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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.

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.

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: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...

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

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.

OBJECTIVE Judicious opioid stewardship would match each patient's prescription to their true medical necessity. However, most prescribing paradigms apply preset quantities and clinical judgment without objective data to predict individual use. We evaluated individual patient and in-hospital parameters as predictors of post-discharge opioid utilization after radical prostatectomy (RP) to provide evidence-based guidance for individualized prescribing. METHODS A prospective cohort of patients who underwent open or robotic RP were followed in the Opioid Reduction Intervention for Open, Laparoscopic, and Endoscopic Surgery (ORIOLES) initiative. Baseline demographics, in-hospital parameters, and inpatient and post-discharge pain medication utilization were tabulated. Opioid medications were converted to oral morphine equivalents (OMEQ). Predictive factors for post-discharge opioid utilization were analyzed by univariable and multivariable linear regression, adjusting for opioid reduction interventions performed in ORIOLES. RESULTS Of 443 patients, 102 underwent open and 341 underwent robotic RP. The factors most strongly associated with post-discharge opioid utilization included inpatient opioid utilization in the final 12 hours before discharge (+39.6 post-discharge OMEQ if inpatient OMEQ was >15 vs. 0), maximum patient-reported pain score (range 0-10) in the 12 hours before discharge (+27.6 OMEQ for pain score ≥6 vs. ≤1), preoperative opioid use (+76.2 OMEQ), and body mass index (BMI; +1.4 OMEQ per 1 kg/m2). A final predictive calculator to guide post-discharge opioid prescribing was constructed. CONCLUSIONS Following RP, inpatient opioid use, patient-reported pain scores, prior opioid use, and BMI are correlated with post-discharge opioid utilization. These data can help guide individualized opioid prescribing to reduce risks of both overprescribing and underprescribing.

Objective To perform an early comparative study of outcomes between single-port and robot-assisted laparoscopic radical prostatectomy (SP-RALRP) and standard RALRP at our institution and pooled analysis of series to date. Patients and Methods Patients with organ-confined prostate cancer undergoing SP-RALRP at a high-volume institution were identified retrospectively along with reported SP-RALRP series to date. Data were compared to a contemporary prospective cohort of men undergoing standard RALRP. Patient demographics, perioperative and postoperative data, and complications categorized by the Clavien-Dindo system were compared for the institutional and pooled SP-RALRP cohorts to standard RALRP. Results A total of 208 SP-RALRP cases were identified (26 from our institution) and compared to 376 standard RALRP cases. In the institutional analysis, there was no difference in operative time, length of stay, overall complications (15.4% vs 17.3%, P= 1.0), major (Clavien ≥III) complications (3.8% vs 3.7%, P = .6), inpatient opioid use, or patient-reported pain scores; median estimated blood loss (100 mL vs 150 mL, P = .02) and number of lymph nodes removed (5.5 vs 9, P = .002) were lower for SP-RALRP. In the pooled analysis, 208 patients receiving SP-RALRP had similar estimated blood loss and complication rates but fewer lymph nodes removed (P = .02) and marginally longer operating time (+16 minutes, P = .01) compared to standard RALRP. The difference in rate of positive surgical margins was not statistically significant (31.3% vs 24.5%, P = .08). Conclusion Based on an early experience with SP-RALRP at a high-volume center and a pooled analysis of SP series to date, perioperative and pathologic outcomes appear nearly equivalent compared to standard RALRP.

Background: Up to half of men with Gleason score 6 (GS6) prostate cancers initially managed with active surveillance (AS) will eventually require definitive therapy, usually due to tumor grade reclassification during follow-up. We examined the association between PTEN status on biopsy and subsequent clinicopathologic outcomes in men with GS6 cancers who enrolled in AS. Methods: We performed a case-control study of men enrolled in the Johns Hopkins AS cohort with diagnostic biopsy tissue available for immunohistochemical (IHC) staining. IHC was performed for PTEN using genetically-validated protocols for all patients. Cases included men who underwent grade reclassification to GS ≥ 3+4=7 on biopsy within two years of follow-up (i.e. early reclassification) or reclassification to GS ≥ 4+3=7 on biopsy or radical prostatectomy during follow-up (i.e. extreme reclassification). Control patients were diagnosed with GS6 cancer and monitored on AS for at least eight years without undergoing biopsy reclassification. Results: Among 67 cases with adequate tissue, 31 men underwent early reclassification and 36 men underwent extreme reclassification. Cases were compared to 65 control patients with adequate tissue for assessment. On initial prostate biopsy, cases were older (median age 67 vs. 65, p=0.024) and were less likely to meet very low risk criteria (64% vs 79%, p=0.042) as compared to controls. Although not statistically significant, PTEN loss was observed in only one (2%) of 65 controls as compared to six (9%) of 67 cases (p=0.062). Conclusions: PTEN loss was rare among men with GS6 prostate cancer enrolled in AS at Johns Hopkins. Despite this, PTEN loss was more frequent among men who underwent early or extreme reclassification to higher-grade cancer as compared to controls. Additional studies in larger low-risk cohorts may better elucidate a potential role for PTEN in selecting patients for AS.

We assessed the risk of locally aggressive behavior in pure Gleason score 6 (Grade Group 1) prostate cancer using contemporary grading criteria. To our knowledge this has been studied in only 1 prior cohort.We evaluated consecutive radical prostatectomy specimens from an academic institution, including those from 3,291 men with Gleason score 6 and 4,202 with Gleason score 3 + 4 = 7 (Grade Group 2) disease between 2005 and 2016. For dichotomous variables the Pearson chi-square test was used.Of the 3,288 Gleason score 6 cancer cases 128 (3.9%) showed focal extraprostatic extension compared to 593 of the 4,202 (14.1%) with Gleason score 3 + 4 = 7 (p0.0001). Of the 3,288 Gleason score 6 cancer cases 79 (2.4%) showed nonfocal extraprostatic extension compared to 639 of the 4,202 (15.2%) with Gleason score 3 + 4 = 7 (p0.0001). The incidence of focal extraprostatic extension with Gleason score 3 + 4 = 7 with less than 5% Gleason pattern 4 was 129 of 1,147 cases (11.2%), which was between Gleason scores 6 and 3 + 4 = 7 with greater than 5% Gleason pattern 4. The incidence of nonfocal extraprostatic extension in Gleason score 3 + 4 = 7 with less than 5% Gleason pattern 4 was 96 of 1,147 cases (8.4%), which was between Gleason scores 6 and 3 + 4 = 7 with greater than 5% Gleason pattern 4. One of the 3,290 Gleason score 6 cases (0.03%) showed seminal vesicle invasion compared to 93 of the 4,202 (2.2%) of Gleason score 3 + 4 = 7 (p 0.0001). A limitation of our study was its retrospective design.It is not rare for pure Gleason score 6 prostate cancer to locally extend out of the prostate 3.9% focally and 2.4% nonfocally. In extremely rare cases Gleason score 6 can be associated with seminal vesicle invasion and yet not lymph node metastases. Our overall findings support the argument for continuing to use the term cancer for these tumors.

