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Background: The optimal treatment of localized prostate cancer (PCa) remains controversial., Objective: To compare long-term survival among men who underwent radical prostatectomy (RP), brachytherapy (BT), external beam radiation therapy (EBRT), primary androgen deprivation therapy (PADT), or monitoring (active surveillance [AS]/watchful waiting [WW]) for PCa., Design, Setting, and Participants: This is a cohort study with long-term follow-up from the multicenter, prospective, largely community-based Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Men with biopsy-proven, clinical T1-3aN0M0, localized PCa were consecutively accrued within 6 mo of diagnosis and had clinical risk data and at least 12 mo of follow-up after diagnosis available., Outcome Measurements and Statistical Analysis: PCa risk was assessed, and multivariable analyses were performed to compare PCa-specific mortality (PCSM) and all-cause mortality by primary treatment, with extensive adjustment for age and case mix using the Cancer of the Prostate Risk Assessment (CAPRA) score and a well-validated nomogram., Results and Limitations: Among 11 864 men, 6227 (53%) underwent RP, 1645 (14%) received BT, 1462 (12%) received EBRT, 1510 (13%) received PADT, and 1020 (9%) were managed with AS/WW. At a median of 9.4 yr (interquartile range 5.8-13.7) after treatment, 764 men had died from PCa. After adjusting for CAPRA score, the hazard ratios for PCSM with RP as the reference were 1.57 (95% confidence interval [CI] 1.24-1.98; p < 0.001) for BT, 1.55 (95% CI 1.26-1.91; p < 0.001) for EBRT, 2.36 (95% CI 1.94-2.87; p < 0.001) for PADT, and 1.76 (95% CI 1.30-2.40; p < 0.001) for AS/WW. In models for long-term outcomes, PCSM differences were negligible for low-risk disease and increased progressively with risk. Limitations include the evolution of diagnostic and therapeutic strategies for PCa over time. In this nonrandomized study, the possibility of residual confounding remains salient., Conclusions: In a large, prospective cohort of men with localized PCa, after adjustment for age and comorbidity, PCSM was lower after local therapy for those with higher-risk disease, and in particular after RP. Confirmation of these results via long-term follow-up of ongoing trials is awaited., Patient Summary: We evaluated different treatment options for localized prostate cancer in a large group of patients who were treated mostly in nonacademic medical centers. Results from nonrandomized trials should be interpret with caution, but even after careful risk adjustment, survival rates for men with higher-risk cancer appeared to be highest for patients whose first treatment was surgery rather than radiotherapy, hormones, or monitoring., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To understand the relationship between common urologic medications phosphodiesterase-5 inhibitors (PDE5i) and anticholinergics (AC) and risk of dementia onset in men who underwent different primary treatments for prostate cancer., Materials and Methods: Patients (>50years) with prostate cancer (1998-2022) without Alzheimer's disease or related dementias were selected from Cancer of the Prostatic Strategic Urologic Research Endeavor Registry. Minimum medication use was 3months. Fine-Gray regression was performed to determine the association between medication exposure and dementia onset ≥12months after primary treatment in men matched on age, race, comorbid conditions, smoking, and type of clinical site, with competing risk of death., Results: Among 5937 men (53% PDE5i; 14% AC), PDE5i users were younger (63 vs 70, P < .01) with less CAD, CVA, DM (all P < .01); AC users were older (68 vs 66, P < .01) with higher incidence of comorbidities (P < .01). Median months of use was 24.3 (IQR 12.1, 48.7) for PDE5i and 12.2 (IQR 6.1, 24.3) for AC users. Cumulative incidence of Alzheimer's disease or related dementias was 6.5% at 15years. PDE5i (P = .07) and AC (P = .06) were not associated with dementia regardless of primary treatment modality., Conclusion: In this retrospective cohort study, PDE5i and AC use do not appear independently associated with risk of dementia. Notably, our cohort was generally healthy and younger which may limit our ability to detect significance. We recommend prospective investigation into association between PDE5i and dementia and advise continued judicious stewardship of AC in older patient populations., Competing Interests: Declaration of Competing Interest No conflict., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To characterize the incidence of stress urinary incontinence (SUI) after radical prostatectomy (RP), its treatment, and impact on quality of life (QoL) and work status 1year after RP., Materials and Methods: Prostate cancer patients treated by RP (1998-2016) were selected from CaPSURE. SUI was defined as any pads per day (ppd) 1 year after RP. SUI procedures were tracked by CPT codes (sling and artificial sphincter). Patients reported work status (full-time, part-time, unpaid), UCLA PCa Index urinary function (UF) and bother (UB) and SF36 Index physical function (PF). Associations of incontinence with UF, UB, and PF and work status changes were assessed (ANOVA). Lifetable estimates and Cox proportional hazards regression evaluated risk of undergoing SUI procedures., Results: 664/2989 (22%) men treated with RP reported SUI at 1 year. More men with SUI had ≥GG2, intermediate to high-risk disease and non-nerve-sparing surgery (all P < .01). Cumulative incidence of SUI procedures was 1.4% at 10years after RP. Age (HR 2.68 per 10years, 95% CI 1.41-5.08) and number of ppd at 1 year (HR 3.20, 95% CI 2.27-4.50) were associated with undergoing SUI procedures. UF declined at 1year after RP, while UB and PF remained stable. UF, UB, and PF were inversely associated with number of ppd (all P < .01). Change in work status was not associated with incontinence or QoL scores., Conclusion: Incontinence affected QoL without impacting work status, suggesting that men with SUI after RP may continue working and go under-treated despite impact on QoL., Competing Interests: Declaration of Competing Interest Peter R. Carroll, MD MPH - Source of Funding (UCSF Goldberg-Benioff Program in Translational Cancer Biology). All the other authors have no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the long-term incidence of treatment-related toxicities and quality of life (QOL) outcomes associated with toxicity after external beam radiotherapy (EBRT) for prostate cancer., Methods: We identified all men who had EBRT between 1994 and 2017 from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a longitudinal, nationwide prostate cancer registry. CaPSURE was queried for patient-reported and International Classification of Diseases-9/10 and Current Procedural Terminology codes. The Medical Outcomes Studies Short Form 36 and the University of California, Los Angeles Prostate Cancer Index were used to provide measures of general health, sexual, urinary, and bowel function. Repeated measures mixed models were used to determine QOL change after onset of toxicity., Results: From a total of 15,332, 1744 (11.4%) men had EBRT. The median follow-up was 7.9years (interquartile range [IQR] 4.3-12.7). The median time to onset of any toxicity including urinary pad usage in 265 (15.4% at 8years) men was 4.3years (IQR 1.8-8.0). The most frequent toxicity was hemorrhagic cystitis (104, 5.9% at 8years) after a median of 3.7years (1.3-7.8), gastrointestinal (48, 2.7% at 8years) after a median of 4.2years (IQR 1.3-7.8), followed by urethral stricture (47, 2.4% at 8years) after a median of 3.7years (IQR 1.9-9.1). Repeated measures mixed models found that onset of hemorrhagic cystitis was associated with change in general health over time., Conclusion: EBRT for prostate cancer is associated with distinct treatment-related toxicities which can occur many years after treatment and can affect QOL. These results may help men understand the long-term implications of treatment decisions., Competing Interests: DECLARATION OF COMPETING INTEREST The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Although the American Urological Association recently dropped the very low-risk (VLR) subcategory for low-risk prostate cancer (PCa) and the European Association of Urology does not substratify low-risk PCa, the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum, which is based on the number of positive biopsy cores, tumor extent in each core, and prostate-specific antigen density. This subdivision may be less applicable in the modern era in which imaging-targeted prostate biopsies are common practice. In our large institutional active surveillance cohort of patients diagnosed from 2000 to 2020 (n = 1276), the number of patients meeting NCCN VLR criteria decreased significantly in recent years, with no patient meeting VLR criteria after 2018. By contrast, the multivariable Cancer of the Prostate Risk Assessment (CAPRA) score effectively substratified patients over the same period and was predictive of upgrading on repeat biopsy to Gleason grade group ≥2 on multivariable Cox proportional-hazards regression modeling (hazard ratio 1.21, 95% confidence interval 1.05-1.39; p < 0.01), independent of age, genomic test results, and magnetic resonance imaging findings. These findings suggest that the NCCN VLR criteria are less applicable in the targeted biopsy era, and that the CAPRA score or similar instruments are better contemporary risk stratification tools for men on active surveillance. PATIENT SUMMARY: We investigated whether the National Comprehensive Cancer Network classification of very low risk (VLR) for prostate cancer is relevant in the modern era. We found that in a large group of patients on active surveillance, no man diagnosed after 2018 satisfied the VLR criteria. However, the Cancer of the Prostate Risk Assessment (CAPRA) score discriminated patients by cancer risk at diagnosis and was predictive of outcomes on active surveillance, and thus may be a more relevant classification scheme in the modern era., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Approximately 0.4-1.3% of the worldwide population is transgender. Although the exact prevalence is unknown, there is an increase in open identification as transgender. Among transgender women (TW), the prostate is retained even after gender-affirmation surgery, thus necessitating ongoing screening for prostate cancer (CaP). However, little is known about CaP screening in this population., Objective: To assess our current understanding of CaP incidence and prostate-specific antigen (PSA) screening in TW., Evidence Acquisition: We performed a nonsystematic