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Purpose: Androgen receptor (AR) antagonism is exacerbated by HOXB13 in castration-resistant prostate cancers (CRPC). However, it is unclear when and how HOXB13 primes CRPCs for AR antagonism. By mass-spectrometry analysis of CRPC extract, we uncovered a novel lysine 13 (K13) acetylation in HOXB13 mediated by CBP/p300. To determine whether acetylated K13-HOXB13 is a clinical biomarker of CRPC development, we characterized its role in prostate cancer biology. Experimental Design: We identified tumor-specific acK13-HOXB13 signal enriched super enhancer (SE)-regulated targets. We analyzed the effect of loss of HOXB13K13-acetylation on chromatin binding, SE proximal target gene expression, self-renewal, enzalutamide sensitivity, and CRPC tumor growth by employing isogenic parental and HOXB13K13A mutants. Finally, using primary human prostate organoids, we evaluated whether inhibiting an acK13-HOXB13 target, ACK1, with a selective inhibitor (R)-9b is superior to AR antagonists in inhibiting CRPC growth. Results: acK13-HOXB13 promotes increased expression of lineage (AR, HOXB13), prostate cancer diagnostic (FOLH1), CRPC-promoting (ACK1), and angiogenesis (VEGFA, Angiopoietins) genes early in prostate cancer development by establishing tumor-specific SEs. acK13-HOXB13 recruitment to key SE-regulated targets is insensitive to enzalutamide. ACK1 expression is significantly reduced in the loss of function HOXB13K13A mutant CRPCs. Consequently, HOXB13K13A mutants display reduced self-renewal, increased sensitivity to enzalutamide, and impaired xenograft tumor growth. Primary human prostate tumor organoids expressing HOXB13 are significantly resistant to AR antagonists but sensitive to (R)-9b. Conclusions: In summary, acetylated HOXB13 is a biomarker of clinically significant prostate cancer. Importantly, PSMA-targeting agents and (R)-9b could be new therapeutic modalities to target HOXB13–ACK1 axis regulated prostate cancers.

To evaluate the hypothesis that there is an improvement in sexual function following smoking cessation (as smoking is a well-established risk factor for sexual dysfunction), we analysed the association between cigarette smoking and smoking cessation with sexual function among participants of the REduction by DUtasteride of prostate Cancer Events (REDUCE) study.We analysed baseline data of 6754 men, aged 50-75 years divided into: lifelong non-smokers, former smokers, and current smokers. We examined total testosterone (TT, normal range ≥10 nmol/L) and sexual function variables: self-reported sexual activity, low libido, and erectile dysfunction (ED). Differences between current vs non-smokers and former vs current smokers were analysed using the chi-square test, linear and logistic regressions.A total of 3069 (45.4%) men were non-smokers, 2673 (39.6%) former smokers, and 1012 (15%) current smokers. Current smokers were significantly younger than former and non-smokers (mean age 61.6, 63.2, and 62.7 years, respectively), leaner (mean body mass index 27.0, 27.7, and 27.2 kg/mCigarette smoking was associated with worse sexual health compared to non-smokers, while former smokers had better erectile function and libido than current smokers. Smoking cessation may improve male sexual health and counselling on smoking cessation may be considered at the time of sexual health evaluations.

Objective Transrectal ultrasound guided biopsy for diagnostic workup for prostate cancer (PCa) has a substantial false negative rate. We sought to estimate PCa incidence and mortality following negative biopsy in a cohort of men undergoing prostate cancer screening. Subjects and Methods The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial randomized participants 55-74 years to an intervention vs control arm. Intervention arm men received annual prostate-specific antigen (PSA) tests for 6 years and digital rectal exams (DRE) for 4 years. We examined the cohort of men with a positive PSA (> 4 ng/mL) or DRE screen followed within one year by a negative biopsy. PCa incidence and mortality rates from time of first negative biopsy were analyzed as a function of PSA level at diagnosis and other factors. Cumulative incidence and mortality rates accounting for competing risk were estimated. Multivariate proportional hazards regression was utilized to estimate hazard ratios (HRs) of PCa outcomes by PSA level, controlling for age and race. Results The negative biopsy cohort included 2855 men. Median (25th/75th) age at biopsy was 65 (61/69) years; biopsies occurred between 1994 and 2006. Median (25/75th) follow-up was 13.2 (6.5/16.8) years for incidence and 16.6 (12.3/19.2) years for mortality. 740 PCa cases were diagnosed, with 33 PCa deaths. Overall 20-year cumulative PCa incidence and mortality rates were 26.4% (95% CI: 24.8-28.1) and 1.2% (95% CI: 0.9-1.7), respectively. HRs for PCa incidence and mortality increased significantly with increasing PSA. Conclusion The mortality rate from PCa through 20 years following a negative biopsy is low.

In men, complaints of nocturia causing poor sleep are often attributed to benign prostatic hyperplasia and treated with benign prostatic hyperplasia medications. We assessed whether treating lower urinary tract symptoms with dutasteride altered either nocturia or sleep quality using data from REDUCE.REDUCE was a 4-year randomized, multicenter trial comparing dutasteride 0.5 mg/day vs placebo for prostate cancer chemoprevention. Study participants were men considered at increased risk for prostate cancer. Eligibility included age 50-75 years, prostate specific antigen 2.5-10 ng/ml, and 1 negative prostate biopsy. At baseline, 2 years and 4 years, men completed the International Prostate Symptom Score and Medical Outcomes Study Sleep Scale, a 6-item scale assessing sleep. To test differences in nocturia and Medical Outcomes Study Sleep Scale over time, we used linear mixed models adjusted for baseline confounders. Subanalyses were conducted in men symptomatic from lower urinary tract symptoms, nocturia, poor sleep, or combinations thereof.Of 6,914 men with complete baseline data, 80% and 59% were assessed at 2 and 4-year followup, respectively. Baseline characteristics were balanced between treatment arms. Dutasteride improved nocturia at 2 (-0.15, 95% CI -0.21, -0.09) and 4 years (-0.24, 95% CI -0.31, -0.18) but did not improve sleep. When limited to men symptomatic from lower urinary tract symptoms, nocturia, poor sleep or combinations thereof, results mirrored findings from the full cohort.In men with poor sleep who complain of nocturia, treatment of lower urinary tract symptoms with dutasteride modestly improves nocturia but has no effect on sleep. These results suggest men with poor sleep who complain of nocturia may not benefit from oral benign prostatic hyperplasia treatment.

Objectives To the best of our knowledge, no study has analyzed the association between cigarette smoking and prostate basal cell proliferation. Therefore, we sought to evaluate whether smoking status is associated with the presence of basal cell hyperplasia (BCH). Methods We performed a retrospective analysis of 8,196 men aged 50 to 75 years with prostate-specific antigen values between 2.5 µg/mL and 10 µg/mL and prior negative biopsy who were enrolled in the (REDUCE) trial. Cigarette smoking status was divided into current, former, or never categories at enrollment. The association between smoking and baseline BCH was evaluated, with logistic regression in univariable and multivariable analysis. Results A total of 1,233 (15.1%) men were current smokers, 3,206 (39.1%) were former smokers, and 3,575 (45.8%) were never smokers. In univariable analysis, current smoking was associated with higher baseline BCH occurrence compared with never (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.14-3.10) and former smokers (OR, 1.77; 95% CI, 1.06-2.95). Similar results were found after adjusting for patient characteristics (current vs never smokers: OR, 1.92; 95% CI, 1.14-3.26; current vs former smokers: OR, 1.71; 95% CI, 1.01-2.91). Conclusions Among men undergoing prostate biopsy, all of whom had a negative biopsy result, current smoking at enrollment was independently associated with BCH in standard peripheral zone prostate biopsies.

