Association of Genomic Prostate Score at positive margin with recurrence after radical prostatectomy.

OBJECTIVES: To evaluate the utility of the 17-gene Genomic Prostate Score® (GPS; MDxHealth, Irvine, CA, USA) performed on prostate cancer at the positive margin of the radical prostatectomy (RP) for its association with risk of subsequent biochemical recurrence (BCR). PATIENTS AND METHODS: We designed a case-cohort for the outcome of BCR, selecting 223 from a cohort of 813 RP patients treated at Johns Hopkins from 2008 to 2017 with positive margins and available clinical data; of these, 213 had available tissue and clinical data. RNA was isolated from formalin-fixed paraffin-embedded tumour tissue adjacent to the positive surgical margin and the GPS was evaluable in 203 of these patients with a score ranging from 0 to 100, with higher scores indicating higher risk. All patients underwent RP with or without adjuvant radiation therapy (ART). The statistical analysis employed Cox proportional hazards regression models for outcome of BCR weighted for case-cohort design. RESULTS: In univariable analysis, every 20-unit increase in the GPS was associated with a nearly threefold increase in risk of BCR (hazard ratio [HR] per 20 units 2.82, P < 0.001). In a multivariable Cox model adjusted for age, race, Cancer of the Prostate Risk Assessment Postsurgical score, Grade Group at the positive margin, and ART, the GPS was significantly associated with BCR (HR 1.56 per 20 units; 95% confidence interval 1.11-2.19; P = 0.011). The study is limited by its retrospective and single institution design. CONCLUSIONS: The GPS at the positive surgical margin could help stratify prognosis and inform clinical decision-making regarding adjuvant therapy after RP.

Development and External Validation of a Machine Learning Model for Prediction of Lymph Node Metastasis in Patients with Prostate Cancer.

BACKGROUND: Pelvic lymph node dissection (PLND) is the gold standard for diagnosis of lymph node involvement (LNI) in patients with prostate cancer. The Roach formula, Memorial Sloan Kettering Cancer Center (MSKCC) calculator, and Briganti 2012 nomogram are elegant and simple traditional tools used to estimate the risk of LNI and select patients for PLND. OBJECTIVE: To determine whether machine learning (ML) can improve patient selection and outperform currently available tools for predicting LNI using similar readily available clinicopathologic variables. DESIGN, SETTING, AND PARTICIPANTS: Retrospective data for patients treated with surgery and PLND between 1990 and 2020 in two academic institutions were used. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We trained three models (two logistic regression models and one gradient-boosted trees-based model [XGBoost]) on data provided from one institution (n = 20267) with age, prostate-specific antigen (PSA) levels, clinical T stage, percentage positive cores, and Gleason scores as inputs. We externally validated these models using data from another institution (n = 1322) and compared their performance to that of the traditional models using the area under the receiver operating characteristic curve (AUC), calibration, and decision curve analysis (DCA). RESULTS AND LIMITATIONS: LNI was present in 2563 patients (11.9%) overall, and in 119 patients (9%) in the validation data set. XGBoost had the best performance among all the models. On external validation, its AUC outperformed that of the Roach formula by 0.08 (95% confidence interval [CI] 0.042-0.12), the MSKCC nomogram by 0.05 (95% CI 0.016-0.070), and the Briganti nomogram by 0.03 (95% CI 0.0092-0.051; all p < 0.05). It also had better calibration and clinical utility in terms of net benefit on DCA across relevant clinical thresholds. The main limitation of the study is its retrospective design. CONCLUSIONS: Taking all measures of performance together, ML using standard clinicopathologic variables outperforms traditional tools in predicting LNI. PATIENT SUMMARY: Determining the risk of cancer spread to the lymph nodes in patients with prostate cancer allows surgeons to perform lymph node dissection only in patients who need it and avoid the side effects of the procedure in those who do not. In this study, we used machine learning to develop a new calculator to predict the risk of lymph node involvement that outperformed traditional tools currently used by oncologists.

ERG Status at the Margin Is Associated With Biochemical Recurrence After Radical Prostatectomy With Positive Surgical Margins.

