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Background: While both seminal vesicle (SVI) and lymph-node invasion (LNI) have been identified as adverse prognostic variables among men undergoing radical prostatectomy (RP), the relative impact of each of these features on subsequent oncologic outcomes has not been well defined. We assessed the impact of LNI on long-term oncologic outcomes among patients with SVI at RP., Methods: We reviewed 19,519 patients who underwent RP and identified 2043 with SVI. Metastasis-free (MFS), cancer-specific (CSS), and overall survival (OS) were estimated for patients with SVI, stratified by the presence and number of pelvic lymph node metastases. Cox proportional hazards models were used to evaluate the independent association of the number of metastatic nodes and lymph node density with oncologic outcomes among patients with SVI, controlling for age, year of surgery, margin status, preoperative PSA, pathologic Gleason score, extraprostatic extension, and use of adjuvant therapies., Results: At a median follow up of 12.1 years (IQR 7.0,18.6), 548 patients developed metastatic disease and 1331 died, including 406 who died from prostate cancer (PCa). We found that, among patients with SVI, the presence of a single positive lymph node was not associated with incrementally adverse oncologic outcomes compared to no nodal metastasis at RP, with 10-year MFS, CSS, and OS rates of 81.3% versus 78.3%(p = 0.18), 86.5% versus 89.8%(p = 0.32), and 72.8% versus 76.7%(p = 0.53), respectively. In contrast, on multivariable analyses, the presence of ≥2 metastatic nodes and a 20% lymph-node density cut off remained independently associated with worse survival., Conclusions: SVI represents an adverse pathologic feature such that the presence of a single positive pelvic lymph node did not further adversely impact prognosis. Meanwhile, a significant number of involved nodes was associated with decreased survival. These findings may aid in risk-stratification as well as clinical trial design for such high-risk patients following surgery., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Extraprostatic extension (EPE) of prostate cancer is usually reported as either focal (F-EPE) or established (E-EPE), but data on the implication for outcomes of this subdivision are conflicting and no systematic review (SR) evaluating this exists. This SR aims to address this gap in the literature, focusing on the impact of F-EPE and E-EPE on outcome in radical prostatectomy (RP) patients. Searches on Embase, Medline(R), and Pubmed databases were conducted. Studies were included if they investigated the extent of EPE in RP patients and correlated this with defined outcomes (biochemical recurrence [BCR], death, metastasis). Quality was assessed using the Newcastle-Ottawa Scale. A random effects model was used for studies reporting hazard ratios (EPE extent and biochemical recurrence). 24 studies, including 49,187 men, were included. Six studies were of high quality. 20 studies reported how they measured EPE. 13 studies reported that the extent of EPE was associated significantly with BCR. Meta-analysis showed there was a significant correlation between BCR and both F-EPE and E-EPE when compared to organ-confined disease; no significant difference was found between F-EPE and E-EPE. This is the only SR to investigate the extent of EPE on outcomes after RP. EPE alone predicts outcome, but the value of subdivision by extent could not be demonstrated. Comparisons are limited due to variability in EPE assessment and in the methods used to report outcomes in the literature. Further work to standardize EPE reporting methods, in larger cohorts, may be helpful to resolve remaining questions., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Background: This study aimed to validate a previously published risk model (RM) which combines clinical and multiparametric MRI (mpMRI) parameters to predict extraprostatic extension (EPE) of prostate cancer (PC) prior to radical prostatectomy (RP)., Materials and Methods: A previously published RM combining clinical with mpMRI parameters including European Society of Urogenital Radiology (ESUR) classification for EPE was retrospectively evaluated in a cohort of two urological university hospitals in Germany. Consecutive patients (n = 205, January 2015 -June 2021) with available preoperative MRI images, clinical information including PSA, prostate volume, ESUR classification for EPE, histopathological results of MRI-fusion biopsy and RP specimen were included. Validation was performed by receiver operating characteristic analysis and calibration plots. The RM's performance was compared to ESUR criteria., Results: Histopathological T3 stage was detected in 43% of the patients (n = 89); 45% at Essen and 42% at Düsseldorf. Discrimination performance between pT2 and pT3 of the RM in the entire cohort was AUC = 0.86 (AUC = 0.88 at site 1 and AUC = 0.85 at site 2). Calibration was good over the entire probability range. The discrimination performance of ESUR classification alone was comparable (AUC = 0.87)., Conclusions: The RM showed good discriminative performance to predict EPE for decision-making for RP as a patient-tailored risk stratification. However, when experienced MRI reading is available, standardized MRI reading with ESUR scoring is comparable regarding information outcome. A main limitation is the potentially limited transferability to other populations because of the high prevalence of EPE in our subgroups., (© 2024. The Author(s).)

