General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med nejm.org This article was published on September 14, 2016, at NEJM.org. DOI: 10.1056/NEJMoa1606220Copyright © 2016 Massachusetts Medical Society. BACKGROUNDThe comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain. METHODSWe compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. RESULTSThere were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P = 0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P = 0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P = 0.004 for the overall comparison). Higher rates of disease progression were seen in the activemonitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). CONCLUSIONSAt a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring.

Background Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. Methods We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. Results The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. Conclusions In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Growth of new blood vessels (angiogenesis), required for all tumor growth, is stimulated by the expression of vascular endothelial growth factor (VEGF). VEGF is up-regulated in all known solid tumors but also in atherosclerosis, diabetic retinopathy, arthritis, and many other conditions. Conventional VEGF isoforms have been universally described as proangiogenic cytokines. Here, we show that an endogenous splice variant, VEGF 165 b, is expressed as protein in normal cells and tissues and is circulating in human plasma. We also present evidence for a sister family of presumably inhibitory splice variants. Moreover, these isoforms are down-regulated in prostate cancer. We also show that VEGF 165 b binds VEGF receptor 2 with the same affinity as VEGF 165

Metastatic cancer cells typically fail to halt migration on contact with non-cancer cells. This invasiveness is in contrast to normal mesenchymal cells that retract on contact with another cell. Why cancer cells are defective in contact inhibition of locomotion is not understood. Here, we analyse the dynamics of prostate cancer cell lines co-cultured with fibroblasts, and demonstrate that a combinatorial code of Eph receptor activation dictates whether cell migration will be contact inhibited. The unimpeded migration of metastatic PC-3 cells towards fibroblasts is dependent on activation of EphB3 and EphB4 by ephrin-B2, which we show activates Cdc42 and cell migration. Knockdown of EphB3 and EphB4 restores contact inhibition of locomotion to PC-3 cells. Conversely, homotypic collisions between two cancer cells results in contact inhibition of locomotion, mediated by EphA-Rho-Rho kinase (ROCK) signalling. Thus, the migration of cancer cells can switch from restrained to invasive, depending on the Eph-receptor profile of the cancer cell and the reciprocal ephrin ligands expressed by neighbouring cells.

Study Type – Symptom prevalence (prospective cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Case series have described lower urinary tract symptoms associated with ketamine use including severe pain, frequency, haematuria and dysuria. Little is known regarding the frequency of symptoms, relationship of symptoms with dose and frequency of use and natural history of symptoms once the ketamine user has stopped. This study describes the prevalence of ketamine use in a population of recreational drug users in a dance music setting. It shows a dose–frequency relationship with ketamine use. It shows that urinary symptoms associated with recreational ketamine use may lead to a considerable demand on health resources in the primary‐, secondary‐ and emergency‐care settings. It shows that symptoms may improve once ketamine use is decreased. OBJECTIVE To investigate the prevalence and natural history of urinary symptoms in a cohort of recreational ketamine users. PATIENTS AND METHODS A purposeful sampling technique was used. Between November 2009 and January 2010 participants were invited to undertake an on‐line questionnaire promoted by a national dance music magazine and website. Data regarding demographics and illicit drug‐use were collected. Among respondents reporting recent ketamine use, additional information detailing their ketamine use, experience of urinary symptoms and use of related healthcare services was obtained. RESULTS In all, 3806 surveys were completed, of which 1285 (33.8%) participants reported ketamine use within the last year. Of the ketamine users, 17% were found to be dependent on the drug; 26.6% (340) of recent ketamine users reported experiencing urinary symptoms. Urinary symptoms were significantly related to both dose of ketamine used and frequency of ketamine use. Of 251 users reporting their experience of symptoms over time in relationship to their use of ketamine, 51% reported improvement in urinary symptoms upon cessation of use with only eight (3.8%) reporting deterioration after stopping use. CONCLUSIONS Urinary tract symptoms are reported in over a quarter of regular ketamine users. A dose and frequency response relationship has been shown between ketamine use and urinary symptoms. Both users and primary‐care providers need to be educated about urinary symptoms that may arise in ketamine users. A multi‐disciplinary approach promoting harm reduction, cessation and early referral is needed to manage individuals with ketamine‐associated urinary tract symptoms to avoid progression to severe and irreversible urological pathologies.

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OBJECTIVE To describe and assess an enhanced recovery protocol (ERP) for the peri‐operative management of patients undergoing radical cystectomy (RC), which was started at our institution on 1 October 2005, as RC is associated with increased morbidity and longer inpatient stays than other major urological procedures. PATIENTS AND METHODS An ERP was introduced in our institution that focused on reduced bowel preparation, and standardized feeding and analgesic regimens. In all, 112 consecutive patients were compared, i.e. 56 before implementing the ERP and 56 since introducing the ERP. The primary outcome measures were duration of total inpatient stay and interval from surgery to discharge, and the morbidity and mortality. Data were analysed retrospectively from cancer network and hospital records. RESULTS The demographics of the two groups showed no significant difference in age, gender distribution, American Society of Anesthesiologists grade, or type of urinary diversion. Re‐admission, mortality and morbidity rates showed no statistically significant difference between the groups. The median (interquartile range) duration of hospital stay was 17 (15–23) days in the no‐ERP group, and 13 (11–17) days in the ERP group (significantly different, P < 0.001, Wilcoxon rank‐sum test). The median duration of recovery after RC was 15 (13–21) days in the no‐ERP group and 12 (10–15) days in the ERP group (significantly different, P = 0.001, Wilcoxon rank‐sum test). CONCLUSION The introduction of an ERP was associated with significantly reduced hospital stay, with no deleterious effect on morbidity or mortality.

Angiogenesis is required for tumour growth and is induced principally by VEGF-A. VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer. In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by SRPK1. Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intra-epithelial neoplasia lesions as well as malignant adenocarcinoma compared to benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in prostate cancer may be under the control of SRPK1 activity. A switch in the expression of VEGF165 towards the anti-angiogenic splice isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knock-down (KD). PC-3 SRPK1-KD cells resulted in tumours that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1-KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Small molecule inhibitors of SRPK1 switched splicing towards the anti-angiogenic isoform VEGF165b in PC3 cells and decreased tumour growth when administered intraperitoneally in an orthotopic mouse model of prostate cancer. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumour angiogenesis by regulation of VEGF splicing can alter prostate tumour growth and supports further studies into the use of SRPK1 inhibition as a potential anti-angiogenic therapy in prostate cancer.