A pilot study of performance enhancement coaching for newly appointed urology registrars.

OBJECTIVES: To assess the feasibility of performance enhancement coaching (PEC) for newly appointed Urology registrars (ST3s), specifically: whether the concept appealed, and which areas beyond technical skills acquisition were felt to be most relevant or useful. SUBJECTS AND METHODS: All delegates on the Urology Bootcamp 2023 were invited to take part in an online survey before and after a 2-hour PEC workshop, collecting: basic demographic data, performance challenges, and the important aspects to include in, and consider with, a coaching programme. The workshop was delivered by a surgeon with a professional coaching qualification, to groups of four delegates at a time over 4 days. Ten pre-defined areas were offered during the session. RESULTS: On a scale of 1 (poor) to 10 (excellent), the 62 participants' overall health was reported as a median of 8/10 (physical) and 7/10 (mental). Anxiety during performance was the most common concern (63%) and was accompanied by a tremor in 55%. The next most popular concerns, with 19% of responses each, were: sleep, insufficient operative skill or expertise, and worry about relationships with trainers. The commonest topics discussed were 'the inner critic' (100%), 'autonomic modulation' (69%), 'not working, well' (13%) and 'optimising study' (6%). Seventy-seven per cent were unaware of PEC for practising surgeons. All respondents felt that they would benefit from PEC to some extent (80% ≥8/10 where 10/10 was 'very useful'), ideally at the ST3 level. Sixty-two percent of respondents said there should be a fee for trainees, whereas 38% thought it should be free and paid for by their training authorities. CONCLUSION: The concept of PEC is acceptable to ST3 Urology trainees, with particular interest in techniques to mitigate negative self-talk and autonomic modulation techniques. Existing barriers to coaching for the surgical community would need to be addressed in designing an acceptable coaching programme.

Exercise-induced attenuation of treatment side-effects in patients with newly diagnosed prostate cancer beginning androgen-deprivation therapy: a randomised controlled trial.

OBJECTIVES: (i) To assess whether exercise training attenuates the adverse effects of treatment in patients with newly diagnosed prostate cancer beginning androgen-deprivation therapy (ADT), and (ii) to examine whether exercise-induced improvements are sustained after the withdrawal of supervised exercise. PATIENTS AND METHODS: In all, 50 patients with prostate cancer scheduled for ADT were randomised to an exercise group (n = 24) or a control group (n = 26). The exercise group completed 3 months of supervised aerobic and resistance exercise training (twice a week for 60 min), followed by 3 months of self-directed exercise. Outcomes were assessed at baseline, 3- and 6-months. The primary outcome was difference in fat mass at 3-months. Secondary outcomes included: fat-free mass, cardiopulmonary exercise testing variables, QRISK® 2 (ClinRisk Ltd, Leeds, UK) score, anthropometry, blood-borne biomarkers, fatigue, and quality of life (QoL). RESULTS: At 3-months, exercise training prevented adverse changes in peak O2 uptake (1.9 mL/kg/min, P = 0.038), ventilatory threshold (1.7 mL/kg/min, P = 0.013), O2 uptake efficiency slope (0.21, P = 0.005), and fatigue (between-group difference in Functional Assessment of Chronic Illness Therapy-Fatigue score of 4.5 points, P = 0.024) compared with controls. After the supervised exercise was withdrawn, the differences in cardiopulmonary fitness and fatigue were not sustained, but the exercise group showed significantly better QoL (Functional Assessment of Cancer Therapy-Prostate difference of 8.5 points, P = 0.034) and a reduced QRISK2 score (-2.9%, P = 0.041) compared to controls. CONCLUSION: A short-term programme of supervised exercise in patients with prostate cancer beginning ADT results in sustained improvements in QoL and cardiovascular events risk profile.

Vigorous intensity aerobic interval exercise in bladder cancer patients prior to radical cystectomy: a feasibility randomised controlled trial.