Background The newly proposed five-tiered prostate cancer grading system (PCGS) divides Gleason score (GS) 8–10 disease into GS 8 and GS 9–10 on the basis of biochemical recurrence (BCR) following radical prostatectomy (RP) as an outcome. However, BCR does not necessarily portend worse survival outcomes. Objective To assess the significance of distinguishing GS 8 versus 9–10 disease in terms of long-term survival outcomes for both the preoperative setting using biopsy (Bx) GS and the postoperative setting with RP GS. Design, setting, and participants Of 23918 men who underwent RP between 1984 and 2014, there were 721 men with biopsy GS 8–10, and 1047 men with RP GS 8–10. Outcome measures and statistical analysis Clinicopathologic characteristics were compared between men with GS 8 and those with GS 9–10. We compared all-cause mortality (ACM) and prostate cancer–specific mortality (PCSM) risk between the groups using Cox regression and competing-risks analyses, adjusting for other perioperative variables and death from other causes as the competing event. Results and limitations Compared to men with GS 8, men with GS 9–10 had later RP year and higher pathologic stage. Among men with Bx GS 8–10, 115 died (82 due to PC) with median follow-up of 3 yr (interquartile range [IQR] 1–7) for both overall and cancer-specific survival. Of men with RP GS 8–10, 221 died (151 due to PC) with median follow-up of 4 yr (IQR 2–8) and 4 yr (IQR 2–9) for overall and cancer-specific survival, respectively. PC-specific survival rates were significantly lower for men with GS 9–10 compared to men with GS 8 for both Bx (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.37–3.30; p p Conclusions Men with GS 9–10 had higher ACM and PCSM rates compared to those with GS 8. GS 8 and GS 9–10 PC should be considered separately in both the preoperative and postoperative setting as suggested by the new PCGS. Patient summary The prostate cancer grading system can predict mortality risk after radical prostatectomy (RP) for men with Gleason score 8–10 disease based on both biopsy and RP Gleason scores. There are significant differences in all-cause mortality and prostate cancer–specific mortality following surgery between men with Gleason score 8 and those with Gleason score 9–10 disease.

African-American (AA) men have a higher risk of lethal prostate cancer (PCa) compared to European-American (EA) men. However, the molecular basis of this difference, if any, remains unclear. In EA PCa, PTEN loss, but not ERG rearrangement, has been associated with poor outcomes in most studies. Although ERG rearrangement is less common in AA compared to EA PCa, the relative frequency of PTEN loss and the association of PTEN/ERG molecular subtypes with outcomes is unknown for AA PCa. We examined PTEN/ERG status by immunohistochemistry in self-identified AA patients undergoing radical prostatectomy at Johns Hopkins with tumor tissue available on tissue microarray (TMA; n=169) and matched these cases by pathologic parameters to 169 EA patients from the same TMAs. The rate of PTEN loss was significantly lower in AA compared to EA PCa (18% vs 34%; p=0.001), similar to the lower rate of ERG expression (25% vs 51%; p0.001). To examine the association of PTEN/ERG status with oncologic outcomes, we created an additional TMA of 87 AA tumors with Gleason score4 + 3 = 7. Among the total population of AA men with outcome data from all TMAs (n=222), PTEN loss was associated with higher risk of biochemical recurrence (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.82) and metastasis (HR 3.90, 95% CI 1.46-10.4) in multivariable models.PTEN and ERG alterations in prostate cancer are less likely in African-American than in European-American men. However, PTEN loss remains associated with poor prostate cancer outcomes among African-American men.

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 ...

BackgroundPathological and clinical stage are associated with prostate cancer-specific survival after prostatectomy. With PSA screening, the post-surgery prognostic utility of clinical stage is debatable in studies seeking to identify new biomarkers. Few studies have investigated clinical stage and lethal prostate cancer association after accounting for pathological stage. We hypothesize that clinical stage provides prognostic information beyond pathological stage in the PSA era.MethodsCox regression models tested associations between clinical and pathological stage and lethal prostate cancer among 3,064 participants from the Health Professionals Follow-Up Study and Physicians' Health Study (HPFS/PHS) who underwent prostatectomy. Likelihood ratio tests and c-statistics were used to assess the models' prognostic utility. Equivalent analyses were performed in 16,134 men who underwent prostatectomy at Johns Hopkins.ResultsIndependently, clinical and pathological stage were associated (pConclusionsDespite stage migration resulting from widespread PSA screening, clinical stage remains associated with progression to lethal prostate cancer independent of pathological stage. Future studies evaluating associations between new factors and poor outcome following prostatectomy should consider including both clinical and pathological stages since the data is already available.

OBJECTIVES To evaluate the effect of a prospective opioid reduction intervention after radical prostatectomy (RP; based on a surgery-specific guideline and education) on post-discharge opioid prescribing, use, disposal, and need for additional opioid medication. PATIENTS AND METHODS A prospective, non-randomised, pre-post interventional trial of patients undergoing RP for prostate cancer (August 2017-November 2018) was conducted as part of the Opioid Reduction Intervention for Open, Laparoscopic, and Endoscopic Surgery (ORIOLES) Initiative. An evidence-based intervention including: a discharge sheet, nursing education, and standardised prescribing guideline, was applied with the primary outcome of total oral morphine equivalents (OMEQ) used after RP. Secondary outcomes included opioid prescribing, opioid disposal, need for additional opioid medication, and presence of incisional/post-surgical abdominal pain at 30 days after RP. RESULTS A total of 214 (Pre-Intervention arm) and 229 (Post-Intervention arm) adult patients were enrolled (100% follow-up). The intervention reduced post-discharge opioid prescribing (from 224.3 to 120.3 mg; -46.4%, P = 0.01), reduced opioid use (from 52.1 to 38.3 mg; -26.5%, P

INTRODUCTION AND OBJECTIVES:Opioid pain medications are overprescribed, but little data is available to appropriately tailor post-discharge opioid prescriptions after urologic surgery. The Opioid R...

247 Background: The cell cycle progression (CCP) score and PTEN have never been evaluated together as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of men with National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa), nor in such patients who also received salvage radiation (SRT) alone or with androgen deprivation (SRT+ADT). This study evaluated CCP score and PTEN in both settings. Methods: Participants were treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to clinical outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. For overall evaluation of CCP and PTEN in intermediate- and high-risk men a case-cohort sample was selected. Intermediate- and high-risk men with biochemical recurrence who received SRT or SRT+ADT were also sampled to provide a population at particularly high risk. Metastasis-free survival (MFS) was analyzed with the proportional hazards model, weighted for case-cohort design for the overall analysis, and adjusted for CAPRA-S. The clinical cell-cycle risk (CCR) score, a fixed algorithm combining CCP and CAPRA-S was also analyzed in both contexts. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: The case-cohort consisted of 209 men, including 47% with Gleason score >4+3, 48% extra-prostatic extension, and 18% with seminal vesicle or lymph node involvement; 42 (20%) developed metastasis. In univariate analyses CCP, CAPRA-S, and PTEN were all highly significant. In multivariable analysis, only CCP and CAPRA-S retained significance (Table section A). CCR was also strongly prognostic, HR=7.9 (95% CI 4.4, 14.5) per unit change, p4+3, 48% extra-prostatic extension, and 34% seminal vesicle or lymph node involvement; 19 (11%) developed metastases. Again, CCP and CAPRA-S, but not PTEN, were statistically significant (Table section B). CCR was also statistically significant, HR=1.7 (95% CI 1.2, 2.4), p=0.002. Conclusions: This is the first comparison, in a recent cohort of intermediate- and high-risk men, of CCP score and PTEN as risk factors for metastasis, and first evaluation in such men receiving SRT. In both multivariable settings, CCP score, but not PTEN, was significantly associated with MFS, adjusted for CAPRA-S. CCR, a fixed algorithm that combines CCP and CAPRA-S was also significant in both settings. [Table: see text]

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.

Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, 8-10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3+4=7 and 4+3=7 are often considered the same prognostic group.To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data.Between 2005 and 2014, 20,845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions.Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores.In the surgery cohort, we found large differences in recurrence rates between both Gleason 3+4 versus 4+3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3+4, 4+3, 8, and 9-10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five-grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death.The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.

Background Current guidelines suggest adjuvant radiation therapy for men with adverse pathologic features (APFs) at radical prostatectomy (RP). We examine at-risk men treated only with RP until the time of metastasis. Objective To evaluate whether clinicopathologic risk models can help guide postoperative therapeutic decision making. Design, setting, and participants Men with National Comprehensive Cancer Network intermediate- or high-risk localized prostate cancer undergoing RP in the prostate-specific antigen (PSA) era were identified ( n =3089). Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis were included. APFs were defined as pT3 disease or positive surgical margins. Outcome measurements and statistical analysis Area under the receiver operating characteristic curve (AUC) for time to event data was used to measure the discrimination performance of the risk factors. Cumulative incidence curves were constructed using Fine and Gray competing risks analysis to estimate the risk of biochemical recurrence (BCR) or metastasis, taking censoring and death due to other causes into consideration. Results and limitations Overall, 43% of the cohort ( n =1327) had APFs at RP. Median follow-up for censored patients was 5 yr. Cumulative incidence of metastasis was 6% at 10 yr after RP for all patients. Cumulative incidence of metastasis among men with APFs was 7.5% at 10 yr after RP. Among men with BCR, the incidence of metastasis was 38% 5 yr after BCR. At 10 yr after RP, time-dependent AUC for predicting metastasis by Cancer of the Prostate Risk Assessment Postsurgical or Eggener risk models was 0.81 (95% confidence interval [CI], 0.72–0.97) and 0.78 (95% CI, 0.67–0.97) in the APF population, respectively. At 5 yr after BCR, these values were lower (0.58 [95% CI, 0.50–0.66] and 0.70 [95% CI, 0.63–0.76]) among those who developed BCR. Use of risk model cut points could substantially reduce overtreatment while minimally increasing undertreatment (ie, use of an Eggener cut point of 2.5% for treatment of men with APFs would spare 46% from treatment while only allowing for metastatic events in 1% at 10 yr after RP). Conclusions Use of risk models reduces overtreatment and should be a routine part of patient counseling when considering adjuvant therapy. Risk model performance is significantly reduced among men with BCR. Patient summary Use of current risk models can help guide decision making regarding therapy after surgery and reduce overtreatment.

Since 2010 pathologists at our institution have routinely been documenting the Gleason score at the margin and length of the positive surgical margin after prostatectomy. In this study we evaluate how the Gleason score and positive surgical margin length correlate with the grade and adverse pathological characteristics of the final specimen, and whether the positive surgical margin Gleason score affects the risk of early biochemical recurrence.A total of 4,082 consecutive patients undergoing radical prostatectomy and pelvic lymph node dissection between 2010 and 2014 for localized prostate cancer were included in the study, of whom 405 had a Gleason score of 7 or greater of the primary nodule and a positive surgical margin with the length and Gleason score recorded at the margin. Concordance rates between the Gleason score at the margin and the final pathological specimen were compared. Logistic regression models were used to predict the risk of unfavorable pathology. Cox proportional hazards models controlling for Gleason score, preoperative prostate specific antigen, pathological stage and adjuvant radiation were used to predict biochemical recurrence, and Kaplan-Meier estimates of recurrence-free survival were calculated by Gleason score.Among patients with positive margins biochemical recurrence was identified in 22% (vs 5.6% without positive margins), metastases in 3% (vs 0.5%) and adjuvant radiation in 30% (vs 4.1%). Mean followup was 22 months (range 12 to 48). The Gleason score at the positive surgical margin was the same as the final pathology specimen in 44% of patients, and a lower Gleason score in 56% of patients. A shorter positive surgical margin was independently associated with a lower Gleason score at the margin (p=0.02). Kaplan-Meier estimates demonstrated improved freedom from biochemical recurrence among patients with a lower Gleason score at the margin. In multivariate Cox models having a lower grade margin was associated with a decreased risk of biochemical recurrence (HR 0.50, OR 0.25-0.97).A lower Gleason score at the positive surgical margin is independently associated with a shorter margin length and a decreased risk of early biochemical recurrence. Thus, the Gleason score at the margin should be documented.

Radical prostatectomy (RP) is a primary treatment option for men with intermediate- and high-risk prostate cancer. Although many are effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic features and clinical disease recurrence. It has been shown that the Decipher test predicts metastatic progression in cohorts that received adjuvant and salvage therapy following RP.To evaluate the Decipher genomic classifier in a natural history cohort of men at risk who received no additional treatment until the time of metastatic progression.Retrospective case-cohort design for 356 men who underwent RP between 1992 and 2010 at intermediate or high risk and received no additional treatment until the time of metastasis. Participants met the following criteria: (1) Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score ≥3; (2) pathologic Gleason score ≥7; and (3) post-RP prostate-specific antigen nadir0.2 ng/ml.The primary endpoint was defined as regional or distant metastases. Time-dependent receiver operating characteristic (ROC) curves, extension of decision curve analysis to survival data, and univariable and multivariable Cox proportional-hazards models were used to measure the discrimination, net benefit, and prognostic potential of genomic and pathologic risk factors. Cumulative incidence curves were constructed using Fine-Gray competing-risks analysis with appropriate weighting of the controls to account for the case-cohort study design.Ninety six patients had unavailable tumor blocks or failed microarray quality control. Decipher scores were then obtained for 260 patients, of whom 99 experienced metastasis. Decipher correlated with increased cumulative incidence of biochemical recurrence, metastasis, and prostate cancer-specific mortality (p0.01). The cumulative incidence of metastasis was 12% and 47% for patients with low and high Decipher scores, respectively, at 10 yr after RP. Decipher was independently prognostic of metastasis in multivariable analysis (hazard ratio 1.26 per 10% increase; p0.01). Decipher had a c-index of 0.76 and increased the c-index of Eggener and CAPRA-S risk models from 0.76 and 0.77 to 0.86 and 0.87, respectively, at 10 yr after RP. Although the cohort was large, the single-center retrospective design is an important limitation.In a patient population that received no adjuvant or salvage therapy after prostatectomy until metastatic progression, higher Decipher scores correlated with clinical events, and inclusion of Decipher scores improved the prognostic performance of validated clinicopathologic risk models. These results confirm the utility already reported for Decipher.The Decipher test improves identification of patients most at risk of metastatic progression and death from prostate cancer after radical prostatectomy.