Background: High-risk prostate cancer is associated with adverse pathology and unfavorable outcomes after radical prostatectomy. 68 Ga-PSMA PET/CT is more accurate than conventional imaging for preoperative staging. We aimed to evaluate whether lymph node involvement on 68 Ga-PSMA PET/CT prior to radical prostatectomy in patients with high-risk prostate cancer is associated with worse short-term oncologic outcomes., Methods: We retrospectively reviewed 149 patients with high-risk localized or locoregional prostate cancer who underwent 68 Ga-PSMA PET/CT prior to radical prostatectomy between 2015 and 2020. None of the patients received neoadjuvant or adjuvant treatment. The study endpoints were PSA persistence and biochemical recurrence. Logistic regression models were used to identify preoperative predictors of PSA persistence. Kaplan-Meier analyses were used to estimate biochemical recurrence-free survival., Results: Of 149 identified patients, 19 (13%) were found to have lymph node involvement on preoperative 68 Ga-PSMA PET/CT. The sensitivity, specificity, and accuracy of 68 Ga-PSMA PET/CT for identifying pathologic lymph node involvement were 68%, 95%, and 92%, respectively. PSA persistence rate was lower among patients with PET-negative lymph nodes than those with PET-positive nodes (15 vs. 84%, p < 0.001). Positive nodes on imaging (OR = 41.03, p < 0.001) and clinical T2c-T3 stage (OR = 6.96, p = 0.002) were associated with PSA persistence on multivariable analysis. Among patients with PET-negative nodes the 1- and 2-year biochemical recurrence-free survival rates were 87% and 76%, respectively., Conclusions: Preoperative staging with 68 Ga-PSMA PET/CT may identify a subgroup of high-risk prostate cancer patients with favorable short-term outcomes after radical prostatectomy without adjuvant treatment. Future studies will evaluate whether these results are sustained during long-term follow-up., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Backgrounds: Aside from Gleason score few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that copy number alterations (CNAs), assessed using CpG methylation probes on Illumina Infinium® Human Methylation450 (HM450K) BeadChip arrays, could identify primary prostate tumors with potential to develop metastatic progression., Methods: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from two cohorts of PCa patients with clinically localized disease who underwent radical prostatectomy (RP) as primary therapy and were followed prospectively for at least 5 years: (1) a Fred Hutchinson (FH) Cancer Research Center-based cohort (n = 323 patients); and (2) an Eastern Virginia (EV) Medical School-based cohort (n = 78 patients). CNAs were identified using the R package ChAMP. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death., Results: We detected 15 recurrent CNAs were associated with metastasis in the FH cohort and replicated in the EV cohort (p < 0.05) without adjusting for Gleason score in the model. Eleven of the recurrent CNAs were associated with metastatic progression in the FH cohort and validated in the EV cohort (p < 0.05) when adjusting for Gleason score., Conclusions: This study shows that CNAs can be reliably detected from HM450K-based DNA methylation data. There are 11 recurrent CNAs showing association with metastatic-lethal events following RP and improving prediction over Gleason score. Genes affected by these CNAs may functionally relate to tumor aggressiveness and metastatic progression.