narrative review of all PubMed publications through June 2022 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. Given the limited primary research on this subject, case reports were also included. Studies were reviewed to understand PSA screening practices and reports of CaP in this population, as applicable., Evidence Synthesis: There is no consensus regarding PSA screening in TW from any of the major societies, and TW are largely absent from guidelines. Case report data suggest that TW with CaP may have more aggressive disease, and these cancers may have been pre-existing prior to present before gender-affirming hormone therapy (GAHT) or be castrate-resistant., Conclusions: We are in the infancy of our understanding of PSA screening in TW. Important avenues for future research include understanding the risks/benefits of PSA screening in TW, how best to mitigate potential negative psychological effects of PSA screening in TW, establishing baseline PSA values for those on GAHT (and determining what values should be considered "elevated"), establishing when to initiate PSA screening for those on GAHT, and establishing the accuracy of biomarkers for those undergoing GAHT., Patient Summary: We examined patterns of prostate cancer screening for transgender women. Little is known about prostate cancer incidence or screening in this population. Additional research is needed to establish guidelines for screening in this population., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate how blood levels of prostate-specific antigen (PSA) relate to prostate volume of benign tissue, Gleason pattern 3 (GP3) and Gleason pattern 4 (GP4) cancer., Methods: The cohort included 2209 consecutive men undergoing radical prostatectomy at 2 academic institutions with pT2N0, Grade Group 1-4 prostate cancer and an undetectable postoperative PSA. Volume of benign, GP3, and GP4 were estimated. The primary analysis evaluated the association between PSA and volume of each type of tissue using multivariable linear regression. R 2 , a measure of explained variation, was calculated using a multivariable model., Results: Estimated contribution to PSA was 0.04/0.06 ng/mL/cc for benign, 0.08/0.14 ng/mL/cc for GP3, and 0.62/0.80 ng/ml/cc for GP4 for the 2 independent cohorts, respectively. GP4 was associated with 6 to 8-fold more PSA per cc compared to GP3 and 15-fold higher compared to benign tissue. We did not observe a difference between PSA per cc for GP3 vs. benign tissue (P = 0.2). R 2 decreased only slightly when removing age (0.006/0.018), volume of benign tissue (0.051/0.054) or GP3 (0.014/0.023) from the model. When GP4 was removed, R 2 decreased 0.051/0.310. PSA density (PSA divided by prostate volume) was associated with volume of GP4 but not GP3, after adjustment for benign volume., Conclusion: Gleason pattern 4 cancer contributes considerably more to PSA and PSA density per unit volume compared to GP3 and benign tissue. Contributions from GP3 and benign are similar. Further research should examine the utility of determining clinical management recommendations by absolute volume of GP4 rather than the ratio of GP3 to GP4., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To determine if older men with Gleason grade group (GG) 1 prostate cancer have a higher risk of having adverse pathology at radical prostatectomy after initially being managed with active surveillance (AS)., Methods: A total of 365 patients with GG1 prostate cancer initially managed with AS followed by delayed radical prostatectomy were identified. The primary outcome was adverse pathology after delayed radical prostatectomy in the men that were <65 years vs. men ≥65 years at the initiation of AS. Adverse pathology was defined as GG ≥3 or pT3 or pN1. Multivariable Cox proportional hazards regression models were used to calculate risk of adverse pathological findings at radical prostatectomy by age group., Results: At diagnosis, there were no significant differences in median prostate specific antigen density, percent positive biopsy cores, multiparametric magnetic resonance imaging (mpMRI) results or composite genomic classifier scores (derived from three commercially available genomic tests) between the two age groups. Men ≥65 years had more adverse pathology at radical prostatectomy (59.2% vs. 44.1%, P <0.01) and lower rates of biopsy upgrade-free survival and adverse pathology-free survival (log-rank P <0.01). On multivariable analysis age ≥65 years (Hazard Ratio (HR) 2.21, 95% Confidence Interval (CI) 1.57, 3.12) was associated with adverse pathology at radical prostatectomy. In separate multivariable analyses done for each age group, mpMRI (HR 3.33, 95% CI 1.01, 10.95) was predictor of adverse pathology in the group ≥65 years., Conclusion: Older patients might require closer monitoring on AS and additional testing such as mpMRI might improve their risk stratification., (Copyright © 2021 Elsevier Inc. All rights reserved.)

18 F-Fluciclovine-based positron emission tomography (PET) imaging is recommended in the USA for biochemical recurrence (BCR) after prostate cancer treatment. However, prostate-specific membrane antigen (PSMA)-based PET imaging is more common worldwide, supported by international guidelines, and is now approved by the Food and Drug Administration in the USA for initial staging of primary prostate cancer. Little is known about the molecular profiles of lesions detected by PSMA-targeted PET/computed tomography (CT) versus 18 F-fluciclovine PET/CT. We examined the expression of PSMA (FOLH1) and the fluciclovine transporter genes LAT1-4 and ASCT1/2 in a combined cohort of more than 18 000 radical prostatectomy specimens and their associations with clinical outcomes. Expression of PSMA and all but one fluciclovine transporter gene was higher in prostate cancer than in benign tissue. PSMA expression was associated with Gleason score (GS) ≥8 and lymph node involvement (LNI), and had a positive linear correlation with Decipher risk score. By contrast, expression of the fluciclovine transporters LAT2, LAT3, and ASCT2 was negatively associated with GS ≥ 8, LNI, and high Decipher score. The top decile of PSMA expression was associated with poorest metastasis-free survival (MFS), while the bottom deciles of LAT3 and ASCT2 expression were associated with poorest MFS. PATIENT SUMMARY: We measured the expression of genes that encode the targets for two different radiotracers in PET (positron emission tomography) scans of the prostate. We found that PSMA gene expression (PSMA-based tracer) is associated with worse clinical outcomes, while expression of ASCT2, LAT2, and LAT3 genes (fluciclovine tracer) is associated with better outcomes., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Molecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use., Objective: To perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC)., Evidence Acquisition: The review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446-52) and American Urology Association (AUA) criteria., Evidence Synthesis: In total, 42 studies and 30407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n=12141), prospective registries (n=17053), and prospective and post hoc randomized trial analyses (n=1213). In 32 studies (n=12600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n=8543). GC use changed the management in active surveillance (number needed to test [NNT]=9) and postprostatectomy (NNT=1.5-4) settings in five studies (n=4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state., Conclusions: Consistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making., Patient Summary: In this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To analyze differences in length of stay, opioid use, and other perioperative outcomes in patients undergoing radical cystectomy with urinary diversion who received either liposomal bupivacaine (LB) or epidural analgesia., Methods: This was a single center, retrospective cohort study of patients undergoing open radical cystectomy with urinary diversion from 2015-2019 in the early recovery after surgery (ERAS) pathway. Patients received either LB or epidural catheter analgesia for post-operative pain control. LB was injected at the time of fascial closure to provide up to 72 hours of local analgesia. The primary outcome was post-operative length of stay. Secondary outcomes were post-operative opioid use, time to solid food, time to ambulation, and direct hospitalization costs. Multivariable Cox proportional hazards regression was used to determine associations between analgesia type and discharge., Results: LB use was independently associated with shorter post-operative length of stay compared to epidural use (median (IQR) 4.9 days (3.9-5.8) vs 5.9 days (4.9-7.9), P<.001), less total opioid use (mean 188.3 vs 612.2 OME, P <.001), earlier diet advancement (mean 1.6 vs 2.4 days, P <.001), and decreased overall direct costs ($23,188 vs $29,628, P <.001). 45% of patients who received LB were opioid-free after surgery, none in the epidural group. On multivariable Cox proportional hazards regression modeling, LB use was independently associated with earlier discharge (HR 2.1, IQR 1.0-4.5)., Conclusion: Use of LB in open radical cystectomy is associated with reduced LOS, less opioid exposure, and earlier diet advancement., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Distinguishing indolent from aggressive prostate cancer remains a key challenge for decision making regarding prostate cancer management. A growing number of biomarkers are now available to help address this need, but these have rarely been examined together in the same patients to determine their potentially additive value., Objective: To determine whether two previously validated plasma markers (transforming growth factor β1 [TGFβ1] and interleukin-6 soluble receptor [IL6-SR]) and two validated tissue scores (the Genomic Evaluators of Metastatic Prostate Cancer [GEMCaP] and cell cycle progression [CCP] scores) can improve on clinical parameters in predicting adverse pathology after prostatectomy, and how much they vary within tumors with heterogeneous Gleason grade., Design, Setting, and Participants: A case-control study was conducted among men with low-risk cancers defined by biopsy grade group (GG) 1, prostate-specific antigen (PSA) ≤10 ng/mL, and clinical stage ≤ T2 who underwent immediate prostatectomy. We collected paraffin-fixed prostatectomy tissue and presurgical plasma samples from 381 cases from the University of California, San Francisco, and 260 cases from the University of Washington., Outcome Measurements and Statistical Analysis: Pathologic outcomes were minor upgrading/upstaging (GG 2 or pT3a) or major