PURPOSE: Strategies to improve pre-operative cardiopulmonary fitness could positively impact recovery after surgery. This study investigated the feasibility of vigorous intensity aerobic interval exercise in bladder cancer patients prior to radical cystectomy (RC). METHODS: A total of 60 patients were randomised (1:1) to exercise or control following a cardiopulmonary exercise test (CPET). The exercise group was offered twice-weekly pre-operative supervised vigorous intensity aerobic interval exercise in addition to standard treatment. The controls received standard treatment only. A repeat CPET was undertaken before surgery and post-operative recovery outcomes were recorded. RESULTS: Over half of the 112 eligible patients approached in the clinic were recruited to the study (53.5%), with recruited patients attending a median of 8 (range 1-10) exercise sessions over a pre-operative period of 3-6 weeks. Improvements in peak values of oxygen pulse (P = 0.001), minute ventilation (P = 0.002) and power output (P < 0.001) were observed at the follow-up CPET in the exercise group versus controls and there were no adverse events. Although this feasibility study was not powered to detect changes in post-operative recovery outcomes, there were marginal (non-significant) differences in favour of the exercise group in post-operative Clavien-Dindo score and need for high dependency unit inotropic support. CONCLUSIONS: Bladder cancer patients respond well to pre-surgical aerobic interval exercise, and the improvements in cardiopulmonary fitness variables could have important implications for post-operative recuperation after RC. These findings provide a strong foundation for an adequately powered randomised controlled trial.

Nephroureterectomy surgery in the UK in 2012: British Association of Urological Surgeons (BAUS) Registry data.

OBJECTIVE: To report registry data obtained by the British Association of Urological Surgeons (BAUS) for nephroureterectomy (NU) surgery in the UK performed between 1 January and 31 December 2012. SUBJECTS/PATIENTS AND METHODS: Registry data entered by each individual surgeon's team (self-reported) on all 6042 nephrectomy surgeries reported to BAUS during 2012 were analysed to identify all NU surgery. Parameters for analysis included demographics, indication, type of surgery, histopathology and complications (Clavien system) of surgery. Data did not include tumour location or multiplicity, preoperative diagnostic evaluation or details of minimally invasive surgery (MIS) undertaken. Before analysis for this report a central process of 'data-cleansing' was undertaken by a BAUS group to address any discrepancy between the listed surgery and the preoperative indication. RESULTS: In all, 863 NU surgeries were included, performed by 220 consultant surgeons in 119 centres, and the median (range) number of NU per surgeon and unit was 3 (1-20) and 6 (1-29), respectively. The most common age group was 71-80 years (40%), most were male (64%), and haematuria was the most common presentation (74%). The dominant pathology was upper tract urothelial cancer (89%, 735), with final stage ≥pT2 in 47% (367), and the grade was 1, 2 or 3 in 6% (38), 36% (228) and 58% (362) respectively. Operative technique included MIS in 85% (720) and total reported operative complication rate (any Clavien) was 15% (128), of which Clavien ≥3 was reported in 4% (36), and perioperative death was reported in nine patients (1%). Advantages in favour of MIS included reduced hospital stay (median 5 vs 8 days), reduced major blood loss (3% vs 14%) and reduced transfusion requirement (6% vs 24%). In all, 76 cases (8%) were excluded from analysis based on benign pathology leading to reassignment to the 'simple nephrectomy' category. CONCLUSIONS: NU is currently a low-volume operation (median 3 cases/year) within the remit of the nephrectomy surgeon, but is a safe procedure with a relatively low complication rate. Most NU surgery in the UK is now performed with laparoscopic assistance, with advantages including reduced major blood loss, reduced transfusion requirement and shorter hospital stay.

Prevalence of ciprofloxacin-resistant Enterobacteriaceae in the intestinal flora of patients undergoing transrectal prostate biopsy in Norwich, UK.

