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The prognostic value for metastasis of the cell-cycle progression score and phosphatase and tensin homolog haven't been evaluated jointly in contemporary men with exclusively intermediate- or high-risk prostate cancer. We evaluated associations of cell-cycle progression and phosphatase and tensin homolog with metastasis-free survival in contemporary intermediate/high-risk prostate cancer patients overall, and intermediate/high-risk men receiving salvage radiotherapy.In a case-cohort of 209 prostatectomy patients with intermediate/high-risk prostate cancer, and a cohort of 172 such men who received salvage radiotherapy, cell-cycle progression score was calculated from RNA expression, and phosphatase and tensin homolog was analyzed by immunohistochemistry. Proportional hazards regression, weighted for case-cohort design or unweighted for the salvage radiotherapy cohort, was used to evaluate associations of cell-cycle progression, phosphatase and tensin homolog with metastasis-free survival. Improvement in model discrimination was evaluated with the concordance index.In the case-cohort 41 men had metastasis, and 17 developed metastasis in the salvage radiotherapy cohort, at median follow-up of 3 and 4 years, respectively. For both case-cohort and salvage radiotherapy cohort, cell-cycle progression was independently associated with metastasis-free survival after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical: hazard ratio (95% confidence interval) = 3.11 (1.70-5.69) and 1.85 (1.19-2.85), respectively. Adding cell-cycle progression to Cancer of the Prostate Risk Assessment Post-Surgical increased the concordance index from 0.861 to 0.899 (case-cohort), and 0.745 to 0.819 (salvage radiotherapy cohort). Although statistically significant in univariate analyses, phosphatase and tensin homolog was no longer significant after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical. Analysis of interaction with National Comprehensive Cancer Network risk group showed that cell-cycle progression had the strongest effect among unfavorable intermediate-risk men.In the first study to evaluate metastasis risk associated with cell-cycle progression and phosphatase and tensin homolog in exclusively intermediate/high-risk prostate cancer, and in such men with salvage radiotherapy, cell-cycle progression but not phosphatase and tensin homolog was associated with significantly increased 2- to 3-fold risk of metastasis after Cancer of the Prostate Risk Assessment Post-Surgical adjustment.

Odds ratios (OR) and 95% confidence intervals (CI) for the association between body mass index (BMI) category and telomere variability* in prostate cancer cells overall and stratified by prostate cancer aggressiveness at surgery among men surgically treated for prostate cancer at Johns Hopkins Hospital, 1992 to 2016.

In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4′,6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m2) and categorize men as normal (T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07–8.75; Ptrend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis.Prevention Relevance:This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.

PDF file - 69KB, Correlation of PTEN protein status by immunohistochemistry (IHC) with PTEN genomic status by sequencing in NCI-60 cell line panel.

Supplementary Table S11: Differentially expressed genes comparing prostate tumors from nicotine-treated TRAMP mice with tumors from untreated mice (reference).

Supplementary Table 9: Genes differently expressed between nicotine-treated and untreated 22Rv1 cells.

Supplementary Table S6: Increased expression of genes regulating synaptic signal transduction in the cancerous prostate of nicotine�treated TRAMP mice.

Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer–prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. Cancer Res; 76(5); 1055–65. ©2015 AACR.

Supplementary Table S1: Clinical characteristics of the study population by smoking status. Supplementary Table S2: Immunoglobulin expression in prostate tumors by smoking status of the patients. Supplementary Table S3: Genes differently expressed between current and never smokers in prostate tumors. Supplementary Table S4: Genes differently expressed between current and never/past smokers in 67 prostate tumors.