We previously demonstrated the ability to detect metastatic prostate cancer using N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC), a low-molecular-weight radiotracer that targets the prostate-specific membrane antigen (PSMA). PSMA has been shown to be associated with higher Gleason grade and more aggressive disease. An imaging biomarker able to detect clinically significant high-grade primary prostate cancer reliably would address an unmet clinical need by allowing for risk-adapted patient management. Methods: We enrolled 13 patients with primary prostate cancer who were imaged with 18F-DCFBC PET before scheduled prostatectomy, with 12 of these patients also undergoing pelvic prostate MR imaging. Prostate 18F-DCFBC PET was correlated with MR imaging and histologic and immunohistochemical analysis on a prostate-segment (12 regions) and dominant-lesion basis. There were no incidental extraprostatic findings on PET suggestive of metastatic disease. Results: MR imaging was more sensitive than 18F-DCFBC PET for detection of primary prostate cancer on a per-segment (sensitivities of up to 0.17 and 0.39 for PET and MR imaging, respectively) and per-dominant-lesion analysis (sensitivities of 0.46 and 0.92 for PET and MR imaging, respectively). However, 18F-DCFBC PET was more specific than MR imaging by per-segment analysis (specificities of 0.96 and 0.89 for PET and MR imaging for corresponding sensitivity, respectively) and specific for detection of high-grade lesions (Gleason 8 and 9) greater than 1.0 mL in size (4/4 of these patients positive by PET). 18F-DCFBC uptake in tumors was positively correlated with Gleason score (ρ = 0.64; PSMA expression, ρ = 0.47; and prostate-specific antigen, ρ = 0.52). There was significantly lower 18F-DCFBC uptake in benign prostatic hypertrophy than primary tumors (median maximum standardized uptake value, 2.2 vs. 3.5; P = 0.004). Conclusion: Although the sensitivity of 18F-DCFBC for primary prostate cancer was less than MR imaging, 18F-DCFBC PET was able to detect the more clinically significant high-grade and larger-volume tumors (Gleason score 8 and 9) with higher specificity than MR imaging. In particular, there was relatively low 18F-DCFBC PET uptake in benign prostatic hypertrophy lesions, compared with cancer in the prostate, which may allow for more specific detection of primary prostate cancer by 18F-DCFBC PET. This study demonstrates the utility of PSMA-based PET, which may be used in conjunction with MR imaging to identify clinically significant prostate cancer.

Regional and local variation in radical prostatectomy rates contribute to overtreatment of low risk prostate cancer. We hypothesized that individual practice variability would be minimal among urologists practicing at a high volume academic center.We assessed the percent of patients at low risk treated with radical prostatectomy in a given year and comorbidity adjusted life expectancy in an institutional database accounting for temporal trends and disease characteristics. Multivariable linear, spline and logistic models were applied with a hierarchical random effects model to estimate the proportion of variance due to surgeon and temporal effects.Of the 20,655 men included in study 11,873 (57.5%) had low risk disease. The Gleason score leading to radical prostatectomy increased with time. Overall the percent of patients at low risk treated with prostatectomy in a given year increased 3.49% yearly from 1991 to 2001 and then decreased by 1.73% yearly from 2001 to 2013. Greater surgeon experience was associated with a higher percent of patients at low risk treated with prostatectomy in a given year from 1991 to 2001 (0.46% per year of experience). High volume surgeons (total more than 1,000 radical prostatectomies) operated on a slightly greater percent of patients at low risk (3.54%). Substantial practice variation existed among surgeons for operating on men 65 years old or older at low risk (OR 3.15, 95% CI 1.62-6.11). There was similar variation when operating on older patients with a life expectancy of less than 15 years. Surgeon level and temporal effects explained 24% and 70%, respectively, of the variance in the percent of patients at low risk treated with radical prostatectomy in a given year.At a high volume academic center substantial practice variation exists among surgeons when selecting patients with prostate cancer to undergo radical prostatectomy based on risk and life expectancy even among older patients. In addition to patient decision support tools, publicly reporting individual practice patterns at the provider level could decrease the overtreatment of low risk prostate cancer.

Author(s): Klaassen, Zachary; Singh, Abhay A; Howard, Lauren E; Feng, Zhaoyong; Trock, Bruce; Terris, Martha K; Aronson, William J; Cooperberg, Matthew R; Amling, Christopher L; Kane, Christopher J; Partin, Alan; Han, Misop; Freedland, Stephen J | Abstract: BackgroundClinical stage T2c (cT2c) is an indeterminate factor in prostate cancer (PC) risk stratification. According to the D'Amico grouping and American Urological Association guidelines, cT2c is a high risk, whereas the National Comprehensive Cancer Network and the European Urological Association classify cT2c as an intermediate risk. This study assessed whether cT2c tumors without other high-risk factors (clinical stage T2c, not otherwise specified [cT2c-NOS]) behaved as an intermediate or high risk through an analysis of biochemical recurrence (BCR) after radical prostatectomy.MethodsTwo thousand seven hundred fifty-nine men from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database and 12,900 men from Johns Hopkins Hospital (JHH) from 1988-2011 and 1982-2012, respectively, were analyzed. Patients were grouped into low-risk (prostate-specific antigen [PSA] l 10 ng/mL, Gleason sum ≤ 6, and cT1-T2a), intermediate-risk (PSA = 10-20 ng/mL, Gleason sum = 7, or cT2b), and high-risk PC categories (PSA g 20 ng/mL, Gleason sum = 8-10, or cT3). Men with cT2c tumors who were not otherwise at high risk (ie, PSAl 20 ng/mL and Gleason sum l 8) were placed into a separate category termed cT2c-NOS. Associations between cT2c-NOS and intermediate- and high-risk patients and BCR were tested with the log-rank test and Cox proportional analysis models.ResultsNinety-nine men (4%) from SEARCH and 202 men (2%) from JHH had tumors classified as cT2c-NOS. The cT2c-NOS patients had a BCR risk similar to that of the intermediate-risk patients (SEARCH, P = .27; JHH, P = .23) but a significantly lower BCR risk in comparison with the high-risk patients (SEARCH, P l .001; JHH, P l .001). When they were specifically compared with intermediate- and high-risk patients, after adjustments for year and center, cT2c-NOS patients had outcomes comparable to those of intermediate-risk patients (SEARCH, P = .53; JHH, P = .54) but significantly better than those of high-risk patients (SEARCH, P = .003; JHH, P l .001).ConclusionsPatients with cT2c disease without other high-risk features had outcomes similar to the outcomes of patients with intermediate-risk PC and significantly better than the outcomes of patients with high-risk PC. These findings suggest that men with cT2c disease should be considered to be at intermediate risk.