OBJECTIVE: To determine the efficacy of fluoroquinolone prophylaxis in patients undergoing transrectal ultrasonography (TRUS)-guided biopsy of the prostate in the Norwich population, and its correlation with ciprofloxacin resistance in the faecal flora. We also aimed to determine the usefulness of a pre-biopsy rectal screen for resistant bacteria in these patients. PATIENTS AND METHODS: The incidence and microbiology of sepsis after TRUS-guided prostate biopsies between 2007 and 2011 was audited retrospectively. Subsequently, in 2012, a prospective study was performed, collecting the same data but also culturing rectal swabs from all patients undergoing TRUS-guided biopsy, with a post-biopsy follow-up period of 6 months. All patients were given prophylactic oral ciprofloxacin, as per Trust policy (750 mg 1 h before biopsy, followed by 250 mg twice daily for 3 subsequent days). RESULTS: Between 2007 and 2011, 3600 patients underwent TRUS-guided biopsy. Among these, 11 (0.3%) were admitted to hospital for post-biopsy related sepsis but only 4 (0.1%) had ciprofloxacin-resistant Escherichia coli confirmed from blood cultures: three had ciprofloxacin-susceptible Enterobacteriaceae, and four had no ciprofloxacin susceptibility data. In 2012, 10 (3.7%) of 267 patients sampled before biopsy had ciprofloxacin-resistant E. coli recovered on rectal swab culture but none of these men presented with post-biopsy sepsis; during the 6-month follow-up period, seven patients were diagnosed with urinary tract infections. CONCLUSION: Ciprofloxacin-resistant Enterobacteriaceae remains rare in the intestinal flora of the Norwich TRUS population, meaning that the drug remains adequate as prophylaxis. Pre-biopsy rectal swabs may be useful for individual departments to periodically assess their own populations and to ensure their antibiotic policy remains valid. In populations where resistance is known to be highly prevalent, pre-biopsy rectal swabs can help guide addition of further antibiotics to prevent post-biopsy septicaemia.

Prostatic urethral lift for subjects in urinary retention (PULSAR): 12-Month results of a prospective controlled trial compared with real-world outcomes.

Objective: To examine the safety and efficacy of prostatic urethral lift (PUL) in acute urinary retention (AUR) patients within a controlled (PULSAR) and real-world setting (Real-World Retrospective study). Materials and methods: PULSAR was a 12-month prospective study of PUL in AUR patients (n = 51) performed at six centres in the United Kingdom; enrolled BPH patients aged ≥50 years, with prostate volume of ≤100 cc. AUR was defined as being catheter dependent with at least one prior failed trial without catheter (TWOC) while on an alpha-blocker. RWR consisted of 3226 consecutive PUL patients across 22 international sites treated between July 2017 and March 2020; 469 of whom were in urinary retention (RWRr), that is, catheter-dependent at the time of their procedure. Symptom response, uroflow and catheter independence rates were compared between PULSAR and RWRr subjects. A logistical regression model was constructed to evaluate patient baseline and dynamic factors predicting success after the procedure. Results: Seventy-three percent of PULSAR subjects were catheter independent and free from surgical reintervention at 12 months post-PUL. Success was associated with higher voiding efficiency during the perioperative period. Slightly higher catheter-independent rates (80%) were seen in RWRr patients; variables that influenced success included age <70 years, lower baseline prostate-specific antigen (PSA), lower baseline post-void residual (PVR) and shorter pre-procedural catheter duration. Logistic regression of the combined PULSAR and RWRr retention groups revealed that procedural age <70 years and higher bladder voiding efficiency (BVE) were associated with success. Conclusions: Lower baseline PSA and PVR, younger age and shorter pre-procedure catheter durations drove successful outcomes in AUR patients undergoing PUL. Post-PUL voiding efficiencies may help ascertain long-term response to treatment.

A Pilot Study Evaluating a Virtual Reality-Based Nontechnical Skills Training Application for Urology Trainees: Usability, Acceptability, and Impact.