upgrading/upstaging (GG ≥ 3 or ≥ pT3b), and multinomial regression was performed to determine putative markers' ability to predict these outcomes, controlling for PSA, percent of positive biopsy cores, age, and clinical site. For upgraded tumors, a secondary analysis of the GEMCaP and CCP scores from the higher-grade tumor was also performed to evaluate for heterogeneity., Results and Limitations: Overall, 357 men had no upgrading/upstaging event at prostatectomy, 236 had a minor event, and 67 had a major event. Neither TGFβ1 nor IL6-SR was statistically significantly associated with any upgrading/upstaging. On the contrary, both the CCP and the GEMCaP score obtained from Gleason pattern 3 tissue were directly associated with minor and major upgrading/upstaging on univariate analysis. The two scores correlated with each other, but weakly. On multinomial analysis including both scores in the model, the CCP score predicted minor upgrading/upstaging (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.05-2.49) and major upgrading/upstaging (OR 2.26, 95% CI 1.05-4.90), p =  0.04), and the GEMCaP score also predicted minor upgrading/upstaging (OR 1.05, 95% CI 1.03-1.08) and major upgrading/upstaging (OR 1.07, 95% CI 1.04-1.11), p <  0.01). The other clinical parameters were not significant in this model. Among upgraded tumors including both Gleason patterns 3 and 4, both the GEMCaP and the CCP score tended to be higher from the higher-grade tumor. The main limitation was the use of virtual biopsies from prostatectomy tissue as surrogates for prostate biopsies., Conclusions: Biomarker signatures based on analyses of both DNA and RNA significantly and independently predict adverse pathology among men with clinically low-risk prostate cancer undergoing prostatectomy., Patient Summary: Validated biomarker scores derived from both prostate cancer DNA and prostate cancer RNA can add independent information to help predict outcomes after prostatectomy., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Multiparametric magnetic resonance imaging (mpMRI) has improved the detection of clinically significant prostate cancer. It remains unclear, however, whether mpMRI can safely replace confirmatory or surveillance biopsies in men with low-risk disease managed with active surveillance (AS). Overall, 166 men were upgraded at a median of 29 mo (interquartile range 13-54). The overall negative predictive value (NPV) of mpMRI was 79.5% and ranged from 74.4% to 84.6% for all AS biopsies up to the fourth surveillance biopsy. In men with prostate-specific antigen density ≥0.15 ng/ml/cm 3 , the overall NPV of mpMRI was 65.5% and ranged from 57.1% to 73.3% across serial mpMRI scans. These findings support the hypothesis that mpMRI is helpful but insufficient to rule out pathological reclassification, especially at confirmatory biopsy or in the presence of other risk factors. PATIENT SUMMARY: Multiparametric magnetic resonance imaging (mpMRI) alone misses a considerable percentage of clinically significant prostate cancers (Gleason grade group ≥2) in men on active surveillance for low-risk prostate cancer. We conclude that mpMRI alone cannot safely replace surveillance prostate biopsies, particularly at confirmatory biopsy or in the presence of other risk factors., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Active surveillance (AS)/watchful waiting (WW) strategy for localized prostate cancer (PCa) is increasingly and broadly endorsed as a preferred option for initial treatment of men with very low- and low-risk PCa, but outcomes can be difficult to analyze in traditional, population-based registries. The recently released Surveillance, Epidemiology, and End Results (SEER) Prostate with WW dataset provides an opportunity to understand national patterns and trends in AS/WW, but the data source itself has not been well described., Objective: To provide a comprehensive description of this dataset and investigate possible biases due to missing data., Design, Setting, and Participants: The SEER is a population-based epidemiologic registry in the USA. Newly diagnosed PCa patient data were collected from 18 SEER registries between 2010 and 2015, with inclusion of a new treatment variable for AS/WW. We identified 316 724 patients in the entire cohort and 257 060 men with clinically localized PCa (T1-2N0M0)., Intervention: Various primary treatments for PCa., Outcome Measurements and Statistical Analysis: The degree of missing data for each variable was measured. In order to investigate possible bias due to missing data for cancer characterization, we compared two versions of the data: one that excluded cases with missing data and one dataset generated applying multiple imputations., Results and Limitations: Only 46% of cases had complete data on basic cancer characteristics for risk stratification. The excluded dataset (N=118 821) differed significantly from the multiple imputation dataset (N=257 060) in the distribution of every reported variable (all p<0.001). The dataset does not distinguish WW from AS, which is a limitation., Conclusions: While the SEER Prostate with WW dataset offers a new method to describe treatment trends for men with PCa, including the use of AS/WW, the amount of missing data should not be ignored., Patient Summary: While the Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting dataset offers a new method to describe treatment trends for men with prostate cancer, including the use of active surveillance, it has a significant amount of missing data, which can be a source of potential bias if not addressed properly., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Valid health utility values are essential for comparative effectiveness analyses. However, subjective utilities in long-term survivors of prostate cancer (PCa) with various oncological and functional outcomes have not been well described., Objective: To quantify utilities in long-term survivors of PCa using the standard gamble method, generally regarded as the approach best grounded in economic theory., Design, Setting, and Participants: We performed a cross-sectional study nested within a prospective cohort-Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). Overall, 1884 (59.7%) of 3155 active participants across all disease states returned the questionnaire., Intervention: Various primary treatments for PCa., Outcome Measurements and Statistical Analysis: Utility values for PCa health, sexual function, urinary function, bowel function, and overall health were measured, based on patients' conditions at the time of the survey. Bias correction methods were employed., Results and Limitations: After exclusion of incomplete or disqualified data, 1740 (92.3% of responding) patients were included in the final analysis. The mean age was 73.1 ± 8.2 yr at a median of 9 yr (interquartile range: 6-11) since diagnosis. Mean utilities for PCa health and overall health were 0.934 ± 0.120 and 0.960 ± 0.100, respectively. After bias correction by probability weighting function, utilities were 0.866 ± 0.154 and 0.897 ± 0.142, and by mixed model correction, 0.845 ± 0.186 and 0.884 ± 0.176, respectively. Measured utilities were similarly high for specific functional outcomes, even with bias corrections. Survivorship bias and skewed proportion of disease status due to natural history of PCa were potential limitations., Conclusions: Standard gamble-based utilities in long-term survivors of PCa were much higher than those determined previously. The results indicate substantial human resilience: most PCa patients adapt to their health status over time even if they experience incomplete functional recovery and would not take risk in pursuit of better quality of life., Patient Summary: We elicited health utilities (measures of quality of life) among long-term survivors of prostate cancer using the most robust method. These were much higher than previously reported values that were based on theoretical scenarios or indirect methods. Long-term survivors of prostate cancer may adapt well to their health conditions over time even if they experience disease-specific or functional problems., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Men with prostate cancer (PCa) on active surveillance (AS) are followed through regular prostate biopsies, a burdensome and often unnecessary intervention, not without risks. Identifying men with at a low risk of disease reclassification may help reduce the number of biopsies., Objective: To assess the external validity of two Canary Prostate Active Surveillance Study Risk Calculators (PASS-RCs), which estimate the probability of reclassification (Gleason grade ≥7 with or without >34% of biopsy cores positive for PCa) on a surveillance biopsy, using a mix of months since last biopsy, age, body mass index, prostate-specific antigen, prostate volume, number of prior negative biopsies, and percentage (or ratio) of positive cores on last biopsy., Design, Setting, and Participants: We used data up to November 2017 from the Movember Foundation's Global Action Plan (GAP3) consortium, a global collaboration between AS studies., Outcome Measurements and Statistical Analysis: External validity of the PASS-RCs for estimating reclassification on biopsy was assessed by calibration, discrimination, and decision curve analyses., Results and Limitations: Five validation cohorts (Prostate Cancer Research International: Active Surveillance, Johns Hopkins, Toronto, Memorial Sloan Kettering Cancer Center, and University of California San Francisco), comprising 5105 men on AS, were eligible for analysis. The individual cohorts comprised 429-2416 men, with a median follow-up between 36 and 84 mo, in both community and academic practices mainly from western countries. Abilities of the PASS-RCs to discriminate between men with and without reclassification on biopsy were reasonably good (area under the receiver operating characteristic curve values 0.68 and 0.65). The PASS-RCs were moderately well calibrated, and had a greater net benefit than most default strategies between a predicted 10% and 30% risk of reclassification., Conclusions: Both PASS-RCs improved the balance between detecting reclassification and performing surveillance biopsies by reducing unnecessary biopsies. Recalibration to the local setting will increase their clinical usefulness and is therefore required before implementation., Patient Summary: Unnecessary prostate biopsies while on active surveillance (AS) should be avoided as much as possible. The ability of two calculators to selectively identify men at risk of progression was tested in a large cohort of men with low-risk prostate cancer on AS. The calculators were able to prevent unnecessary