Phase 2 Trial of Atezolizumab in Bacillus Calmette-Guérin-unresponsive High-risk Non-muscle-invasive Bladder Cancer: SWOG S1605.

BACKGROUND: Although radical cystectomy (RC) is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC), many patients are ineligible for surgery or elect bladder preservation. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab in BCG-unresponsive high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm phase 2 trial in patients with BCG-unresponsive high-risk NMIBC who were ineligible for or declined RC. INTERVENTION: Intravenous atezolizumab every 3 wk for 1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the pathological complete response (CR) rate for patients with carcinoma in situ (CIS) determined via mandatory biopsy at 6 mo. Event-free survival (EFS) at 18 mo for patients with non-CIS tumors and treatment-related adverse events (TRAEs) were key secondary endpoints. RESULTS AND LIMITATIONS: Of 172 patients enrolled in the trial, 166 received at least one dose of atezolizumab (safety analysis) and 129 were eligible (efficacy analysis). Of the 74 patients with CIS, 20 (27%) experienced a CR at 6 mo. The median duration of response was 17 mo, and 56% (95% confidence interval [CI] 34-77%) of the responses were durable to at least 12 mo. The 18-mo actuarial EFS rate among 55 patients with Ta/T1 disease was 49% (90% CI 38-60%). Twelve of 129 eligible patients experienced progression to muscle-invasive or metastatic disease. Grade 3-5 TRAEs occurred in 26 patients (16%), including three treatment-related deaths. The study was limited by the small sample size and a high rate of patient ineligibility. CONCLUSIONS: The efficacy of atezolizumab observed among patients with BCG-unresponsive NMIBC is similar to results from similar trials with other agents, but did not meet the prespecified efficacy threshold. Modest efficacy needs to be balanced with a significant rate of TRAEs and the risk of disease progression when considering systemic immunotherapy in early-stage bladder cancer. PATIENT SUMMARY: We tested intravenous immunotherapy (atezolizumab) in patients with high-risk non-muscle-invasive bladder cancer that recurred after BCG (bacillus Calmette-Guérin) treatment. Although we found similar outcomes to previous trials, the benefit of this therapy is modest and needs to be carefully balanced with the significant risk of side effects. This trial is registered on ClinicalTrials.gov as NCT02844816.

Impact of choosing wisely on imaging in men with newly diagnosed prostate cancer.

INTRODUCTION: Encouraging the appropriate use of staging imaging in patients with newly diagnosed prostate cancer remains a challenge. Assessing the effects of national efforts may help guide future initiatives in curtailing low-value care. The purpose of this study was to determine the impact of the Choosing Wisely campaign on imaging utilization among men with prostate cancer. METHODS: Surveillance, Epidemiology, and End Results - Medicare data were used to complete a longitudinal population-based study of men diagnosed with prostate cancer from 2007 to 2015. An interrupted time series analysis evaluated the impact of the Choosing Wisely campaign on trends of imaging utilization. RESULTS: From 2007 to 2015 imaging utilization in low-risk patients decreased, with computed tomography (CT) usage declining from 45.0% to 34.4% (P<0.001) and nuclear medicine bone scan (NMBS) from 27.8% to 11.7% (P<0.001). Choosing Wisely likely contributed to an absolute reduction of 2.9% (P=0.03) in utilization of NMBS in the low-risk population. Imaging usage for all modalities increased in the high-risk population, but with 32.8% continuing to not receive guideline-supported imaging. CONCLUSIONS: In 2012, the Choosing Wisely campaign sought to decrease inappropriate staging imaging for men with low-risk prostate cancer and encourage stewardship of medical resources. Overall decreases in staging imaging trends suggest a move towards higher value care. However, this study found that the Choosing Wisely recommendations had a modest impact on utilization of NMBS, but not CT or PET scans. These results may help inform future efforts to promote guideline concordant imaging.

Clinical Germline Testing Results of Men With Prostate Cancer: Patient-Level Factors and Implications of NCCN Guideline Expansion.

