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.

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.

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.

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.

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.

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.

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.

Utility of multiparametric magnetic resonance imaging in the risk stratification of men with Grade Group 1 prostate cancer on active surveillance.

OBJECTIVE: To assess if the adoption of multiparametric magnetic resonance imaging (mpMRI) in active surveillance (AS) has improved the identification of occult higher-grade prostate cancer (PCa). PATIENTS AND METHODS: We retrospectively identified men from the Johns Hopkins AS registry enrolled since 2013 (year of mpMRI adoption) with Grade Group (GG) 1 PCa and who underwent a single mpMRI. Men in this group were dichotomised by the presence (n = 207) or absence (negative mpMRI, n = 225) of one or more lesions with a Prostate Imaging-Reporting and Data System (PI-RADS) score of ≥ 3. Both groups were compared to a third cohort of men with GG1 PCa enrolled in AS prior to 2013 (pre-mpMRI era, n = 669). The risk of upgrading to GG ≥ 2 PCa on follow-up biopsies (performed with or without MRI targeting) was evaluated among the groups using survival analysis. RESULTS: Men in both mpMRI groups underwent a median (interquartile range [IQR]) of 2 (2-3) biopsies separated by a median (IQR) interval of 13 (12-16) months, whereas men in the pre-MRI era underwent a median (IQR) of 3 (2-5) biopsies, separated by a median (IQR) interval of 12 (12-14) months. The 2- and 4-year upgrade-free survival rates were 93% and 83%, 74% and 59%; and, 87% and 76% for the negative mpMRI, PI-RADS ≥ 3, and pre-mpMRI-era groups, respectively (P < 0.001). On multivariable analysis, both mpMRI groups had significantly different risk of upgrading compared to pre-mpMRI-era group (negative mpMRI group: hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.39-0.95, P = 0.03; PI-RADS ≥ 3 group: HR 1.96, 95% CI 1.36-2.82, P < 0.001). CONCLUSIONS: mpMRI improves the risk stratification of men on AS and should be used to aid enrolment and monitoring decisions.

Adjuvant radiation with androgen-deprivation therapy for men with lymph node metastases after radical prostatectomy: identifying men who benefit.

OBJECTIVES: To perform a comparative analysis of three current management strategies for patients with lymph node metastases (LNM; pN1) following radical prostatectomy (RP): observation, androgen-deprivation therapy (ADT), and external beam radiation therapy (EBRT) + ADT. PATIENTS AND METHODS: Patients with LNM after RP were identified using the National Cancer Database (2004-2013). Exclusion criteria included any use of radiation therapy or ADT before RP, clinical M1 disease, or incomplete follow-up data. Patients were categorised according to postoperative management strategy. The primary outcome was overall survival (OS). Kaplan-Meier curves and adjusted multivariable Cox proportional hazards models were employed. Sub-analyses further evaluated patient risk stratification and time to receipt of adjuvant therapy. RESULTS: A total of 8 074 patients met the inclusion criteria. Postoperatively, 4 489 (55.6%) received observation, 2 065 (25.6%) ADT, and 1 520 (18.8%) ADT + EBRT. The mean (median; interquartile range) follow-up was 52.3 (48.0; 28.5-73.5) months. Patients receiving ADT or ADT + EBRT had higher pathological Gleason scores, T-stage, positive surgical margin rates, and nodal burden. Adjusted multivariable Cox models showed improved OS for ADT + EBRT vs observation (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.64-0.94; P = 0.008) and vs ADT (HR 0.76, 95% CI: 0.63-0.93; P = 0.007). There was no difference in OS for ADT vs observation (HR 1.01, 95% CI: 0.87-1.18; P = 0.88). Findings were similar when restricting adjuvant cohorts for timing of adjuvant therapy. There was no difference in OS between groups for up to 2 549 (31.6%) patients lacking any of the following adverse features: ≥pT3b disease, Gleason score ≥9, three or more positive nodes, or positive surgical margin. CONCLUSIONS: For patients with LNM after RP, the use of adjuvant ADT + EBRT improved OS in the majority of patients, especially those with adverse pathological features. Conversely, adjuvant therapy did not confer significant OS benefit in up to 30% of patients without high-risk features, who may be managed with observation and forego the morbidity associated with immediate ADT or radiation.