biopsies in some men. Usefulness of the calculators can be increased by adjusting them to the characteristics of the population of the clinic in which the calculators will be used., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To determine trends and predictors of adjuvant therapy in patients with adverse features at radical prostatectomy (RP), and to investigate the associations of adjuvant therapy and adverse feature type with survival., Methods: From the Cancer of the Prostate Strategic Urologic Research Endeavor registry (1990-2017), 2209 men with adverse features (pT3N0M0 disease and/or positive surgical margins), and 108 men with positive lymph nodes (pN1) at RP were identified. Temporal trends were evaluated, and predictors of adjuvant therapy were assessed with multivariate logistic regression. Kaplan-Meier analysis and competing risks regression were used to test cumulative incidence and risk of all-cause and prostate cancer-specific mortality., Results: Of 2209 men with adverse features and pN0 disease, 89 (4.0%), 82 (3.7%), and 30 (1.4%) received adjuvant external beam radiation therapy (ERBT) alone, androgen deprivation therapy (ADT) alone, or combined EBRT and ADT, respectively. Of 108 men with pN1 disease, 54 (50%) received ADT with or without EBRT. Adjuvant treatment for patients with adverse features decreased from 13.3% (1990-1994) to 6% or less (2005-2017, P trend <.001). Patients with margin positive pT3a (odds ratio 4.13; 95% confidence interval 2.21-7.73; P<.01) and margin positive pT3b disease (odds ratio 7.09; 95% confidence interval 3.66-1.73; P<.01) had greater odds of receiving adjuvant therapy compared to patients with margin negative pT3a disease. Adverse feature type was associated with prostate cancer-specific mortality in univariate analysis (log-rank P <.01), but not in competing risks regression (P= .06)., Conclusion: Adjuvant therapy declined for men with adverse features at RP. Providers do not treat all adverse feature types the same way, despite broad treatment recommendations in guidelines., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To identify locations of recurrence after radical prostatectomy (RP) with prostate-specific antigen (PSA) <2 by Gallium-68 prostate-specific membrane antigen (PSMA)-11 Positron Emission Tomography (PET) imaging, and to determine whether standard nodal radiation fields would cover the location of prostate cancer recurrence., Materials and Methods: We performed a retrospective review of patients with PSMA-PET imaging for biochemical recurrence following RP with PSA ≤2.0 ng/mL and assessed if the recurrent disease was within standard radiation target volumes. We compared patient and clinical variables between men with recurrences covered by standard salvage radiation fields and those with recurrences outside of standard fields., Results: We identified 125 patients for study inclusion. The median PSA at imaging was 0.40 ng/mL (interquartile range 0.28-0.63). PSMA-avid disease was found in 66 patients (53%). Of these, 25 patients (38%) had PSMA-avid lesions found outside of the pelvis, 33 (50%) had lesions confined to the pelvic lymph nodes and prostate bed, and 8 (12%) men had PSMA-avid recurrence only in the prostate bed. Salvage radiation including standard Intensity Modulated Radiation Therapy (IMRT) pelvic nodal volumes would not cover PSMA-avid nodal disease in 38 men (30%). PSA at the time of imaging was statistically associated with having PSMA-avid disease outside of standard nodal fields (P <.01)., Conclusion: The 68Ga-PSMA-11 PET detects disease in a majority of patients with PSA ≤2.0 following RP. Nearly one-third of men had PSMA-avid disease that would be missed by standard radiation fields. This imaging modality may dramatically impact the design and use of post-RP salvage radiotherapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Increasing evidence suggests that lifestyle factors may decrease the risk of prostate cancer progression. Lifestyle guidelines and tools may support lifestyle modification after diagnosis., Objective: To determine the feasibility and acceptability of a digital lifestyle intervention among men with prostate cancer., Design, Setting, and Participants: A 12-wk pilot randomized controlled trial among 76 men with clinical stage T1-T3a prostate cancer. Eligibility included Internet access, no contraindications to aerobic exercise, and engaging in four or fewer of eight targeted behaviors at baseline., Intervention: Website, Fitbit One, and text messaging to facilitate adoption of eight behaviors: vigorous activity, smoking cessation, and six diet improvements., Outcome Measurements and Statistical Analysis: Our primary outcomes were feasibility and acceptability based on recruitment and user data, and surveys, respectively. Secondarily, we evaluated the change in eight lifestyle behaviors, and also objective physical activity. Each factor was assigned one point, for an overall "P8 score" (range 0-8). Analysis of covariance (ANCOVA) was conducted. Exploratory outcomes included quality of life, anthropometrics, and circulating biomarkers after 12wk, and behaviors after 1yr., Results and Limitations: At baseline, men in both arms met a median of three targeted behaviors. Sixty-four men (n=32 per arm) completed the study; 88% completed 12-wk assessments (intervention, 94%; control, 82%). Intervention participants wore their Fitbits a median of 82d (interquartile range [IQR]: 72-83), replied to a median of 71% of text messages (IQR: 57-89%), and visited the website a median of 3d (IQR: 2-5) over 12wk. Median (IQR) absolute changes in the P8 score from baseline to 12wk were 2 (1, 3) for the intervention and 0 (-1, 1) for the control arm. The estimated mean score of the intervention arm was 1.5 (95% confidence interval: 0.7, 2.3) higher than that of the control arm at 12wk (ANCOVA p<0.001). Changes were driven by diet rather than exercise. Limitations include self-reported diet and exercise data., Conclusions: Overall, in this novel pilot trial, the intervention was feasible and acceptable to men with prostate cancer. Next steps include improving the intervention to better meet individuals' needs and focusing on increasing physical activity in men not meeting nationally recommended physical activity levels., Patient Summary: Tailored print materials combined with technology integration, including the use of a website, text messaging, and physical activity trackers, helped men with prostate cancer adopt healthy lifestyle habits, in particular recommended dietary changes, in the Prostate 8 pilot trial., (Copyright © 2018. Published by Elsevier B.V.)

Objective: To evaluate the impact of staging 68 Ga-PSMA-11 PET imaging on radiotherapy (RT) dose and volumes in patients with prostate cancer., Methods: Forty-five patients (89% high or very high risk by NCCN criteria) who underwent 68 Ga-PSMA-11 PET imaging prior to definitive treatment for prostate cancer between December 2015 and December 2016 were included. Locations of 68 Ga-PSMA-11-avid lesions were compared to Radiation Therapy Oncology Group consensus pelvic nodal volumes (clinical target volume [CTV]); coverage of lesions outside the consensus CTV was considered a major change, while dose-escalation to lesions within the consensus CTV was considered a minor change., Results: All patients had 68 Ga-PSMA-11 PET uptake in the prostate. Twenty-five patients (56%) had N1/M1a disease on 68 Ga-PSMA-11 PET scan, of whom 21 (47%) were previously N0. Six patients (13%) had bone metastases on 68 Ga-PSMA-11 PET scan, of whom 4 had prior negative bone scans. Eight patients (18%) had lymph node metastases outside the consensus CTV. Twelve patients (27%) received a RT boost to nodes within the consensus CTV. Six patients (13%) had limited bone metastases treated with focal RT. Overall PSMA PET imaging resulted in major and/or minor changes to RT plans in 24 patients (53%)., Conclusion: 68 Ga-PSMA-11 PET imaging resulted in RT changes in 53% of patients. Prospective investigation is needed to evaluate the clinical benefit of RT changes based on staging 68 Ga-PSMA-11 PET imaging., (Published by Elsevier Inc.)

Background: Despite the availability of numerous genomic predictors of prostate cancer (PCa) outcome, few comparative studies have been performed., Objective: To compare the prognostic utility of previously validated immunohistochemical (IHC) markers with an expression-based cell-cycle progression (CCP) score., Design, Setting, and Participants: We identified 424 men with localized PCa treated with radical prostatectomy (RP). IHC analysis was performed using a tissue microarray to examine the expression status of PTEN, Ki-67, and ERG compared with previously calculated CCP scores derived from 31 genes normalized to 15 housekeeper genes., Outcome Measurements and Statistical Analysis: Associations of IHC status and CCP scores, adjusted for clinical and pathologic characteristics were performed using Cox regression and competing risks regression to examine risk of biochemical recurrence (BCR), and metastasis or PCa-specific mortality (PCSM). We compared models using concordance index (c-index) testing., Intervention: RP., Results and Limitations: Median age at treatment was 59 yr, and patients were followed for a median of 114 mo after RP. By 10 yr after RP, 27% experienced BCR and 4% developed metastasis or PCSM. In a multivariable model adjusted for Cancer of the Prostate Risk Assessment score (CAPRA-S), CCP was associated with risks of recurrence (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.08-2.11) and metastasis/PCSM (HR 2.15, 95% CI 1.36-3.39). PTEN loss was not associated with recurrence but was associated with metastasis/PCSM (HR 5.26, 95% CI 2.57-10.7), adjusted for CAPRA-S. The c-index for models consisting of PTEN status and CAPRA-S was similar (0.80) for risk of metastasis/PCSM when compared with CCP and CAPRA-S (0.81). Integration of Ki-67 and ERG status did not improve the c-index relative to CAPRA-S and PTEN alone., Conclusions: PTEN status offered comparable discrimination of the risk of metastasis or death from PCa relative to a commercial RNA amplification-based CCP assay. Efforts are warranted to reduce the cost of PCa prognostic tools in order to expand access., Patient Summary: We compared a commercial genomic signature and the expression status of single genes to predict outcomes in men with prostate cancer who were treated with surgical removal. When accounting for clinical information about the patient's cancer, the status of the PTEN gene alone matched a multigene panel to predict which patient's cancer would metastasize or lead to death from the disease., (Published by Elsevier B.V.)

Background: Among men with clinically low-risk prostate cancer, we have previously documented heterogeneity in terms of clinical characteristics and genomic risk scores., Objective: To further study the underlying tumor biology of this patient population, by interrogating broader patterns of gene expression among men with clinically low-risk tumors., Design, Setting, and Participants: Prostate biopsies from 427 patients considered potentially suitable for active surveillance underwent central pathology review and genome-wide expression profiling. These cases were compared with 1290 higher-risk biopsy cases with diverse clinical features from a prospective genomic registry., Outcome Measurements and Statistical Analysis: Average genomic risk (AGR) was determined from 18 published prognostic signatures, and MSigDB hallmark gene sets were analyzed using bootstrapped clustering methods. These sets were examined in relation to clinical variables and pathological and biochemical outcomes using multivariable regression analysis., Results and Limitations: A total of 408 (96%) biopsies passed RNA quality control. Based on AGR quartiles defined by the high-risk multicenter cases, the University of California, San Francisco (UCSF) low-risk patients were distributed across the quartiles as 219 (54%), 107 (26%), 61 (15%), and 21 (5%). Unsupervised clustering analysis of the hallmark gene set scores revealed three clusters, which were enriched for the previously described PAM50 luminal A, luminal B, and basal subtypes. AGR, but not the clusters, was associated with both pathological (odds ratio 1.34, 95% confidence interval [CI] 1.14-1.58) and biochemical outcomes (hazard ratio 1.53, 95% CI 1.19-1.93). These results may underestimate within-prostate genomic heterogeneity., Conclusions: Prostate cancers that are homogeneously low risk by traditional characteristics demonstrate substantial diversity at the level of genomic expression. Molecular substratification of low-risk prostate cancer will yield a better understanding of its divergent biology and, in the future may help personalize treatment recommendations., Patient Summary: We studied the genomic characteristics of tumors from men diagnosed with low-risk prostate cancer. We found three main subtypes of prostate cancer with divergent tumor biology, similar to what has previously been found in women with breast cancer. In addition, we found that genomic risk scores were associated with worse pathology findings and prostate-specific antigen recurrence after surgery. These results suggest even greater genomic diversity among low-risk patients than has previously been documented with more limited signatures., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: For men on active surveillance for prostate cancer, utility of prostate-specific antigen (PSA) kinetics (PSAk) in predicting pathologic reclassification remains controversial., Objective: To develop prediction methods for utilizing serial PSA and evaluate frequency of collection., Design, Setting, and Participants: Data were collected from men enrolled in the multicenter Canary Prostate Active Surveillance Study, for whom PSA data were measured and biopsies performed on prespecified schedules. We developed a PSAk parameter based on a linear mixed-effect model (LMEM) that accounted for serial PSA levels., Outcome Measurements and Statistical Analysis: The association of diagnostic PSA and/or PSAk with time to reclassification (increase in cancer grade and/or volume) was evaluated using multivariable Cox proportional hazards models., Results and Limitations: A total of 851 men met the study criteria; 255 (30%) had a reclassification event within 5 yr. Median follow-up was 3.7 yr. After adjusting for prostate size, time since diagnosis, biopsy parameters, and diagnostic PSA, PSAk was a significant predictor of reclassification (hazard ratio for each 0.10 increase in PSAk=1.6 [95% confidence interval 1.2-2.1, p<0.001]). The PSAk model improved stratification of risk prediction for the top and bottom deciles of risk over a model without PSAk. Model performance was essentially identical using PSA data measured every 6 mo to those measured every 3 mo. The major limitation is the reliability of reclassification as an end point, although it drives most treatment decisions., Conclusions: PSAk calculated using an LMEM statistically significantly predicts biopsy reclassification. Models that use repeat PSA measurements outperform a model incorporating only diagnostic PSA. Model performance is similar using PSA assessed every 3 or 6 mo. If validated, these results should inform optimal incorporation of PSA trends into active surveillance protocols and risk calculators., Patient Summary: In this report, we looked at whether repeat prostate-specific antigen (PSA) measurements, or PSA kinetics, improve prediction of biopsy outcomes in men using active surveillance to manage localized prostate cancer. We found that in a large multicenter active surveillance cohort, PSA kinetics improves the prediction of surveillance biopsy outcome., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Many patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident., Objective: To define the association between negative surveillance PNBs and risk of reclassification on AS., Design, Setting, and Participants: All men were enrolled in the Canary Prostate Active Surveillance Study (PASS) between 2008 and 2016. Men were included if they had Gleason ≤3+4 prostate cancer and <34% core involvement ratio at diagnosis. Men were prescribed surveillance PNBs at 12 and 24 mo after diagnosis and then every 24 mo., Outcome Measurements and Statistical Analysis: Reclassification was defined as an increase in Gleason grade and/or an increase in the ratio of biopsy cores to cancer to ≥34%. PNB outcomes were defined as follows: (1) no cancer on biopsy, (2) cancer without reclassification, or (3) reclassification. Kaplan-Meier and Cox proportional hazard models were performed to assess the risk of reclassification., Results and Limitations: A total of 657 men met inclusion criteria. On first surveillance PNB, 214 (32%) had no cancer, 282 (43%) had cancer but no reclassification, and 161 (25%) reclassified. Among those who did not reclassify, 313 had a second PNB. On second PNB, 120 (38%) had no cancer, 139 (44%) had cancer but no reclassification, and 54 (17%) reclassified. In a multivariable analysis, significant predictors of decreased future reclassification after the first PNB were no cancer on PNB (hazard ratio [HR]=0.50, p=0.008), lower serum prostate-specific antigen, larger prostate size, and lower body mass index. A finding of no cancer on the second PNB was also associated with significantly decreased future reclassification in a multivariable analysis (HR=0.15, p=0.003), regardless of the first PNB result. The major limitation of this study is a relatively small number of patients with long-term follow-up., Conclusions: Men who have a surveillance PNB with no evidence of cancer are significantly less likely to reclassify on AS in the PASS cohort. These findings have implications for tailoring AS protocols., Patient Summary: Men on active surveillance for prostate cancer who have a biopsy showing no cancer are at a decreased risk of having worse disease in the future. This may have an impact on how frequently biopsies are required to be performed in the future., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Identifying the optimal surgical approach for patients with localized prostate cancer (PCa) managed in the community setting remains controversial due to the lack of robust, prospective data., Objective: To assess surgical outcomes and changes in urinary and sexual quality of life (QOL) over time in patients undergoing radical prostatectomy (RP)., Design, Setting, and Participants: Our study included patients enrolled in Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a large, prospective, mostly community-based, nationwide PCa registry, who underwent RP between 2004 and 2016., Intervention: Open (ORP) versus robot-assisted radical prostatectomy (RARP) for localized PCa., Outcome Measurements and Statistical Analysis: Demographic and clinicopathologic data and surgical outcomes were compared between ORP and RARP. Self-reported, validated questionnaires (scaled 0-100 with higher numbers indicating better function) were used to evaluate urinary and sexual QOL at different time points. Repeated measures mixed-models assessed changes in function and bother over time in each domain., Results and Limitations: Among 1892 men (n = 1137 ORP; n = 755 RARP), Cancer of the Prostate Risk Assessment score, Gleason grade at biopsy and RP, and pT-stage were lower in ORP patients (all p < 0.01). Men undergoing RARP had comparable surgical margin rates, lymph node yields, and biochemical recurrence rates. In a subset analysis with 1451 men reporting baseline and follow-up QOL data, ORP patients reported superior scores in urinary incontinence (ORP mean ± standard deviation 69 ± 26 vs RARP 62 ± 27) and bother (ORP 75±29 vs RARP 68±28, both p < 0.01) only in the 1st yr after RP. Differences in sexual outcomes did not differ between groups, nor did any QOL scores beyond 1 yr. Limitations include a decrease in the rate of questionnaire response during follow-up, potential selection biases in terms of patient assignment to ORP versus RARP and survey completion rates, and the fact that RARP cases likely included the initial learning curve for the CaPSURE surgeons., Conclusions: Most patients experienced changes in urinary and sexual QOL in the 1st 3 yr following RP. The pattern of recovery over time was similar between ORP and RARP groups. Patients should not expect different oncologic or QOL outcomes based on surgical approach., Patient Summary: Aside from a small, early, and temporary advantage in terms of urinary incontinence and bother favoring open surgery, minimal differences in outcomes are observed when comparing men who undergo open versus robot-assisted prostatectomy in the community setting., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Diagnosis of Gleason 6 prostate cancer can leave uncertainty about the presence of undetected aggressive disease., Objective: To evaluate the utility of a four kallikrein (4K) panel in predicting the presence of high-grade cancer in men on active surveillance., Design, Setting, and Participants: Plasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. We developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA)., Outcome Measurements and Statistical Analysis: The endpoint was reclassification to Gleason ≥7. We used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit., Results and Limitations: Significant predictors for reclassification were 4Kpanel (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81) or PSA (OR 2.11, 95% CI 1.53-2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33-3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04-0.85), prostate volume (OR 0.47, 95% CI 0.31-0.70), and body mass index (OR 1.09, 95% CI 1.04-1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use., Conclusions: The 4Kpanel provided incremental value over routine clinical information in predicting high-grade cancer in the first biopsy after diagnosis. The 4Kpanel did not add predictive value to the base model at subsequent surveillance biopsies., Patient Summary: Active surveillance is a management strategy for many low-grade prostate cancers. Repeat biopsies monitor for previously undetected high-grade cancer. We show that a model with clinical variables, including a panel of four kallikreins, indicates the presence of high-grade cancer before a biopsy is performed., (Copyright © 2016 European Association of Urology. All rights reserved.)