Purpose: Positive surgical margins increase the risk of biochemical recurrence after radical prostatectomy by 2 to 4-fold. The risk of biochemical recurrence may be influenced by the anatomical location and extent of positive surgical margins. In a multicenter study we analyzed the predictive usefulness of several subclassifications of positive surgical margins., Materials and Methods: The clinical information and followup data of 7,160 patients treated with radical prostatectomy alone at 1 of 3 institutions between 1995 and 2006 were modeled using Cox proportional hazards regression analysis for biochemical recurrence. Positive surgical margins were analyzed as solitary vs multiple, focal vs extensive and apical location vs other. The usefulness of these subclassifications was assessed by the improvement in predictive accuracy of nomograms containing these parameters compared to one in which the surgical margin was modeled simply as positive vs negative., Results: The 7-year progression-free probability was 60% in patients with positive surgical margins. A positive surgical margin was significantly associated with biochemical recurrence (HR 2.3, p <0.001) after adjusting for age, prostate specific antigen, pathological Gleason score, pathological stage and year of surgery. An increased risk of biochemical recurrence was associated with multiple vs solitary positive surgical margins (adjusted HR 1.4, p = 0.002) and extensive vs focal positive surgical margins (adjusted HR 1.3, p = 0.004) on multivariable analysis. However, neither parameter improved the predictive accuracy of a nomogram compared to one in which surgical margin status was modeled as positive vs negative (concordance index 0.851 vs 0.850 vs 0.850)., Conclusions: The number and extent of positive surgical margin significantly influence the risk of biochemical recurrence after radical prostatectomy. However, the empirical prognostic usefulness of subclassifications of positive surgical margins is limited.

Objectives: Commonly used definitions for high-risk prostate cancer identify men at increased risk of PSA relapse after radical prostatectomy (RP). We assessed how accurately these definitions identify patients likely to receive secondary cancer therapy, experience metastatic progression, or die of prostate cancer., Materials and Methods: Among 5960 men with clinically localized or locally advanced prostate cancer who underwent RP, we identified eight different high-risk subsets, each comprising 4-40% of the study population. Estimates of freedom from radiation therapy, hormonal therapy, and metastatic progression after surgery were generated for each high-risk cohort with the Kaplan-Meier method, and hazard ratios (HR) were calculated with a Cox proportional hazards regression. The cumulative incidence and HR for prostate cancer-specific mortality (PCSM) were estimated with competing risk analysis., Results: Each of the studied high-risk criteria was associated with increased hazard of secondary cancer therapy (HR=1.3-5.2, p<0.05) and metastatic progression (HR=2.1-6.9, p<0.05). However, depending on the definition, the probability of freedom from additional therapy 10 yr after surgery ranged from 35% to 76%. The 10-yr cumulative incidence of PCSM in high-risk patients ranged from 3% to 11% (HR=3.2-10.4, p<0.0005)., Conclusions: Commonly used definitions for high-risk prostate cancer identify men at increased risk of secondary cancer therapy, metastatic progression, and PCSM following RP. However, a substantial proportion of high-risk patients remain free from additional therapy or metastatic disease many years after surgery. The risk of PCSM within 10 yr of treatment is remarkably low, even for patients at the highest risk of recurrent disease.

Purpose: Standardized criteria are lacking to define high risk, clinically localized prostate cancer before definitive treatment. Reliance on simple risk stratification schemes to define high risk cancers has led many physicians and patients toward therapeutic nihilism, inappropriately selecting androgen deprivation instead of definitive local therapy. Of patients undergoing radical prostatectomy we identified those at high risk based on 8 previously described definitions. We examined pathological characteristics and prostate specific antigen outcomes., Materials and Methods: The study population included 4,708 men treated with radical prostatectomy alone between 1985 and 2004. Estimates of prostate specific antigen relapse for patients at high risk were generated with the Kaplan-Meier method. Cox proportional hazards regression was used to estimate the HR for recurrence in high risk vs nonhigh risk cohorts., Results: Depending on the definition used patients at high risk composed 3% to 38% of the study population. The proportion of patients with extracapsular extension, seminal vesicle invasion and lymph node metastasis among men with high risk cancer was 35% to 71%, 10% to 33% and 7% to 23%, respectively. Of the high risk tumors 22% to 63% proved to be confined to the prostate pathologically. While patients at high risk had a 1.8 to 4.8-fold increased hazard of prostate specific antigen relapse, their 5-year relapse-free probability after radical prostatectomy alone was 49% (95% CI 39 to 58) to 80% (95% CI 77 to 83). Of patients at high risk who had relapse 25% across all definitions experienced relapse more than 2 years after surgery and in 26% to 39% prostate specific antigen doubling time at recurrence was 10 months or greater., Conclusions: Patients diagnosed with high risk cancer by currently available definitions do not have a uniformly poor prognosis after radical prostatectomy. Many cancers classified clinically as high risk are actually confined to the prostate pathologically. The risk of extraprostatic disease and prostate specific antigen relapse varies greatly depending on the definition used.