Purpose: Analytically validated assays to interrogate biomarker status in clinical samples are crucial for personalized medicine. PTEN is a tumor suppressor commonly inactivated in prostate cancer that has been mechanistically linked to disease aggressiveness. Though deletion of PTEN, as detected by cumbersome FISH spot counting assays, is associated with poor prognosis, few studies have validated immunohistochemistry (IHC) assays to determine whether loss of PTEN protein is associated with unfavorable disease.Experimental Design: PTEN IHC was validated by employing formalin fixed and paraffin-embedded isogenic human cell lines containing or lacking intact PTEN alleles. PTEN IHC was 100% sensitive and 97.8% specific for detecting genomic alterations in 58 additional cell lines. PTEN protein loss was then assessed on 376 prostate tumor samples, and PTEN FISH or high resolution single nucleotide polymorphism microarray analysis was done on a subset of these cases.Results: PTEN protein loss, as assessed as a dichotomous IHC variable, was highly reproducible, correlated strongly with adverse pathologic features (e.g., Gleason score and pathologic stage), detected between 75% and 86% of cases with PTEN genomic loss, and was found at times in the absence of apparent genomic loss. In a cohort of 217 high risk surgically treated patients, PTEN protein loss was associated with decreased time to metastasis.Conclusion: These studies validate a simple method to interrogate PTEN status in clinical specimens and support the utility of this test in future multicenter studies, clinical trials, and ultimately perhaps for routine clinical care. Clin Cancer Res; 17(20); 6563–73. ©2011 AACR.

Supplemetary Table 5: Genes differently expressed between current and never and between current and past/never smokers in the combined cohort of 67 prostate tumors

Supplementary Table 7: Genes differently expressed between current and never smokers in microdissected prostate tumors.

Supplementary Figure S1: Weight curves for untreated TRAMP mice and TRAMP mice treated with nicotine for 80 days. Supplementary Figure S2: Ig lambda� and Ig kappa�positive B lymphocytes in cancerous prostate tissue by in�situ hybridization. Supplementary Figure S3: qRT�PCR validation of six genes up�regulated among current smokers. Supplementary Figure S4: Analysis of prostate tumors using Bioconductor limma R. Supplementary Figure S5: Gene Set Enrichment Analysis (GSEA) highlighting common features between smoking�related gene signatures in prostate tumors, nicotine�induced gene signatures in human prostate cancer cells, and gene signatures archived in the GSEA database. Supplementary Figure S6: Expression of various nicotinic acetylcholine receptor (AChR) subunits in human prostate cancer cell lines, prostate tumors, and adjacent non�tumor prostate tissues. Supplementary Figure S7: Nicotine�mediated Akt activation in human immortalized prostate epithelial cells and prostate cancer cell lines. Supplementary Figure S8: Effect of nicotine on the mobility of human prostate cancer cell lines. Supplementary Figure S9: Nicotine enhances cell surface integrin expression and extracellular matrix binding (ECM) of 22Rv1 human prostate cancer cells. Supplementary Figure S10: Nicotine enhances proliferation of RWPE�1 in complete K�SFM medium but not in K�SFM medium without EGF and bovine pituitary extract. Supplementary Figure S11: Nicotine did not enhance proliferation of 22Rv1 and PC�3 human prostate cancer cells. Supplementary Figure S12: Lymphotoxin�β plasma levels in prostate cancer patients (Case) and population�based controls (Control) by smoking status.

Supplemetary Table 8: Genes differently expressed between current and never in microdissected tumors using the Bioconductor limma R package.

Supplementary Tables 1-3, Figures 1-7 from Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate Cancer

PurposeCurrent biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision-making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells – the telomere biomarker – is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators.Experimental DesignWe optimized our method allowing for semi-automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in tissue microarrays from five cohort studies of men surgically treated for clinically localized disease (N=2,255). We estimated the relative risk (RR) of progression to metastasis (N=311) and prostate cancer death (N=85) using models appropriate to each study’s design adjusting for age, prostatectomy stage, and tumor grade, which then we meta-analyzed using inverse variance weights.ResultsCompared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer-associated stromal cells, men with the combination of more variable and shorter telomere length, had 3.76-times the risk of prostate cancer death (95% CI 1.37-10.3; p=0.01) and had 2.23-times the risk of progression to metastasis (95% CI 0.99-5.02, P=0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (Grade Groups 2/3: RR=9.18, 95% CI 1.14- 74.0, p=0.037) and with PTEN intact tumors (RR=6.74, 95% CI 1.46-37.6, p=0.015).ConclusionsThe telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically-treated men.Translational RelevanceCurrent prognostic biomarkers in localized prostate cancer are inadequate imperfect predictors; therefore, new biomarkers are needed to improve the prognostic classification and management of these patients. In a five-cohort study, we confirmed that the tissue-based telomere biomarker – the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells – was associated with progression to metastasis and prostate cancer death independent of currently used prognostic indicators after prostatectomy for clinically-localized disease. Importantly, the telomere biomarker was associated with poor outcome in men with intermediate risk disease, as well as in men with intact PTEN tumors. Thus, this tissue-based telomere biomarker has the translational potential to improve treatment and surveillance decision-making.