Context: The incidence of low-risk prostate cancer (PCa) has increased as a consequence of prostate-specific antigen testing., Objective: In this collaborative review article, we examine recent literature regarding low-risk PCa and the available prognostic and therapeutic options., Evidence Acquisition: We performed a literature review of the Medline, Embase, and Web of Science databases. The search strategy included the terms: prostate cancer, low risk, active surveillance, focal therapy, radical prostatectomy, watchful waiting, biomarker, magnetic resonance imaging, alone or in combination., Evidence Synthesis: Prospective randomized trials have failed to show an impact of radical treatments on cancer-specific survival in low-risk PCa patients. Several series have reported the risk of adverse pathologic outcomes at radical prostatectomy. However, it is not clear if these patients are at higher risk of death from PCa. Long-term follow-up indicates the feasibility of active surveillance in low-risk PCa patients, although approximately 30% of men starting active surveillance undergo treatment within 5 yr. Considering focal therapies, robust data investigating its impact on long-term survival outcomes are still required and therefore should be considered experimental. Magnetic resonance imaging and tissue biomarkers may help to predict clinically significant PCa in men initially diagnosed with low-risk disease., Conclusions: The incidence of low-risk PCa has increased in recent years. Only a small proportion of men with low-risk PCa progress to clinical symptoms, metastases, or death and prospective trials have not shown a benefit for immediate radical treatments. Tissue biomarkers, magnetic resonance imaging, and ongoing surveillance may help to identify those men with low-risk PCa who harbor more clinically significant disease., Patient Summary: Low-risk prostate cancer is very common. Active surveillance has excellent long-term results, while randomized trials have failed to show a beneficial impact of immediate radical treatments on survival. Biomarkers and magnetic resonance imaging may help to identify which men may benefit from early treatment., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Fusion biopsy using multiparametric magnetic resonance imaging (MRI) and transrectal ultrasound has demonstrated favorable detection rates of high-grade prostate cancer (PCa) among previously undiagnosed men. However, the diagnostic yield among men with active surveillance (AS) remains undefined., Objective: To determine the utility of MRI-ultrasound fusion biopsy during AS by reporting rates of PCa upgrading and comparing findings with systematic biopsy., Design, Setting, and Participants: We identified patients with low- and intermediate-risk PCa enrolled in AS who received MRI-ultrasound fusion surveillance biopsies. All completed prostate multiparametric MRI with 3-T and endorectal coil reviewed by radiologists selecting regions of interest, and all underwent MRI-ultrasound fusion biopsy with concurrent systematic biopsy., Outcome Measurements and Statistical Analysis: We report MRI-ultrasound fusion biopsy findings, rates of Gleason score (GS) upgrading to ≥3 + 4 (any upgrading) and to ≥4 + 3 (major upgrading), tumor involvement estimates using descriptive statistics, McNemar's test of symmetry, and multivariate logistic regression., Results and Limitations: Overall, 207 men underwent MRI-ultrasound fusion biopsy following radiologic suspicion on multiparametric MRI and met inclusion criteria. Agreement between systematic and MRI-ultrasound fusion biopsy GS was borderline statistically significant (p<0.047). In total, 83 men (40%) experienced any upgrading, including 49 (24%) on systematic sampling, 30 (14%) on MRI-targeted cores, and four (2%) on both. Among those with negative results on MRI-ultrasound fusion biopsy, seven (9%) exhibited major upgrading with systematic biopsy. MRI suspicion scores were high (4/5) for all but two patients with any upgrading and for all who experienced major upgrading. On multivariate analysis, older age was associated with higher odds of any upgrading for men with GS ≤3 + 3 on previous biopsy (odds ratio: 1.10; 95% confidence interval, 1.01-1.20; p=0.03)., Conclusions: MRI-ultrasound fusion biopsy resulted in upgrading otherwise undetected by systematic biopsy among a proportion of men with PCa managed with AS. However, upgrading also occurred in areas outside targeted biopsy, suggesting that systematic sampling should be offered to men with AS even with history of extended sextant biopsy., Patient Summary: This study examined the role of magnetic resonance imaging (MRI)-ultrasound fusion biopsy for men with prostate cancer managed with active surveillance (AS). In some patients, MRI-ultrasound fusion biopsy resulted in the detection of upgrade otherwise missed with systematic sampling. The findings indicate that MRI-ultrasound fusion biopsy may help with better sampling during AS., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: There is growing enthusiasm for the adoption of a novel grade grouping system to better represent Gleason scores., Objective: To evaluate the ability of prognostic Gleason grade groups to predict prostate cancer (PCa)-specific mortality (PCSM) and bone metastatic progression., Design, Setting, and Participants: We identified patients with PCa enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry across treatment strategies, including conservative and nondefinitive therapy., Outcome Measurements and Statistical Analysis: We examined the prognostic ability of Gleason grade groups to predict risk of PCSM and bone metastasis using the Kaplan-Meier method and unadjusted and adjusted Cox proportional hazards models., Results and Limitations: We identified 10529 men with PCa followed for a median of 81 mo (interquartile range 40-127), including 64% in group I (< 3 + 4); 17% in group II (3+4); 9% in group III (4+3); 6% in group IV (4+4); and 4% in group V (≥ 4 + 5). Relative to grade group I, the unadjusted risks of PCSM and bone metastasis were significantly associated with prognostic grade groupings for both biopsy and prostatectomy samples (all p<0.01). Pairwise comparisons within Gleason sums collapsed within grade group V were not significant; however, this analysis was limited by a small representation of men with Gleason pattern ≥ 4 + 5., Conclusions: The prognostic grade grouping system is associated with risk of PCSM and metastasis across management strategies, including definitive therapy, conservative management, and primary androgen deprivation., Patient Summary: A five-level reporting system for prostate cancer pathology is associated with the risk of late prostate cancer endpoints., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To perform patient-specific meta-analysis (MA) of two independent clinical validation studies of a 17-gene biopsy-based genomic assay as a predictor of favorable pathology at radical prostatectomy., Materials and Methods: Patient-specific MA was performed on data from 2 studies (732 patients) using the Genomic Prostate Score (GPS; scale 0-100) together with Cancer of the Prostate Risk Assessment (CAPRA) score or National Comprehensive Cancer Network (NCCN) risk group as predictors of the likelihood of favorable pathology (LFP). Risk profile curves associating GPS with LFP by CAPRA score and NCCN risk group were generated. Decision curves and receiver operating characteristic curves were calculated using patient-specific MA risk estimates., Results: Patient-specific MA-generated risk profiles ensure more precise estimates of LFP with narrower confidence intervals than either study alone. GPS added significant predictive value to each clinical classifier. A model utilizing GPS and CAPRA provided the most risk discrimination. In decision-curve analysis, greater net benefit was shown when combining GPS with each clinical classifier compared with the classifier alone. The area under the receiver operating characteristic curve improved from 0.68 to 0.73 by adding GPS to CAPRA, and 0.64 to 0.70 by adding GPS to NCCN risk group. The proportion of patients with LFP >80% increased from 11% using NCCN risk group alone to 23% using GPS with NCCN. Using GPS with CAPRA identified the highest proportion-31%-of patients with LFP >80%., Conclusion: Patient-specific MA provides more precise risk estimates that reflect the complete body of evidence. GPS adds predictive value to 3 widely used clinical classifiers, and identifies a larger proportion of low-risk patients than identified by clinical risk group alone., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Men on active surveillance (AS) face repeated biopsies. Most biopsy specimens will not show disease progression or change management. Such biopsies do not contribute to patient management and are potentially morbid and costly., Objective: To use a contemporary AS prospective trial to develop a tool to predict AS biopsy outcomes., Design, Setting, and Participants: Biopsy samples (median: 2; range: 2-9 per patient) from 859 men participating in the Canary Prostate Active Surveillance Study and with Gleason 6 prostate cancer (median follow-up: 35.8 mo; range: 3.0-148.7 mo) were analyzed., Outcome Measurements and Statistical Analysis: Logistic regression was used to predict progression, defined as an increase in Gleason score from ≤6 to ≥7 or increase in percentage of cores positive for cancer from <34% to ≥34%. Fivefold internal cross-validation was performed to evaluate the area under the receiver operating characteristic curve (AUC)., Results and Limitations: Statistically significant risk factors for progression on biopsy were prostate-specific antigen (odds ratio [OR]: 1.045; 95% confidence interval [CI], 1.028-1.063), percentage of cores positive for cancer on most recent biopsy (OR: 1.401; 95% CI, 1.301-1.508), and history of at least one prior negative biopsy (OR: 0.524; 95% CI, 0.417-0.659). A multivariable predictive model incorporating these factors plus age and number of months since last biopsy achieved an AUC of 72.4%., Conclusions: A combination of readily available clinical measures can stratify patients considering AS prostate biopsy. Risk of progression or upgrade can be estimated and incorporated into clinical practice., Patient Summary: The Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator, an online tool, can be used to guide patient decision making regarding follow-up prostate biopsy., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Few studies have reported on late declines and long-term health-related quality of life (HRQOL) after prostate cancer (PCa) treatment., Objective: We assessed long-term HRQOL following various treatments for localized PCa., Design, Setting, and Participants: This cohort study of HRQOL up to 10 yr after treatment used a prospectively accrued, nationwide PCa registry that collects longitudinal patient-reported HRQOL., Intervention: Various primary treatments for localized PCa., Outcome Measurements and Statistical Analysis: The Medical Outcomes Studies 36-item Short Form and the University of California, Los Angeles, Prostate Cancer Index characterized physical function, mental health, and sexual, urinary, and bowel function and bother. Repeated measures mixed-model analysis assessed change in HRQOL by treatment over time, and logistic regression was used to measure the likelihood of a clinically significant decline in HRQOL., Results and Limitations: Among 3294 men, 1139 (34%) underwent nerve-sparing radical prostatectomy (NSRP), 860 (26%) underwent non-NSRP, 684 (21%) underwent brachytherapy, 386 (12%) underwent external beam radiotherapy, 161 (5%) underwent primary androgen deprivation therapy, and 64 (2%) pursued watchful waiting/active surveillance. Median follow-up was 74 mo (interquartile range: 50-102). Most treatments resulted in early declines in HRQOL, with some recovery over the next 1-2 yr and a plateau in scores thereafter. Surgery had the largest impact on sexual function and bother and on urinary function, radiation had the strongest effect on bowel function, and androgen deprivation therapy had the strongest effect on physical function. The main limitation was attrition among the cohort., Conclusions: Although most men experience initial declines in HRQOL in the first 2 yr after treatment, there is little change from 3 to 10 yr and