Evaluating the impact of length of time from diagnosis to surgery in patients with unfavourable intermediate-risk to very-high-risk clinically localised prostate cancer.

OBJECTIVE: To evaluate the impact of length of time from diagnostic biopsy to radical prostatectomy (RP) on oncological outcomes amongst men diagnosed with unfavourable intermediate- to very-high-risk clinically localised prostate cancer. PATIENTS AND METHODS: We performed a retrospective review of men with a diagnosis of grade group (GG) ≥3 prostate cancer on biopsy, who underwent RP within 6 months of diagnosis, at our institution between 2005 and 2018. We assessed patient demographics, pre-biopsy disease characteristics, and receipt of neoadjuvant therapy. We categorised time between biopsy and RP into two intervals: <3 and 3-6 months. For each GG, we compared receipt of adjuvant therapy, pathological outcomes at RP (positive surgical margin [PSM], extraprostatic extension [EPE], seminal vesicle invasion [SVI], and lymph node involvement [LNI]), risk of 2- and 5-year biochemical recurrence-free survival (BCRFS), and 2-, 5-, and 10-year metastasis-free survival (MFS) between patients who underwent RP at <3 vs 3-6 months after diagnosis. RESULTS: Amongst 2303 men who met the study inclusion criteria, 1244 (54%) had GG 3, 608 (26%) had GG 4, and 451 (20%) had GG 5 disease. In all, 72% underwent RP at <3 months after diagnosis. For each diagnostic GG, there was no significant difference in rates of adjuvant therapy, PSM, EPE, SVI, or LNI in men who had RP at <3 vs 3-6 months after diagnosis. In all, 1568 men had follow-up after RP of >1 year. For each diagnostic GG, there was no significant difference in 2- and 5-year BCRFS between patients who had RP at <3 vs 3-6 months after diagnosis (GG 3: 78% vs 83% and 69% vs 66%, respectively, P = 0.6; GG 4: 68% vs 74% and 51% vs 57%, respectively, P = 0.4; GG 5: 58% vs 74% and 48% vs 54%, respectively, P = 0.2). Similarly, for each diagnostic GG, there was no significant difference in 2-, 5-, and 10-year MFS between patients who had RP at <3 vs 3-6 months after diagnosis, although we were not able to calculate 10-year MFS for patients with GG 5 disease due to limited follow-up in that group (GG 3: 98%, 92%, and 84% vs 97%, 95%, and 91%, respectively, P = 0.4; GG 4: 97%, 90%, and 72% vs 94%, 91%, and 81%, respectively, P = 0.8; GG 5: 89% and 81% vs 91% and 71%, respectively, P = 0.9). CONCLUSIONS: Waiting for RP up to 6 months after diagnosis is not associated with adverse outcomes amongst patients with unfavourable intermediate- to very-high-risk prostate cancer.

Subtyping the Risk of Intermediate Risk Prostate Cancer for Active Surveillance Based on Adverse Pathology at Radical Prostatectomy.