To report race-based outcomes after radical prostatectomy (RP) in a cohort stratified by National Comprehensive Cancer Network (NCCN) risk category with updated follow-up.Studies describing racial disparities in outcomes after RP are conflicting. We studied 15,993 white and 1634 African American (AA) pretreatment-naïve men who underwent RP at our institution (1992-2013) with complete preoperative and pathologic data. Pathologic outcomes were compared between races using appropriate statistical tests; biochemical recurrence (BCR) for men with complete follow-up was compared using multivariate models that controlled separately for preoperative and postoperative covariates.Very low- and low-risk AA men were more likely to have positive surgical margins (P.01), adverse pathologic features (P.01), and be upgraded at RP (P.01). With a median follow-up of 4.0 years after RP, AA race was an independent predictor of BCR among NCCN low-risk (HR, 2.16; P.001) and intermediate-risk (hazard ratio [HR], 1.34; P = .024) classes and pathologic Gleason score ≤ 6 (HR, 2.42; P.001) and Gleason score 7 (HR, 1.71; P.001). BCR-free survival for very low-risk AA men was similar to low-risk white men (P = .890); BCR-free survival for low-risk AA men was similar to intermediate-risk white men (P = .060).When stratified by NCCN risk, AA men with very low-, low-, or intermediate-risk prostate cancer who undergo RP are more likely to have adverse pathologic findings and BCR compared with white men. AA men with "low risk" prostate cancer, especially those considering active surveillance, should be counseled that their recurrence risks can resemble those of whites in higher risk categories.

Obesity is a modifiable risk factor associated with worse outcomes for many cancers, yet implications for prostate cancer are not well understood. Notably the impact of body mass index on long-term survival after treatment is unclear. We performed a retrospective cohort study on a large series of men who underwent radical prostatectomy to assess the impact of obesity on long-term biochemical recurrence-free survival, prostate cancer specific survival and overall survival.Between 1982 and 2012, 11,152 men underwent radical prostatectomy at a single tertiary referral center. Patients were stratified according to body mass index as normal weight (body mass index less than 25 kg/m(2)), overweight (body mass index 25 to less than 30 kg/m(2)), mild obesity (body mass index 30 to less than 35 kg/m(2)) and moderate/severe obesity (body mass index 35 kg/m(2) or greater), comprising 27.6%, 56.0%, 14.1% and 2.3% of the cohort, respectively. Covariates included age, preoperative prostate specific antigen, surgery year, Gleason score, pathological stage, surgical margin and race. Predictors of biochemical recurrence-free survival, prostate cancer specific survival and overall survival were identified using Cox proportional hazard models.Median followup was 5 years (range 1 to 27). Actuarial 20-year biochemical recurrence-free survival for mild and moderate/severe obesity was 65% and 51%, respectively, compared to 76% for normal weight men (p ≤0.001). In a multivariate model obesity was a significant predictor of biochemical recurrence-free survival (mild HR 1.30, p = 0.002; moderate/severe HR 1.45, p = 0.028) and overall survival (mild HR 1.41, p = 0.003; moderate/severe HR 1.81, p = 0.033). However, only mild obesity was significantly associated with prostate cancer specific survival (HR 1.51, p = 0.040), whereas moderate/severe obesity was not (HR 1.58, p = 0.356).Obese men have higher rates of biochemical recurrence than normal weight patients during long-term followup. Obesity at the time of surgery independently predicts overall survival and biochemical recurrence-free survival but not prostate cancer specific survival.

Objective To investigate the post-prostatectomy and long-term outcomes of men presenting with an elevated pretreatment prostate-specific antigen (PSA) level (>10 ng/mL), but otherwise low-risk features (biopsy Gleason score ≤6 and clinical stage ≤T2a). Patients and Methods PSA-incongruent intermediate-risk (PII) cases were defined as those patients with preoperative PSA >10 and ≤20 ng/mL but otherwise low-risk features, and PSA-incongruent high-risk (PIH) cases were defined as men with PSA >20 ng/mL but otherwise low-risk features. Our institutional radical prostatectomy database (1992–2012) was queried and the results were stratified into D’Amico low-, intermediate- and high risk, PSA-incongruent intermediate-risk and PSA-incongruent high-risk cases. Prostate cancer (PCa) features and outcomes were evaluated using appropriate comparative tests. Multivariable analyses were adjusted for age, race and year of surgery. Results Of the total cohort of 17 608 men, 1132 (6.4%) had PII-risk disease and 183 (1.0%) had PIH-risk disease. Compared with the low-risk group, the odds of upgrading at radical prostatectomy (RP) were 2.20 (95% CI 1.93–2.52; P < 0.001) for the PII group and 3.58 (95% CI 2.64–4.85; P < 0.001) for the PIH group, the odds of extraprostatic disease at RP were 2.35 (95% CI 2.05–2.68; P < 0.001) for the PII group and 6.68 (95% CI 4.89–9.15; P < 0.001) for the PIH group, and the odds of positive surgical margins were 1.97 (95% CI 1.67–2.33; P < 0.001) for the PII group and 3.54 (95% CI 2.50–4.95, P < 0.001) for the PIH group. Compared with low-risk disease, PII-risk disease was associated with a 2.85-, 2.99- and 3.32-fold greater risk of biochemical recurrence (BCR), metastasis and PCa-specific mortality, respectively, and PIH-risk disease was associated with a 5.32-, 6.14- and 7.07-fold greater risk of BCR, metastasis and PCa-specific mortality, respectively (P ≤ 0.001 for all comparisons). For the PII group, the higher risks of positive surgical margins, upgrading, upstaging and BCR were dependent on PSA density (PSAD): men in the PII group who had a PSAD 20 ng/mL or men with PSA >10 and ≤20 ng/mL with a PSAD ≥0.15 ng/mL/g, but otherwise low-risk PCa, are at greater risk of adverse pathological and oncological outcomes and may be inappropriate candidates for active surveillance. These men are at greater risk of having anterior tumours that are undersampled at biopsy, so if treatment is deferred, ancillary testing such as anterior zone sampling or magnetic resonance imaging should be strongly encouraged. Men with elevated PSA levels >10 and ≤20 ng/mL but low PSAD have outcomes similar to those in the low-risk group, and consideration of surveillance is appropriate in these cases.

Blood transfusion (BT) is among the most common hospital procedures, with an estimated 15 million units transfused annually in the United States alone.1 Ideally, indications for BT should be optimized to prevent overuse of a costly resource with potential harms. Accumulating data support a restrictive transfusion strategy with a low hemoglobin threshold (7–8 g/dL) to achieve this goal.2–4 While improved screening has significantly curtailed transmission of viral pathogens, noninfectious hazards of BT are less well understood. Immunosuppression has been observed both clinically and in the laboratory, with prolonged renal allograft survival in patients receiving pretransplant allogeneic BTs.5 Also, nonanemic patients with little operative blood loss who receive BT have a greater risk of perioperative death than their nontransfused counterparts.4,6 The most provocative findings associate increased rates of cancer recurrence and mortality with perioperative BT in colorectal, esophageal, liver, breast, renal, and lung cancer patients.7–11 This observation, which may result from an immunosuppressive effect of allogeneic BT, is regarded as controversial and has been disputed.8,10,11 An alternative explanation for worse outcomes in transfused patients is simple confounding, as patient comorbidities, disease burden, and perioperative complications underlie the decision to transfuse.8,12 Radical prostatectomy (RP) patients comprise a unique population well suited to clarify the relationship of BT with cancer recurrence and mortality. RP is generally recommended for men with long life expectancy and limited comorbidities.13 Modern improvements in surgical technique have largely eliminated life-threatening hemorrhage, but need for BT in these patients persists, prompting some men to donate autologous blood preoperatively. In fact, some have reported absence of an association between autologous or allogeneic BT and prostate cancer recurrence.14–16 Investigations of the association between BT and survival after RP in small series have yielded conflicting results.16–18 The serum prostate-specific antigen (PSA) test facilitates early detection of cancer recurrence, but to capture both cancer-specific and overall mortality outcomes, long-term follow-up is essential due to the protracted clinical course of prostate cancer. We investigated whether perioperative BT (autologous vs. allogeneic) impacts recurrence, as well as cancer-specific survival (CSS) and overall survival (OS) after RP using a large tertiary referral center RP database.

