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In this study, abiraterone acetate inhibited androgen synthesis and prolonged survival by 4 months among men with castration-resistant prostate cancer that had progressed with docetaxel chemotherapy. For the past 70 years, depleting or blocking the action of androgens has been the standard of care for men with advanced prostate cancer. 1 Androgen deprivation results in a decrease in the concentration of prostate-specific antigen (PSA) as well as tumor regression and relief of symptoms in most patients, but the response to treatment is not durable in patients with advanced cancer, and with time, PSA concentrations increase, indicating reactivated androgen-receptor signaling and a transition to a castration-resistant state that is invariably fatal. 2 Many endocrine therapies have been evaluated in these patients, but none have prolonged survival. 3 Three nonhormonal systemic . . .

Prostate cancer might have high radiation-fraction sensitivity, implying a therapeutic advantage of hypofractionated treatment. We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy. We did a multicentre, randomised study and recruited men with localised prostate cancer between Oct 18, 2002, and Aug 12, 2006, at 11 UK centres. Patients were randomly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy, and all were given with 3–6 months of neoadjuvant androgen suppression. Computer-generated random permuted blocks were used, with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors. The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy. The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy, or 19 fractions to a total of 57 Gy. The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group (RTOG) scale. The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment. Treatment allocation was not masked and clinicians were not blinded. Stage 3 of this trial completed the planned recruitment in June, 2011. This study is registered, number ISRCTN97182923. 153 men recruited to stages 1 and 2 were randomly assigned to receive conventional treatment of 74 Gy, 153 to receive 60 Gy, and 151 to receive 57 Gy. With 50·5 months median follow-up (IQR 43·5–61·3), six (4·3%; 95% CI 1·6–9·2) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years, as did five (3·6%; 1·2–8·3) of 137 men in the 60 Gy group, and two (1·4%; 0·2–5·0) of 143 men in the 57 Gy group. For bladder toxicities, three (2·2%; 0·5–6·2) of 138 men, three (2·2%; 0·5–6·3) of 137, and none (0·0%; 97·5% CI 0·0–2·6) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years. Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years. Stage 1 was funded by the Academic Radiotherapy Unit, Cancer Research UK programme grant; stage 2 was funded by the Department of Health and Cancer Research UK.

Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial. The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b–T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923. 2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4–64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months. The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer. Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923. Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported. Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

David B. Whitehouse died on 17 February 2013 at the age of 71. A great and innovative scholar, he was also a courteous and gently entertaining person.

Background This study aimed to evaluate whether the use of preoperative ultrasound (US)-guided wire localization of metastatic axillary lymph nodes (LN) assessed previously by core needle biopsy (CNB) and clip placement in breast cancer patients improves successful surgical removal. Methods A retrospective review examined breast cancer patients who underwent US-guided CNB of an axillary LN and biopsy clip placement as well as axillary lymph node dissection (ALND) or sentinel node lymph node biopsy (SLNB) from 1 January 2010 to 30 September 2013. Preoperative needle localization status, neoadjuvant chemotherapy, and type of axillary LN surgery were reviewed. Confirmation that the metastatic LN had been surgically removed was determined on the specimen image, by pathologic report confirmation, or by pre-radiation therapy computed tomography (CT) scan. Results Preoperative US-guided needle localization was performed for 68.2 % (73/107) of the patients, with 97.3 % ( n  = 71) demonstrating confirmation of biopsy clip and LN removal versus 79.4 % ( n  = 27) of the 34 patients showing no performance of needle localization ( p  = 0.0043). Subgroup analysis showed a significant difference in removal of metastatic LN between the patients who received neoadjuvant chemotherapy [97 % of LNs removed with wire localization ( n  = 65/67) vs. 83.3 % of LNs removed without wire localization ( n  = 20/24; p  = 0.04)] and the patients who had ALND, [96.3 % of LNs removed with wire localization ( n  = 52/54) vs. 77.8 % of LNs removed without wire localization ( n  = 21/27; p  = 0.015)]. Conclusion US-guided wire localization of metastatic axillary LNs that have had biopsy with clip placement significantly improves the success rate of surgical removal, allowing more accurate staging and decreasing the false-negative rates of SLNB after neoadjuvant therapy.