PURPOSE: To determine whether pollen triggers urologic chronic pelvic pain syndrome (UCPPS) flares. MATERIALS AND METHODS: We assessed flare status every two weeks for one year as part of the Multidisciplinary Approach to the study of Chronic Pelvic Pain (MAPP) case-crossover study of flare triggers. Flare symptoms, flare start date, and exposures in the three days before a flare were queried for the first three flares and at three randomly selected non-flare times. These data were linked to daily pollen count by date and the first three digits of participants’ zip codes. Pollen count in the 3 days before and day of a flare, as well as pollen rises past established thresholds, were compared to non-flare values by conditional logistic regression. Poisson regression was used to estimate flare rates in the three weeks following pollen rises past established thresholds in the full longitudinal study. Analyses were performed in all participants and separately in those who reported allergies or respiratory tract disorders. RESULTS: Although no associations were observed for daily pollen count and flare onset, positive associations were observed for pollen count rises past medium or higher thresholds in participants with allergies or respiratory tract disorders in the case-crossover (odds ratio=1.31, 95% confidence interval [CI]: 1.04-1.66) and full longitudinal (relative rate=1.23, 95% CI: 1.03-1.46) samples. CONCLUSIONS: We found some evidence to suggest that rising pollen count may trigger UCPPS flares. If confirmed in future studies, these findings may help to inform flare pathophysiology, prevention, treatment, and control over the unpredictability of flares.

Background Existing evidence suggests that there is an association between body size and prevalent Benign Prostatic Hyperplasia (BPH)-related outcomes and nocturia. However, there is limited evidence on the association between body size throughout the life-course and incident BPH-related outcomes. Methods Our study population consisted of men without histories of prostate cancer, BPH-related outcomes, or nocturia in the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (n = 4710). Associations for body size in early- (age 20), mid- (age 50) and late-life (age ≥ 55, mean age 60.7 years) and weight change with incident BPH-related outcomes (including self-reported nocturia and physician diagnosis of BPH, digital rectal examination-estimated prostate volume ≥ 30 cc, and prostate-specific antigen [PSA] concentration > 1.4 ng/mL) were examined using Poisson regression with robust variance estimation. Results Men who were obese in late-life were 25% more likely to report nocturia (Relative Risk (RR): 1.25, 95% Confidence Interval (CI): 1.11–1.40; p-trendfor continuous BMI overweight: 1.13, 95% CI 1.07–1.21; RRobese: 1.10, 95% CI 1.02–1.19; p-trendfor continuous BMI = 0.017) as compared to normal weight men. Obesity at ages 20 and 50 was similarly associated with both nocturia and prostate volume ≥ 30 cc. Considering trajectories of body size, men who were normal weight at age 20 and became overweight or obese by later-life had increased risks of nocturia (RRnormal to overweight: 1.09, 95% CI 0.98–1.22; RRnormal to obese: 1.28, 95% CI 1.10–1.47) and a prostate volume ≥ 30 cc (RRnormal to overweight: 1.12, 95% CI 1.05–1.20). Too few men were obese early in life to examine the independent effect of early-life body size. Later-life body size modified the association between physical activity and nocturia. Conclusions We found that later-life body size, independent of early-life body size, was associated with adverse BPH outcomes, suggesting that interventions to reduce body size even late in life can potentially reduce the burden of BPH-related outcomes and nocturia.

Aims The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments. Methods This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol. Results Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing. Conclusions This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions.

BACKGROUND: To investigate whether meteorological factors (temperature, barometric pressure, relative humidity, ultraviolet index [UVI], and seasons) trigger flares in male and female urologic chronic pelvic pain patients. METHODS: We assessed flare status every two weeks in our case-crossover study of flare triggers in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain one-year longitudinal study. Flare symptoms, flare start date, and exposures in the three days preceding a flare or the date of questionnaire completion were assessed for the first three flares and at three randomly selected non-flare times. We linked these data to daily temperature, barometric pressure, relative humidity, and UVI values by participants’ first 3 zip code digits. Values in the three days before and the day of a flare, as well as changes in these values, were compared to non-flare values by conditional logistic regression. Differences in flare rates by astronomical and growing seasons were investigated by Poisson regression in the full study population. RESULTS: 574 flare and 792 non-flare assessments (290 participants) were included in the case-crossover analysis, and 966 flare and 5,389 non-flare (409 participants) were included in the full study analysis. Overall, no statistically significant associations were observed for daily weather, no patterns of associations were observed for weather changes, and no differences in flare rates were observed by season. CONCLUSIONS: We found minimal evidence to suggest that weather triggers flares, although we cannot rule out the possibility that a small subset of patients are susceptible.

Multiparametric (mp) magnetic resonance imaging (MRI) has become an important tool for the detection of clinically significant prostate cancer. However, diagnostic accuracy is affected by variability between radiologists.To determine the accuracy and variability in prostate mpMRI interpretation among radiologists, both individually and in teams, in a blinded fashion.A study cohort (n=32) was created from our prospective registry of patients who received prostate mpMRI with subsequent biopsy. The cohort was then independently reviewed by four radiologists of varying levels of experience, who assigned a Prostate Imaging Reporting and Data System (PI-RADS) classification, blinded to all clinical information. Consensus interpretation by teams of two radiologists was evaluated after a 12-wk wash-out period. Interpretive accuracy was calculated with various cutoffs for PI-RADS classification and Gleason score. Variability among individual radiologists and teams was calculated using the Fleiss kappa and intraclass correlation coefficient (ICC).Using PI-RADS 3+/Gleason 7+ (p0.01) and PI-RADS 4+/Gleason 6+ (p=0.02) as cutoffs, significant differences in accuracy among the four radiologists were noted. At no cutoff for PI-RADS classification or Gleason score did a team read achieve higher accuracy than the most accurate radiologist. The kappa and ICC ranged from 0.22 to 0.29 for the individuals and from 0.16 to 0.21 for the teams (poor agreement). A larger sample size may be needed to adequately power differences in accuracy among individual radiologists.At various cutoffs for PI-RADS classification and Gleason score, we find significant differences in individual radiologist accuracy, as well as a poor agreement among individual radiologists. Consensus interpretations-as teams of two radiologists-did not improve accuracy or reduce variability.This study investigated radiologist variability and differences in accuracy using multiparametric magnetic resonance imaging for the diagnosis of prostate cancer. Despite attempts to standardize interpretation within the field, we found substantial variability and significant differences in accuracy among individual radiologists.

PURPOSE: Men with unfavorable intermediate-risk (UIR-PCa) or high-risk prostate cancer (HR-PCa) are often treated with definitive external beam radiotherapy (EBRT) plus androgen deprivation therapy (ADT). Treatment is frequently intensified by electively treating the pelvic lymph nodes (LN) with whole pelvis radiotherapy (WPRT), but practice patterns and the benefits of WPRT are not well defined. We hypothesized that men treated with WPRT would have improved overall survival (OS) relative to men treated with prostate-only radiotherapy. MATERIALS AND METHODS: National Cancer Database records of men diagnosed between 2008–2015 with UIR-PCa or HR-PCa and treated with prostate EBRT±ADT (72–86.4 Gy) with (n=15,175) or without (n=13,549) WPRT were reviewed. Risk of LN involvement was calculated using the Memorial Sloan Kettering Cancer Center Nomogram. Measured confounders were balanced with inverse probability of treatment weighting and OS hazard ratios (HRs) were generated using multivariable Cox regression. RESULTS: 53% of men received WPRT. Every 1% increase in risk of LN involvement correlated with a 1% increase in risk of death (P

