles. These data were used to calculate representative mid-range and upper-bound concentrations relevant to chronic exposures for 267 pollutants and representative peak concentrations relevant to acute exposures for five activity-associated pollutants. Representative concentrations are compared to available chronic and acute health standards for 97 pollutants. Fifteen pollutants appear to exceed chronic health standards in a large fraction of homes. Nine other pollutants are identified as potential chronic health hazards in a substantial minority of homes, and an additional nine are identified as potential hazards in a very small percentage of homes. Nine pollutants are identified as priority hazards based on the robustness of measured concentration data and the fraction of residences that appear to be impacted: acetaldehyde; acrolein; benzene; 1,3-butadiene; 1,4-dichlorobenzene; formaldehyde; naphthalene; nitrogen dioxide; and PM(2.5). Activity-based emissions are shown to pose potential acute health hazards for PM(2.5), formaldehyde, CO, chloroform, and NO(2). PRACTICAL IMPLICATIONS: This analysis identifies key chemical contaminants of concern in residential indoor air using a comprehensive and consistent hazard-evaluation protocol. The identification of a succinct group of chemical hazards in indoor air will allow for successful risk ranking and mitigation prioritization for the indoor residential environment. This work also indicates some common household activities that may lead to the acute levels of pollutant exposure and identifies hazardous chemicals for priority removal from consumer products and home furnishings.

Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer.

OBJECTIVE: To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing. METHODS: In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days' once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days' once-daily dosing. RESULTS: Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0 - 36.3 ml/min in Japanese patients and 7.8 - 29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9 - 29.1 l in Japanese patients and 9.6 - 23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7 - 18.8 h in Japanese patients and 5.0 - 22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations. CONCLUSIONS: There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC.