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Purpose/objective(s): Occult non-localized disease (N1 or M1) at the time of definitive treatment of high-risk prostate cancer (HR-PCa) underlies most treatment failures. We recently developed a nomogram tuned to the identification of non-localized disease on prostate specific membrane antigen PET/CT (PSMA PET/CT) in patients with cN0M0 HR-PCa by conventional imaging, which incorporates iPSA, percent positive core on biopsy, Gleason Grade and cT stage. We systematically compared the prognostic performance of the PSMA nomogram against other validated risk stratification tools for HR-PCa.Materials/methods: We identified 5275 men from a multi-institutional database treated with radical prostatectomy (55%), external beam radiation therapy (EBRT, 31%), or EBRT and brachytherapy (14%). The prognostic performance of the PSMA nomogram was compared against the STAR-CAP score, the Cancer of the Prostate Risk Assessment (CAPRA) score, Cambridge Prognostic Groups (CPG) risk group, and Memorial Sloan Kettering Cancer Center (MSKCC) nomogram of 5-year recurrence probability. Accuracy was determined for 5- and 10-year distant metastasis (DM) and prostate cancer specific mortality (PCSM) using the concordance index (C-index).Results: Median follow-up was 50.3 months (interquartile range 28.1-84.5 months). Overall, 16.1% developed DM, and 4.6% died from PCa. C-indices for the PSMA nomogram were 0.67 and 0.67 for 5- and 10-year DM, and 0.69 and 0.73 for 5- and 10-year PCSM, respectively. The PSMA nomogram outperformed CAPRA, CPG, and MSKCC for all endpoints, outperformed STAR-CAP for 10-year DM, and performed similarly to STAR-CAP for all other endpoints (see Table). The comparative performance between the tools was generally maintained at different follow-up times and in subgroup analyses stratified by primary treatment modalities.Conclusion: A nomogram tuned to the detection of non-localized disease on PSMA/PET in HR-PCa patients is significantly prognostic of important clinical endpoints, with performance comparable to STAR-CAP and superior to other tools. These data strongly suggest that upstaging based on PSMA PET/CT provides clinically relevant information and warrant prospective validation. [ABSTRACT FROM AUTHOR]

Objective: To determine if accurate documentation of bladder cancer risk was associated with a clinician surveillance recommendation that is concordant with AUA guidelines among patients with nonmuscle invasive bladder cancer (NMIBC)., Methods: We prospectively collected data from cystoscopy encounter notes from four Department of Veterans Affairs (VA) sites to ascertain whether they included accurate documentation of bladder cancer risk and a recommendation for a guideline-concordant surveillance interval. Accurate documentation was a clinician-recorded risk classification matching a gold standard assigned by the research team. Clinician recommendations were guideline-concordant if the clinician recorded a surveillance interval that was in line with the AUA guideline., Results: Among 296 encounters, 75 were for low-, 98 for intermediate-, and 123 for high-risk NMIBC. 52% of encounters had accurate documentation of NMIBC risk. Accurate documentation of risk was less common among encounters for low-risk bladder cancer (36% vs 52% for intermediate- and 62% for high-risk, P < .05). Guideline-concordant surveillance recommendations were also less common in patients with low-risk bladder cancer (67% vs 89% for intermediate- and 94% for high-risk, P < .05). Accurate documentation was associated with a 29% and 15% increase in guideline-concordant surveillance recommendations for low- and intermediate-risk disease, respectively (P < .05)., Conclusion: Accurate risk documentation was associated with more guideline-concordant surveillance recommendations among low- and intermediate-risk patients. Implementation strategies facilitating assessment and documentation of risk may be useful to reduce overuse of surveillance in this group and to prevent unnecessary cost, anxiety, and procedural harms., Competing Interests: Declaration of Competing Interest Florian R. Schroeck reports research funding from Pacific Edge, Ltd., (Published by Elsevier Inc.)

Importance: Understanding variation in patient-reported outcomes following radical prostatectomy may inform efforts to reduce morbidity after this procedure., Objective: To describe patient-reported urinary outcomes following radical prostatectomy in the diverse practice settings of a statewide quality improvement program and to explore whether surgeon-specific variations in observed outcomes persist after accounting for patient-level factors., Design, Setting, and Participants: This prospective population-based cohort study included 4582 men in the Michigan Urological Surgery Improvement Collaborative who underwent radical prostatectomy as primary management of localized prostate cancer between April 2014 and July 2018 and who agreed to complete validated questionnaires prior to surgery and at 3, 6, and 12 months after surgery. Data were analyzed from 2019 to June 2019., Exposures: Radical prostatectomy., Main Outcomes and Measures: Patient- and surgeon-level analyses of patient-reported urinary function 3 months after radical prostatectomy. Outcomes were measured using validated questionnaires with results standardized using previously published methods. Urinary function survey scores are reported on a scale from 0 to 100 with good function established as a score of 74 or higher., Results: For the 4582 men undergoing radical prostatectomy within the Michigan Urological Surgery Improvement Collaborative who agreed to complete surveys, mean (SD) age was 63.3 (7.1) years. Survey response rates varied: 3791 of 4582 (83%) responded at baseline, 3282 of 4137 (79%) at 3 months, 2975 of 3770 (79%) at 6 months, and 2213 of 2882 (77%) at 12 months. Mean (SD) urinary function scores were 88.5 (14.3) at baseline, 53.6 (27.5) at 3 months, 68.0 (25.1) at 6 months, and 73.7 (23.0) at 12 months. Regression analysis demonstrated that older age, lower baseline urinary function score, body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 or higher, clinical stage T2 or higher, and lack of bilateral nerve-sparing surgery were associated with a lower probability of reporting good urinary function 3 months after surgery. When evaluating patients with good baseline function, the rate at which individual surgeons' patients reported good urinary function 3 months after surgery varied broadly (0% to 54.5%; P < .001). Patients receiving surgery from top-performing surgeons were more likely to report good 3-month function. This finding persisted after accounting for patient risk factors., Conclusions and Relevance: In this study, patient- and surgeon-level urinary outcomes following prostatectomy varied substantially. Documenting surgeon-specific variations after accounting for patient factors may facilitate identification of surgical factors associated with superior outcomes.