Positive surgical margins at radical prostatectomy are associated with an increased risk of biochemical recurrence (BCR). However, there is considerable variability in outcomes, suggesting that molecular biomarkers-when assessed specifically at the margin tumor tissue-may be useful to stratify prognosis in this group. We used a case-cohort design for the outcome of BCR, selecting 215 patients from a cohort of 813 patients undergoing prostatectomy treated at the Johns Hopkins from 2008 to 2017 with positive margins and available clinical data. Tissue microarrays were created from the tumor adjacent to the positive margin and stained for PTEN, ERG, and Ki-67. Cases were scored dichotomously (PTEN and ERG) or by the Ki-67 staining index using previously validated protocols. The analysis used Cox proportional hazards models weighted for the case-cohort design. Overall, 20% (37/185) of evaluable cases had PTEN loss and 38% (71/185) had ERG expression, and the median Ki-67 expression was 0.42%. In multivariable analysis adjusting for the CAPRA-S score, adjuvant radiation, and grade group at the positive margin, ERG-positive tumors were associated with a higher risk of BCR compared to those that were ERGnegative (hazard ratio [HR], 2.4; 95% CI, 1.2-4.9; P = .012) regardless of PTEN status at the margin, and adding ERG to clinicopathologic variables increased the concordance index from 0.827 to 0.847. PTEN loss was associated with an increased risk of BCR on univariable analysis (HR, 3.19; 95% CI, 1.72-5.92; P = .0002), but this association did not remain after adjusting for clinicopathologic variables (HR, 1.06; 95% CI, 0.49-2.29; P = .890). Thus, in the setting of prostate tumors with positive surgical margins after prostatectomy, ERG-positive tumors with or without PTEN loss at the positive margin are associated with a significantly higher risk of BCR after adjusting for clinicopathologic variables. If validated, ERG status may be helpful in decision-making surrounding adjuvant therapy after prostatectomy.

Urinary PSA and Serum PSA for Aggressive Prostate Cancer Detection.

Serum PSA, together with digital rectal examination and imaging of the prostate gland, have remained the gold standard in urological practices for the management of and intervention for prostate cancer. Based on these adopted practices, the limitations of serum PSA in identifying aggressive prostate cancer has led us to evaluate whether urinary PSA levels might have any clinical utility in prostate cancer diagnosis. Utilizing the Access Hybritech PSA assay, we evaluated a total of n = 437 urine specimens from post-DRE prostate cancer patients. In our initial cohort, PSA tests from a total of one hundred and forty-six (n = 146) urine specimens were obtained from patients with aggressive (Gleason Score ≥ 8, n = 76) and non-aggressive (Gleason Score = 6, n = 70) prostate cancer. A second cohort, with a larger set of n = 291 urine samples from patients with aggressive (GS ≥ 7, n = 168) and non-aggressive (GS = 6, n = 123) prostate cancer, was also utilized in our study. Our data demonstrated that patients with aggressive disease had lower levels of urinary PSA compared to the non-aggressive patients, while the serum PSA levels were higher in patients with aggressive prostate disease. The discordance between serum and urine PSA levels was further validated by immuno-histochemistry (IHC) assay in biopsied tumors and in metastatic lesions (n = 62). Our data demonstrated that aggressive prostate cancer was negatively correlated with the PSA in prostate cancer tissues, and, unlike serum PSA, urinary PSA might serve a better surrogate for capitulating tissue milieus to detect aggressive prostate cancer. We further explored the utility of urine PSA as a cancer biomarker, either alone and in combination with serum PSA, and their ratio (serum to urine PSA) to predict disease status. Comparing the AUCs for the urine and serum PSA alone, we found that urinary PSA had a higher predictive power (AUC= 0.732) in detecting aggressive disease. Furthermore, combining the ratios between serum to urine PSA with urine and serum assay enhanced the performance (AUC = 0.811) in predicting aggressive prostate disease. These studies support the role of urinary PSA in combination with serum for detecting aggressive prostate cancer.

Cell Cycle Progression Score, but Not Phosphatase and Tensin Homolog Loss, Is an Independent Prognostic Factor for Metastasis in Intermediate- and High-risk Prostate Cancer in Men Treated With and Without Salvage Radiotherapy.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Interim analysis of companion, prospective, phase II, clinical trials assessing the efficacy and safety of multi-modal total eradication therapy in men with synchronous oligometastatic prostate cancer.