Germline likely pathogenic or pathogenic variants (PVs) have been identified in up to 17% of men with prostate cancer (PC) and may drive disease severity or be targetable by novel therapies. National Comprehensive Cancer Network (NCCN) guidelines encouraging germline testing in metastatic PC were recently expanded to include all men with high-risk, very high-risk, or regional PC. Our aim was to assess the impact of expanded NCCN guidelines on the detection rate of germline PVs and to determine patient-level factors associated with a PV germline testing result. PATIENTS AND METHODS: Men with PC underwent multigene germline genetic testing for PVs from June 2016 to December 2018, and trends were compared. The association of patient-level factors with a PV germline testing result, where ≥ 1 PV was identified, was assessed using analysis of variance and univariate logistic regression. Sensitivity analyses were limited to clinically actionable variants and those associated with disease severity or progression (BRCA1/2 and ATM). RESULTS: Of 408 men undergoing germline testing, 42 (10.3%) men had PVs and 366 (89.7%) men did not have PVs identified. The proportion of men identified with a germline PV remained stable following testing criteria expansion (9.4% v 10.6%, P = .73). No patient-level factors were significantly associated with increased odds of a PV germline testing result, including age at diagnosis, race, pretreatment prostate-specific antigen, Gleason grade group, NCCN risk group, and family history of cancer (breast and/or ovarian, prostate, or any cancer). CONCLUSION: This study demonstrated a stable PV detection rate in men with PC using expanded criteria aligned to the updated NCCN testing guidelines. However, we did not find strong evidence to suggest that patient-level factors are associated with PV germline testing results. These findings support the recent expansion of NCCN germline testing guidelines in PC.

Decision fatigue in low-value prostate cancer screening.

BACKGROUND: Low-value prostate-specific antigen (PSA) testing is common yet contributes substantial waste and downstream patient harm. Decision fatigue may represent an actionable target to reduce low-value urologic care. The objective of this study was to determine whether low-value PSA testing patterns by outpatient clinicians are consistent with decision fatigue. METHODS: Outpatient appointments for adult men without prostate cancer were identified at a large academic health system from 2011 through 2018. The authors assessed the association of appointment time with the likelihood of PSA testing, stratified by patient age and appropriateness of testing based on clinical guidelines. Appointments included those scheduled between 8:00 am and 4:59 pm, with noon omitted. Urologists were examined separately from other clinicians. RESULTS: In 1,581,826 outpatient appointments identified, the median patient age was 54 years (interquartile range, 37-66 years), 1,256,152 participants (79.4%) were White, and 133,693 (8.5%) had family history of prostate cancer. PSA testing would have been appropriate in 36.8% of appointments. Clinicians ordered testing in 3.6% of appropriate appointments and in 1.8% of low-value appointments. Appropriate testing was most likely at 8:00 am (reference group). PSA testing declined through 11:00 am (odds ratio [OR], 0.57; 95% CI, 0.50-0.64) and remained depressed through 4:00 pm (P < .001). Low-value testing was overall less likely (P < .001) and followed a similar trend, declining steadily from 8:00 am (OR, 0.48; 95% CI, 0.42-0.56) through 4:00 pm (P < .001; OR, 0.23; 95% CI, 0.18-0.30). Testing patterns in urologists were noticeably different. CONCLUSIONS: Among most clinicians, outpatient PSA testing behaviors appear to be consistent with decision fatigue. These findings establish decision fatigue as a promising, actionable target for reducing wasteful and low-value practices in routine urologic care. LAY SUMMARY: Decision fatigue causes poorer choices to be made with repetitive decision making. This study used medical records to investigate whether decision fatigue influenced clinicians' likelihood of ordering a low-value screening test (prostate-specific antigen [PSA]) for prostate cancer. In more than 1.5 million outpatient appointments by adult men without prostate cancer, the chances of both appropriate and low-value PSA testing declined as the clinic day progressed, with a larger decline for appropriate testing. Testing patterns in urologists were different from those reported by other clinicians. The authors conclude that outpatient PSA testing behaviors appear to be consistent with decision fatigue among most clinicians, and interventions may reduce wasteful testing and downstream patient harms.

Prostate-specific antigen testing among young men: an opportunity to improve value.