PURPOSE: Intermediate risk prostate cancer is a heterogenous classification with favorable proposed criteria based on men treated with radiation therapy. However, there is uncertain application to active surveillance. We quantified the rate of adverse surgical pathology and implications for survival in patients at favorable intermediate risk compared to those with low risk prostate cancer. MATERIALS AND METHODS: We performed a comparative cohort study of men with prostate cancer from 2009 to 2013 in the National Cancer Database who underwent radical prostatectomy. The study primary end point was adverse pathology, defined as Grade Group 3 or greater/pT3b/pN1. Various favorable intermediate risk definitions were evaluated, including the Memorial Sloan Kettering Cancer Center definition of Grade Group 2 or less with only 1 intermediate risk factor (Grade Group 2/cT2b/prostate specific antigen 10 to 20 ng/ml), which we defined as type 1 intermediate risk. The remaining patients at intermediate risk were classified as type 2 intermediate risk. Log binomial, logistic and Cox proportional hazards regression models were applied. RESULTS: Adverse pathological findings were noted in 3,519 of the 51,688 patients (6.8%) at low risk and 8,888 of the 42,720 Grade Group 2 patients (20.8%) at intermediate risk (RR 3.06, 95% CI 2.95-3.17, p <0.001). Stratification by prostate specific antigen and volume minimally impacted the absolute rate. Results were similar for the Memorial Sloan Kettering Cancer Center definition (type 1 intermediate risk). Type 2 intermediate risk led to a greater risk of adverse pathology (RR 8.52, 8.23-8.82, p <0.001) and Grade Group 1 intermediate risk led to lower risk (RR 2.00, 1.86-2.16, p <0.001). Patients at favorable intermediate risk had worse overall survival than patients at low risk in adjusted models due to adverse pathology. CONCLUSIONS: Adverse pathology at radical prostatectomy was observed at a threefold higher rate in patients classified at favorable intermediate risk compared to low risk, leading to worse overall survival. Men at intermediate risk may be better classified as types 1 and 2 since none showed pathological outcomes similar to those of men at low risk.

Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer.

PURPOSE: Studies demonstrating bacterial DNA and cultivable bacteria in urine samples have challenged the clinical dogma that urine is sterile. Furthermore, studies now indicate that dysbiosis of the urinary microbiome is associated with pathological conditions. We propose that the urinary microbiome may influence chronic inflammation observed in the prostate, leading to prostate cancer development and progression. Therefore, we profiled the urinary microbiome in men with positive vs negative biopsies for prostate cancer. MATERIALS AND METHODS: Urine was collected from men prior to biopsy for prostate cancer. DNA was extracted from urine pellet samples and subjected to bacterial 16S rDNA Illumina® sequencing and 16S rDNA quantitative polymerase chain reaction. We determined the association between bacterial species and the presence or absence of cancer, cancer grade, and type and degree of prostate inflammation. RESULTS: Urine samples revealed diverse bacterial populations. There were no significant differences in α or ß diversity and no clear hierarchical clustering of benign or cancer samples. We identified a cluster of pro-inflammatory bacteria previously implicated in urogenital infections in a subset of samples. Many species, including known uropathogens, were significantly and differentially abundant among cancer and benign samples, in low vs higher grade cancers and in relation to prostate inflammation type and degree. CONCLUSIONS: To our knowledge we report the most comprehensive study to date of the male urinary microbiome and its relationship to prostate cancer. Our results suggest a prevalence of pro-inflammatory bacteria and uropathogens in the urinary tract of men with prostate cancer.

Prostate Specific Membrane Antigen Targeted 18F-DCFPyL Positron Emission Tomography/Computerized Tomography for the Preoperative Staging of High Risk Prostate Cancer: Results of a Prospective, Phase II, Single Center Study.