OBJECTIVE: This study aimed to develop and evaluate a virtual reality (VR)-based nontechnical skills (NTS) training application for urology trainees and assess its effectiveness in improving their skills and confidence. DESIGN: A mixed-methods study was conducted to develop and evaluate a VR-based NTS training application for 32 urology trainees. The development process involved collaboration with 5 urology experts, 2 medical education specialists, and a human factors researcher. The study evaluated the application's usability, acceptability, and efficacy through 3 phases: scenario development with expert feedback integration, storyboarding and creation processes with facilitators and urology trainees, and a final evaluation by trainees. SETTING: The data were collected during a 4-day urology boot camp in October 2022. PARTICIPANTS: Thirty-two urology trainees participated in the study and completed 2 VR scenarios designed to enhance their NTS skills RESULTS: The System Usability Scale (SUS) showed a moderate usability score of 66. The Training Evaluation Inventory (TEI) and additional feedback demonstrated positive effects on trainees' learning and confidence in their NTS abilities. Most participants found the application easy to use, and effective and they expressed interest in using similar VR applications for other aspects of surgical training. CONCLUSIONS: VR-based NTS training applications show potential for enhancing urology trainees' nontechnical skills. The integration of expert feedback and immersive technology offers a promising, accessible, and cost-effective solution to the challenges of delivering NTS training. Future research should explore the long-term impact of VR-based NTS training on trainees' performance and patient outcomes and consider incorporating advanced AI technologies for personalized and dynamic learning experiences.

Sepsis rates after template prostate biopsy with single-dose prophylactic antibiotic.

Introduction: Urosepsis is a significant risk associated with prostate biopsy. Resistance of microorganisms to antibiotics is a challenging issue for clinicians in everyday practice. In the current study, we investigated the rates of sepsis and hospital admissions following transperineal (TP) prostate biopsies using a single dose of gentamicin. Material and methods: Data for consecutive patients who underwent TP prostate biopsies (March 2019-March 2020) were included. Patients received a single-dose of prophylactic gentamicin 120 mg IV and had skin preparation with antiseptic povidone-iodine or chlorhexidine solution prior to the procedure. Patient's electronic records were reviewed for rates of sepsis and readmission to hospital within 7 days following TP prostate biopsy. Results: A total of 365 consecutive patients were included in the study. After exclusion of non-eligible patients, 280 patients were included in final analysis. The median age was 67 years (32-83), the median prostate-specific antigen (PSA) level was 8.5 ng/ml (0.2-58), and the median prostate size was 44 cc (10-188). Approximately 58% of patients had one or more comorbidities in the form of diabetes mellitus (DM), hypertension, asthma, chronic kidney disease, or ischemic heart disease. Adenocarcinoma was found in 71.7% of patients. None of the 280 patients developed sepsis. Urinary tract infection (UTI) occurred in 2.8% of patients with E.coli, none of them required hospital readmission. Conclusions: Our single centre experience showed a 0% sepsis rate after TP prostate biopsy with single prophylactic dose of gentamicin. Future randomized controlled trials (RCTs) should explore the possibility of performing these procedures without antibiotic prophylaxis in order to reduce the unnecessary use of antibiotics.

A Prospective Multi-Institutional Evaluation of Iatrogenic Urethral Catheterization Injuries.