INTRODUCTION: Prostate cancer screening using prostate-specific antigen (PSA) testing remains widespread. The prevalence of PSA testing in young men is unknown and may be an appropriate target for improving health care by decreasing low-value testing in this age group. The purpose of this study was to determine PSA testing rates in men younger than current guidelines support. MATERIALS AND METHODS: Health Informational National Trends Surveys (HINTS) from 2011 to 2014 and 2017 were analyzed to establish the prevalence of PSA testing in young men and to evaluate the differences in testing rates based on race. RESULTS: The combined survey data included 5178 men, with 2393 reporting previous PSA screening. Of men ages 18-39, 7% recalled receipt of PSA testing. Twenty-two percent of men between the ages of 40 and 44 had been tested. Among men under age 40, PSA testing was more common among black men (14%) compared to white men (7%), Hispanics (6%), and men of Asian descent (8%). Logistic regression modeling demonstrates that black men under the age of 40 were more likely to undergo PSA testing than other racial or ethnic groups (odds ratio 2.14; 95% CI 1.17, 3.93). CONCLUSIONS: Current guidelines do not recommend routine PSA testing in average-risk men under the age of 40. This study found that a significant number of young men are exposed to testing, with the greatest risk among black men. This suggests that there is an opportunity to improve the value of PSA testing by decreasing testing in young men.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

PURPOSE: The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. RESULTS: The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. CONCLUSIONS: This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART I.

PURPOSE: The summary presented herein represents Part I of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. Please refer to Part II for discussion of the management of castration-resistant disease. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. RESULTS: The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. CONCLUSIONS: This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

Feasibility of wearable activity trackers in cystectomy patients to monitor for postoperative complications.

BACKGROUND: To determine the feasibility of using wearables in patients undergoing radical cystectomy to monitor postoperative heart rate and activity and attempt to correlate these factors to complications and readmissions. MATERIALS AND METHODS: We conducted a prospective study of 20 patients undergoing radical cystectomy for bladder cancer between June 2017 and March 2018. Each patient was provided with a Garmin Vívofit heart rate (HR) activity tracker and instructed to wear it on their wrist for 30 days postoperatively. Heart rate, steps, and sleep data were collected during this time. Patients were called at 10-day intervals and surveyed for complications and device compliance. Univariable mixed effects logistic regression models were used to compare daily activity tracker measures with occurrence of an adverse event. Odds ratios, 95% confidence intervals, and p-values were reported. RESULTS: Median age was 65 (interquartile range 61-74) years. Patients had usable data for a median of 59.3% (interquartile range 25-71.7%) of the time. Five patients experienced a postoperative event (1 readmission for sepsis from urinary tract source, 1 inpatient rapid response called for tachycardic event, 3 unscheduled visits related to dehydration), where event data was recorded over a total of 17 days. Higher step count was associated with reduced odds of an adverse event (odds ratio 0.31, 95% confidence interval 0.10-0.98 per 1000 steps, p = 0.047). CONCLUSIONS: Postoperative activity and heart rate monitoring in cystectomy patients is feasible though current wearables are not well suited for this task.

Metastasis, Mortality, and Quality of Life for Men With NCCN High and Very High Risk Localized Prostate Cancer After Surgical and/or Combined Modality Radiotherapy.

PURPOSE: To compare metastasis-free survival, overall survival, and patient-reported quality of life (QOL) of men with National Comprehensive Cancer Network high or very high risk prostate cancer after definitive surgery and/or multimodal radiotherapy (RT). PATIENTS AND METHODS: We studied a retrospective cohort study of 586 patients treated between the years 2000 and 2017 receiving radical prostatectomy with or without postoperative RT, external-beam RT (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy (Brachy) boost + ADT. Patient-reported QOL for urinary, bowel, sexual, and overall physical and mental functioning was assessed using the American Urological Association symptom scale, the Sexual Health Inventory in Men, the Rectal-Function Assessment Scale, the Expanded Prostate Cancer Index Composite, and the Veterans RAND 12-Item Health Survey. RESULTS: Median follow-up for survival was 5 years. No significant differences between the treatments were observed for overall survival or metastasis-free survival at the P < .05 threshold. The propensity-adjusted 5-year metastasis-free survival estimates for EBRT + ADT, EBRT + Brachy + ADT, and surgery were 74.6%, 94.8%, and 83.1%, respectively. The EBRT + Brachy + ADT and surgery cohorts had significantly worse mean American Urological Association symptom scores at 6 months than the EBRT + ADT cohort, which resolved by 1 year. Surgical patients had better rectal function scores than EBRT + ADT patients at years 1 to 3, but similar function thereafter. Adjuvant or salvage RT resulted in significant declines in various Expanded Prostate Cancer Index Composite urinary, sexual, and bowel domains, and Veterans RAND 12-Item Health Survey physical but not mental domains. CONCLUSION: Men with very and/or high-risk localized prostate cancer are likely to require multimodal therapy. The overall differences in survival and long-term QOL are similar for men choosing surgical versus RT pathways.