PURPOSE: We prospectively evaluated the diagnostic performance of prostate specific membrane antigen targeted 18F-DCFPyL positron emission tomography/computerized tomography in the preoperative staging of men at high risk for harboring metastatic prostate cancer despite a negative conventional staging evaluation. MATERIALS AND METHODS: Men with clinically localized high or very high risk prostate cancer were imaged with 18F-DCFPyL positron emission tomography/computerized tomography before undergoing radical prostatectomy with standardized pelvic lymph node dissection. The scans were interpreted by 2 blinded nuclear medicine readers and assessed for interreader variability as well as diagnostic accuracy for pelvic lymph node staging. Surgical pathology served as the reference standard to which 18F-DCFPyL scan findings were compared. RESULTS: A total of 25 men contributed analyzable data to this study. Seven of these patients (28%) were found to have 1 or more positive lymph nodes on surgical pathology. Sites of radiotracer uptake were identified in the prostate of all imaged patients. The 2 readers identified the same number of prostatic lesions in 22 patients (88%), of whom all had at least 1 intraprostatic lesion in common between the 2 reads. Additionally, the readers assigned the same N stage to 46 of 50 individual lymph node packets (92%). Following reconciliation of the relatively few discordant imaging reads, 7 patients (28%) were found to have 1 or more sites of radiotracer uptake in the pelvis consistent with N1 disease, resulting in 71.4% sensitivity (95% CI 29.0-96.3) and 88.9% specificity (95% CI 65.3-98.6). Analysis at the level of individual nodal packets resulted in 66.7% sensitivity (95% CI 29.9-92.5) and 92.7% specificity (95% CI 80.1-98.5). Three men (12%) had evidence of M1a disease. CONCLUSIONS: 18F-DCFPyL positron emission tomography/computerized tomography allowed for accurate detection of prostate cancer sites in men believed to have clinically localized disease based on conventional imaging. Our results support the need for a larger study to more precisely define the diagnostic accuracy of this novel molecular imaging test.

Combining Prostate Health Index density, magnetic resonance imaging and prior negative biopsy status to improve the detection of clinically significant prostate cancer.

OBJECTIVES: To determine the performance of Prostate Health Index (PHI) density (PHID) combined with MRI and prior negative biopsy (PNB) status for the diagnosis of clinically significant prostate cancer (PCa). PATIENTS AND METHODS: Patients without a prior diagnosis of PCa, with elevated prostate-specific antigen and a normal digital rectal examination who underwent PHI testing prospectively prior to prostate biopsy were included in this study. PHID was calculated retrospectively using prostate volume derived from transrectal ultrasonography at biopsy. Univariable and multivariable logistic regression modelling, along with receiver-operating characteristic (ROC) curve analysis, was used to determine the ability of serum biomarkers to predict clinically significant PCa (defined as either grade group [GG] ≥2 disease or GG1 PCa detected in >2 cores or >50% of any one core) on biopsy. Age, PNB status and Prostate Imaging Reporting and Data System (PI-RADS) score were incorporated into the regression models. RESULTS: Of the 241 men who qualified for the study, 91 (37.8%) had clinically significant PCa on biopsy. The median (interquartile range) PHID was 0.74 (0.44-1.24); it was 1.18 (0.77-1.83) and 0.55 (0.38-0.89) in those with and without clinically significant PCa on biopsy, respectively (P < 0.001). On univariable logistic regression, age and PNB status were associated with clinically significant cancer. Of the tested biomarkers, PHID demonstrated the highest discriminative ability for clinically significant disease (area under the ROC curve [AUC] 0.78 for the univariable model). That continued to be the case in multivariable logistic regression models incorporating age and PNB status (AUC 0.82). At a threshold of 0.44, representing the 25th percentile of PHID in the cohort, PHID was 92.3% sensitive and 35.3% specific for clinically significant PCa; the sensitivity and specificity were 93.0% and 32.4% and 97.4% and 29.1% for GG ≥2 and GG ≥3 disease, respectively. In the 104 men who underwent MRI, PI-RADS score was complementary to PHID, with a PI-RADS score ≥3 or, if PI-RADS score ≤2, a PHID ≥0.44, detecting 100% of clinically significant disease. For that subgroup, of the biomarkers tested, PHID (AUC 0.90) demonstrated the highest discriminative ability for clinically significant disease on multivariable logistic regression incorporating age, PNB status and PI-RADS score. CONCLUSIONS: In this contemporary cohort of men undergoing prostate biopsy for the diagnosis of PCa, PHID outperformed PHI and other PSA derivatives in the diagnosis of clinically significant cancer. Incorporating age, PNB status and PI-RADS score led to even further gains in the diagnostic performance of PHID. Furthermore, PI-RADS score was found to be complementary to PHID. Using 0.44 as a threshold for PHID, 35.3% of unnecessary biopsies could have been avoided at the cost of missing 7.7% of clinically significant cancers. Despite these encouraging results, prospective validation is needed.