OBJECTIVES: To perform a multi-institutional investigation of incidence and outcomes of urethral trauma sustained during attempted catheterization. PATIENTS & METHODS: A prospective, multi-center study was conducted over a designated 3-4 month period, incorporating seven academic hospitals across the UK and Ireland. Cases of urethral trauma arising from attempted catheterization were recorded. Variables included sites of injury, management strategies and short-term clinical outcomes. The catheterization injury rate was calculated based on the estimated total number of catheterizations occurring in each center per month. Anonymised data were collated, evaluated and described. RESULTS: Sixty-six urethral catheterization injuries were identified (7 centers; mean 3.43 months). The mean injury rate was 6.2 ± 3.8 per 1000 catheterizations (3.18-14.42/1000). All injured patients were male, mean age 76.1 ± 13.1 years. Urethral catheterization injuries occurred in multiple hospital/community settings, most commonly Emergency Departments (36%) and medical/surgical wards (30%). Urological intervention was required in 94.7% (54/57), with suprapubic catheterization required in 12.3% (n = 7). More than half of patients (55.56%) were discharged with an urethral catheter, fully or partially attributable to the urethral catheter injury. At least one further healthcare encounter on account of the injury was required for 90% of patients post-discharge. CONCLUSIONS: This is the largest study of its kind and confirms that iatrogenic urethral trauma is a recurring medical error seen universally across institutions, healthcare systems and countries. In addition, urethral catheter injury results in significant patient morbidity with a substantial financial burden to healthcare services. Future innovation to improve the safety of urinary catheterization is warranted.

Microbiomes of Urine and the Prostate Are Linked to Human Prostate Cancer Risk Groups.

BACKGROUND: Bacteria play a suspected role in the development of several cancer types, and associations between the presence of particular bacteria and prostate cancer have been reported. OBJECTIVE: To provide improved characterisation of the prostate and urine microbiome and to investigate the prognostic potential of the bacteria present. DESIGN, SETTING, AND PARTICIPANTS: Microbiome profiles were interrogated in sample collections of patient urine (sediment microscopy: n = 318, 16S ribosomal amplicon sequencing: n = 46; and extracellular vesicle RNA-seq: n = 40) and cancer tissue (n = 204). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Microbiomes were assessed using anaerobic culture, population-level 16S analysis, RNA-seq, and whole genome DNA sequencing. RESULTS AND LIMITATIONS: We demonstrate an association between the presence of bacteria in urine sediments and higher D'Amico risk prostate cancer (discovery, n = 215 patients, p < 0.001; validation, n = 103, p < 0.001, χ2 test for trend). Characterisation of the bacterial community led to the (1) identification of four novel bacteria (Porphyromonas sp. nov., Varibaculum sp. nov., Peptoniphilus sp. nov., and Fenollaria sp. nov.) that were frequently found in patient urine, and (2) definition of a patient subgroup associated with metastasis development (p = 0.015, log-rank test). The presence of five specific anaerobic genera, which includes three of the novel isolates, was associated with cancer risk group, in urine sediment (p = 0.045, log-rank test), urine extracellular vesicles (p = 0.039), and cancer tissue (p = 0.035), with a meta-analysis hazard ratio for disease progression of 2.60 (95% confidence interval: 1.39-4.85; p = 0.003; Cox regression). A limitation is that functional links to cancer development are not yet established. CONCLUSIONS: This study characterises prostate and urine microbiomes, and indicates that specific anaerobic bacteria genera have prognostic potential. PATIENT SUMMARY: In this study, we investigated the presence of bacteria in patient urine and the prostate. We identified four novel bacteria and suggest a potential prognostic utility for the microbiome in prostate cancer.

Patient perspectives of vigorous intensity aerobic interval exercise prehabilitation prior to radical cystectomy: a qualitative focus group study.

PURPOSE: Preoperative cardiopulmonary fitness is increasingly being recognized as an important factor influencing postoperative recovery outcomes in cancer patients. The aim of this study was to explore patient perspectives of preoperative high intensity aerobic interval exercise before radical cystectomy. MATERIALS AND METHODS: Focus groups involving a purposive convenience sample of patients with bladder cancer (N = 14; mean age ± SD: 72.3 ± 6.0 years) were undertaken in a hospital education department. Data were analyzed using Framework analysis. RESULTS: Participants identified physical (e.g., fitness) psychological (e.g., preparing for their operation) and social (e.g., peer support) benefits of the program. Key motivational factors for engaging in exercise prehabiliation were identified as social support, previous exercise experience and objective measures of progression. The need for clear information from healthcare providers to ensure that patients are adequately prepared for sessions was highlighted. CONCLUSIONS: This qualitative study provides new insights into the perspectives and experiences of patients with bladder cancer regarding participation in preoperative vigorous intensity aerobic exercise. The study yielded novel perceptions on the physical, psychological and social health benefits accruing from the exercise program and patient views on program design features, which are important for informing future interventions and implementation strategies.IMPLICATIONS FOR REHABILITATIONA preoperative high intensity aerobic interval exercise program before radical cystectomy provides physical, psychological and social benefits to individuals living with bladder cancer.Supervised exercise, objective improvement, and peer and family support all contribute to motivation to engage with preoperative high intensity aerobic interval exercise.Individuals may require support post-radical cystectomy in order to continue with exercise due to the uncertainty around this.