Objective To compare test performance of multiparametric magnetic resonance imaging (mpMRI) for detection of prostate cancer (PCa) in African-American men (AAM) and white men (WM) using the Prostate Imaging Reporting and Data System in unmatched groups as well as a cohort matched for clinical factors. Methods We examined our database of men who underwent prostate mpMRI prior to biopsy between October 2014 and June 2017 (n = 601; 60 AAM, 541 WM). Test performance was defined using Prostate Imaging Reporting and Data System classification 4 or 5 considered test positive and Gleason grade group 2 or greater from any biopsy core considered outcome positive. A subset analysis was performed using a propensity score caliper matching algorithm to match AAM to WM in a 1:2 ratio using the variables age, PSA, and PSA density. Results No significant differences in test performance were found with similar sensitivity (86.7% vs 83.6, P = 1.00), specificity (45.9% vs 49.1%, P = .71), positive predictive value (50.0% vs 46.9%), and negative predictive value (85.0% vs 84.8%, P = 1.00) for AAM and WM. Similar results were noted in our matched comparison. The rate of upgrading between targeted and systematic biopsy cores did not statistically differ between AAM and WM in both unmatched (12.2% vs. 15.8%, P = .66) and matched (12.2% vs 12.8%, P = .92) comparisons. Conclusion Our findings provide supporting evidence that AAM have similar outcomes to WM in PCa detection using mpMRI. We suggest that mpMRI should not be withheld or offered preferentially on the basis of race when used for the detection of PCa.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers800 and peak antibody fold change8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Benign prostatic hyperplasia (BPH) is a common disease often manifested by lower urinary tract symptoms (LUTS). We previously found statins were associated with modest attenuations in prostate growth over time in REDUCE. We tested whether statins were associated with LUTS incidence in asymptomatic men and LUTS progression in symptomatic men.We performed a post-hoc analysis of REDUCE in 3,060 "asymptomatic" men with baseline International Prostate Symptom Score (IPSS)8 and in 2,198 symptomatic men with baseline IPSS ≥8 not taking α-blockers or 5α-reductase inhibitors. We used multivariable Cox regression models to assess associations between statin use at baseline and LUTS incidence and progression. Among asymptomatic men, incident LUTS was defined as the first reported medical or surgical treatment for BPH or sustained clinically significant LUTS (2 reports of IPSS14). Among symptomatic men, LUTS progression was defined as IPSS increase ≥4 points from baseline, any surgical procedure for BPH, or initiation of a BPH drug.Among asymptomatic and symptomatic men, 550 (18%) and 392 (18%) used statins at baseline, respectively. On multivariable analysis, statin use was not associated with LUTS incidence (HR 1.05; 95% CI 0.78-1.41, p=0.74) in asymptomatic men, or with LUTS progression (HR 1.13; 95% CI 0.96-1.33, p=0.15) in symptomatic men. Similar results were seen in the dutasteride and placebo arms when stratified by treatment assignment.In REDUCE, statin use was not associated with either incident LUTS in asymptomatic men or LUTS progression in symptomatic men. These data do not support a role for statins in LUTS prevention or management.

Several liquid biomarker tests have been developed to account for the limitations of prostate specific antigen (PSA) screening prior to prostate biopsy. African ancestry is an established risk factor for prostate cancer (PCa) and must be particularly considered when evaluating patients with liquid biomarkers. While multiple tests have been developed over decades of exploration, recent advances can help patients and physicians incorporate data into a broader clinical context.We sought to review currently available liquid biomarker tests in a practical, clinically directed fashion with particular focus on performance in men with African ancestry. We reviewed discovery and validation studies and highlight important considerations for each test.We discuss the advantages and limitations of percent free PSA, Prostate Health Index, Progensa® PCA3, ExoDx® Prostate Test, SelectMDx®, 4Kscore® Test, and Mi-Prostate Score and summarize salient studies on their use. A literature review of evidence specifically for men with African ancestry was conducted and available studies were summarized.Liquid biomarkers can be useful tools for aiding in risk stratification prior to prostate biopsy. Use of such tests should be individualized based on a thorough knowledge of supporting evidence and the goals of the patient and physician. Further study should prioritize evaluation of such biomarkers in men with African ancestry.

PURPOSE: To evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study. MATERIALS AND METHODS: We evaluated men with localized prostate cancer at eleven high-volume academic medical centers in the United States from the PROST-QA (2003–2006) and the PROST-QA/RP2 cohorts (2010–2013) with a pre-specified goal of comparing RALP (N = 549) and ORP (N = 545). We measured longitudinal patient-reported health related quality of life (HRQOL) at pre-treatment, 2, 6, 12, and 24 months, and pathologic and peri-operative outcomes/complications. RESULTS: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p

OBJECTIVE: To investigate changes in whole body pain during urologic chronic pelvic pain syndrome (UCPPS) flares. MATERIALS AND METHODS: UCPPS participants at one site of the multidisciplinary approach to the study of chronic pelvic pain research network reported their daily flare status and pain levels in 7 pelvic/genital and 42 extrapelvic body areas (scale = 0-10) for 10 days at baseline and during their first flare. Linear mixed models and conditional logistic regression were used to investigate symptom changes during flares. Analyses were stratified by chronic overlapping pain condition (COPC) status. RESULTS: Fifty-five out of 60 participants completed the study, 27 of whom provided information on both nonflare (n = 281) and flare (n = 208) days. Pelvic/genital pain intensity (mean change = 3.20 of 10) and widespreadness (mean = 1.48) increased significantly during flares for all participants (all P interaction > .1), whereas extrapelvic pain intensity increased significantly only among participants with COPCs (mean = 2.09; P interaction < .0001). Pelvic/genital and extrapelvic pain also varied on nonflare days but symptom fluctuations were generally ≤1 point (80.0%-100% of participants). Increases of ≥2 points in pelvic/genital pain intensity (odds ratio (OR) = 22.0, 95% confidence interval (CI) = 4.0-118.6) and ≥1 point in urination-related pain (OR = 9.10, 95% CI = 1.74-47.7) were independently associated with flare onset for all participants. CONCLUSION: Our observations of extrapelvic pain increases during flares for patients with COPCs and our independent associations between pelvic/genital/urination-related pain intensity and flare onset may provide insight into mechanisms underlying flare development (eg, common biologic pathways between UCPPS phenotypes and flares), flare management (eg, local vs systemic therapies by COPC status), and patient flare definitions.

Background Local‐regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity/mortality. Postoperative radiotherapy (PORT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of PORT would improve OS in LABC in a large nationwide oncology database. Methods We identified ≥ pT3pN0‐3M0 LABC patients in the National Cancer Database diagnosed 2004‐2014 who underwent RC ± PORT. OS was calculated using Kaplan‐Meier and Cox proportional hazards regression modeling was used to identify predictors of OS. Propensity matching was performed to match RC patients who received PORT vs those who did not. Results 15,124 RC patients were identified with 512 (3.3%) receiving PORT. Median OS was 20.0 months (95% CI, 18.2‐21.8) for PORT vs 20.8 months (95% CI, 20.3‐21.3) for no PORT (P = 0.178). In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78‐0.97); P = 0.008. A one‐to‐three propensity match yielded 1,858 patients (24.9% receiving PORT and 75.1% without). In the propensity‐matched cohort, median OS was 19.8 months (95% CI, 18.0‐21.6) for PORT vs 16.9 months (95% CI, 15.6‐18.1) for no PORT (P = 0.030). In the propensity‐matched cohort of urothelial carcinoma patients (N = 1,460), PORT was associated with improved OS for pT4, pN+, and positive margins (P

To evaluate whether the presence of basal cell hyperplasia (BCH) in negative biopsies is associated with concurrent lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH), clinical prostatitis, and future prostate cancer (PCa) in repeat prostate biopsy.We performed a retrospective analysis of 6471 men, 50-75 years old with prostate-specific antigen between 2.5 and 10 ng/ml and prior negative biopsy who were enrolled in the Reduction by Dutasteride of PCa Events trial and underwent a 2-year repeat biopsy. The association between baseline BCH and risk of PCa, BPH/LUTS and clinical prostatitis measured at baseline were evaluated with logistic regression in uni/multivariable analysis, controlling for baseline patient characteristics.Among 6471 men enrolled, 84 (1.3%) had BCH in the baseline prostate biopsy. BCH was associated less chronic inflammation and more prostate atrophy (P0.05) and was unrelated to baseline patient characteristics. In both uni/multivariable analyses, BCH was not associated with PCa in repeat biopsy (univariable odds ratio [OR] = 0.98, 95% confidence interval [CI] = 0.53-1.82, P0.05; multivariable OR=1.15, 95% CI = 0.61-2.16, P0.05), BPH/LUTS (univariable OR = 1.13, 95% CI = 0.71-1.81, P0.05; multivariable OR = 1.20, 95% CI = 0.74-1.94, P0.05), or clinical prostatitis (univariable OR = 0.56, 95% CI = 0.18-1.81, P0.05; multivariable OR = 0.57, 95% CI = 0.18-1.83, P0.05).Among men undergoing repeat prostate biopsy with a baseline negative biopsy, BCH was associated with more histological atrophy and less chronic prostatitis, but was unrelated to LUTS/BPH, clinical prostatitis or future PCa risk.