Risk factors for metastatic prostate cancer: A sentinel event case series.

BACKGROUND: Root cause analysis is a technique used to assess systems factors related to "sentinel events"-serious adverse events within healthcare systems. This technique is commonly used to identify factors, which allowed these adverse events to occur, to target areas for improvement and to improve health care delivery systems. We sought to apply this technique to men presenting with metastatic prostate cancer (PCa). METHODS: We performed an in-depth case series analysis of 15 patients, who presented with metastatic disease at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center using root cause analysis to refine a list of health system factors that lead to late stage presentation in the current era. RESULTS: Key factors in late diagnosis of PCa included lack of insurance, lack of routine PSA testing, comorbidities, reticence of patients to follow up actionable PSA, and aggressive disease. Three patients had aggressive disease that would not have been discovered at an early stage in the disease process, despite routine screening. However, analysis of the remaining 12 patients illuminated health system factors led to missing important diagnostic information, which might have led to diagnosis of PCa at a curable stage. CONCLUSIONS: The cases help highlight the need for systems based approaches to early diagnosis of PCa. A heterogeneous group of barriers to early diagnosis were identified in our series of patients including economic, health systems, and cultural factors. These findings underscore the need for individualized approaches to preventing delayed diagnosis of PCa. While limited by our single-institution scope, this approach provides a model for research and quality improvement initiatives to identify modifiable systems factors impeding appropriate diagnoses of PCa.

Implementation of a Surgeon-Level Comparative Quality Performance Review to Improve Positive Surgical Margin Rates during Radical Prostatectomy.

PURPOSE: Success in the era of value-based payment will depend on the capacity of health systems to improve quality while controlling costs. Comparative quality performance review can be used to drive improvements in surgical outcomes and thereby reduce costs. We sought to determine the efficacy of a comparative quality performance review to improve a surgeon-level measure of surgical oncologic quality, that is the positive surgical margin rate at the time of radical prostatectomy. MATERIALS AND METHODS: Eight surgeons who performed consecutive radical prostatectomies at a single high volume institution between January 1, 2015 and December 31, 2015 were included in analysis. Individual surgeons were provided with confidential report cards every 6 months detailing their case mix, case volume and pT2 radical prostatectomy positive surgical margin rate relative to 1) their own self-matched data, 2) the de-identified data of their colleagues and 3) institutional aggregate data during the study period. Positive surgical margin rates were compared before and after intervention. Hierarchal logistic regression analysis was used to examine the association of study period on the odds of positive surgical margins, adjusted for prostate specific antigen level and National Comprehensive Cancer Network® risk group. RESULTS: Overall, 1,822 (1,392 before and 430 after intervention) radical prostatectomies were performed that met study inclusion criteria. The aggregate departmental unadjusted positive surgical margin rates were 10.6% and 7.4% in the pre-intervention and post-intervention groups, respectively. After adjusting for higher risk cancer in the post-intervention group, there was a significant protective association of post-intervention status on positive margins (OR 0.64, 95% CI 0.43-0.97, p = 0.03). All 5 surgeons with positive surgical margin rates higher than the aggregate department rate in the pre-intervention period showed improvement after intervention. CONCLUSIONS: Comparative quality performance review can be implemented at the surgeon level and can promote improvement in an objective measure of surgical oncology quality.

The Impact of Downgrading from Biopsy Gleason 7 to Prostatectomy Gleason 6 on Biochemical Recurrence and Prostate Cancer Specific Mortality.