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.

Prospective Multicenter Comparison of Open and Robotic Radical Prostatectomy: The PROST-QA/RP2 Consortium.

PURPOSE: Our goal was 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 11 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 (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative 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 <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL; p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep venous thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain. CONCLUSIONS: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, deep venous thromboses, and bladder neck contractures.

Adjuvant Versus Early Salvage Radiation Therapy for Men at High Risk for Recurrence Following Radical Prostatectomy for Prostate Cancer and the Risk of Death.

PURPOSE: Adjuvant compared with early salvage radiation therapy (sRT) following radical prostatectomy (RP) has not been shown to reduce progression-free survival in randomized controlled trials. However, these trials might have missed a benefit in men with adverse pathology at RP given that these men were under-represented and immortal time bias might have been present; herein, we investigate this possibility. METHODS: We evaluated the impact of adjuvant versus early sRT on all-cause mortality (ACM) risk in men with adverse pathology defined as positive pelvic lymph nodes (pN1) or pGleason score 8-10 prostate cancer (PC) and disease extending beyond the prostate (pT3/4). We used a treatment propensity score to minimize potential treatment selection bias when estimating the causal effect of adjuvant versus early sRT on ACM risk and a sensitivity analysis to assess the impact that varying definitions of adverse pathology had on ACM risk adjusting for age at RP, PC prognostic factors, site, and the time-dependent use of post-RP androgen deprivation therapy. RESULTS: After a median follow-up (interquartile range) of 8.16 (6.00-12.10) years, of the 26,118 men in the study cohort, 2,104 (8.06%) died, of which 539 (25.62%) were from PC. After excluding men with a persistent prostate-specific antigen, adjuvant compared with early sRT was associated with a significantly lower ACM risk among men with adverse pathology at RP when men with pN1 PC were excluded (0.33 [0.13-0.85]; P = .02) or included (0.66 [0.44-0.99]; P = .04). CONCLUSION: Adjuvant radiation therapy should be considered in men with pN1 or pGleason score 8 to 10 and pT3/4 PC given the possibility that a significant reduction in ACM risk exists.

Effect of Erythropoietin on Erectile Function after Radical Prostatectomy: The ERECT Randomized Clinical Trial.

PURPOSE: Erectile dysfunction significantly impacts quality of life for men undergoing radical prostatectomy for prostate cancer. Erythropoietin is a promising neurotrophic factor for neurogenic erectile dysfunction based on preclinical and retrospective data. MATERIALS AND METHODS: ERECT (NCT00737893) is a phase 2, double-blinded, randomized, placebo-controlled trial (July 2017-December 2019) evaluating the impact of perioperative erythropoietin on recovery of erectile function and other patient-reported, health-related quality of life outcomes after bilateral nerve-sparing radical prostatectomy (3, 6, 9, and 12 months). Erythropoietin (20,000 units) or saline placebo was injected subcutaneously the day before, day of, and day after surgery for 3 total doses. RESULTS: Of 63 patients assessed for eligibility, 56 patients were randomized. Arms (29 erythropoietin, 27 placebo) were well balanced (89.3% robotic, median age 55.5 years). International Index of Erectile Function-Erectile Function Domain (IIEF-EF) scores increased from median 12.5 at 3 months to 24.5 at 12 months. Median 2-week serum hemoglobin was higher for the erythropoietin arm compared to placebo (14.7 vs 13.6, p=0.02). There was no statistically significant difference in IIEF-EF scores at 6 months comparing erythropoietin to placebo (p=0.50) or at other time points (mixed model regression coefficient: -1.7, 95% CI -6.1-2.7, p=0.45). Excellent nerve-sparing rating (10/10) was associated with improved IIEF-EF recovery (+5.2, p=0.022). Other patient-reported, health-related quality of life domains as well as oncologic outcome and complications were similar between arms during followup. CONCLUSIONS: In the context of brief perioperative dosing, erythropoietin did not improve recovery of erectile function for men undergoing radical prostatectomy for prostate cancer compared to placebo. Further research to identify effective adjuncts to improve health-related quality of life for these men is needed.