To compare test performance of multiparametric magnetic resonance imaging (mpMRI) for detection of prostate cancer between individual radiologists using the Prostate Imaging Reporting and Data System (PI-RADS) and to identify clinical factors that may predict test performance.We examined our database of consecutive men who received prostate mpMRI prior to biopsy between September 2014 and December 2016 (n = 459). Test performance (eg, sensitivity, specificity, positive predictive value [PPV] and negative predictive value) were defined with PI-RADS classification 4 or 5 considered test positive and Gleason score ≥7 on biopsy from any targeted core considered outcome positive. Multivariate logistic regression was performed to identify clinical variables that affect test performance.No significant differences in test performance were found among individual radiologists. Prior biopsy (odds ratio [OR] 0.10, P = .01), radiologist experience500 prostate mpMRI (OR 0.18, P = .04), transition zone location (OR 0.10, P = .04), and posterior location (OR 0.04, P = .03) were predictors of diminished sensitivity. Location of the mpMRI lesion in the TZ was a predictor of improved specificity (OR 2.53, P = .04). Increasing age (OR 1.07, P.01) and prostate-specific antigen (OR 1.10, P.01) predicted increased PPV, while prior biopsy predicted decreased PPV (OR 0.50, P.01).Although variation exists in test performance among individual radiologists using PI-RADS, significant differences were not observed. Additional prostate mpMRI experience was not beneficial in improving accuracy of interpretation. Nonmodifiable patient variables-including prostate lesion location, prior biopsy history, prostate-specific antigen, and age-are predictive of prostate mpMRI test performance.

International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Neural circuitry regulating urine storage in humans has been largely inferred from fMRI during urodynamic studies driven by catheter infusion of fluid into the bladder. However, urodynamic testing may be confounded by artificially filling the bladder repeatedly at a high rate and examining associated time-locked changes in fMRI signals. Here we describe and test a more ecologically-valid paradigm to study the brain response to bladder filling by (1) filling the bladder naturally with oral water ingestion, (2) examining resting state fMRI (rs-fMRI) which is more natural since it is not linked with a specific stimulus, and (3) relating rs-fMRI measures to self-report (urinary urge) and physiologic measures (voided volume). To establish appropriate controls and analyses for future clinical studies, here we analyze data collected from healthy individuals (N = 62) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Participants orally ingested approximately 350 mL of water, and had a 10 min “fuller bladder” rs-fMRI scan approximately 1 h later. A second 10 min “empty bladder” rs-fMRI scan was conducted immediately following micturition. We examined multiple spatial scales of brain function, including local activity, circuits, and networks. We found changes in brain function distributed across micturition loci (e.g., subregions of the salience, sensorimotor, and default networks) that were significantly related to the stimulus (volume) and response (urinary urge). Based on our results, this paradigm can be applied in the future to study the neurobiological underpinnings of urologic conditions.

Purpose: Multiparametric MRI (mpMRI) has become an indispensable radiographic tool in diagnosing prostate cancer. However, mpMRI fails to visualize approximately 15% of clinically significant prostate cancer (csPCa). The molecular, cellular, and spatial underpinnings of such radiographic heterogeneity in csPCa are unclear. Experimental Design: We examined tumor tissues from clinically matched patients with mpMRI-invisible and mpMRI-visible csPCa who underwent radical prostatectomy. Multiplex immunofluorescence single-cell spatial imaging and gene expression profiling were performed. Artificial intelligence–based analytic algorithms were developed to examine the tumor ecosystem and integrate with corresponding transcriptomics. Results: More complex and compact epithelial tumor architectures were found in mpMRI-visible than in mpMRI-invisible prostate cancer tumors. In contrast, similar stromal patterns were detected between mpMRI-invisible prostate cancer and normal prostate tissues. Furthermore, quantification of immune cell composition and tumor-immune interactions demonstrated a lack of immune cell infiltration in the malignant but not in the adjacent nonmalignant tissue compartments, irrespective of mpMRI visibility. No significant difference in immune profiles was detected between mpMRI-visible and mpMRI-invisible prostate cancer within our patient cohort, whereas expression profiling identified a 24-gene stromal signature enriched in mpMRI-invisible prostate cancer. Prostate cancer with strong stromal signature exhibited a favorable survival outcome within The Cancer Genome Atlas prostate cancer cohort. Notably, five recurrences in the 8 mpMRI-visible patients with csPCa and no recurrence in the 8 clinically matched patients with mpMRI-invisible csPCa occurred during the 5-year follow-up post-prostatectomy. Conclusions: Our study identified distinct molecular, cellular, and structural characteristics associated with mpMRI-visible csPCa, whereas mpMRI-invisible tumors were similar to normal prostate tissue, likely contributing to mpMRI invisibility.

We investigated whether baseline acute or chronic prostate inflammation among men with initial negative biopsies for prostate cancer was associated with cancer grade in 2-year repeat biopsies.Retrospective analyses were conducted of 889 men aged 50 to 75 years old with negative baseline prostate biopsy and 2-year repeat biopsy positive for prostate cancer in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study. Acute and chronic prostate inflammation and cancer grade were determined by central pathology during the REDUCE study. The association of inflammation in baseline and 2-year repeat biopsy and prostate cancer grade in 2-year repeat biopsy was evaluated with Student's t-test, chi-squared test and multivariable logistic regression.Chronic, acute inflammation and both were detected in 533 (60%), 12 (1%) and 85 (10%) baseline biopsies, respectively. Presence of acute and chronic inflammation were significantly associated with each other (p0.001). Both types of inflammation were unrelated to race, body mass index, prostate specific antigen or digital rectal exam. At the 2-year biopsy, 621 (70%) tumors were low grade (Gleason scores 2-6) and 268 (30%) were high grade (Gleason scores 7-10). In univariable and multivariable analyses, men with baseline chronic inflammation had significantly fewer high grade tumors (univariable OR 0.64, 95% CI 0.47-0.87, p=0.004; multivariable OR=0.68, 95% CI0.50-0.93, p=0.016) than those without baseline chronic inflammation. Baseline acute inflammation was not associated with tumor grade (univariable OR 0.74, 95% CI 0.45-1.20, p=0.22; multivariable OR 0.78, 95% CI 0.48-1.29, p=0.34).Chronic inflammation in a negative biopsy was associated with lower prostate cancer grade among men with cancer on follow-up 2-year biopsy.

Background: Global prostate cancer incidence rates are lower in Asian men than Caucasian men. Whether this is the result of less screening in Asian men remains to be determined. We examined whether Asian race was associated with prostate cancer diagnosis in the Reduction by Dutasteride of Cancer Events (REDUCE) study. Methods: REDUCE was a 4-year, multicenter, randomized trial of dutasteride versus placebo for prostate cancer prevention among men who underwent prostate-specific antigen (PSA)-independent biopsies at 2 and 4 years. Eligible men were ages 50 to 75 years, had PSA between 2.5 and 10 ng/mL, and a negative prestudy prostate biopsy. We tested the association between Asian and Caucasian race and prostate cancer diagnosis using logistic regression. Results: Of 8,122 men in REDUCE, 5,755 (71%) were Caucasian and 105 (1.8%) were Asian. Asians had lower body mass index (24.8 vs. 26.9 kg/m2, P < 0.001), had smaller prostate volume (35.0 vs. 43.5 cc, P < 0.001), and were less likely to have abnormal digital rectal exams (P = 0.048), but were similar in baseline age, PSA, family history of prostate cancer, and smoking status compared with Caucasian men (all P ≥ 0.164). Asian men were equally likely to receive any on-study biopsy compared with Caucasian men (P = 0.634). After adjusting for potential confounders, Asian men were less likely to be diagnosed with prostate cancer during the 4-year study (OR = 0.49; 95% confidence interval, 0.28–0.88; P = 0.016), compared with Caucasian men. Conclusions: In REDUCE, where all men underwent biopsies largely independent of PSA, Asian race was associated with lower prostate cancer diagnosis. Impact: These findings suggest that lower prostate cancer risk in Asian men may be due to biological, genetic, and/or lifestyle factors.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