Development and validation of risk score for predicting positive repeat prostate biopsy in patients with a previous negative biopsy in a UK population.

BACKGROUND: Little evidence is available to determine which patients should undergo repeat biopsy after initial benign extended core biopsy (ECB). Attempts have been made to reduce the frequency of negative repeat biopsies using PSA kinetics, density, free-to-total ratios and Kattan's nomogram, to identify men more likely to harbour cancer but no single tool accurately predicts biopsy outcome. The objective of this study was to develop a predictive nomogram to identify men more likely to have a cancer diagnosed on repeat prostate biopsy. METHODS: Patients with previous benign ECB undergoing repeat biopsy were identified from a database. Association between age, volume, stage, previous histology, PSA kinetics and positive repeat biopsy was analysed. Variables were entered stepwise into logistic regression models. A risk score giving the probability of positive repeat biopsy was estimated. The performance of this score was assessed using receiver characteristic (ROC) analysis. RESULTS: 110 repeat biopsies were performed in this period. Cancer was detected in 31% of repeat biopsies at Hospital (1) and 30% at Hospital (2). The most accurate predictive model combined age, PSA, PSA velocity, free-to-total PSA ratio, prostate volume and digital rectal examination (DRE) findings. The risk model performed well in an independent sample, area under the curve (AUCROC) was 0.818 (95% CI 0.707 to 0.929) for the risk model and 0.696 (95% CI 0.472 to 0.921) for the validation model. It was calculated that using a threshold risk score of > 0.2 to identify high risk individuals would reduce repeat biopsies by 39% while identifying 90% of the men with prostate cancer. CONCLUSION: An accurate multi-variable predictive tool to determine the risk of positive repeat prostate biopsy is presented. This can be used by urologists in an outpatient setting to aid decision-making for men with prior benign histology for whom a repeat biopsy is being considered.

The type 1 insulin-like growth factor receptor is over-expressed in bladder cancer.

OBJECTIVE: To analyse bladder cancer biopsies and investigate the pattern of expression of the type 1 insulin-like growth factor receptor (IGF1R), a receptor tyrosine kinase that mediates tumour cell proliferation, motility and protection from apoptosis. MATERIALS AND METHODS: Formalin-fixed specimens of bladder cancer (40 whole-mount, 80 cores on a tumour microarray) and normal bladder (15 samples) were stained immunohistochemically for the IGF1R. The IGF1R expression was also measured by quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR) on RNA extracted from fresh frozen bladder cancers (61) and benign bladder (12). RESULTS: Of the 15 samples of normal bladder, 14 showed negligible (1+) or light (2+) IGF1R immunostaining. By contrast moderate (3+) or heavy (4+) staining for IGF1R was detected in 89 (74%) of the 120 samples of malignant urothelium. Q-RT-PCR showed significantly higher levels of steady-state IGF1R mRNA in tumours (all cases, Ta-T4) than in normal bladder (P < 0.05), indicating up-regulation at the transcriptional level. This difference was particularly evident when comparing normal urothelium with superficial (Ta-T1) or invasive (T2-4) tumours; only the latter showed significant IGF1R over-expression at the RNA level (P < 0.05 vs normal bladder). CONCLUSION: The IGF1R is up-regulated in bladder cancer compared with non-malignant bladder, and might contribute to a propensity for invasion.