most differences between treatments attenuated over time., Patient Summary: Various treatments for prostate cancer result in a distinct constellation of adverse effects on health-related quality of life, which may have a long-term impact. These findings are helpful regarding shared decision making over choice of primary treatment., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Biopsy progression on active surveillance (AS) for prostate cancer (PCa) often reflects failure of the initial biopsy to detect cancer present at enrollment. The risks for delayed treatment among men who progress on AS are not well defined., Objective: To report outcomes for men who underwent surgery after AS compared to men who underwent immediate surgery and the influence of selection bias on this outcome., Design, Setting, and Participants: AS-eligible (ASE) men who underwent radical prostatectomy (RP) after a median of 20 mo of AS were compared to ASE men who underwent RP within 6 mo of diagnosis. A subset of men on AS who underwent RP after upgrade to Gleason 3+4 was compared to matched controls with similar pretreatment biopsy features who underwent immediate RP., Outcome Measurement and Statistical Analysis: Rates of adverse pathology (upstaging, positive surgical margin, or Gleason upgrading) were examined. Logistic regression was used to determine associations between treatment subgroup and adverse pathology., Results and Limitations: Of 157 ASE men who underwent delayed RP after AS, 54 were upgraded to Gleason 3+4 before surgery. ASE men who underwent immediate RP had lower probability of adverse pathology than ASE men who underwent delayed RP (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.21-0.55). The rate of adverse pathology did not differ between immediate and delayed RP patients matched for pretreatment characteristics (HR 0.79, 95% CI 0.27-2.28). The observational design of this study is its main limitation., Conclusions: When compared to men with similar pretreatment biopsy features, those who underwent delayed RP were not at higher risk of adverse pathology., Patient Summary: The oncologic safety of delayed treatment when indicated for men enrolled in active surveillance for prostate cancer is important. We found that men who underwent delayed surgery had similar outcomes to men who underwent immediate prostatectomy., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Men aged >65 yr are less likely to receive local therapy for prostate cancer (PCa), perhaps because of concerns about quality-of-life (QOL) outcomes., Objective: To describe QOL before and after PCa treatment in men of varying ages., Design, Setting, and Participants: Participants enrolled in CaPSURE who underwent radical prostatectomy, brachytherapy, external beam radiation, androgen deprivation therapy, or active surveillance for localized PCa., Outcome Measurements and Statistical Analysis: QOL changes over time were assessed among age groups using repeated-measures mixed models adjusted for race, year, clinical risk, treatment, comorbidities, and an age-time interaction term. Differences are reported as adjusted least-square means and percentage decline. Secondary analyses evaluated age and QOL for local (prostatectomy, radiation) compared to nonlocal treatment (hormonal, surveillance)., Results and Limitations: Older men had lower mean unadjusted pre- and post-treatment QOL scores for nearly all domains. Of the domains evaluated, adjusted mean sexual function, sexual bother, and urinary function showed greater declines from baseline to 2 yr. At 2 yr, more men <60 yr than those >70 yr experienced declines in urinary function (14% vs 9%) and sexual bother (39% vs 17%). Declines in these domains were also greater for local than for nonlocal treatment., Conclusions: Definitive treatment for localized disease should not be deferred for older men because of fears regarding QOL declines. Younger men should be counseled about potential post-treatment declines in QOL despite higher absolute QOL scores. Communicating these differences to patients will facilitate more appropriate treatment decision-making in men of all ages., Patient Summary: In this study we evaluated quality of life before and after treatment for localized prostate cancer in a diverse patient population. Declines in quality of life after treatment varied according to age and treatment. We conclude that counseling about quality of life will help patients of all ages to make more appropriate treatment decisions., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: African American (AA) men suffer a higher prostate cancer (PCa) burden than other groups., Objective: We aim to determine the impact of race on the risk of upgrading, upstaging, and positive surgical margins (PSM) at radical prostatectomy (RP) among men eligible for active surveillance., Design, Setting, and Participants: We studied men with low-risk PCa treated with RP at two centers. Low clinical risk was defined by National Comprehensive Cancer Network criteria. Outcome variables were upgrading, upstaging, and PSMs at surgery. Associations between race and the outcomes were evaluated with logistic regression adjusted for age, relationship status, diagnostic prostate-specific antigen level, percentage of positive biopsy cores, surgical approach, year of diagnosis, and clinical site., Results and Limitations: Of 9304 men diagnosed with PCa, 4231 were low risk and underwent RP within 1 yr. Men were categorized as AA (n=273; 6.5%), Caucasian (n=3771; 89.1%), or other racial/ethnic group (Other; n=187; 4.4%). AA men had a significantly younger mean age (58.7 yr; standard deviation: ±7.06), and fewer (85%) were married or had a partner. Upgrading (34%) and upstaging (13%) rates did not significantly differ among the groups. The PSM rate was significantly higher in AA men (31%) than in the Caucasian (21%) and Other (20%) groups (p<0.01). We found an association between race group and PSM rate (p<0.03), with higher odds of PSMs in AA men versus Caucasian men (odds ratio [OR]: 1.64; 95% confidence interval [CI], 1.08-2.47). No statistically significant associations between race and rates of upgrading and upstaging were found. This study was limited by the relatively low proportion of AA men in the cohort., Conclusions: Among clinically low-risk men who underwent RP, AA men had a higher likelihood of PSMs compared with Caucasian men. We did not find statistically significantly different rates of upgrading and upstaging between the race groups., Patient Summary: We analyzed two large groups of men with what appeared to be low-risk prostate cancer based on the initial biopsy findings. The likelihood of finding worse disease (higher grade or stage) at the time of surgery was similar across different racial groups., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Prostate tumor heterogeneity and biopsy undersampling pose challenges to accurate, individualized risk assessment for men with localized disease., Objective: To identify and validate a biopsy-based gene expression signature that predicts clinical recurrence, prostate cancer (PCa) death, and adverse pathology., Design, Setting, and Participants: Gene expression was quantified by reverse transcription-polymerase chain reaction for three studies-a discovery prostatectomy study (n=441), a biopsy study (n=167), and a prospectively designed, independent clinical validation study (n=395)-testing retrospectively collected needle biopsies from contemporary (1997-2011) patients with low to intermediate clinical risk who were candidates for active surveillance (AS)., Outcome Measures and Statistical Analysis: The main outcome measures defining aggressive PCa were clinical recurrence, PCa death, and adverse pathology at prostatectomy. Cox proportional hazards regression models were used to evaluate the association between gene expression and time to event end points. Results from the prostatectomy and biopsy studies were used to develop and lock a multigene-expression-based signature, called the Genomic Prostate Score (GPS); in the validation study, logistic regression was used to test the association between the GPS and pathologic stage and grade at prostatectomy. Decision-curve analysis and risk profiles were used together with clinical and pathologic characteristics to evaluate clinical utility., Results and Limitations: Of the 732 candidate genes analyzed, 288 (39%) were found to predict clinical recurrence despite heterogeneity and multifocality, and 198 (27%) were predictive of aggressive disease after adjustment for prostate-specific antigen, Gleason score, and clinical stage. Further analysis identified 17 genes representing multiple biological pathways that were combined into the GPS algorithm. In the validation study, GPS predicted high-grade (odds ratio [OR] per 20 GPS units: 2.3; 95% confidence interval [CI], 1.5-3.7; p<0.001) and high-stage (OR per 20 GPS units: 1.9; 95% CI, 1.3-3.0; p=0.003) at surgical pathology. GPS predicted high-grade and/or high-stage disease after controlling for established clinical factors (p<0.005) such as an OR of 2.1 (95% CI, 1.4-3.2) when adjusting for Cancer of the Prostate Risk Assessment score. A limitation of the validation study was the inclusion of men with low-volume intermediate-risk PCa (Gleason score 3+4), for whom some providers would not consider AS., Conclusions: Genes representing multiple biological pathways discriminate PCa aggressiveness in biopsy tissue despite tumor heterogeneity, multifocality, and limited sampling at time of biopsy. The biopsy-based 17-gene GPS improves prediction of the presence or absence of adverse pathology and may help men with PCa make more informed decisions between AS and immediate treatment., Patient Summary: Prostate cancer (PCa) is often present in multiple locations within the prostate and has variable characteristics. We identified genes with expression associated with aggressive PCa to develop a biopsy-based, multigene signature, the Genomic Prostate Score (GPS). GPS was validated for its ability to predict men who have high-grade or high-stage PCa at diagnosis and may help men diagnosed with PCa decide between active surveillance and immediate definitive treatment., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: A better understanding of the independent predictors of disease progression for prostate cancer (PCa) patients is needed to improve the selection of ideal candidates for active surveillance (AS) and refine the surveillance regimen., Objective: To examine the association of clinical and pathologic characteristics, as well as patterns of surveillance biopsy results, with the risk of progression in men on AS., Design, Setting, and Participants: The retrospective study consisted of men with PCa who were on AS in the prospectively maintained University of California, San Francisco, institutional database from 1996 to 2011. Strict criteria for AS were prostate-specific antigen (PSA) ≤10 ng/ml, clinical stage T1 or T2, biopsy Gleason grade 6, <33% positive cores, and <50% tumor in any single core. Men were then categorized based on results of their confirmatory surveillance biopsy., Outcome Measurements and Statistical Analysis: Disease progression was defined as an increase in Gleason grade and/or biopsy volume beyond prespecified cut points. Serial biopsy patterns over the course of surveillance were stratified by confirmatory biopsy findings: negative, positive without progression, and positive with progression. Multivariable logistic regression models were used to evaluate predictors of progression during AS., Results and Limitations: A total of 465 men met inclusion criteria (median follow-up: 51 mo). Of these men, 23% had negative confirmatory biopsies. Only 3% of the men (1 of 30) progressed by the fourth surveillance biopsy following a biopsy pattern of negative confirmatory and negative third biopsy findings. Negative confirmatory biopsy and lower PSA density (both p<0.01) were independently associated with decreased odds of biopsy progression at 3 yr. The main limitation of this study is its observational nature., Conclusions: The patterns of surveillance biopsy results yield additional important information in AS. Negative confirmatory biopsy and PSA density are important independent predictors of progression on AS and may be used to better counsel men opting for AS., (Copyright © 2013. Published by Elsevier B.V.)