Advances in the selection of patients with prostate cancer for active surveillance.

Early identification and management of prostate cancer completely changed with the discovery of prostate-specific antigen. However, improved detection has also led to overdiagnosis and consequently overtreatment of patients with low-risk disease. Strategies for the management of patients using active surveillance - the monitoring of clinically insignificant disease until intervention is warranted - were developed in response to this issue. The success of this approach is critically dependent on the accurate selection of patients who are predicted to be at the lowest risk of prostate cancer mortality. The Epstein criteria for clinically insignificant prostate cancer were first published in 1994 and have been repeatedly validated for risk-stratification and selection for active surveillance over the past few decades. Current active surveillance programmes use modified criteria with 30-50% of patients receiving treatment at 10 years. Nonetheless, tools for prostate cancer diagnosis have continued to evolve with improvements in biopsy format and targeting, advances in imaging technologies such as multiparametric MRI, and the identification of serum-, tissue- and urine-based biomarkers. These advances have the potential to further improve the identification of men with low-risk disease who can be appropriately managed using active surveillance.

Feasibility of integrating canine olfaction with chemical and microbial profiling of urine to detect lethal prostate cancer.

Prostate cancer is the second leading cause of cancer death in men in the developed world. A more sensitive and specific detection strategy for lethal prostate cancer beyond serum prostate specific antigen (PSA) population screening is urgently needed. Diagnosis by canine olfaction, using dogs trained to detect cancer by smell, has been shown to be both specific and sensitive. While dogs themselves are impractical as scalable diagnostic sensors, machine olfaction for cancer detection is testable. However, studies bridging the divide between clinical diagnostic techniques, artificial intelligence, and molecular analysis remains difficult due to the significant divide between these disciplines. We tested the clinical feasibility of a cross-disciplinary, integrative approach to early prostate cancer biosensing in urine using trained canine olfaction, volatile organic compound (VOC) analysis by gas chromatography-mass spectroscopy (GC-MS) artificial neural network (ANN)-assisted examination, and microbial profiling in a double-blinded pilot study. Two dogs were trained to detect Gleason 9 prostate cancer in urine collected from biopsy-confirmed patients. Biopsy-negative controls were used to assess canine specificity as prostate cancer biodetectors. Urine samples were simultaneously analyzed for their VOC content in headspace via GC-MS and urinary microbiota content via 16S rDNA Illumina sequencing. In addition, the dogs' diagnoses were used to train an ANN to detect significant peaks in the GC-MS data. The canine olfaction system was 71% sensitive and between 70-76% specific at detecting Gleason 9 prostate cancer. We have also confirmed VOC differences by GC-MS and microbiota differences by 16S rDNA sequencing between cancer positive and biopsy-negative controls. Furthermore, the trained ANN identified regions of interest in the GC-MS data, informed by the canine diagnoses. Methodology and feasibility are established to inform larger-scale studies using canine olfaction, urinary VOCs, and urinary microbiota profiling to develop machine olfaction diagnostic tools. Scalable multi-disciplinary tools may then be compared to PSA screening for earlier, non-invasive, more specific and sensitive detection of clinically aggressive prostate cancers in urine samples.

Transperineal Prostate Biopsy Improves the Detection of Clinically Significant Prostate Cancer among Men on Active Surveillance.