Up-regulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer.

PURPOSE: Angiogenesis and vascular endothelial growth factor (VEGF) expression are associated with a poor outcome in bladder cancer. To understand more about the mechanisms, we studied the role of delta-like 4 (DLL4), an endothelial-specific ligand of the Notch signaling pathway, in bladder cancer angiogenesis. EXPERIMENTAL DESIGN: The expression of DLL4, CD34, and VEGF were studied in a cohort of 60 bladder tumors and 10 normal samples using quantitative PCR. In situ hybridization was used to study the pattern of DLL4 expression in 22 tumor and 9 normal samples. Serial sections were also stained for CD34 and alpha-smooth muscle actin (alpha-SMA) using conventional immunohistochemistry. RESULTS: The expression of DLL4 was significantly up-regulated in superficial (P < 0.01) and invasive (P < 0.05) bladder cancers. DLL4 expression significantly correlated with CD34 (P < 0.001) and VEGF (P < 0.001) expression. The in situ hybridization studies showed that DLL4 was highly expressed within bladder tumor vasculature. Additionally, DLL4 expression significantly correlated with vessel maturation as judged by periendothelial cell expression of alpha-SMA, 98.7% of DLL4-positive tumor vessels coexpressed alpha-SMA, compared with 64.5% of DLL4-negative tumor vessels (P < 0.001). High DLL4 expression may have prognostic value in superficial and invasive bladder. CONCLUSION: DLL4 expression is associated with vascular differentiation in bladder cancer; thus, targeting DLL4 may be a novel antiangiogenic therapy.

Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer.

The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed in prostate cancer, and mediates proliferation, motility, and survival. Many prostate cancers harbor inactivating PTEN mutations, enhancing Akt phosphorylation. This activates the principal antiapoptotic pathway downstream of the IGF1R, calling into question the value of IGF1R targeting in this tumor. The aim of the current study was to assess the effect of IGF1R gene silencing in prostate cancer cells that lack functional PTEN protein. In human DU145, LNCaP and PC3 prostate cancer cells, transfection with IGF1R small interfering RNA induced significant enhancement of apoptosis and inhibition of survival, not only in PTEN wild-type DU145 but also in PTEN mutant LNCaP and PC3. This was attributed to attenuation of IGF signaling via Akt, ERKs and p38. In both DU145 and PC3, IGF1R knockdown led to enhancement of sensitivity to mitoxantrone, etoposide, nitrogen mustard and ionizing radiation. There was no sensitization to paclitaxel or 5-fluorouracil, which do not damage DNA, suggesting that chemosensitization results from impairment of the DNA damage response, in addition to removal of apoptosis protection. These results support the concept of IGF1R targeting in prostate cancer, and indicate that PTEN loss does not render tumor cells refractory to this strategy.

Mutation detection in formalin-fixed prostate cancer biopsies taken at the time of diagnosis using next-generation DNA sequencing.

AIMS: Assessing whether next-generation DNA sequencing (NGS) can be used to screen prostate cancer for multiple gene alterations in men routinely diagnosed with this disease and/or who are entered into clinical trials. Previous studies are limited and have reported only low success rates. METHODS: We marked areas of cancer on H&E-stained sections from formalin-fixed needle biopsies, and used these as templates to dissect cancer-rich tissue from adjacent unstained sections. DNA was prepared using a Qiagen protocol modified to maximise DNA yield. The DNA was screened simultaneously for mutations in 365 cancer-related genes using an Illumina HiSeq 2000 NGS platform. RESULTS: From 63 prostate cancers examined, 59(94%) of the samples yielded at least 30 ng of DNA, the minimum amount of DNA considered suitable for NGS analysis. Patients in the D'Amico high-risk group yielded an average of 1033 ng, intermediate-risk patients 401 ng, and low-risk patients 97 ng. NGS of eight samples selected from high-risk and intermediate-risk groups gave a median exon read depth of 962 and detected TMPRRS2-ERG fusions, as well as a variety of mutations including those in the SPOP, TP53, ATM, MEN1, NBPF10, NCOR2, PIK3CB and MAP2K5 (MEK5) genes. CONCLUSIONS: Using the methods presented here, NGS technologies can be used to screen a high proportion of patients with prostate cancer for mutations in cancer-related genes in tissue samples opening up its general use in the context of clinical trials or routine diagnosis.

Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks.

BACKGROUND AND PURPOSE: IGF-1R depletion sensitizes prostate cancer cells to ionizing radiation and DNA-damaging cytotoxic drugs. This study investigated the hypothesis that IGF-1R regulates DNA double strand break (DSB) repair. METHODS: We tested effects of IGF-1R siRNA transfection on the repair of radiation-induced DSBs by immunoblotting and immunofluorescence for γH2AX, and pulsed-field gel electrophoresis. Homologous recombination (HR) was quantified by reporter assays, and cell cycle distribution by flow cytometry. RESULTS: We confirmed that IGF-1R depletion sensitized DU145 and PC3 prostate cancer cells to ionizing radiation. DU145 control transfectants resolved radiation-induced DSBs within 24 h, while IGF-1R depleted cells contained 30-40% unrepaired breaks at 24 h. IGF-1R depletion induced significant reduction in DSB repair by HR, although the magnitude of the repair defect suggests additional contributory factors. Radiation-induced G2-M arrest was attenuated by IGF-1R depletion, potentially suppressing cell cycle-dependent processes required for HR. In contrast, IGF-1R depletion induced only minor radiosensitization in LNCaP cells, and did not influence repair. Cell cycle profiles were similar to DU145, so were unlikely to account for differences in repair responses. CONCLUSIONS: These data indicate a role for IGF-1R in DSB repair, at least in part via HR, and support use of IGF-1R inhibitors with DNA damaging cancer treatments.

Self Management Activation Randomised Trial for Prostatitis (SMART-P): study protocol for a randomised controlled trial.

BACKGROUND: Chronic prostatitis otherwise known as chronic pelvic pain syndrome is a common urological diagnosis that causes many men significant morbidity and has a detrimental effect on their quality of life. Standard treatment with antibiotics and simple analgesia are often ineffective and many patients are managed by the chronic pain services.Cognitive behavioural therapy has been shown to be helpful in the management of many chronic diseases and has recently been proposed as an effective treatment for chronic prostatitis. Furthermore, a self management programme administered to groups of men with lower urinary tract symptoms has been shown to be more effective than standard treatments including surgery.Therefore, we have developed a cognitive behavioural therapy programme specifically for men with chronic prostatitis. This novel treatment approach will be compared to conventional therapy in the pain clinic such as atypical analgesia and local anaesthetic injections in the context of a randomised controlled trial. METHODS/DESIGN: Men will be recruited from general urology outpatient clinics following the exclusion of other diagnoses that could be responsible for their symptoms. Men will be randomised to attend either a self management healthcare and education programme or to pain clinic referral alone. The self management programme will be administered by a clinical psychologist to small groups of men over six consecutive weekly sessions each lasting two hours. Patients will be taught techniques of problem-solving and goal-setting and will learn coping mechanisms and how to modify catastrophic cognition.The primary outcome will be change from baseline in the National Institute of Health Chronic Prostatitis Symptom Index, a validated instrument for the assessment of men with chronic prostatitis. Secondary outcomes include generic quality of life scores and analgesic and drug usage. Outcomes will be assessed at 2, 6 and 12 months. DISCUSSION: If this group administered self management programme is shown to be effective in the treatment of men with chronic prostatitis it may become the new standard of care for these patients. Furthermore, it may be adapted for use in women with interstitial cystitis, a condition which is analogous to chronic prostatitis in men. TRIAL REGISTRATION: Current Controlled Trials ISRCTN21012555.