BACKGROUND Men destined to have early biochemical recurrence (BCR) following radical prostatectomy (RP) may be optimal candidates for multimodal treatment. Here we identified pre-operative predictors of early BCR within a surgical cohort who recurred. METHODS An institutional prostate cancer (PCa) database containing over 20,000 patients was queried to identify 1,471 men who had BCR after RP, and pre-operative predictors of early versus late BCR were assessed. Early BCR was defined as recurrence within 1 year after RP. Within the recurrence cohort, those with National Comprehensive Cancer Network (NCCN) high-risk features were more likely to experience early BCR. Therefore, in all NCCN high-risk men in the database, we abstracted detailed pathologic biopsy data. Among 753 high-risk men, 41 alternate multivariable criteria were assessed for their ability to predict early BCR in crude and adjusted logistic regression models. RESULTS The criteria that best identified those likely to experience early BCR are primary Gleason pattern 5 on biopsy or ≥4 cores containing pattern 4 (odds ratio 3.17, P

e16575 Background: To evaluate the cell cycle progression (CCP) score and PTEN as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of NCCN intermediate and high risk prostate cancer. Methods: This IRB-approved case-cohort study included men treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to study outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. Metastasis-free survival (MFS) was analyzed with the Cox proportional hazards model, weighted for case-cohort design. CCP and PTEN were analyzed independently, and adjusted for CAPRA-S. The CCR score, which combines CCP and CAPRA-S, was also analyzed. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: There were 209 patients, of whom 42 were cases (metastasis). Median age was 59 years, 47% had Gleason 4+3 or higher, 48% had non-organ confined tumor, and 18% had seminal vesicle or lymph node involvement. NCCN risk was intermediate in 77% and high in 23%. Median follow-up was 4 years. Both CCP and PTEN, as well as CCR score, were statistically significant in univariate analyses, but only CCP retained statistical significance in a multivariable model of CCP, PTEN, and CAPRA-S (Table). Conclusions: This is the first comparison of the CCP score and PTEN as risk factors for metastasis in a recent RP cohort of patients at NCCN intermediate or high risk. Both CCP score and PTEN were strongly associated with MFS in univariate analyses, but only CCP score retained significance in a multivariable analysis with both biomarkers adjusted for CAPRA-S. [Table: see text]

There is a paucity of data on the prognosis after radical prostatectomy for Gleason score 9-10 disease on needle biopsy. To our knowledge we report the largest study to date to specifically analyze the correlation of Gleason score 9-10 on needle core biopsy with radical prostatectomy outcomes.We identified 259 men with Gleason score 9-10 on biopsy who underwent radical prostatectomy from 1987 to 2012 at our institution. Preoperative variables analyzed were age, race, preoperative prostate specific antigen, adenocarcinoma site, perineural invasion, number of total biopsy cores, number of total positive cores, number of positive cores with Gleason score 9-10, maximum percent of core length with Gleason score 9-10 and maximum percent of adenocarcinoma overall. We determined pathological outcomes on univariate and multivariate analysis, including organ confinement, seminal vesicle invasion, margin status, lymph node metastasis, and biochemical-free and cancer specific survival.Statistically significant predictors of radical prostatectomy outcome were organ confinement (total cores with Gleason score 9-10, maximum percent overall and perineural invasion), margin status (preoperative prostate specific antigen and clinical stage), seminal vesicle invasion (maximum percent overall, perineural invasion and clinical stage), lymph node metastasis (total number of cores with Gleason score 9-10 and clinical stage) and biochemical-free survival (maximum percent of Gleason score 9-10, maximum percent overall and clinical stage) (each p0.05).In the highly select subset of patients who are good surgical candidates and have the appropriate combination of preoperative variables postoperative findings are sufficiently favorable to justify radical prostatectomy.

At our institution the eligibility criteria used to enroll patients in active surveillance are clinical stage T1, prostate specific antigen density less than 0.15 ng/ml, biopsy Gleason score 6 or less, 2 or fewer positive biopsy cores and 50% or less involvement of any biopsy core. We hypothesized that these criteria may be excessively strict, precluding many men from active surveillance.We studied pathological outcomes in men treated with radical prostatectomy between 1995 and 2012 who met 4 or more of the 5 active surveillance criteria. Outcomes included a definition of significant tumor (pathological Gleason 7 or greater, or nonorgan confined). We compared adverse pathology rates between men who met all 5 vs 4 of 5 active surveillance criteria.Of 8,261 men 1,890 (22.9%) met all active surveillance eligibility criteria and 2,133 (25.8%) met 4. Men with values exceeding prostate specific antigen density and biopsy Gleason criteria were at increased risk for adverse pathological outcomes. Clinical stage greater than T1 was not associated with adverse pathological findings. The risk of significant tumors in men with clinical stage T2 lesions, 3 or fewer positive biopsy cores and less than 60% core involvement was comparable to that of men who met all active surveillance criteria.Prostate specific antigen density greater than 0.15 ng/ml and biopsy Gleason score 7 or greater are strongly associated with adverse pathological findings at radical prostatectomy. Our findings suggest that active surveillance criteria should be expanded to include men with clinical stage T2 lesions and a greater number of positive biopsy cores of low grade. Based on these preliminary findings, we are in the process of reassessing active surveillance eligibility criteria using more detailed pathological analysis.

BACKGROUND We report the 30-year institutional experience of radical prostatectomy (RP) for men with clinically localized prostate cancer (PC) found to have lymph node (LN) metastases at surgery. METHODS The Johns Hopkins RP Database (1982–2011) was queried for 505 (2.5%) men with node-positive (N1) PC. Survival analysis was completed using the Kaplan–Meier method and proportional hazard regression models. RESULTS The proportion of men with N1PC was 8.3%, 3.5%, and 1.4% in the pre- (1982–1990), early- (1991–2000), and contemporary-PSA eras (2001–2011), respectively. A trend toward decreasing PSA, less palpable disease but more advanced Gleason sum was noted in the most contemporary era. Median total and positive nodes were 13.2 (1–41) and 1.7 (1–12), respectively. Of 135 patients with a unilateral tumor, 80 (59.3%), 28 (20.7%), and 15 (11.1%) had ipsilateral, contralateral, and bilateral positive LN. 15-year biochemical-recurrence free, metastases-free and cancer-specific survival was 7.1%, 41.5%, and 57.5%, respectively. Predictors of biochemical-recurrence, metastases and death from PC in multivariate analysis included Gleason sum at RP, the number and percent of positive LN; notably total number of LN dissected did not predict outcome. CONCLUSIONS In this highly-selected RP cohort, men found to have N1PC disease at RP can experience a durable long-term metastases-free and cancer-specific survival. Predictors of survival include Gleason sum, number, and percentage of positive LN. While total number of LN dissected was not predictive, approximately 30% of men with N1PC will have positive LN contralateral to the primary prostatic lesion highlighting the importance of a thorough, bilateral pelvic LN dissection. Prostate 73: 1673–1680, 2013. © 2013 Wiley Periodicals, Inc.