Background: The University of California, San Francisco, Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score uses pathologic data from radical prostatectomy (RP) to predict prostate cancer recurrence and mortality. However, this clinical tool has never been validated externally., Objective: To validate CAPRA-S in a large, multi-institutional, external database., Design, Setting, and Participants: The Shared Equal Access Regional Cancer Hospital (SEARCH) database consists of 2892 men who underwent RP from 2001 to 2011. With a median follow-up of 58 mo, 2670 men (92%) had complete data to calculate a CAPRA-S score., Intervention: RP., Outcome Measurements and Statistical Analysis: The main outcome was biochemical recurrence. Performance of CAPRA-S in detecting recurrence was assessed and compared with a validated postoperative nomogram by concordance index (c-index), calibration plots, and decision curve analysis. Prediction of cancer-specific mortality was assessed by Kaplan-Meier analysis and the c-index., Results and Limitations: The mean age was 62 yr (standard deviation: 6.3), and 34.3% of men had recurrence. The 5-yr progression-free probability for those patients with a CAPRA-S score of 0-2, 3-5, and 6-10 (defining low, intermediate, and high risk) was 72%, 39%, and 17%, respectively. The CAPRA-S c-index was 0.73 in this validation set, compared with a c-index of 0.72 for the Stephenson nomogram. Although CAPRA-S was optimistic in predicting the likelihood of being free of recurrence at 5 yr, it outperformed the Stephenson nomogram on both calibration plots and decision curve analysis. The c-index for predicting cancer-specific mortality was 0.85, with the caveat that this number is based on only 61 events., Conclusions: In this external validation, the CAPRA-S score predicted recurrence and mortality after RP with a c-index >0.70. The score is an effective prognostic tool that may aid in determining the need for adjuvant therapy., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Although the value of prostate-specific antigen (PSA) velocity or doubling time has never been seriously questioned for aiding the clinical management of recurrent or advanced cancer, there has historically been considerable uncertainty about PSA kinetics for decisions about biopsy and initial treatment. Recent studies, including analyses of cohorts from all the major randomized trials of localized prostate cancer, have failed to find any evidence that PSA velocity and application of PSA cutpoints are of benefit in this setting. Given current data on PSA velocity and doubling time, we propose the following "take home" messages for the practicing urologist: (1) High PSA velocity is not an indication for biopsy; (2) for men with a low total PSA but a high PSA velocity, consideration should be given to having PSA taken at a shorter interval; (3) men with an indication for biopsy should be biopsied irrespective of PSA velocity; (4) changes in PSA after negative biopsy findings do not determine the need for repeat biopsy; (5) monitoring PSA over time can aid judgment in decisions about biopsy, as informed by the clinical context; (6) PSA velocity is uninformative of risk at diagnosis; (7) high PSA velocity is not an indication for treatment in men on active surveillance; (8) PSA velocity at the time of recurrence should be entered into prediction models (or "nomograms") to aid patient counseling; (9) PSA changes after treatment for advanced disease can help indicate therapeutic response., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To describe the effect of serial prostate biopsy on lower urinary tract symptoms (LUTS) in men who undergo active surveillance (AS) at a large academic institution., Materials and Methods: This is a retrospective study of men enrolled in AS for ≥6 months who underwent ≥1 biopsy and completed ≥1 International Prostate Symptom Score (IPSS) questionnaire. In additional to total IPSS, we report the mean difference between the first and last questionnaires for patients who completed ≥2 questionnaires. Multivariate models, adjusting for disease features, age, race, prostate volume and baseline, or incident benign prostatic hypertrophy (BPH), were used to assess relationships between IPSS and total biopsy exposure., Results: Four hundred eighty-two men were eligible, and 291 completed ≥2 IPSS questionnaires. Overall, mean (standard deviation) age was 61.7 (7.8) years, and median prostate volume (interquartile range) was 42 (34-61) mL. At baseline, 11% provided history of BPH. Among men who completed multiple questionnaires, 25% experienced clinically significant worsening (IPSS increase ≥4 points). In regression model, total IPSS was not significantly associated with greater biopsy exposure (P = .25). IPSS change from initial and the latest questionnaire was not significantly associated with initial or interval biopsy exposure in an adjusted longitudinal model (P = .64 and .50, respectively), but a trend was observed with greater age decade (+4.07 points, 95% CI -0.30 to 8.4; P = .07)., Conclusion: Repeated prostate biopsy does not appear to independently pose additional risk of LUTS in an AS population. In unadjusted analyses, greater biopsy exposure is a surrogate for increasing follow-up time, age, and BPH risk, and thus, risk of LUTS onset and progression., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To determine whether the presence of benign glandular tissue at the radical prostatectomy surgical margin is associated with technique (open radical prostatectomy [ORP] or robotic-assisted laparoscopic radical prostatectomy [RALRP]) and if benign glandular tissue increases the risk of biochemical recurrence., Methods: Surgical specimens from men with clinical T1-T2 disease who underwent radical prostatectomy (RP) between 2004 and 2010 were re-reviewed by a single uropathologist, examining all sections from the prostate apex and base for the presence of benign glandular tissue and tumor at the margin. Regression analysis was used to examine associations of benign glandular tissue with surgical approach and biochemical recurrence., Results: Of 934 cases reviewed, 431 were managed by ORP and 503 by RALRP with a median follow-up of 49 and 28 months, respectively. Overall, benign glandular tissue was found in 274 cases (29%): 98 (36%) at the apex, 138 (50%) at the base, and 38 (14%) at both. Compared with those who underwent ORP, patients who underwent RALRP had 3-fold greater odds of benign glandular tissue at the margin (P <.01), including significantly greater number of cases with benign glandular tissue at the base (P <.01). However, recurrence-free survival rates were similar between patients with and without benign glands at the surgical margin (BGM) regardless of surgical approach and across all clinical risk groups (log-rank P = .20)., Conclusion: Patients undergoing RALRP were more likely to have benign glandular tissue at the surgical margin. However, the presence of benign glandular tissue was not an independent risk factor for biochemical recurrence., (Published by Elsevier Inc.)

Objective: To describe how demographic and diagnostic characteristics of men with prostate cancer in the United States have changed since 1999, using data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry., Methods: The medical records of patients enrolled in CaPSURE between 1999 and 2011 were evaluated. Baseline demographics, disease features, and imaging use were assessed. Mantel-Haenszel chi-square was used to test for trends across diagnostic years., Results: Between 1999 and 2011, a total of 9572 patients were diagnosed with prostate cancer and enrolled in CaPSURE at community (36), academic (3), and Veteran's Affairs (4) hospitals. Over the study period, mean age at diagnosis decreased, P <.01. In 2008-2011, a significant increase in diagnostic Gleason 7 or higher was observed relative to 1999-2001 (50% vs 36%, P <.01), congruent with recent guideline modifications of the Gleason classification system. An increase in the mean number of diagnostic biopsy cores (13.3 vs 8.3, P <.01) was also observed. A significant decrease in use of any imaging modality was seen (19% vs 45%, P <.01). Average pretreatment urinary and bowel function scores did not change, although there were significant increases in sexual function observed overall (P <.01)., Conclusion: In the United States, several trends in the demographics and disease profile of men with newly diagnosed prostate cancer were observed over the past 12 years. Decreased imaging use and increased number of cores taken during diagnostic biopsy are in line with national urologic guidelines on prostate cancer diagnosis and management., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: ImmunoCyt/uCyt (Scimedx, Denville, NJ, USA) is a well-established urinary marker assay with high sensitivity for the diagnosis of urothelial carcinoma (UC) and can function as a second-level test to arbitrate atypical reads of urine cytology., Objective: To determine the utility of uCyt as a reflex test for atypical cytology in patients undergoing a hematuria evaluation or surveillance with a history of UC., Design, Setting, and Participants: The uCyt assay was performed as a second-level reflex test on all voided urine cytology tests read as atypical between January 2007 and June 2010 in an academic medical center. Records were retrospectively reviewed. Three hundred twenty-four patients underwent a total of 506 uCyt assays., Intervention: Reflex uCyt assay on atypical urine cytology., Outcome Measurements and Statistical Analysis: The uCyt test characteristics include sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV)., Results and Limitations: Reflex uCyt was performed on 506 atypical voided urine samples that were followed by cystoscopy within 90 d. Reflex uCyt with a history of UC showed a sensitivity of 73%, a specificity of 49%, and an NPV of 80%. In those with a history of low-grade UC, reflex uCyt had a sensitivity of 75%, a specificity of 50%, and an NPV of 82%, while in those with a history of high-grade UC, it had a sensitivity of 74%, a specificity of 44%, and an NPV of 79%. Without prior history of UC, reflex uCyt had a sensitivity of 85%, a specificity of 59%, and an NPV of 94%. This study's limitations include its retrospective design and interobserver variability inherent to cystoscopy, which was used as the reference test., Conclusions: When used as a reflex test on atypical urine cytology, negative uCyt may predict a negative cystoscopy in select patients and modulate the urgency and further work-up in those with no prior history or low-grade disease., (Published by Elsevier B.V.)

Context: Prostate cancer (PCa) remains an increasingly common malignancy worldwide. The optimal management of clinically localized, early-stage disease remains unknown, and profound quality of life issues surround PCa interventions., Objective: To systematically summarize the current literature on the management of low-risk PCa with active surveillance (AS), with a focus on patient selection, outcomes, and future research needs., Evidence Acquisition: A comprehensive search of the PubMed and Embase databases from 1980 to 2011 was performed to identify studies pertaining to AS for PCa. The search terms used included prostate cancer and active surveillance or conservative management or watchful waiting or expectant management. Selected studies for outcomes analysis had to provide a comprehensive description of entry characteristics, criteria for surveillance, and indicators for further intervention., Evidence Synthesis: Data from seven large AS series were reviewed. Inclusion criteria for surveillance vary among studies, and eligibility therefore varies considerably (4-82%). PCa-specific mortality remains low (0-1%), with the longest published median follow-up being 6.8 yr. Up to one-third of patients receive secondary therapy after a median of about 2.5 yr of surveillance. Surveillance protocols and triggers for intervention vary among institutions. Most patients are treated for histologic reclassification (27-100%) or prostate-specific antigen doubling time <3 yr (13-48%), while 7-13% are treated with no evidence of progression. Repeat prostate biopsy with a minimum of 12 cores appears to be important for monitoring patients for changes in tumor histology over time., Conclusions: AS for PCa offers an opportunity to limit intervention to patients who will likely benefit the most from radical treatment. This approach confers a low risk of disease-specific mortality in the short to intermediate term. An early, confirmatory biopsy is essential for limiting the risk of underestimating tumor grade and amount., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)