Objective: To determine whether time from diagnosis to treatment impacted outcomes in a multicentre cohort of high- and very-high-risk (VHR) patients with prostate cancer undergoing radical prostatectomy (RP)., Patients and Methods: In all, 1392 patients from three tertiary centres who underwent RP for either high-risk or VHR disease, from 2005 to 2015, were identified. The cohort was divided into tertiles based on time from diagnostic biopsy to RP. Cumulative incidence of biochemical recurrence (BCR), metastasis, and prostate cancer-specific mortality (PCSM) were calculated for each tertile. The Kaplan-Meier method was used to evaluate for differences in all-cause mortality (ACM) amongst tertiles. Competing risks regression models, as well as Cox proportional hazards regression models, were fitted to assess the association between time-to-event outcomes and patient characteristics., Results: The median (interquartile range [IQR]) time from biopsy to RP was 68 (50-94) days. The median (IQR) follow-up was 31 (12.1-55.7) months. The cumulative incidence of BCR (P = 0.14), metastasis (P = 0.15), and PCSM (P = 0.69) did not differ amongst time-to-treatment tertiles of VHR patients. Also, Kaplan-Meier estimates of ACM (P = 0.53) did not differ amongst time-to-treatment tertiles. Similarly, BCR, metastasis, PCSM, and ACM did not significantly differ amongst time-to-treatment tertiles in multivariable modelling., Conclusion: In this pooled meta-dataset of patients with high-risk or VHR prostate cancer, time from diagnosis to RP did not appear to significantly contribute to differences in clinical outcomes. This finding supports the safety of enrollment of such patients into neoadjuvant clinical trials., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Background: Prostate cancer remains the second leading cause of cancer related death in men. Immune check point blocking antibodies have revolutionized treatment of multiple solid tumors, but results in prostate cancer remain marginal. Previous reports have suggested that local therapies, in particular cryoablation might increase tumor immunogenicity. In this work, we examine potential synergism between tumor cryoabalation and check point blocking antibodies., Methods: FVB/NJ mice were injected subcutaneously into each flank with either 1 × 10 6 or 0.2 × 10 6 isogenic hormone sensitive Myc-Cap cells to establish synchronous grafts. Mice were treated with four intraperitoneal injections of anti-PD-1 (10 mg/kg), anti-CTLA-4 (1 mg/kg), or isotype control antibody with or without adjuvant cryoablation of the larger tumor graft and with or without neo-adjuvant androgen deprivation with degarelix (ADT). Mouse survival and growth rates of tumor grafts were measured. The immune dependency of observed oncological effects was evaluated by T cell depletion experiments., Results: Treatment with anti-CTLA-4 antibody and cryoablation delayed the growth of the distant tumor by 14.8 days (p = 0.0006) and decreased the mortality rate by factor of 4 (p = 0.0003) when compared to cryoablation alone. This synergy was found to be dependent on CD3 +  and CD8 +  cells. Combining PD-1 blockade with cryoablation did not show a benefit over use of either treatment alone. Addition of ADT to anti-PD1 therapy and cryoablation doubled the time to accelerated growth in the untreated tumors (p = 0.0021) and extended survival when compared to cryoablation combined with ADT in 25% of the mice. Effects of combining anti-PD1 with ADT and cryoablation on mouse survival were obviated by T cell depletion., Conclusion: Trimodal therapy consisting of androgen deprivation, cryoablation and PD-1 blockade, as well as the combination of cryoablation and low dose anti-CTLA-4 blockade showed that local therapies with cryoablation could be considered to augment the effects of checkpoint blockade in prostate cancer.

Purpose: We determined how frequently histological Gleason 3 + 3 = 6 tumors have the molecular characteristics of disease with metastatic potential., Materials and Methods: We analyzed prostatectomy tissue from 337 patients with Gleason 3 + 3 disease. All tissue was re-reviewed in blinded fashion by genitourinary pathologists using 2005 ISUP (International Society of Urological Pathology) Gleason grading criteria. A previously validated Decipher® metastasis signature was calculated in each case based on a locked model. To compare patient characteristics across pathological Gleason score categories we used the Fisher exact test or the ANOVA F test. The distribution of Decipher scores among different clinicopathological groups was compared with the Wilcoxon rank sum test. The association of Decipher score with adverse pathology features was examined using logistic regression models. The significance level of all statistical tests was 0.05., Results: Of men with Gleason 3 + 3 = 6 disease only 269 (80%) had a low Decipher score with intermediate and high scores in 43 (13%) and 25 (7%), respectively. Decipher scores were significantly higher among pathological Gleason 3 + 3 = 6 specimens from cases with adverse pathological features such as extraprostatic extension, seminal vesicle involvement or positive margins (p <0.001). The median Decipher score in patients with margin negative pT2 disease was 0.23 (IQR 0.09-0.42) compared to 0.30 (IQR 0.17-0.42) in patients with pT3 disease or positive margins (p = 0.005)., Conclusions: Using a robust and validated prognostic signature we found that a small but not insignificant proportion of histological Gleason 6 tumors harbored molecular characteristics of aggressive cancer. Molecular profiling of such tumors at diagnosis may better select patients for active surveillance at diagnosis and trigger appropriate intervention during followup., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