Cardiac transplantation replaces a severely damaged non-functioning heart with a healthy heart from a donor. Within the UK, the number of cardiac transplants being performed each year is increasing, with significant improvements in longer-term survival. Dental professionals are therefore more likely to see and manage these patients in the pre- and post-transplant periods. This paper proposes a protocol for the dental management of these patients, reinforced by a case series from Scotland and London. Key points Provides dental teams with knowledge on the background and process of cardiac transplant. Explains the implications for oral health and dental management. Provides dental teams with advice on the assessment and treatment of pre- and post-cardiac transplant patients, using a proposed protocol with illustrative clinical cases.

Study designInterviews using the benefit-harm trade-off method and an online survey.ObjectivesTo determine the smallest worthwhile effect (SWE) of motor training on strength for people with spinal cord injury (SCI).SettingSCI units, Australia.MethodsForty people with recent SCI who had participated in motor training as part of their rehabilitation program (patient participants) and 37 physiotherapists (physiotherapist participants) working in SCI were recruited. The patient participants underwent an iterative process using the benefit-harm trade-off method to determine the SWE of motor training on strength. The physiotherapist participants were given an online survey to determine the SWE for five different scenarios. Both groups considered the SWE of a physiotherapy intervention involving an additional 12 h of motor training for 10 weeks on top of usual care. They were required to estimate the smallest improvement in strength (points on the Total Motor Score of the International Standards for Neurological Classification of SCI) to justify the effort and associated costs, risks or inconveniences of the motor training.ResultsThe median (interquartile range) smallest improvement in strength that patient and physiotherapist participants deemed worth the effort and associated costs, risks or inconveniences of the motor training was 3 (1–5) points, and 9 (7–13) points, respectively.ConclusionsPeople with recent SCI are willing to devote 12 h a week for 10 weeks to motor training in addition to their usual care to gain small changes in strength. Physiotherapists wanted to see greater improvements to justify the intervention.

Purpose The purpose of this study is to report empirical research on gender managerial obstacles in UAE private organizations. It identifies the barriers that limit opportunities for gender equality promotion in managerial level positions. Design/methodology/approach Primary data were gathered from 384 female managers operating in UAE organizations using Survey Monkey and ANOVA for statistical analysis. Two variables (years of experience and industry) were used to compare the average means across the responses and the differences among the group. Findings The situation of gender equality in UAE management currently shows a positive trend. The females who participated in the survey have considerable work experience and jobs in a vital economic sector of the UAE industry. The earlier cultural stereotypes that worked against the interests of women in the UAE society are no longer relevant except for informal barriers and the level of cooperation among female leaders. We found differences among industry, service and transportation sectors in which gender managerial level in a private industry is dependent upon the number of years of experience for female managers. Research limitations/implications The limitation of the study is the online survey was affected by the COVID-19 pandemic during the lockdown period in the spring of 2020, which led to a low number of participants responding to the questionnaire. Additionally, the survey did not include a nationality question to distinguish Emiratis from non-Emirati. Social implications This study indicates a need to coordinate UAE female leaders' actions to protect their rights, develop formal and informal mechanisms of gender inequality realization in business and promote professional skills, orientation on social networks, and mentoring programs for female leaders. These initiatives improve the positions of female leaders. Originality/value The study of the UAE case adds to the existing literature on gender studies because the survey-based research in the UAE context contributes to the limited knowledge of Middle Eastern countries. The females’ employment and their representation in managerial levels remain lower compared to males. Differences exist among the industry, service and transportation sectors.

Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART). Methods. HIV-positive adults receiving ART for ≥96 weeks with undetectable viremia for ≥48 weeks and CD4⁺ T-cell counts <350 cells/mm³ were randomized 2:1 to rifaximin versus no study treatment for 4 weeks. T-cell activation, LPS, and soluble CD 14 were measured at baseline and at weeks 2,4, and 8. Wilcoxon rank sum tests compared changes between arms. Results. Compared with no study treatment (n = 22), rifaximin (n = 43) use was associated with a significant difference between study arms in the change from baseline to week 4 for CD8⁺ T-cell activation (median change, 0.0% with rifaximin vs +0.6% with no treatment; P = .03). This difference was driven by an increase in the no-study-treatment arm because there was no significant change within the rifaximin arm. Similarly, although there were significant differences between study arms in change from baseline to week 2 for LPS and soluble CD 14, there were no significant changes within the rifaximin arm. Conclusions. In immune nonresponders to ART, rifaximin minimally affected microbial translocation and CD8⁺ T-cell activation.