PURPOSE: Transperineal prostate biopsy offers improved sampling of the anterior prostate compared to the transrectal approach. The objective of this study was to determine if transperineal prostate biopsy is associated with an increased incidence of cancer upgrading among men on active surveillance for very low or low risk prostate cancer. MATERIALS AND METHODS: Our active surveillance registry was queried to identify patients who underwent a surveillance biopsy following the introduction of transperineal prostate biopsy at our institution. Patients were dichotomized by the type of biopsy performed. The baseline characteristics and rates of cancer upgrading were compared between groups. RESULTS: Between November 2017 and June 2020, 790 men with very low or low risk prostate cancer underwent a surveillance biopsy. In total, 59 of 279 men (21.2%) in the transperineal prostate biopsy group were upgraded to grade group ≥2 as compared to 75 of 511 (14.7%) in the transrectal biopsy group (p=0.01). Among patients who were upgraded to grade group ≥2, 26 of 59 (44%) had grade group ≥2 detected in the anterior/transition zone with transperineal prostate biopsy compared to 14 of 75 (18.7%) with transrectal biopsy (p=0.01). Additionally, 17 of 279 men (6.1%) who underwent transperineal prostate biopsy were upgraded to grade group ≥3 vs 17 of 511 (3.3%) who underwent transrectal biopsy (p=0.05). After adjusting for age, prostate specific antigen density, use of magnetic resonance imaging, and number of prior transrectal biopsies, transperineal prostate biopsy was significantly associated with upgrading to grade group ≥2 (OR 1.49, 95% CI 1.11-2.19, p=0.01). CONCLUSIONS: Among men on active surveillance for very low or low risk prostate cancer, transperineal prostate biopsy was associated with an increased likelihood of upgrading to clinically significant prostate cancer. This is likely due to improved sampling of the anterior prostate with the transperineal approach.

Contemporary Assessment of the Most Cited Clinical, Basic Science, and Guidelines Papers in Urology: A Reference for Urology Journal Club.

OBJECTIVE: To perform bibliometric analysis of the top cited articles in urology as a guide for journal club article selection. METHODS: Bibliometric citation analysis was performed using Scopus. Tables illustrating the top cited clinical, basic science, and guidelines/position statements papers were constructed. Linear regression was used to determine association between h-index and number of citations. RESULTS: A total of 3,188,861 publications from 1788 to 2020 were analyzed. The top 100 cited clinical papers from 1788 to 2020, top 100 cited contemporary clinical papers from 2000 to 2020, top 25 cited basic science papers, and the top 25 cited guidelines/position statement papers were reported. Median number of citations in the top 100 cited clinical papers was 1463 (interquartile range 1186-1821). Memorial Sloan Kettering Cancer Center (12), Johns Hopkins University (6), and Harvard University (6) contributed the most top cited clinical papers in urology. Urologic oncology was the most represented subspecialty in both clinical (75%) and basic science (96%) papers. First author and last author h-index were found to correlate with the number paper citations in the top 100 cited clinical papers from 1788 to 2020 (first author ß:5.3, P= .003, last author ß:4.5, P= .03). Only 7% of the most cited clinical papers in urology were from female first authors, which was not statistically significantly different from those reported in prior publications published in 2009 and 2013. CONCLUSION: Contemporary citation analysis of indexed manuscripts in urology may serve as a valuable educational tool for urologists and trainees.

Complications after open and robot-assisted radical prostatectomy and association with postoperative opioid use: an analysis of data from the PREVENTER trial.

OBJECTIVE: To evaluate perioperative complications for open radical prostatectomy (ORP) and robot-assisted RP (RARP) for patients enrolled in the PREvention of VENous ThromboEmbolism Following Radical Prostatectomy (PREVENTER; ClinicalTrials.gov Identifier: NCT03006562) trial, to determine predictors and impact on opioid consumption. PATIENTS AND METHODS: A prospective cohort of 500 patients undergoing ORP and RARP was followed to determine rates of complications and opioid use. Complications were classified 30 days after RP using the Clavien-Dindo system. Patient characteristics and outcomes were compared using appropriate statistical tests. Logistic and linear regressions were performed to identify predictors of complications and evaluate the relationship between complications and postoperative opioid use. RESULTS: A total of 124 (24.8%) men underwent ORP and 376 (75.2%) RARP, with 418 (83.6%) receiving pelvic lymph node dissection (PLND). While 83 patients (16.6%) had complications, only 19 (3.8%) were major (Clavien-Dindo Grade ≥III), with no differences by surgical approach. PLND (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.25-8.71; P = 0.03) and Stage pT3b (OR 2.76, 95% CI 1.23-6.00;P = 0.01) were the only predictors of complications after controlling for potential confounders. Patients who had complications had greater inpatient (P = 0.02) and outpatient (P = 0.005) opioid use, which persisted after controlling for patient-reported pain, attending surgeon variation, surgical approach, and undergoing PLND (inpatient ß:77.2, 95% CI 17.9-136.5,P = 0.03; and outpatient ß:21.9, 95% CI 4.7-39.1,P = 0.01). CONCLUSION: In an analysis of prospectively collected data, overall and major complications rates did not differ by surgical approach. Patients receiving PLND and with Stage pT3b disease had more complications. Complications were independently associated with higher inpatient and outpatient postoperative opioid use.