Purpose Active surveillance (AS) is a treatment option for men with very low–risk prostate cancer (PCa); however, favorable outcomes achieved for men in AS are based on cohorts that under-represent African American (AA) men. To explore whether race-based health disparities exist among men with very low–risk PCa, we evaluated oncologic outcomes of AA men with very low–risk PCa who were candidates for AS but elected to undergo radical prostatectomy (RP). Patients and Methods We studied 1,801 men (256 AA, 1,473 white men, and 72 others) who met National Comprehensive Cancer Network criteria for very low–risk PCa and underwent RP. Presenting characteristics, pathologic data, and cancer recurrence were compared among the groups. Multivariable modeling was performed to assess the association of race with upgrading and adverse pathologic features. Results AA men with very low–risk PCa had more adverse pathologic features at RP and poorer oncologic outcomes. AA men were more likely to experience disease upgrading at prostatectomy (27.3% v 14.4%; P < .001), positive surgical margins (9.8% v 5.9%; P = .02), and higher Cancer of the Prostate Risk Assessment Post-Surgical scoring system (CAPRA-S) scores. On multivariable analysis, AA race was an independent predictor of adverse pathologic features (odds ratio, [OR], 3.23; P = .03) and pathologic upgrading (OR, 2.26; P = .03). Conclusion AA men with very low–risk PCa who meet criteria for AS but undergo immediate surgery experience significantly higher rates of upgrading and adverse pathology than do white men and men of other races. AA men with very low–risk PCa should be counseled about increased oncologic risk when deciding among their disease management options.

What's known on the subject? and What does the study add? Standard clinical care pathways to discharge have been established for a number of operations including radical prostatectomy (RP). The pathway after RP has changed dramatically over the past two decades due to improvements in surgical technique, anaesthesia and most recently, the introduction of minimally invasive RP (MIRP). This study adds evidence that the emergence of MIRP is associated with a decrease in LOS for all patients undergoing RP. In addition, it catalogues the development of the clinical care pathway over 20 years at a large, tertiary care hospital with extensive experience in RP. Finally, it defines the common reasons patients fall ‘off-pathway’ (ileus, urine leak, anaemia and re-exploration for bleeding) and defines the immediate perioperative morbidity profile of RP. Specifically, it addresses approach-specific morbidities and indicates that MIRP is associated with higher rates of ‘off-pathway’ discharge, most often due to ileus. Objective To investigate the development of the clinical care pathway to discharge after radical prostatectomy (RP) at a large, academic medical centre over the past 20 years, focusing on the rates and reasons for deviation. Patients and Methods In all, 18 049 men were identified from the Johns Hopkins RP database who had undergone surgery since 1991. Patients in whom the length of stay (LOS) was ≤95th percentile, defined the clinical care pathway to discharge and those in whom LOS was ≥98th percentile were termed ‘off-pathway’. Results The mean LOS decreased from 7.7 days in 1991 to 1.6 days in 2010. Of 7126 patients undergoing RP since 2005, 1803(25.3%), 4881(68.5%) and 312 (4.4%) were discharged on postoperative day (POD) 1, 2 and 3, respectively; 126 (1.8%) patients, discharged on POD4–21 were ‘off-pathway’. The most common reasons for delay of discharge were ileus (44, 0.615%), urine leak (12, 0.17%), anaemia requiring blood transfusion (nine, 0.126%) and bleeding requiring re-exploration (six, 0.08%). The proportion of patients ‘off-pathway’ was 1.20%, 1.06% and 4.01% for retropubic RP (RRP), laparoscopic RP (LRP) and robot-assisted laparoscopic RP (RALRP), respectively (P < 0.001). Ileus delayed discharge in 0.28%, 0.37% and 1.9% of patients undergoing RRP, LRP and RALRP, respectively (P < 0.001). Conclusions The clinical care pathway to discharge after RP has changed dramatically at our institution over the past 20 years. RALRP appears to result in a higher proportion of ‘off-pathway’ patients, primarily due to ileus, compared with RRP and LRP. However, very few patients were discharged ‘off-pathway’.

What's known on the subject? and What does the study add? The ideal treatment for men with high-risk prostate cancer is controversial, although most physicians agree that a multimodal approach, including radiation and hormone therapy with or without surgery, offers the best chance of cancer control. Minimally-invasive radical prostatectomy has emerged as a treatment option for clinically localized cancer; however, critics argue that the open approach may afford advantages of tactile feedback and a better lymph node dissection. The present study demonstrates that open and minimally-invasive radical prostatectomy offer equivalent short-term outcomes for men with high-risk prostate cancer at a highly experienced centre. Objectives To analyze pathological and short-term oncological outcomes in men undergoing open and minimally-invasive radical prostatectomy (MIRP) for high-risk prostate cancer (HRPC; prostate-specific antigen level [PSA] >20 ng/mL, ≥ cT2c, Gleason score 8–10) in a contemporaneous series. Patients and Methods In total, 913 patients with HRPC were identified in the Johns Hopkins Radical Prostatectomy Database subsequent to the inception of MIRP at this institution (2002–2011) Of these, 743 (81.4%) underwent open radical retropubic prostatectomy (ORRP), 105 (11.5%) underwent robot-assisted laparoscopic radical prostatectomy (RALRP) and 65 (7.1%) underwent laparoscopic radical prostatectomy (LRP) for HRPC. Appropriate comparative tests were used to evaluate patient and prostate cancer characteristics. Proportional hazards regression models were used to predict biochemical recurrence. Results Age, race, body mass index, preoperative PSA level, clinical stage, number of positive cores and Gleason score at final pathology were similar between ORRP and MIRP. On average, men undergoing MIRP had smaller prostates and more organ-confined (pT2) disease (P = 0.02). The number of surgeons and surgeon experience were greatest for the ORRP cohort. Overall surgical margin rate was 29.4%, 34.3% and 27.7% (P = 0.52) and 1.9%, 2.9% and 6.2% (P = 0.39) for pT2 disease in men undergoing ORRP, RALRP and LRP, respectively. Biochemical recurrence-free survival among ORRP, RALRP and LRP was 56.3%, 67.8% and 41.1%, respectively, at 3 years (P = 0.6) and the approach employed did not predict biochemical recurrence in regression models. Conclusions At an experienced centre, MIRP is comparable to open radical prostatectomy for HRPC with respect to surgical margin status and biochemical recurrence.