ImportanceEvaluation of trainees in graduate medical education training programs using Milestones has been in place since 2013. It is not known whether trainees who have lower ratings during the last year of training go on to have concerns related to interactions with patients in posttraining practice.ObjectiveTo investigate the association between resident Milestone ratings and posttraining patient complaints.Design, Setting, and ParticipantsThis retrospective cohort study included physicians who completed Accreditation Council for Graduate Medical Education (ACGME)–accredited programs between July 1, 2015, and June 30, 2019, and worked at a site that participated in the national Patient Advocacy Reporting System (PARS) program for at least 1 year. Milestone ratings from ACGME training programs and patient complaint data from PARS were collected. Data analysis was conducted from March 2022 to February 2023.ExposuresLowest professionalism (P) and interpersonal and communication skills (ICS) Milestones ratings 6 months prior to the end of training.Main Outcomes and MeasuresPARS year 1 index scores, based on recency and severity of complaints.ResultsThe cohort included 9340 physicians with median (IQR) age of 33 (31-35) years; 4516 (48.4%) were women physicians. Overall, 7001 (75.0%) had a PARS year 1 index score of 0, 2023 (21.7%) had a score of 1 to 20 (moderate), and 316 (3.4%) had a score of 21 or greater (high). Among physicians in the lowest Milestones group, 34 of 716 (4.7%) had high PARS year 1 index scores, while 105 of 3617 (2.9%) with Milestone ratings of 4.0 (proficient), had high PARS year 1 index scores. In a multivariable ordinal regression model, physicians in the 2 lowest Milestones rating groups (0-2.5 and 3.0-3.5) were statistically significantly more likely to have higher PARS year 1 index scores than the reference group with Milestones ratings of 4.0 (0-2.5 group: odds ratio, 1.2 [95% CI, 1.0-1.5]; 3.0-3.5 group: odds ratio, 1.2 [95% CI, 1.1-1.3]).Conclusions and RelevanceIn this study, trainees with low Milestone ratings in P and ICS near the end of residency were at increased risk for patient complaints in their early posttraining independent physician practice. Trainees with lower Milestone ratings in P and ICS may need more support during graduate medical education training or in the early part of their posttraining practice career.

Background Direct high-quality evidence is lacking evaluating perioperative pharmacologic prophylaxis (PP) after radical prostatectomy (RP) to prevent venous thromboembolism (VTE) leading to significant practice variation. Objective To study the impact of in-hospital PP on symptomatic VTE incidence and adverse events after RP at 30 d, with the secondary objective of evaluating overall VTE in a screening subcohort. Design, setting, and participants A prospective, phase 4, single-center, randomized trial of men with prostate cancer undergoing open or robotic-assisted laparoscopic RP was conducted (July 2017–November 2018). Intervention PP (subcutaneous heparin) plus routine care versus routine care alone. The screening subcohort was offered lower extremity duplex ultrasound at 30 d. Outcomes measurements and statistical analysis The primary efficacy outcome was symptomatic VTE incidence (pulmonary embolism [PE] or deep venous thrombosis [DVT]). Primary safety outcomes included the incidence of symptomatic lymphocele, hematoma, or bleeding after surgery. Secondary outcomes were overall VTE, estimated blood loss, total surgical drain output, complications, and surveillance imaging bias. Fisher’s exact test and modified Poisson regression were performed. Results and limitations A total of 501 patients (75% robotic) were randomized and >99% (500/501) completed follow-up. At second interim analysis (N = 445), the symptomatic VTE rate was 2.3% (four PE + DVT and one DVT) for routine care versus 0.9% (one PE + DVT and one DVT) for PP (relative risk 0.40 [95% confidence interval 0.08–2.03], p = 0.3) meeting a futility threshold for early stopping. In the screening subcohort, the overall VTE rate was 3.3% versus 2.4% (p = 0.7). Results were similar at the final analysis (symptomatic VTE: 2.0% vs 0.8%, p = 0.3; overall VTE: 2.9% vs 2.8%, p = 1). No differences were observed in safety or secondary outcomes. All VTE events (seven symptomatic and three asymptomatic) occurred in patients undergoing pelvic lymph node dissection. Conclusions This study was not able to demonstrate a statistically significant reduction in symptomatic VTE associated with PP. There was no increase in the development of symptomatic lymphoceles, bleeding, or other adverse events. Given that the event rate was lower than powered for, further research is needed among high-risk patients (Caprini score ≥8) or patients receiving pelvic lymph node dissection. Patient summary In this report, we randomized patients undergoing radical prostatectomy to perioperative pharmacologic prophylaxis or routine care alone. We found that pharmacologic prophylaxis did not reduce postoperative symptomatic venous thromboembolism significantly for men at routine risk. Importantly, pharmacologic prophylaxis did not increase adverse events, such as formation of lymphoceles or bleeding, and can safely be implemented when indicated for patients with risk factors undergoing radical prostatectomy.

Aim: A maximum surgical blood order schedule (MSBOS) was implemented at our institution to optimize preoperative blood ordering and reduce unnecessary blood preparation for patients undergoing radical prostatectomy (RP), a common urologic procedure. Materials & methods: We conducted a retrospective review of patients who underwent RP from 2010 to 2016 and categorized patients by date of RP (pre- or post-MSBOS) and compared preoperative blood-ordering practices. Results: After MSBOS implementation, preoperative blood orders changed from predominantly type and cross-match 2 units (53%) to no sample (56%) for robot-assisted laparoscopic RP, and from mostly type and cross-match 2 units (62%) to type and screen (75%) for open RP with resultant cost savings. Conclusion: MSBOS implementation and compliance decreases unnecessary preoperative blood orders.

To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n=482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p=0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n=332; HR 2.64; p=0.02) and also biochemical recurrence (Canary; n=988; HR 1.51; p=0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements.

Multimodal therapies were combined to eradicate the primary site, metastatic, and micrometastatic disease in men with newly diagnosed, synchronous, oligometastatic prostate cancer. The investigation included companion, phase II studies: total eradication therapy-1 (TET-1) for those treatment-naïve and total eradication therapy-2 (TET-2) for those post-prostatectomy. The treatment-naive protocol included androgen deprivation and docetaxel (with concurrent abiraterone added in a protocol amendment), followed by a prostatectomy, adjuvant radiation (if positive margins, T3/4, or detectable PSA), and metastasis-directed therapy. The post-prostatectomy protocol assigned the same therapies (omitting the prostatectomy). The primary endpoint was an undetectable PSA with recovered testosterone. The safety boundaries were ≤ 50% for grade 3/4 neutropenic and ≤ 20% for grade 3/4 surgical- and radiation-related toxicities. Enrollment was planned for 60 patients per protocol, to detect a PSA progression-free survival ≥ 32%, as compared to 15% in a historic control. Enrollment closed early. An interim analysis was conducted once 50% of patients were evaluable for the primary endpoint. The primary endpoint duration was assessed by median progression-free survival. 52 patients were enrolled (n = 26 per protocol). Medium follow-up was 30.3 months. 80% (24/30) of evaluable patients achieved the primary endpoint; the duration was not reached. Of those not evaluable, 77% (17/22) had not reached the endpoint and 23% (5/22) had exited. There were 8% (4/52) grade 3/4 neutropenic and 2% (1/48) grade 3/4 surgical or radiation-induced toxicities. Interim findings suggest the trials' endpoints were met, advancing the concept of total eradication therapy in men with oligometastatic prostate cancer.

INTRODUCTION AND OBJECTIVE:There has been an increasing interest recently in understanding physician-level discrepancies in patient outcomes as part of healthcare reform. We aim to evaluate urologi...