To evaluate the addition of software-assisted fusion magnetic resonance imaging (MRI) targeted biopsy to systematic biopsy and determine clinical and imaging factors associated with improved prostate cancer (PCa) detection.We analyzed 454 patients who had prostate MRI and underwent combined systematic and software-assisted fusion MRI-targeted biopsy at 2 academic centers between July 2015 and December 2017. For our analysis, we compared the Gleason grade group of cores obtained systematically to cores obtained using MRI-targeting. Using multivariable analysis, we examined clinical and imaging factors associated with higher grade group disease in MRI-targeted cores.Software assisted fusion MRI-targeted biopsy detected higher grade group disease in 18.3% of patients. Factors associated with higher grade group disease in MRI-targeted cores included anterior MRI lesion location (odds ratio [OR] 3.15, P0.01) and multiple lesions on MRI (OR 2.47, P = 0.01). Increasing prostate volume per cubic centimeter was noted to be negatively associated (OR 0.98, P = 0.02). Notably, factors not found to be associated with improved detection included PIRADS classification 5 compared to 3 (OR 2.47, P = 0.08), PIRADS classification 4 compared to 3 (OR 1.37, P = 0.50), previous negative biopsy (OR 1.48, P = 0.29), inclusion on an active surveillance protocol (OR 1.36, P = 0.48), transitional zone lesion location (OR 0.72, P = 0.45), and institution at which biopsy was performed (OR 1.81, P = 0.16).Adding software-assisted fusion MRI-targeting to systematic prostate biopsy offers benefit for men with an anterior and multiple MRI lesions. In absence of these factors, systematic biopsy alone or with cognitive fusion may be considered.

BACKGROUND: Disrupted sleep has been associated with increased risk of certain cancers. Little data exist in prostate cancer. We tested the association between sleep quality and prostate cancer diagnosis overall and by tumor grade in the Reduction by Dutasteride of Prostate Cancer Events chemoprevention trial. We hypothesized that worse sleep quality would be associated with increased tumor aggressiveness.METHODS: At baseline, 5614 men completed a validated six-item questionnaire on sleep quality. We generated a composite score categorized into tertiles to measure overall sleep quality and assessed each sleep quality question individually. Logistic regression was used to test associations between baseline sleep quality and overall, low-grade and high-grade prostate cancer diagnosis at 2-year study-mandated biopsy. Models were stratified by nocturia.RESULTS: Overall sleep quality was unrelated to overall or low-grade prostate cancer. Worse overall sleep quality was associated with elevated odds of high-grade prostate cancer (odds ratio [OR]T3vsT1 1.15; 95% confidence interval [CI]: 0.83-1.60 and ORT2vsT1 1.39; 95% CI: 1.01-1.92). Men reporting trouble falling asleep at night sometimes vs never had elevated odds of high-grade prostate cancer (OR: 1.51; 95% CI: 1.08-2.09) while trouble staying awake during the day was associated with decreased odds of low-grade prostate cancer (OR: 0.65; 95% CI: 0.49-0.86). Results were similar within strata of nocturia severity.CONCLUSIONS: Overall, associations between sleep quality and prostate cancer were inconsistent. However, there was some evidence for a positive association between insomnia and high-grade prostate cancer, and an inverse relationship between daytime sleepiness and low-grade prostate cancer; findings that should be validated by future studies.

Sleep health is postulated as a multi-dimensional construct comprised of sleepiness/alertness, timing, duration, efficiency, and satisfaction. New questionnaires for its measurement have been proposed. We performed secondary data analyses and analyzed responses on a widely used, well-established sleep questionnaire to determine whether the construct might be detectable with an existing questionnaire. Healthy men (n = 7604) aged 55-75 completed the six-item Medical Outcomes Study Sleep Questionnaire (MOSSQ) at baseline in a large, randomized clinical trial [the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial). Two components clearly emerged from a Principal Components Analysis, suggesting that both sleep disturbance and sleep satisfaction are differentiated by the MOSSQ. Selected elements of sleep health are accessible with relatively few questionnaire items. Widespread previous usage of the MOSSQ in both descriptive and interventional research suggests that many previously collected databases could address at least two components of this construct.

Introduction To evaluate whether the presence of prostate atrophy (P.A.) in negative prostate biopsy is associated with prostate cancer (P.C.a) grade at surgical pathology among men who are ultimately diagnosed with P.C.a and undergo radical prostatectomy (R.P.). Methods A retrospective analysis was performed of 136 men from the placebo arm of the Reduction by Dutasteride of P.C.a Events (R.E.D.U.C.E.) trial who had a baseline prostate biopsy negative for P.C.a, and were later diagnosed with P.C.a on biopsy and underwent radical prostatectomy over the 4-year study period. The association of baseline P.A. (present/absent) with P.C.a grade (W.H.O./I.S.U.P. grade group 1 or ≥2) at surgical pathology was evaluated with logistic regression in uni- and multivariable analyses, controlling for baseline patient characteristics. Results P.A. was observed in 74 prostate biopsies (54%). P.A. was not associated with baseline characteristics (age, body mass index, prostate-specific antigen level, prostate volume, race, family history of P.C.a, and digital rectal exam), except for chronic inflammation (p = 0.001). The presence of P.A. in baseline prostate biopsies was associated with lower risk of W.H.O./I.S.U.P. grade group ≥2 P.C.a in R.P. specimens on both univariable (O.R. = 0.39, 95% C.I. = 0.19-0.78, p = 0.008) and multivariable (O.R. = 0.43, 95% C.I. = 0.20-0.92, p = 0.029) analyses. Conclusions Among men with a baseline prostate biopsy negative for P.C.a who were later found to have P.C.a and underwent R.P., baseline P.A. is independently associated with lower risk of W.H.O./I.S.U.P. grade group ≥2 P.C.a on surgical pathology. P.A. may be used to identify subjects at lower risk for W.H.O./I.S.U.P. ≥ 2 P.C.a and select optimal candidates for active surveillance.

Objective To examine prostate cancer (PCa) incidence and mortality by arm in the randomized Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Patients and methods Patients aged 55-74 years at 10 screening centres were randomized between 1993 and 2001 to an intervention or usual care arm. Patients in the intervention arm received six annual prostate-specific antigen (PSA) tests and four annual digital rectal examinations. The patients were followed for PCa incidence and for mortality via active follow-up processes and by linkage to state cancer registries and the National Death Index. For cancers identified through active follow-up, trial abstractors recorded the mode of diagnosis (screen-detected, symptomatic, other). Results A total of 38 340 patients were randomized to the intervention arm and 38 343 to a usual care arm. The median follow-up for mortality was 16.9 (intervention) and 16.7 years (usual care). There were 333 (intervention) and 352 (usual care) PCa cancer deaths, giving rates (per 10 000 person-years) of 5.5 and 5.9, respectively, and a rate ratio (RR) of 0.93 (95% confidence interval [CI] 0.81-1.08; P = 0.38). The RR for overall PCa incidence was 1.05 (95% CI 1.01-1.09). The RRs by Gleason category were 1.17 (95% CI 1.11-1.23) for Gleason 2-6, 1.00 (95% CI 0.93-1.07) for Gleason 7 and 0.89 (95% CI 0.80-0.99) for Gleason 8-10 disease. By mode of detection, during the trial's screening phase, 13% of intervention arm vs 27% of usual care arm cases were symptomatic; post-screening, these percentages were 18% in each arm. Conclusion After almost 17 years of median follow-up, there was no significant reduction in PCa mortality in the intervention compared with the usual care arm. There was a significant increase in Gleason 2-6 disease and a significant reduction in Gleason 8-10 disease in the intervention compared with the usual care arm.