Harnessing Population Pedigree Data and Machine Learning Methods to Identify Patterns of Familial Bladder Cancer Risk.

BACKGROUND: Relatives of patients with bladder cancer have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking-related behaviors that may concentrate in some families. We demonstrate a novel approach to simultaneously assess risks for multiple cancers to identify distinct multicancer configurations (multiple different cancer types that cluster in relatives) surrounding patients with familial bladder cancer. METHODS: This study takes advantage of a unique population-level data resource, the Utah Population Database (UPDB), containing vast genealogy and statewide cancer data. Familial risk is measured using standardized incidence risk (SIR) ratios that account for sex, age, birth cohort, and person-years of the pedigree members. RESULTS: We identify 1,023 families with a significantly higher bladder cancer rate than population controls (familial bladder cancer). Familial SIRs are then calculated across 25 cancer types, and a weighted Gower distance with K-medoids clustering is used to identify familial multicancer configurations (FMC). We found five FMCs, each exhibiting a different pattern of cancer aggregation. Of the 25 cancer types studied, kidney and prostate cancers were most commonly enriched in the familial bladder cancer clusters. Laryngeal, lung, stomach, acute lymphocytic leukemia, Hodgkin disease, soft-tissue carcinoma, esophageal, breast, lung, uterine, thyroid, and melanoma cancers were the other cancer types with increased incidence in familial bladder cancer families. CONCLUSIONS: This study identified five familial bladder cancer FMCs showing unique risk patterns for cancers of other organs, suggesting phenotypic heterogeneity familial bladder cancer. IMPACT: FMC configurations could permit better definitions of cancer phenotypes (subtypes or multicancer) for gene discovery and environmental risk factor studies.

The Relative Importance of Race Compared to Health Care and Social Factors in Predicting Prostate Cancer Mortality: A Random Forest Approach.

PURPOSE: There is a differential in prostate cancer mortality between black and white men. Advances in precision medicine have shifted the research focus toward underlying genetic differences. However, nonbiological factors may have a large role in these observed disparities. Therefore, we sought to measure the relative importance of race compared to health care and social factors on prostate cancer specific mortality. MATERIALS AND METHODS: Using the SEER (Surveillance, Epidemiology, and End Results) database we identified 514,878 men diagnosed with prostate cancer at age 40 years or greater between 2004 and 2012. We also selected a subset of black and white men matched by age, stage and birth year. We stratified patients by age 40 to 54, 55 to 69 and 70 years or older and disease stage, resulting in 18 groups. By applying random forest methods with variable importance measures we analyzed 15 variables and interactions across 4 categories of factors (tumor characteristics, race, and health care and social factors) and the relative importance for prostate cancer specific mortality. RESULTS: Tumor characteristics at diagnosis were the most important factors for prostate cancer mortality. Across all groups race was less than 5% as important as tumor characteristics and only more important than health care and social factors in 2 of the 18 groups. Although race had a significant impact, health care and social factors known to be associated with racial disparities had greater or similarly important effects across all ages and stages. CONCLUSIONS: Eradicating disparities in prostate cancer survival will require a multipronged approach, including advances in precision medicine. Disparities will persist unless health care access and social equality are achieved among all populations.

Histone Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced Urothelial Carcinoma.

Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response to belinostat, and one patient with advanced urothelial carcinoma who had a partial response to panobinostat. The archived tumors of the responders were genomically characterized in comparison to others with urothelial carcinoma on the trials. Urothelial carcinoma cell lines treated with panobinostat and belinostat were studied to elucidate the mechanisms of benefit. Notably, the urothelial carcinoma tumors that responded to HDAC inhibition had ARID1A mutations. ARID1A mutations were also noted in the tumors of three patients who had stable disease as their best response to HDAC inhibition. Corroborating the basis of sensitivity, transcriptional profiling of platinum-resistant ARID1A-mutated HT1197 cells treated with panobinostat reveals negative enrichment for both cyto-proliferative (MYC and E2F targets) and DNA repair gene sets, and positive enrichment for TP53 and inflammatory gene sets. Our study identifies ARID1A loss as a basis for clinical response to pan HDAC inhibition and offers avenues for potential rational therapeutic combinations with HDAC inhibitors in advanced urothelial carcinoma.

Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018.

PURPOSE: The purpose of this amendment is to incorporate newly-published literature to provide a rational basis for the management of patients with non-metastatic castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: The original systematic review and meta-analysis of the published literature yielded 303 studies published from 1996 through 2013. This review informed the majority of the guideline statements from the 2013 guideline. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence. The guideline was subsequently amended in April 2014 and March 2015. The current 2018 amendment search yielded 770 references with 47 studies eventually providing relevant data. The resulting amendment focuses on the incorporation of information relating to the treatment of patients with non-metastatic CRPC. RESULTS: Guideline statements based on six Index Patients developed to represent the most common scenarios encountered in clinical practice were amended appropriately. The additional literature provided the basis for an update of current supporting text as well as the incorporation of new guideline statements for asymptomatic non-metastatic CRPC. CONCLUSIONS: Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of individual patients' treatment goals. Shared decision-making incorporating patients' preferences and personal goals should be implemented when choosing management strategies. This guideline will be continually updated as new literature emerges.

Familial Cancer Clustering in Urothelial Cancer: A Population-Based Case-Control Study.

Background: Family history of bladder cancer confers an increased risk for concordant and discordant cancers in relatives. However, previous studies investigating this relationship lack any correction for smoking status of family members. We conducted a population-based study of cancer risks in relatives of bladder cancer patients and matched controls with exclusion of variant subtypes to improve the understanding of familial cancer clustering. Methods: Case subjects with urothelial carcinoma were identified using the Utah Cancer Registry and matched 1:5 to cancer-free controls from the Utah Population Database. Cox regression was used to determine the risk of cancer in first-degree relatives, second-degree relatives, first cousins, and spouses. A total of 229 251 relatives of case subjects and 1 197 552 relatives of matched control subjects were analyzed. To correct for smoking status, we performed a secondary analysis excluding families with elevated rates of smoking-related cancers. All statistical tests were two-sided. Results: First- and second-degree relatives of case subjects had an increased risk for any cancer diagnosis (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 1.03 to 1.09, P < .001; HR = 1.04, 95% CI = 1.02 to 1.07, P = .001) and urothelial cancer (HR = 1.73, 95% CI = 1.50 to 1.99, P < .001; HR = 1.35, 95% CI = 1.21 to 1.51, P < .001). Site-specific analysis found increased risk for bladder (HR = 1.69, 95% CI = 1.47 to 1.95, P < .001), kidney (HR = 1.30, 95% CI = 1.08 to 1.57, P = .006), cervical (HR = 1.25, 95% CI = 1.06 to 1.49, P = .01), and lung cancer (HR = 1.34, 95% CI = 1.19 to 1.51, P < .001) in first-degree relatives. Second-degree relatives had increased risk for bladder (HR = 1.35, 95% CI = 1.2 to 1.5, P < .001) and thyroid cancer (HR = 1.18, 95% CI = 1.03 to 1.35, P = .02). Spouses showed an increased risk for laryngeal (HR = 2.68, 95% CI = 1.02 to 7.05, P = .04) and cervical cancer (HR = 1.57, 95% CI = 1.13 to 2.17, P = .007). These results did not substantively change after correction for suspected smoking behaviors. Conclusion: Our results suggest familial urothelial cancer clustering independent of smoking, with increased risk in relatives for both concordant and discordant cancers, suggesting shared genetic or environmental roots. Identifying families with statistically significant risks for non-smoking-related urothelial cancer would be extremely informative for genetic linkage studies.

Gender Differences in Publication Productivity Among Academic Urologists in the United States.

OBJECTIVE: To describe the publication productivity of academic urologists in the United States by gender. MATERIALS AND METHODS: Gender inequality is prevalent in most surgical subspecialties, including urology. Despite small numbers of women in academic positions, differences in scholarly impact by gender are relatively unknown. We assembled a list of 1922 academic urologists (1686 men (87.7%), 236 women (12.3%)) at 124 academic institutions throughout the United States as of February 2016. Scopus and Google Scholar were queried for bibliometric data on each individual, including h-index and m-quotient. We analyzed these metrics for both genders by educational background, subspecialty, National Institutes of Health funding, and academic rank. RESULTS: Men had higher median h-indices than women overall (P < .05), and had higher successive academic ranks (P < .05). Proportionally fewer women attained senior academic ranking (professor/chair), (P < .05). There was no difference in research productivity by successive rank after controlling for career duration (m-quotient). Women were more likely to choose a practice that specialized in pediatric urology or female urology/pelvic reconstructive surgery than their male counterparts (P < .05). CONCLUSION: Women represent a growing proportion of academic urology faculty, but despite the recent increase in number entering the field, relatively few women occupy senior leadership positions. Improving psychosocial barriers to advancement such as lack of mentorship or discriminatory policies may help pioneering female urologists as they progress in their careers.