A prospective comparative study of routine versus deferred pelvic drain placement after radical prostatectomy: impact on complications and opioid use.

PURPOSE: To evaluate the association of post-RP drain placement with post-operative complications and opioid use at a high-volume institution. METHODS: A prospective, comparative cohort study of patients undergoing robot-assisted or open RP was conducted. Patients for two surgeons did not routinely receive pelvic drains ("No Drain" arm), while the remainder routinely placed drains ("Drain" arm). Outcomes were evaluated at 30 days including Clavien-Dindo complications and opioid use. Intention-to-treat primary analysis and additional secondary analyses were performed using appropriate statistical tests and logistic regression. RESULTS: Of 498 total patients, 144 (28.9%) were in the No Drain arm (all robot-assisted) and 354 (71.1%) in the Drain arm. In the No Drain arm, 19 (13.2%) intraoperatively were chosen to receive drains. There was no difference in overall or major (Clavien ≥ 3) complications between groups (p = 0.2 and 0.4, respectively). Drain deferral did not predict complications on multivariable analysis adjusted for age, BMI, comorbidities, clinical risk, surgical approach, operating time, lymphadenectomy, and number of nodes removed [OR 0.61, 95% CI 0.34-1.11, p = 0.10]; nor did it predict symptomatic fluid collection, adjusting for lymphadenectomy and nodes removed [OR 1.14, 95% CI 0.43-3.60, p = 0.8]. Drain deferral did not decrease opioid use (p = 0.5). Per protocol analysis and restriction to robot-assisted cases demonstrated similar results. CONCLUSION: There was no difference in adverse events, complications, symptomatic collections, or opioid use with deferral of routine drain placement after RP. Experienced surgeons may safely defer drain placement in the majority of robot-assisted RP cases.

A novel method for detection of exfoliated prostate cancer cells in urine by RNA in situ hybridization.

BACKGROUND: In the current study, we explore the feasibility of detecting exfoliated prostate cancer cells in urine using an RNA in situ hybridization (RISH) assay. We hypothesized that robust and specific labeling of prostate cancer cells could be achieved in post-digital rectal examination (DRE) urine samples using RISH. METHODS: We focused on method development, optimization, and analytical evaluation of RISH-based detection of prostate cancer in urine. We optimized a sample collection, processing, and target detection workflow for urine cytology specimens in conjunction with RNA target detection by RISH. We screened a panel of 11 prostate-specific RNA targets, and selected NKX3-1 and PRAC1 as markers for cells of prostate origin and PCA3 as a marker of prostate malignancy. Following analytical validation of a multiplexed NKX3-1/PRAC1/PCA3 assay, we evaluated whether prostate cancer cells can be detected in a pilot cohort of 19 post-DRE specimens obtained from men diagnosed with prostate cancer. RESULTS: Using cytology specimens prepared from spiked urine samples, we established the analytical validity of the RISH assay for detection and visualization of prostate cells in urine. Cells of prostate origin could be readily and specifically identified and separated into benign and malignant cell populations based on the multiplex test that consisted of markers specific for prostate cells (NKX3-1, PRAC1) and prostate cancer cells (PCA3). Upon evaluation of post-DRE urine from a pilot cohort of prostate cancer patients, we identified 11 samples in which prostate cells were present, 6 of which were also positive for prostate cancer cells. CONCLUSIONS: Multiplex RISH enables the direct visualization and molecular characterization of individual exfoliated prostate cells in urine. This proof-of-principle study provides evidence supporting the application of RISH as a potential noninvasive tool for prostate cancer detection.

Effect of Pharmacologic Prophylaxis on Venous Thromboembolism After Radical Prostatectomy: The PREVENTER Randomized Clinical Trial.

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.

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer.

PURPOSE: Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. PATIENTS AND METHODS: We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. RESULTS: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8+ T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8+ T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone. CONCLUSIONS: Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.