Objective To compare the diagnostic performance of the 2 most common approaches of magnetic resonance imaging targeted biopsy (TB)—cognitive registration targeted biopsy (COG-TB) and software fusion targeted biopsy (FUS-TB)—we assessed our institutional experience with both methods. TB has emerged to complement systematic template biopsy (SB) in prostate cancer (PCa) diagnosis; however, which magnetic resonance imaging targeting methodology is diagnostically better remains unclear. Materials and methods A total of 510 patients underwent TB at our institution before and after the adoption of fusion software with the UroNav platform (Invivo Corporation, Gainsville, FL). All patients had concurrent 12-core SB. We compared rates of clinically significant PCa detection, and rates of upstaging and missed diagnosis in reference to SB among patients who received COG-TB and patients who received FUS-TB. We also compared both COG-TB and FUS-TB results to their paired SB results. Results The rates of upstaging or missing clinically significant PCa with FUS-TB (in reference to SB) was not significantly different from COG-TB (P = 0.172), nor was the risk of missing clinically significant PCa different between FUS-TB vs COG-TB on logistic regression ( Odds ratio = 0.55, P = 0.106). No significant difference in biopsy outcomes was observed between FUS-TB and COG-TB (P = 0.171). We did find significant differences between FUS-TB and SB and between COG-TB and SB, with SB finding more clinically insignificant PCa (P Conclusion In our institutional experience, no significant difference was observed between the diagnostic ability of COG-TB vs FUS-TB for detecting clinically significant PCa. Greater evidence demonstrating an advantage of FUS-TB over COG-TB would be required for clear recommendations in favor of FUS-TB.

Key Points Question Is family history sufficient to identify men at high risk of prostate cancer? Findings In a cohort study of 3225 men, family history alone identified 14% at high risk of prostate cancer and 86% at low or average risk; men with a positive family history of prostate cancer had a median diagnosis-free survival of 73 years, while men with a negative family history had a median diagnosis-free survival of 77 years. A combination of family history and single-nucleotide polymorphism–based genetic risk score, however, identified 30% of men at high genetic risk of prostate cancer, 52% of men at average genetic risk, and 19% of men at low genetic risk; the median diagnosis-free survival was 74 years for men at high genetic risk, 77 years for men at average genetic risk, and more than 80 years for men at low genetic risk. Meaning Combining family history and genetic risk score can better stratify inherited risk to develop personalized prostate cancer screening strategies., Importance Few studies have evaluated the association between a single-nucleotide polymorphism–based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis. Objectives To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification. Design, Setting, and Participants A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019. Interventions A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk–associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (80 years) for men at average genetic risk, and more than 80 years (95% CI, >80 to >80 years) for men at low genetic risk. In contrast, the median PCa diagnosis–free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH. Conclusions and Relevance This study suggests that a GRS is significantly associated with patient age at PCa diagnosis. Combining FH and GRS may better stratify inherited risk than FH alone for developing personalized PCa screening strategies., This cohort study examines the association between a single-nucleotide polymorphism (SNP)–based genetic risk score and patient age at prostate cancer diagnosis and compares the performance of the genetic risk score with that of family history in prostate cancer risk stratification.

BACKGROUND Despite disparities in prostate cancer incidence and mortality rates between black and white men, there is still insufficient data available to assess potential differences in the benefits and harms of prostate cancer screening by race. Although the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial is underpowered to detect a difference by race in prostate-cancer specific mortality, because of the large study size, there are still sufficient numbers to examine secondary screening outcomes. The objective of this analysis is to examine whether differences exist between black and white participants with respect to screening false-positive rates, biopsy follow-up of men with positive screens, tumor characteristics, and overdiagnosis of prostate cancer. METHODS Participants from the PLCO included men aged 55-74 years at baseline. Cancer diagnoses and deaths were identified through study update questionnaires, records of biopsy procedures, and linkage with the National Death Index. Cancer characteristics were obtained by medical abstractors. We used chi-squared tests to assess differences in false-positive rates, biopsy follow-up, and tumor characteristics. We used Cox proportional hazards models to compare incidence and mortality rates adjusting for age and survival rates adjusting for Gleason scores. RESULTS Black men were slightly more likely (14.5%) to have a false-positive PSA test compared to white men (12.4%; P = 0.02) but less likely to have a false-positive digital rectal exam (DRE) (10.9% vs 14.2%, respectively; P

Objective To provide a training tool to address the technical challenges of robot-assisted laparoscopic partial nephrectomy, we created silicone renal tumor models using 3-dimensional printed molds of a patient's kidney with a mass. In this study, we assessed the face, content, and construct validity of these models. Materials and Methods Surgeons of different training levels completed 4 simulations on silicone renal tumor models. Participants were surveyed on the usefulness and realism of the model as a training tool. Performance was measured using operation-specific metrics, self-reported operative demands (NASA Task Load Index [NASA TLX]), and blinded expert assessment (Global Evaluative Assessment of Robotic Surgeons [GEARS]). Results Twenty-four participants included attending urologists, endourology fellows, urology residents, and medical students. Post-training surveys of expert participants yielded mean results of 79.2 on the realism of the model's overall feel and 90.2 on the model's overall usefulness for training. Renal artery clamp times and GEARS scores were significantly better in surgeons further in training (P ≤.005 and P ≤.025). Renal artery clamp times, preserved renal parenchyma, positive margins, NASA TLX, and GEARS scores were all found to improve across trials (P Conclusion Face, content, and construct validity were demonstrated in the use of a silicone renal tumor model in a cohort of surgeons of different training levels. Expert participants deemed the model useful and realistic. Surgeons of higher training levels performed better than less experienced surgeons in various study metrics, and improvements within individuals were observed over sequential trials. Future studies should aim to assess model predictive validity, namely, the association between model performance improvements and improvements in live surgery.

To examine the incremental value of prostate magnetic resonance imaging (MRI) when used in combination with the currently available preoperative risk stratification tool, the Memorial Sloan Kettering Cancer Center (MSKCC) preradical prostatectomy nomogram.We reviewed our institutional database of prostate MRI performed before radical prostatectomy between December 2014 and March 2016 (n = 236). We generated a logistic regression model based on observed final pathology results and the MSKCC nomogram predictions for organ-confined disease, extracapsular extension (ECE), seminal vesicle invasion, and lymph node involvement (LNI) ("MSKCC only"). We then generated a combined regression model incorporating both the MSKCC nomogram prediction with the degree of prostate MRI suspicion ("MSKCC + MRI"). Receiver operating characteristic curves were generated, and the area under the curves (AUCs) were compared.When independently examining the MSKCC nomogram predicted risk and the degree of prostate MRI suspicion, MRI was a predictor for ECE (odds ratio 2.8, P .01) and LNI (odds ratio 5.6, P = .01). When examining the "MSKCC + MRI" and "MSKCC only" models, the incremental benefit in risk discrimination from the combined model ("MSKCC + MRI") was not significant for organ-confined disease, ECE, seminal vesicle invasion, or LNI (ΔAUC +0.03, P = .10; ΔAUC +0.03, P = .08; ΔAUC 0.63, P = .63; ΔAUC +0.04, P = .42; respectively).A combined model with prostate MRI and the MSKCC nomogram provides no additional risk discrimination over the MSKCC nomogram-based model alone. Evaluation of prostate MRI as a predictive tool should be performed in combination with, not independent of, these clinical risk stratification models.