The risk of recurrence for prostatic adenocarcinoma after prostatectomy, as detected by prostate-specific antigen or other modalities, is based primarily on Gleason score along with pathologic tumor stage and surgical margin status. Recent large multi-institutional data spanning the last decade have supported modification of risk of recurrence stratification based on grade groups: grade group 1 (3+3=6), grade group 2 (3+4=7), grade group 3 (4+3=7), grade group 4 (4+4=8), and grade group 5 (Gleason scores 9 and 10). Using currently accepted grading definitions of grade patterns and grading rules, this study examines how the introduction of a limited, less than 5%, Gleason pattern 5 component at prostatectomy affects prognosis and fits into the grade group schema and reporting. The aggregate data from 2 independent major academic medical centers comprising 7606 patient records were analyzed with respect to biochemical recurrence-free survival. The presence of a limited (tertiary) Gleason pattern 5 component in the context of Gleason scores 3+4=7 (grade group 2) and 4+3=7 (grade group 3) imparts an intermediate prognosis relative to the next highest grade group. As such, we suggest that an additional comment and designation to the grade groups be provided reflecting the increased risk of recurrence in such cases (such as grade group 2+ or 3+). In contrast, the presence of limited (

OBJECTIVE To assess factors associated with lymphatic drainage and lymph node (LN) metastasis to the prostatic anterior fat pad (PAFP) in men with prostate cancer and the utility of routine PAFP analysis at the time of radical prostatectomy (RP). PATIENTS AND METHODS Our institution began to prospectively collect PAFP tissue in 2010. The PAFP was removed at the time of RP and sent as a pathological specimen separate from the pelvic LNs and prostate. Consecutive RPs performed at our institution in which the PAFP was removed were reviewed to determine the rate of LNs in the PAFP, the rate of metastatic LNs in the PAFP, and the association of metastatic PAFP LN with clinical and pathological features. The impact on biochemical recurrence (BCR) was assessed with a Cox's proportional hazard model. RESULTS In all, 2 413 PAFP specimens were available for analysis. LNs were found in the PAFP in 255 (10.6%) cases and metastatic LNs in the PAFPs were found in 14 (0.6%) cases. Metastatic PAFP LNs were associated with anterior tumours in 11 of the 14 cases (P = 0.01), and were present only in preoperative D'Amico intermediate- (six of 14) and high- (eight of 14) risk patients (P < 0.001). Metastatic PAFP LNs were associated with extraprostatic disease in 13 of the 14 cases, although concomitant pelvic LN involvement was present in only four of the 14 cases. With a mean follow-up of 1.5 years, three of the 14 patients with metastatic PAFP LN developed BCR. Positive LN involvement in either the pelvic LN or PAFP had worse BCR than LN-negative patients (P < 0.001); however, there was no difference in BCR between patients with positive pelvic LN and positive PAFP LN (P = 0.5). CONCLUSION Metastatic PAFP LNs are rare and always occur in the presence of other adverse pathological features. The routine pathological analysis of PAFP as a separate specimen, especially in low-risk disease, may not be warranted.

PURPOSE: Prostate cancer is clinically and molecularly heterogeneous. We determined the prognosis of men with ERG-ETS fusions and SPINK1 over expression. MATERIALS AND METHODS: Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy before metastasis. A case-cohort design sampled a cohort (262) enriched with metastasis from the entire cohort and a cohort (213) enriched with metastasis from patients with biochemical recurrence. We analyzed transcriptomic profiles and subtyped tumors as m-ERG(+), m-ETS(+), m-SPINK1(+) or Triple Negative (m-ERG(−)/m-ETS(−)/m-SPINK1(−)), and multivariable logistic regression analyses, Kaplan-Meier and multivariable Cox models were used to evaluate subtypes as predictors of clinical outcomes. RESULTS: Overall 36%, 13%, 11% and 40% of prostate cancer was classified as m-ERG(+), m-ETS(+), m-SPINK1(+) and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1(+) tumors were more common in African-American men (OR 5, 95% CI 1.6–16) but less commonly associated with positive surgical margins (OR 0.16, 95% CI 0.03–0.69) compared to the m-ERG(+) group. Compared to the Triple Negative group, m-SPINK1(+) showed similar associations with race and surgical margins in univariable and multivariable analyses across the entire cohort. Survival analyses did not show significant differences among m-ERG(+), m-ETS(+) and Triple Negative cases. m-SPINK1(+) independently predicted prostate cancer specific mortality after metastasis (HR 2.48, 95% CI 0.96–6.4) and biochemical recurrence (HR 3, 95% CI 1.1–8). CONCLUSIONS: SPINK1 over expression is associated with prostate cancer specific mortality in at risk men with biochemical and clinical recurrence after prostatectomy. ERG-ETS alterations are not prognostic for outcome.

INTRODUCTION AND OBJECTIVES: Downgrading from biopsy Gleason score (Bx GS) 7 to radical prostatectomy (RP) GS 6 could occur if tangentially-sectioned small glands of Gleason 3 on Bx are overgraded as pattern 4, or alternatively if small foci of pattern 4 in the RP specimen are not recorded or unsampled deeper within the paraffin block. In the later scenario, downgraded men might have a worse prognosis than those with Bx and RP GS 6. We investigated whether there was a difference in biochemical recurrence-free survival (BCRFS) rates based on downgrading status. METHODS: Among 24,536 men with RP between 1984 and 2015, we reviewed 15,586 men (group I [Bx GS 6 to RP GS 6]1⁄4 10,538 [67.6%], group II [Bx GS 7 to RP GS 6]1⁄4 941 [6.0%], and group III [Bx GS 7 to RP GS 7]1⁄4 4,107 [26.4%]). For men with complete follow-up, the log-rank test was used to compare BCRFS between the groups. Cox regression analyses were used to determine the impact of downgrading on BCR. RESULTS: At a median follow-up of 5 years (IQR 2-12), 1,025 men experienced BCR. There were significant differences in age, preoperative prostate-specific antigen (PSA), year of surgery, clinicopathological stage, and positive surgical margin (PSM) between groups (all p

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

The prognostic value of phosphatase and tensin homolog (PTEN) loss in prostate cancer has primarily been evaluated by either fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC). Previously, we found that PTEN loss by IHC was associated with increased risk of upgrading from biopsy (Gleason 3 + 3) to prostatectomy (Gleason 7+). Now, using an evaluable subset of 111 patients with adjacent biopsy sections, we analyzed the association between PTEN deletion in cancer and the odds of upgrading by a highly sensitive and specific four-color FISH assay. We also compared the concordance of PTEN loss by IHC and PTEN deletion by FISH. PTEN deletion was found in 27 % (12/45) of upgraded cases compared with 11 % (7/66) of controls (P = 0.03). Cancers with PTEN deletions were more likely to be upgraded than those without deletions (adjusting for age odds ratio = 3.40, 95 % confidence interval 1.14–10.11). With respect to concordance, of 93 biopsies with PTEN protein detected by IHC, 89 (96 %) had no PTEN deletion by FISH, and of 18 biopsies without PTEN protein by IHC, 15 had homozygous or hemizygous PTEN deletion by FISH. Only 4 biopsies of the 93 (4 %) with PTEN protein intact had PTEN deletion by FISH. When the regions of uncertainty in these biopsies were systematically studied by FISH, intra-tumoral variation of PTEN deletion was found, which could account for variation in immunoreactivity. Thus, FISH provides a different approach to determining PTEN loss when IHC is uncertain. Both FISH and IHC are concordant, showing consistent positive associations between PTEN loss and upgrading.