Purpose: We evaluated patients at our institution who underwent radical prostatectomy for clinical stage T3 prostate cancer to determine their long-term clinical outcomes., Materials and Methods: We reviewed our prospective surgical database and identified 176 men who underwent radical retropubic prostatectomy for clinical stage T3 prostate cancer from 1983 to 2003. Clinical and pathological data were reviewed and evaluated in a Cox proportional hazards model to determine preoperative predictors of biochemical recurrence. Clinical progression following biochemical recurrence was evaluated and clinical failure was defined as the development of clinical metastases or progression to hormone refractory prostate cancer., Results: Of the 176 patients with cT3 prostate cancer 64 (36%) received neoadjuvant hormonal therapy. At a mean followup of 6.4 years 84 (48%) patients had disease recurrence with a median time to biochemical recurrence of 4.6 years. The actuarial 10-year probability of freedom from recurrence was 44%. On multivariate analysis biopsy Gleason score, pretreatment serum prostate specific antigen and year of surgery were independent predictors of biochemical recurrence. Neoadjuvant hormonal therapy was not a significant predictor of biochemical recurrence. Following biochemical recurrence clinical failure developed in 30 of 84 (36%) men with a median time of 11 years. Overall the 5, 10 and 15-year probabilities of death from prostate cancer were 6%, 15% and 24%, respectively., Conclusions: More than half (52%) of our patients remained free of disease recurrence following radical prostatectomy. In our series neoadjuvant hormonal therapy offered no advantage with respect to disease recurrence. Radical prostatectomy remains an integral component in the treatment of select patients with clinical stage T3 prostate cancer.

Purpose: Traditionally black men undergoing radical prostatectomy have presented with higher serum prostate specific antigen (PSA) levels, Gleason grade and pathological stage compared to white men. We evaluated men undergoing radical prostatectomy at our institutions to determine if race was an independent predictor of neurovascular bundle resection and if racial differences existed with regard to clinical and pathological outcomes in men undergoing a nerve sparing procedure., Materials and Methods: Between July 1995 and March 2000, 316 men underwent radical retropubic prostatectomy for clinically localized prostate cancer. Patient data were gathered prospectively and reviewed with regard to age, race, preoperative serum PSA, operative procedure, pathological findings and patient followup. Racial differences were analyzed by the chi-square test or student's t statistic. Predictors of neurovascular bundle resection were evaluated using multiple logistic regression., Results: Of the 316 men who underwent a radical retropubic prostatectomy, 126 were black and 190 were white. Overall, a nerve sparing procedure was performed in 77 (40.5%) white men and 44 (34.9%) black men. When evaluating only potent men preoperatively, a nerve sparing prostatectomy was performed in 69.3% of white men and 58.6% of black men. There was no statistically significant racial difference with regard to the proportions of men undergoing a nerve sparing procedure. Predictors of neurovascular bundle resection during radical prostatectomy were preoperative erectile function, serum PSA level before prostate biopsy, biopsy Gleason score and number of cores positive for cancer. In men undergoing a nerve sparing radical prostatectomy there were no significant racial differences with regard to age, preoperative serum PSA, Gleason score, pathological stage, postoperative potency, continence or disease-free survival (mean followup 44 months)., Conclusions: At our institutions a similar proportion of black and white men undergo nerve sparing radical prostatectomy, which appears to produce similar clinical outcomes in black and white men.