Childhood Cancer Risk in the Siblings and Cousins of Men with Poor Semen Quality.

PURPOSE: Poor semen quality is associated with reduced somatic health and increased cancer risk. Infertility and cancer are increasingly being linked by epidemiologists and basic scientists. We sought to identify semen parameters associated with an increased childhood cancer risk in the family members of subfertile men. MATERIALS AND METHODS: We performed a retrospective cohort study in men from the SHARE (Subfertility Heath and Assisted Reproduction) study who underwent semen analysis between 1994 and 2011. We used fertile population controls from the Utah Population Data Base. Our primary outcome was the risk of any childhood (18 years or younger) cancer in the siblings and cousins of men who underwent semen analysis compared to fertile, age matched controls. Cox proportional hazard regression models were used to test the association between semen quality and childhood cancer incidence. RESULTS: We selected 10,511 men with complete semen analysis and an equal number of fertile controls. These men had a total of 63,891 siblings and 327,753 cousins. A total of 170 and 958 childhood cancers were identified in siblings and cousins, respectively. The 3 most common cancers diagnosed in siblings were acute lymphoblastic leukemia in 37, brain cancer in 35 and Hodgkin lymphoma in 15. Oligozoospermia was associated with a twofold increased risk of any childhood cancer and a threefold increased risk of acute lymphoblastic leukemia in the siblings of subfertile men compared to fertile controls (HR 2.09, 95% CI 1.18-3.69 vs HR 3.07, 95% CI 1.11-8.46). CONCLUSIONS: Siblings of men with oligozoospermia are at increased risk for any-site cancer and acute lymphoblastic leukemia. This suggests a shared genetic/epigenetic insult or an environmental exposure that merits further investigation.

Risk of childhood mortality in family members of men with poor semen quality.