INTRODUCTION AND OBJECTIVE:The cell cycle progression (CCP) score and PTEN have never been evaluated together for metastasis-free survival (MFS) in a prostatectomy (RP) cohort of men with intermedi...

INTRODUCTION AND OBJECTIVE:Clinical guidelines now include germline testing for prostate cancer (PCa). Currently, only 11 genes are routinely evaluated for rare pathogenic mutations (RPMs). Common ...

ImportanceFinancial incentives and conflicts of interest may influence physician decision-making. It is important to understand financial interactions between the pharmaceutical and medical device industries and newly independent physicians who have recently completed their graduate medical education using a national transparency program.ObjectiveTo identify trends in industry payments to recent graduates of Accreditation Council for Graduate Medical Education–accredited residency or fellowship programs in orthopedic surgery, neurosurgery, and internal medicine.Design, Setting, and ParticipantsThis retrospective cohort study analyzed Open Payments reports of industry payments made between July 1, 2015, and June 30, 2021, to newly independent physicians from residency or fellowship programs in neurosurgery, orthopedic surgery, and internal medicine who graduated between January 1, 2015, and December 31, 2019.ExposuresSpecialties (neurosurgery and orthopedic surgery, with internal medicine as a comparison group).Main Outcomes and MeasuresIndustry payments to newly independent physicians, including any general payments (noninvestment or nonresearch) and at least $5000 of general payments in aggregate value per year, which are considered significant financial conflicts of interest. The percentage of newly independent physicians accepting general payments during the first 6 years after graduation was analyzed by specialty and sex using cumulative incidence curves and hazard ratios (HRs) in univariable and multivariable analyses.ResultsThere were 45 745 recent graduates (28 137 men [62%]; median age at graduation, 33.0 [IQR, 31.0-35.0 years]) in neurosurgery (n = 595), orthopedic surgery (n = 3481), and internal medicine (n = 41 669). In the first 2 years of independent practice, 95% (n = 3297), 92% (n = 546), and 59% (n = 24 522) of newly independent physicians in orthopedic surgery, neurosurgery, and internal medicine, respectively, accepted any general payments. A higher percentage of the newly independent physicians in orthopedic surgery and neurosurgery accepted any general payments (orthopedic surgery vs internal medicine: HR, 5.36 [95% CI, 4.42-6.51] for women and 7.01 [95% CI, 6.35-7.73] for men; neurosurgery vs internal medicine: HR, 3.25 [95% CI, 2.24-4.72] for women and 4.08 [95% CI, 3.37-4.94] for men; P = .03). A higher percentage of male physicians compared with female physicians accepted any general payments (orthopedic surgery, 2884 of 3026 [95%] vs 413 of 455 [91%]; P P = .01; and internal medicine, 15 462 of 24 609 [63%] vs 9043 of 17 034 [53%]; P P P P Conclusions and RelevanceIn this cohort study of newly independent physicians in orthopedic surgery, neurosurgery, and internal medicine, the financial relationship with potential conflicts of interest between newly independent physicians and industry began to develop soon after training programs and continued to expand in the early years of newly independent physician practice. Newly independent physicians in surgical specialties and male physicians accepted significantly higher industry payments. Further studies are needed to evaluate whether modifiable factors are associated with the future outcome of newly independent physicians accepting general payments.