Although lower urinary tract symptoms and sleep problems often develop together, to our knowledge it is unknown whether sleep disturbances are linked to lower urinary tract symptoms development and progression. As measured by the 6-item MOS-Sleep (Medical Outcomes Study Sleep Scale) survey we examined the relationship between sleep problems, and the development and progression of lower urinary tract symptoms in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study.REDUCE was a randomized trial testing prostate cancer chemoprevention with dutasteride in men with prostate specific antigen 2.5 to 10 ng/ml and a negative biopsy. At baseline men completed MOS-Sleep and a scaled average was used to calculate the sleep score. Men were followed for 4 years and I-PSS (International Prostate Symptom Score) was completed at baseline and every 6 months. Asymptomatic men had I-PSS less than 8 while symptomatic men had I-PSS 8 or greater. In the placebo arm of 2,588 men not receiving α-blockers or 5α-reductase inhibitors at baseline we tested the association between sleep problems and lower urinary tract symptom development and progression using Cox models.During followup lower urinary tract symptoms developed in 209 of 1,452 asymptomatic men (14%) and 580 of 1,136 (51%) with lower urinary tract symptoms demonstrated progression. On multivariable analysis higher sleep scores were suggestively associated with increased lower urinary tract symptoms in asymptomatic men (quartile 4 vs 1 HR 1.41, 95% CI 0.92-2.17, p = 0.12) and with lower urinary tract symptom progression in symptomatic men (per 10 points of sleep score HR 1.06, 95% CI 1.01-1.12, p = 0.029).Among men with lower urinary tract symptoms worse sleep scores were associated with the progression of lower urinary tract symptoms and among asymptomatic men worse sleep scores were suggestively associated with the development of lower urinary tract symptoms. If confirmed, these data suggest that sleep problems may precede such symptoms. Whether treating sleep problems would improve lower urinary tract symptoms requires further testing.

Prostate atrophy (PA) is commonly identified in prostate biopsies. Previous studies suggest PA may be associated with lower PCa risk. However, it remains unclear whether PA is associated with smaller, less aggressive, and less advanced tumors. Thus, we sought to determine whether the presence and severity of baseline PA in men with initial biopsy negative for prostate cancer (PCa) is associated with PCa volume at 2- and 4-year repeat biopsy. We performed a retrospective analysis of 927 men 50–75-years-old with negative baseline biopsy and positive 2- or 4-year repeat biopsy for PCa in the Reduction by Dutasteride of PCa Events study. PA (present or absent), PA severity (mild or moderate/marked), and tumor volume were determined by central pathology. The association of baseline PA with repeat biopsy PCa volume was evaluated with linear and Poisson regressions in uni- and multivariable analyses. PA was identified in 559 (60%) baseline biopsies and was mild in 491 (88%) and moderate/marked in 68 (12%). PA was associated with larger prostate volumes (P

To evaluate whether baseline prostate atrophy (PA) extent is associated with prostate cancer (PCa) incidence at 2-year repeat prostate biopsy in a clinical trial with systematic biopsies.We performed a retrospective analysis of 3165 men 50-75 years old with prostate-specific antigen between 2.5 and 10 ng/mL and a prior negative biopsy in the placebo arm of the Reduction by Dutasteride of PCa Events trial who underwent a 2-year repeat biopsy. PA extent was defined as the percentage of cores with atrophic changes. The association of baseline PA with positive 2-year biopsies was evaluated with logistic regression in uni- and multivariable analysis, controlling for baseline covariates.PA involving none, 1%-25%, 26%-50%, 51%-75%, and75% of the baseline cores was observed in 966 of 3165 (30.5%), 1189 of 3165 (37.6%), 677 of 3165 (21.4%), 209 of 3165(6.6%), and 124 of 3165 (3.9%) cases, respectively. More extensive PA was associated with older age, lower prostate-specific antigen, larger prostate volume, and higher prevalence of acute and chronic inflammations (all P .05). Compared to subjects without PA, those with 1%-25%, 26%-50%, 51%-75%, and75% core involvement had an odds ratio for PCa of 0.65 (95% confidence interval [CI] = 0.52-0.81), 0.60 (95% CI = 0.46-0.78), 0.56 (95% CI = 0.37-0.86), and 0.35 (95% CI = 0.19-0.67), respectively. In multivariable analysis, the extent of PA was independently associated with lower PCa risk (P .001). More extensive PA was associated with lower incidence of low-grade (Gleason 2-6) and high-grade (Gleason 7-10) PCa.The extent of baseline PA is independently associated with lower PCa risk in a dose-dependent fashion.

To test the association between statin use and prostate volume (PV) change over time using data from the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, a 4-year randomised controlled trial testing dutasteride for prostate cancer chemoprevention.We identified men with a baseline negative prostate biopsy from REDUCE who did not undergo prostate surgery or develop prostate cancer over the trial period. Men reported statin use at baseline. PV was determined from transrectal ultrasonography performed to guide prostate biopsy at baseline, and 2- and 4-years after randomisation. Multivariable generalised estimating equations tested differences in PV change over time by statin use, overall and stratified by treatment arm. We tested for interactions between statins and time in association with PV using the Wald test.Of 4106 men, 17% used statins at baseline. Baseline PV did not differ by statin use. Relative to non-users, statin users had decreasing PVs over the trial period (P = 0.027). Similar patterns were seen in the dutasteride and placebo arms, although neither reached statistical significance. The mean estimated PV was modestly but significantly lower in statin users relative to non-users in the dutasteride arm at 2-years (4.5%, P = 0.032) and 4-years (4.0%, P = 0.033), with similar (3-3.3%) but non-significant effects in the placebo arm.If confirmed, our present findings support a role for statins in modestly attenuating PV growth, with a magnitude of effect in line with previously reported prostate-specific antigen-lowering effects of statins (~4%). Future studies are needed to assess whether this putative role for statins in PV growth could impact lower urinary tract symptom development or progression.

To evaluate whether total serum PSA, free-PSA ratio and PSA density have similar diagnostic properties for detecting prostate cancer (PCa) and clinically-significant (cs) PCa in men with normal testosterone compared to men with low testosterone with a prior negative biopsy.We conducted a retrospective analysis of 3295 men undergoing a 2-year prostate biopsy following a negative prestudy biopsy in the placebo arm of the Reduction by Dutasteride of PCa Events (REDUCE) study. Men were divided in 2 groups based on testosterone levelor ≥300 ng/dL. Diagnostic properties of total serum PSA, free-PSA ratio, and PSA density to predict PCa and csPCa, defined as Gleason score ≥7, were determined for several thresholds and plotted as receiver operator characteristic curves.A total of 603 men (18.3%) had low testosterone. The prevalence of PCa and csPCa was 92 (15.3%) and 27 (4.5%), respectively, for low testosterone men compared to 458 (17.0%) and 138 (5.1%), correspondingly, for normal testosterone men. Total PSA, free-PSA ratio and PSA density showed similar sensitivity, specificity, and accuracy to predict PCa and csPCa among low testosterone men compared to normal testosterone men.Among subjects in a clinical trial with a prior negative biopsy, total PSA, free-PSA ratio and PSA density have comparable diagnostic characteristics for PCa screening in low and normal testosterone men.

Objective To describe the frequency, intensity and duration of urological chronic pelvic pain syndrome symptom exacerbations ('flares'), as well as risk factors for these features, in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Epidemiology and Phenotyping longitudinal study. Participants and methods Current flare status ('urological or pelvic pain symptoms that are much worse than usual') was ascertained at each bi-weekly assessment. Flare characteristics, including start date, and current intensity of pelvic pain, urgency and frequency (scales of 0-10), were assessed for participants' first three flares and at three randomly selected times when they did not report a flare. Generalized linear and mixed effects models were used to investigate flare risk factors. Results Of the 385 eligible participants, 24.2% reported no flares, 22.9% reported one flare, 28.3% reported 2-3 flares, and 24.6% reported ≥4 flares, up to a maximum of 18 during the 11-month follow-up (median incidence rate = 0.13/bi-weekly assessment, range = 0.00-1.00). Pelvic pain (mean = 2.63-point increase) and urological symptoms (mean = 1.72) were both significantly worse during most flares (60.6%), with considerable within-participant variability (26.2-37.8%). Flare duration varied from 1 to 150 days (94.3% within-participant variability). In adjusted analyses, flares were more common, symptomatic, and/or longer-lasting in women and in those with worse non-flare symptoms, bladder hypersensitivity, and chronic overlapping pain conditions. Conclusion In this foundational flare study, we found that pelvic pain and urological symptom flares were common, but variable in frequency and manifestation. We also identified subgroups of participants with more frequent, symptomatic, and/or longer-lasting flares for targeted flare management/prevention and further study.