STUDY QUESTION: What is the familial childhood mortality in first-degree (FDR) and second-degree relatives (SDR) of patients undergoing semen analysis (SA)? SUMMARY ANSWER: The relationship between infertility and congenital malformations (CM) in offspring is complex, with an increased risk of death due to CM in FDR, but not SDR, of men with lower semen parameters. WHAT IS KNOWN ALREADY: Semen quality is an established predictor of men's somatic health. We can gain a better understanding of possible genetic or environmental determinants of the infertility phenotype by exploring familial aggregation of childhood mortality in relatives of men with poor semen quality. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study from the Subfertility, Health and Assisted Reproduction study (cohort compiled 1996-2011) linked with patient/familial information from the Utah Population Database (UPDB). Index cases included a clinic-referred sample of 12 889 men who underwent SA and had adequate familial and follow-up data in the UPDB. Parameters of semen quality included: semen concentration, sperm count, motility, total motile count, sperm head morphology, sperm tail morphology and vitality. PARTICIPANTS/MATERIALS, SETTING, METHODS: SA data were collected from two tertiary medical center andrology laboratories that have captured ~90% of all SA performed in Utah since 2004. Age- and sex-matched fertile controls were selected to create the comparison group for determining risk of childhood death (to age 20 years) in family members. A total of 79 750 siblings and 160 016 aunts/uncles were used to investigate the familial aggregation of childhood mortality. The main outcome was childhood mortality in FDR and SDR of men with SA and their matched controls. All-cause and cause-specific Cox proportional hazard models were used to test the association between semen quality and childhood mortality in family members. Cause-specific models were considered for cancer and CM. MAIN RESULTS AND THE ROLE OF CHANCE: In the cohort of men with SA, there were 406 (1.0%) deaths in FDR and 772 (1.1%) deaths in SDR due to any cause. There was no significant difference in the risk of all-cause childhood mortality between the relatives of men with SA and the fertile control group [hazard ratio (HR)Female = 1.08, 95% CI = 0.88, 1.32; HRMale = 0.88, 95% CI = 0.75, 1.04]. We found no association between semen quality and risk for childhood cancer mortality in FDR or SDR (HRFDR = 0.98, 95% CI = 0.62, 1.54; HRSDR = 1.12, 95% CI = 0.83, 1.50). The FDR of men with SA and fertile controls were followed on average for 19.71 and 19.73 years, respectively. During this period of follow-up, FDR of men with SA had an unadjusted 40% relative risk of increased CM-related death. After stratifying by semen parameters and adjusting for birth year, we found FDR of men with worse semen quality, and notably azoospermic men (HR = 2.69, 95% CI = 1.24,5.84), were at higher risk of CM-related death. LIMITATIONS REASONS FOR CAUTION: A large proportion of men with SA in the study had normal semen parameters. It is important to note that these men themselves may not be subfertile, but they were subfertile at the couple level (i.e. the female partner may be infertile). In addition, care is needed when interpreting our results, as we do not have semen measures on our sample of fertile men. Second, we were unable to include potential confounders such as medical comorbidities, smoking status, or environmental exposures. Third, men with SA were seen at the University of Utah or Intermountain Health Care clinics for a fertility evaluation thereby suggesting a more select population. Fourth, we chose to categorize morphology into equally distributed quartiles as a response to the fact that the World Health Organization threshold for normal motility changed multiple times during our study period. Lastly, we do not know the proportion of female partners with diagnosed infertility. We chose not to subcategorize each infertile male by infertile diagnosis because our goal was to understand how semen parameters influenced familial childhood mortality. WIDER IMPLICATIONS OF THE FINDINGS: We are not the first study to show a relationship between fertility and CMs. Children conceived through ART may be at higher risk of birth defects, however it is not known if the relationship is causal or if there is some underlying factor linking infertility and birth outcomes. This study provides further evidence that the increased risk of congenital birth defects may not be due to the ART, but rather genetic or environmental factors that link the two outcomes. We encourage further research in order to confirm a relationship between semen quality and increased risk for CM. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Institutes of Health - National Institute of Aging [Grant numbers 1R21AG036938-01, 2R01 AG022095 and 1K12HD085852-01]. Authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

Management of Radiation Therapy Oncology Group grade 4 urinary adverse events after radiotherapy for prostate cancer.

OBJECTIVE: To describe the management of Radiation Therapy Oncology Group (RTOG) grade 4 urinary adverse events (UAEs) after radiotherapy (RT) for prostate cancer (PCa). METHODS: We conducted a single-centre retrospective review, over a 6-year period (2010-2015), to identify men with RTOG grade 4 UAEs after RT for PCa. RT was classified as combined therapy (radical prostatectomy [RP] followed by external beam radiotherapy [EBRT], EBRT + low-dose-rate [LDR] brachytherapy, EBRT + high-dose-rate [HDR] brachytherapy or other combinations of RT) or monotherapy RT. UAEs were classified as outlet (urethral stricture, bladder neck contracture, prostate necrosis, or recto-urethral fistula) or bladder (contraction, necrosis, fistula, ureteric stricture or haemorrhage) UAEs. RESULTS: We identified 73 men with a mean age of 73 years. Of these, 44 (60%) received combined therapy, consisting of RP + EBRT (n = 19), HDR brachytherapy + EBRT (n = 19), LDR brachytherapy + EBRT (n = 5), and other combined RT (n = 1). Twenty-nine (40%) patients had monotherapy consisting of EBRT (n = 4), HDR brachytherapy (n = 11), LDR brachytherapy (n = 12), or proton beam therapy (n = 2). UAEs were isolated to the bladder in six men (8%), the outlet in 52 men (71%), and to both in 15 men (21%). UAE management included: conservative in 21 (29%), indwelling catheters in 12 (16%), reconstructive in 19 (26%), and urinary diversion (UD) in 23 men (32%). Reconstruction included: ureteric (n = 4), recto-urethral fistula repair (n = 2), and posterior urethroplasty (n =13), of which 14/16 surgeries (88%) with follow-up >90 days were successful. CONCLUSIONS: Although the incidence of RTOG grade 4 UAEs after PCa radiation treatment is not well defined, their associated morbidity is significant, and approximately one third of patients with these high-grade complications require UD. Conversely, only about a quarter of patients can be managed with conservative strategies or local surgeries. Reconstruction is successful in selected patients.