In 2005, the International Society of Urological Pathology (ISUP) introduced several modifications to the original Gleason system that were intended to enhance the prognostic power of Gleason score (GS). The objective of this study was to clinically validate the 2005 ISUP Gleason grading system for its ability to detect metastasis. We queried our institutional RP database for men with NCCN clinically localized intermediate to high-risk disease undergoing radical prostatectomy (RP) between 1992 and 2010 with no additional treatment until the time of metastatic progression. A case-cohort design was utilized. A total of 333 available RP samples were re-reviewed and GS was reassigned per the 2005 ISUP Gleason system. Cumulative incidence of metastasis was 0%, 8.4%, 24.5% and 44.4% among specimens that were downgraded, unchanged, had one point GS increase and two point GS increase, respectively. The hazard ratio for metastasis raised in GS 8 and 9 compared to GS 7 from 2.77 and 5.91 to 3.49 and 9.31, respectively. The survival c-index of GS increased from 0.70 to 0.80 when samples were re-graded at 5 years post RP. The c-index of the reassigned GS was higher than the original GS (0.77 vs 0.64) for predicting PCSM at 10 years post RP. The regraded GS improved the prediction of metastasis and PCSM. This validates the updated Gleason grading system using an unambiguous clinical endpoint and highlights the need for reassignment of Gleason grading according to 2005 ISUP system when considering comparisons of novel biomarkers to clinicopathological variables in archival cohorts.

Purpose of Review: To determine whether alpha-blockers, commonly used for the treatment of benign prostatic hyperplasia, are associated with prostate cancer risk., Recent Findings: Alpha-blockers have been associated with a reduced risk of prostate cancer aggressiveness in some observational studies and an increased risk in other studies. However, this relationship is complex as different alpha-blockers have divergent effects in laboratory studies and there are many confounders in daily practice such as differential screening practices., Summary: Both benign prostatic hyperplasia and prostate cancer are common conditions in the aging male population, such that an interaction between alpha-blockers and prostate cancer risk is clinically relevant. Prospective evidence is necessary to establish a definitive link.

The discovery of prostate-specific antigen (PSA) as a biomarker represented a major discovery in the early diagnosis and monitoring of prostate cancer. However, the use of PSA is limited by the lack of specificity and an inability to differentiate indolent from life-threatening disease reliably at the time of diagnosis. A multitude of studies have aimed to improve the performance of PSA as well as identify additional biomarkers. The purpose of this study is to review available data on prostate cancer biomarkers for prostate cancer screening and prognostication, including prostatic acid phosphatase, PSA, PSA derivatives (PSA density, free PSA, pro PSA, and PSA kinetics), PCA3, GSTP1, AMACR, and other newly emerging molecular and genetic markers.

The androgen receptor (AR) is involved in the initiation and progression of prostate cancer and its transition to androgen independence. Genetic variation in AR may contribute to disease risk and has been studied for a polymorphic N-terminal glutamine (Q) tract that shows population heterogeneity. While the length of this tract is known to affect AR in vitro, association with disease is complicated by genetic and environmental factors that have led to discordant epidemiological findings. To clarify the effect of Q tract polymorphism on prostate cancer, we created mice bearing humanized AR genes (h/mAr) varying in Q tract length. ARs with short Q tracts (12Q), which are transcriptionally more active, induce earlier disease in the transgene-induced TRAMP prostate cancer model than alleles with median (21Q) or long (48Q) tracts. Disease length varies within each genotype, with greater differentiation and AR expression in slower growing tumors. Remarkably, following androgen ablation, Q tract length has effects that are also allele-dependent and in directions opposite to those in hormone intact mice. Differences in AR activity conferred by Q tract length thus appear to direct distinct pathways of androgen-independent as well as androgen-dependent progression, and highlight substantial risk that may be associated with alterations in the androgen axis. This AR allelic series in humanized mice provides an experimental paradigm to dissect the role of AR in prostate cancer initiation and progression, to model response to treatment and to test therapies targeted specifically to the human AR.