Background: Efforts are ongoing to try and find ways to reduce the number of unnecessary prostate biopsies without missing clinically significant prostate cancers (csPCa). The utility of multiparametric magnetic resonance imaging (mpMRI) in detecting prostate cancer (PCa) shows promise to be used as triage test for systematic prostate biopsy. Our aim is to Study clinical parameters and oncological outcomes in men with negative mpMRI (nMRI; PI-RADS v2 scores of ≤ 2) who underwent robot-assisted radical prostatectomy (RARP) to evaluate nMRI's practicality as a biopsy triage test., Methods: Retrospective analysis of 331 men with nMRI who underwent RARP between 2014 and 2020 compared with men with positive mpMRI (pMRI; PI-RADS v2 scores ≥ 3, N = 1770). csPCa was defined as Gleason score ≥ 3 + 4 and biochemical recurrence (BCR) was defined as PSA > 0.2 ng/ml on two occasions. Biopsies were graded with the International Society of Urologic Pathology [ISUP] grade. Descriptive statistics for nMRI and pMRI were performed. Mann-Whitney U test was used for continuous variables and χ 2 for categorical variables. Univariable and multivariable regression analyses were performed., Results: Univariable analysis shows statistically significant difference (p < .05) between median age (nMRI-61 years vs. pMRI 63 years), race (higher incidence of nMRI in African American men), use of 5-alpha reductase inhibitors (higher rate in nMRI). While incidence rates of family history of PCa, suspicious digital rectal examination (DRE) findings, median PSA levels and 4Kscore, were lower in nMRI versus pMRI. Rates of positive surgical margins and BCR were comparable in nMRI versus pMRI. Biopsy ISUP Grades I and II upgraded by 51% and 12%, respectively in final pathology. African American race and no history of the prior negative biopsy were significant predictors for upgrading., Conclusion: Men with nMRI pose diagnostic challenges as they tend to be younger patients with lower rates of suspicious DRE findings and lower 4K scores, yet comparable oncological outcomes in csPCa rates, positive surgical margins, and BCR rates., (© 2021 Wiley Periodicals LLC.)

Purpose: We evaluated patients at our institution who underwent radical prostatectomy for clinical stage T3 prostate cancer to determine their long-term clinical outcomes. Materials and Methods: We reviewed our prospective surgical database and identified 176 men who underwent radical retropubic prostatectomy for clinical stage T3 prostate cancer from 1983 to 2003. Clinical and pathological data were reviewed and evaluated in a Cox proportional hazards model to determine preoperative predictors of biochemical recurrence. Clinical progression following biochemical recurrence was evaluated and clinical failure was defined as the development of clinical metastases or progression to hormone refractory prostate cancer. Results: Of the 176 patients with cT3 prostate cancer 64 (36%) received neoadjuvant hormonal therapy. At a mean followup of 6.4 years 84 (48%) patients had disease recurrence with a median time to biochemical recurrence of 4.6 years. The actuarial 10-year probability of freedom from recurrence was 44%. On multivariate analysis biopsy Gleason score, pretreatment serum prostate specific antigen and year of surgery were independent predictors of biochemical recurrence. Neoadjuvant hormonal therapy was not a significant predictor of biochemical recurrence. Following biochemical recurrence clinical failure developed in 30 of 84 (36%) men with a median time of 11 years. Overall the 5, 10 and 15-year probabilities of death from prostate cancer were 6%, 15% and 24%, respectively. Conclusions: More than half (52%) of our patients remained free of disease recurrence following radical prostatectomy. In our series neoadjuvant hormonal therapy offered no advantage with respect to disease recurrence. Radical prostatectomy remains an integral component in the treatment of select patients with clinical stage T3 prostate cancer. [Copyright &y& Elsevier]