Background The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial assessed the effect of screening with prostate-specific antigen and a digital rectal examination on prostate cancer mortality. Another endpoint of interest was the burden of total metastatic disease. Methods All men in PLCO were assessed for metastatic prostate cancer at diagnosis; men with clinical stage I/II disease were assessed for metastatic progression. The rate of total metastatic disease was defined as metastases found either at diagnosis or through progression divided by person-years (PYs) of follow-up for all men in the trial. Metastatic progression rates were computed among men with clinical stage I/II prostate cancer. Survival among men with metastases at diagnosis was compared with survival among men with metastatic progression. Results Among 38,340 men in the intervention arm and 38,343 men in the control arm in PLCO, there were 4974 and 4699 prostate cancer cases, respectively. The rates of total metastatic disease were 4.72 and 4.83 per 10,000 PYs in the intervention and control arms, respectively (rate ratio, 0.98; 95% CI, 0.81-1.18). The rates of metastatic progression among men with clinical stage I/II prostate cancer were 43.7 and 50.5 per 10,000 PYs in the intervention and control arms, respectively (P = .30). Prostate cancer-specific 5- and 10-year survival rates were significantly worse for men with metastatic progression (24% and 19%, respectively) than men with metastases at diagnosis (40% and 26%, respectively). Conclusions Rates of total metastatic disease and metastatic progression were similar across arms in PLCO. Survival was worse for men with metastatic progression in comparison with those with metastatic disease at diagnosis.

Objective To document patient-reported interstitial cystitis/bladder pain syndrome (IC/BPS) flare management strategies and triggers. Materials and Methods Twenty-four male and 29 female participants enrolled at the Washington University site of the MAPP Research Network completed a questionnaire on strategies they utilized to manage flares and factors they believed triggered their flares (eg, specific food items, physical activities, sexual activities, infections, and stress). Participants were also asked about the diurnal timing of their flares. Results A total of 96.2% of participants reported having ever experienced a symptom flare. Participants treated or managed their flares using a wide variety of strategies, ranging from common strategies, such as drinking additional water or fluid (74.5%), to less common strategies, such as acupuncture/acupressure (5.9% of participants). Participants also reported a wide range of perceived flare triggers, including previously reported factors (citrus fruits, tomatoes, spicy food, alcoholic and caffeinated beverages, driving/sitting in forms of transportation, urinary tract infections, stress, and tight clothing), as well as some less common, previously undocumented factors (eg, certain foods, nongenitourinary infections, wearing high-heeled shoes/boots or perfume, hair dye, and toothpaste). In general, female participants and those with somatic sensory hypersensitivity reported greater numbers of therapies and triggers. Finally, flares were reported most commonly in the afternoon or evening. Conclusion IC/BPS participants reported diverse flare management strategies and numerous perceived triggers. These findings, together with those from the small body of literature to date, provide a wide array of candidates and hypotheses for future global and tailored flare management and prevention interventions.

Background Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naive metastatic castration-resistant prostate cancer. Objective To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. Design, setting, and participants One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide ( n =872) or placebo ( n =845). Subgroup analyses included nonvisceral (only bone and/or nodal; n =1513), visceral (lung and/or liver; n =204), low-volume bone disease ( n =867), high-volume bone disease (≥4 bone metastases; n =850), lymph node only disease ( n =195). Intervention Oral enzalutamide (160mg) or placebo once daily while continuing androgen deprivation therapy. Outcome measurements and statistical analysis Coprimary endpoints (rPFS, OS) were prospectively evaluated in nonvisceral and visceral subgroups. All other efficacy analyses were post hoc. Results and limitations Enzalutamide improved rPFS versus placebo in patients with nonvisceral disease (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.14–0.22), visceral disease (HR, 0.28; 95% CI, 0.16–0.49), low- or high-volume bone disease (HR, 0.16; 95% CI, 0.11–0.22; HR, 0.22; 95% CI, 0.16–0.29, respectively), and lymph node only disease (HR, 0.09; 95% CI, 0.04–0.19). For OS, HRs favored enzalutamide ( 1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55–1.23). Enzalutamide was well tolerated in patients with or without visceral disease. Conclusions Enzalutamide provided clinically significant benefits in men with chemotherapy-naive metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. Patient summary Patients with metastatic castration-resistant prostate cancer—including those with or without visceral disease or widespread bone disease—benefitted from enzalutamide, an active well-tolerated therapy.

Despite routine use of phosphodiesterase type 5 inhibitor to treat erectile dysfunction the role in prostate cancer chemoprevention remains unclear. Only a few studies have explored the link between phosphodiesterase type 5 inhibitor use and prostate cancer. We tested the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial.REDUCE was a 4-year multicenter study testing the effect of daily dutasteride on prostate cancer risk in men with prostate specific antigen 2.5 to 10.0 ng/ml and negative biopsy who underwent study mandated biopsies at 2 and 4 years. The association of phosphodiesterase type 5 inhibitor with overall prostate cancer risk and disease grade (Gleason 2-6 and 7-10) was examined using adjusted logistic and multinomial regression analysis. Secondary analysis was performed to explore the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in North American men, given the significantly higher use of phosphodiesterase type 5 inhibitor in these subjects.Phosphodiesterase type 5 inhibitor was not associated with prostate cancer diagnosis (OR 0.90, 95% CI 0.68-1.20, p = 0.476), low grade disease (OR 0.93, 95% CI 0.67-1.27, p = 0.632) or high grade disease (OR 0.85, 95% CI 0.51-1.39, p = 0.508). An inverse trend was seen between phosphodiesterase type 5 inhibitor and prostate cancer diagnosis in North American men but this was not statistically significant (OR 0.67, 95% CI 0.42-1.07, p = 0.091).Phosphodiesterase type 5 inhibitor use was not associated with decreased prostate cancer diagnoses on post-hoc analysis of REDUCE. In North American men, who had much higher baseline use of phosphodiesterase type 5 inhibitor, this treatment was associated with an inverse trend of prostate cancer diagnosis that approached but did not reach statistical significance.

Purpose: To evaluate a physician's impression of a urinary stone patient's dietary intake and whether it was dependent on the medium through which the nutritional data were obtained. Furthermore, we sought to determine if using an electronic food fre- quency questionnaire (FFQ) impacted dietary recommendations for these patients. Materials and Methods: Seventy-six patients attended the Stone Clinic over a period of 6 weeks. Seventy-five gave consent for enrollment in our study. Patients completed an office-based interview with a fellowship-trained endourologist, and a FFQ admin- istered on an iPad. The FFQ assessed intake of various dietary components related to stone development, such as oxalate and cal- cium. The urologists were blinded to the identity of patients' FFQ results. Based on the office-based interview and the FFQ results, the urologists provided separate assessments of the impact of nutrition and hydration on the patient's stone disease (nutrition im- pact score and hydration impact score, respectively) and treatment recommendations. Multivariate logistic regressions were used to compare pre-FFQ data to post-FFQ data. Results: Higher FFQ scores for sodium (odds ratio (OR), 1.02; p=0.02) and fluids (OR, 1.03, p=0.04) were associated with a higher nutritional impact score. None of the FFQ parameters impacted hydration impact score. A higher FFQ score for oxalate (OR, 1.07; p=0.02) was associated with the addition of at least one treatment recommendation. Conclusions: Information derived from a FFQ can yield a significant impact on a physician's assessment of stone risks and decision for management of stone disease.

BACKGROUND Study compliance is crucial when the study outcome is determined by an invasive procedure, such as prostate biopsy. To investigate predictors of compliance in study-mandated prostate biopsies, we analyzed demographic, clinical and reported lifestyle data from the REDUCE trial. METHODS We retrospectively identified 8025 men from REDUCE with at least 2 years of follow-up, and used multivariable logistic regression to test the association between baseline demographic and clinical characteristics and undergoing the study-mandated prostate biopsy at 2 years. We then examined whether missing any of these data was associated with undergoing a biopsy. RESULTS In REDUCE, 22% of men did not undergo a 2-year biopsy. On multivariable analysis, the non-North American region was predictive of 42-44% increased likelihood of undergoing a 2-year biopsy (P⩽0.001). Being enrolled at a center that enrolled >10 subjects (2nd and 3rd tertile) was associated with a 42-48% increased likelihood of undergoing a 2-year biopsy (P