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

Germline mutations in DNA repair genes and KLK3 have been associated with adverse prostate cancer (PCa) outcomes in separate studies but never jointly. The objective of this study is to simultaneously assess these two types of germline mutations.Germline rare pathogenic mutations (RPMs) in 9 commonly tested DNA repair genes and KLK3 variants were tested for their associations with PCa progression in two PCa cohorts: (1) hospital-based PCa patients treated with radical surgery at the Johns Hopkins Hospital (JHH, N = 1943), and (2) population-based PCa patients in the UK Biobank (UKB, N = 10,224). Progression was defined as metastasis and/or PCa-specific death (JHH) and PCa-specific death (UKB). RPMs of DNA repair genes were annotated using the American College of Medical Genetics recommendations. Known KLK3 variants were genotyped. Associations were tested using a logistic regression model adjusting for genetic background (top ten principal components).In the JHH, 3.2% (59/1,843) of patients had RPMs in 9 DNA repair genes; odds ratio (OR, 95% confidence interval) for progression was 2.99 (1.6-5.34), P 0.001. In comparison, KLK3 I179T mutation was more common; 9.7% (189/1,943) carried the mutation, OR = 1.6 (1.05-2.37), P = 0.02. Similar results were found in the UKB. Both types of mutations remained statistically significant in multivariable analyses. In the combined cohort, compared to patients without any mutations (RPMs-/KLK3-), RPMs-/KLK3+ patients had modestly increased risk for progression [OR = 1.54 (1.15-2.02), P = 0.003], and RPMs+/KLK3+ patients had greatly increased risk for progression [OR = 5.41 (2.04-12.99), P 0.001]. Importantly, associations of mutations with PCa progression were found in patients with clinically defined low- or intermediate risk for disease progression.Two different cohorts consistently demonstrate that KLK3 I179T and RPMs of nine commonly tested DNA repair genes are complementary for predicting PCa progression. These results are highly relevant to PCa germline testing and provide critical information for KLK3 I179T to be considered in guidelines.

Prostatic adenocarcinoma with extraprostatic extension detected on prostate needle biopsy is an uncommon finding. We describe clinical and pathological findings in a large cohort of patients with prostatic adenocarcinoma who were treated with radical prostatectomy and in whom extraprostatic extension was identified on prostate needle biopsy.Using our institutional pathology database we identified 83 patients with prostatic adenocarcinoma and with extraprostatic extension on prostate needle biopsy between 2000 to 2018 who underwent radical prostatectomy and had clinical followup information. Clinical and pathological outcomes were examined.Of the 83 patients 54 (65%) presented with clinical stage T2 or greater disease. On biopsy 50 of the 83 patients (60%) had Grade Group 4-5 and 66 (81%) had perineural invasion. Extraprostatic extension was confirmed in the radical prostatectomy specimen in 81 of 83 cases (98%). At radical prostatectomy 49 of 83 patients (59%) had positive surgical margins, 37 (45%) had seminal vesicle invasion and 30 (37%) had lymph node involvement. Median followup after radical prostatectomy was 2 years. Overall 34 of 76 men (45%) received postoperative radiation a median of 1 year after radical prostatectomy and 8 (11%) received chemotherapy a median of 2 years after radical prostatectomy. The 3-year biochemical recurrence-free survival rate was 48.4% (95% CI 0.345-0.610) and the 3-year metastasis-free survival rate was 75.2% (95% CI 0.603-0.851).Patients in whom extraprostatic extension is detected on prostate needle biopsy almost always have extraprostatic disease and markedly adverse pathology findings at radical prostatectomy. Many of them experience biochemical recurrence and most will require multimodal therapy. These data can be useful to counsel such patients in regard to the treatment approach and the expected outcomes after surgery.

Opioid pain medications are overprescribed, but few data are available to help in appropriate tailoring of postdischarge opioid prescriptions after surgery. Prior studies are retrospective and based on incomplete responses ( 80% of patients and compare open and robotic surgery. A total of 205 adult patients were enrolled, with 100% completing follow-up. In units of oral morphine equivalents (OMEQ), a median of 225mg was prescribed and 22.5mg used. There was no difference by surgical approach or among patients with a history of pain-related diagnoses. Overall, 77% of postdischarge opioid medication was unused, with 84% of patients requiring ≤112.5mg OMEQ. Only 9% of patients appropriately disposed of leftover medication. Approximately 5% reported continued incisional pain due to surgery at 30d, but none required continued opioid medication use. Prescribing more opioids was independently associated with greater opioid use in adjusted models. PATIENT SUMMARY: In this report, we looked at opioid medication use following discharge after radical prostatectomy. We found that 77% of opioid pain medication prescribed was unused, with 84% of patients using less than half of their prescription. Prescribing more opioids was associated with greater use; only 9% of patients appropriately disposed of leftover medication.