PURPOSE: Gleason score is one of the most important prognostic indicators for prostate cancer. Downgrading from biopsy Gleason score 7 to radical prostatectomy Gleason score 6 occurs commonly and yet to our knowledge the impact on survival outcomes is unknown. We examined biochemical recurrence and prostate cancer specific mortality risk in a large cohort evaluated by a single group of expert urological pathologists. MATERIALS AND METHODS: Of 23,918 men who underwent radical prostatectomy at our institution between 1984 and 2014, 10,236 with biopsy and radical prostatectomy Gleason score 6 or 7 without upgrading were included in analysis. The cohort was divided into 3 groups, including group 1-biopsy and radical prostatectomy Gleason score 6 in 6,923 patients (67.6%), group 2-Gleason score 7 downgraded to radical prostatectomy Gleason score 6 in 648 (6.3%) and group 3-biopsy and radical prostatectomy Gleason score 7 in 2,665 (26.0%). Biochemical recurrence and prostate cancer specific mortality risks were compared using Cox regression and competing risk analyses adjusting for clinicopathological variables. RESULTS: At a median followup of 5 years (range 1 to 29), 992 men experienced biochemical recurrence and 95 had died of prostate cancer. Biochemical recurrence-free survival in downgraded cases (group 2) was better than in group 3 cases, which had Gleason score 7 on biopsy and radical prostatectomy (p <0.001), but worse than group 1 cases, which had Gleason score 6 on biopsy and radical prostatectomy (p <0.001). Downgrading was independently associated with biochemical recurrence (adjusted HR 1.87, p <0.0001) but not with prostate cancer specific mortality (adjusted HR 1.65, p = 0.636). CONCLUSIONS: Downgrading from biopsy Gleason score 7 to radical prostatectomy Gleason score 6 was an independent predictor of biochemical recurrence but not prostate cancer specific mortality, likely due to the presence of minor amounts of Gleason pattern 4.

Prediction of pathological stage based on clinical stage, serum prostate-specific antigen, and biopsy Gleason score: Partin Tables in the contemporary era.

OBJECTIVE: To update the Partin Tables for prediction of pathological stage in the contemporary setting and examine trends in patients treated with radical prostatectomy (RP) over the past three decades. PATIENTS AND METHODS: From January 2010 to October 2015, 4459 men meeting inclusion criteria underwent RP and pelvic lymphadenectomy for histologically confirmed prostate cancer at the Johns Hopkins Hospital. Preoperative clinical stage, serum prostate-specific antigen (PSA) level, and biopsy Gleason score (i.e. prognostic Grade Group) were used in a polychotomous logistic regression model to predict the probability of pathological outcomes categorised as: organ-confined (OC), extraprostatic extension (EPE), seminal vesicle involvement (SV+), or lymph node involvement (LN+). Preoperative characteristics and pathological findings in men treated with RP since 1983 were collected and clinical-pathological trends were described. RESULTS: The median (range) age at surgery was 60 (34-77) years and the median (range) PSA level was 4.9 (0.1-125.0) ng/mL. The observed probabilities of pathological outcomes were: OC disease in 74%, EPE in 20%, SV+ in 4%, and LN+ in 2%. The probability of EPE increased substantially when biopsy Gleason score increased from 6 (Grade Group 1, GG1) to 3 + 4 (GG2), with smaller increases for higher grades. The probability of LN+ was substantially higher for biopsy Gleason score 9-10 (GG5) as compared to lower Gleason scores. Area under the receiver operating characteristic curves for binary logistic models predicting EPE, SV+, and LN+ vs OC were 0.724, 0.856, and 0.918, respectively. The proportion of men treated with biopsy Gleason score ≤6 cancer (GG1) was 47%, representing a substantial decrease from 63% in the previous cohort and 77% in 2000-2005. The proportion of men with OC cancer has remained similar during that time, equalling 73-74% overall. The proportions of men with SV+ (4.1% from 3.4%) and LN+ (2.3% from 1.4%) increased relative to the preceding era for the first time since the Partin Tables were introduced in 1993. CONCLUSIONS: The Partin Tables remain a straightforward and accurate approach for projecting pathological outcomes based on readily available clinical data. Acknowledging these data are derived from a tertiary care referral centre, the proportion of men with OC disease has remained stable since 2000, despite a substantial decline in the proportion of men with biopsy Gleason score 6 (GG1). This is consistent with the notion that many men with Gleason score 6 (GG1) disease were over treated in previous eras.