Objective: Using multi-parametric magnetic resonance imaging (mpMRI) to identify patients with clinical T3a (cT3a) who were overestimated on mpMRI with final pathological T2 (pT2). To suggest that the neurovascular bundle (NVB) can be preserved by evaluating the characteristics of patients according to their pathological grade among cT3a prostate cancer (PCa) patients using mpMRI. Materials and methods: Patients who underwent robot-assisted laparoscopic radical prostatectomy (RALP) were retrospectively analyzed and those patients with clinical T3aN0M0 were enrolled. These enrolled patients were divided into a localized cancer group with pT2 PCa and a locally advanced group with pT3a or higher. Factors affecting the diagnosis of localized PCa after RALP in patients with cT3a PCa were evaluated. Results: Among the preoperative parameters of patients with cT3a PCa, the prostate specific antigen density (PSAD) (OR: 3.76, 95% CI: 1.85-7.64, p<0.001), international society of urological pathology (ISUP) grade (p<0.05), and index lesion size (OR: 1.44, 95% CI: 1.85-7.64, p<0.001) were significantly associated with pathological locally advanced PCa. Optimal cut-off values for prediction of pT3a or higher were 0.36 ng/mL2 for PSAD (sensitivity: 55.7%, specificity: 70.8%), 1.77 cm for index lesion size (sensitivity: 54.3%, specificity: 66.0%), and 2.5 for ISUP grading (sensitivity: 67.6%, specificity: 53.2%). For prediction of pT3a or higher among patients with cT3a PCa, a nomogram was developed using ISUP grade, index lesion size, and PSAD on prostate biopsy (area under the curve: 0.71, 95% CI: 0.670-0.754, p<0.001). PSAD less than 0.36 index lesion size less than 1.77 cm, and biopsy ISUP grade 1-2 are highly likely to indicate that there is no actual extracapsular extension in cT3a PCa patients. Conclusions: PSAD, ISUP, and index lesion size showed significant associations with the classification of pathologic localized and locally advanced PCa in patients with cT3a PCa. A nomogram including these features can predict the diagnosis of locally advanced PCa in patients with cT3a PCa. [ABSTRACT FROM AUTHOR]

Although salvage prostate bed radiotherapy is highly effective in biochemically-relapsing prostate cancer patients following prostatectomy, relapses remain frequent and improvements are needed. Randomized phase 3 trials have shown the benefit of adding androgen-depriving therapy to irradiation, but not all patients benefit from this combination. Preclinical studies have shown that novel agents targeting the androgen receptor, DNA repair, PI3K/AKT/mTOR pathways, or the hypoxic microenvironment may help increase the response to prostate bed irradiation while minimizing potential side effects. This perspective review focuses on the most relevant molecules that may have an impact when combined with salvage radiotherapy, and underlines the strategies that need to be developed to increase the efficacy of salvage post-prostatectomy radiotherapy in prostate cancer patients. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the predictive effect of the presence of chronic prostatitis associated with prostate cancer (PCa) in prostate biopsy on Gleason score upgrade (GSU) in radical prostatectomy (RP) specimens. Materials and methods: The data of 295 patients who underwent open or robotic RP with a diagnosis of localized PCa following biopsy were retrospectively analyzed. Patients were divided into two groups with and without GSU following RP. Predictive factors affecting GSU on biopsy were determined. The impact of chronic prostatitis associated with prostate cancer on GSU was examined via logistic regression analysis. Results: Out of 224 patients with Gleason 3+3 scores on biopsy, 145 (64.7%) had Gleason upgrade, and 79 (35.2%) had no upgrade. Whilst comparing the two groups with and without Gleason upgrade in terms of patient age, prostate-specific antigen (PSA) value, PSA density (PSAD), prostate volume (PV), neutrophil/lymphocyte (N/L) ratio, number of positive cores, percentage of positive cores, and Prostate Imaging Reporting and Data System version 2 score, no statistically significant difference was detected. The presence of chronic prostatitis associated with PCa was higher in the patient cohort with GSU in contrast to the other group (p < 0.001). According to the uni-variate logistic regression analysis, the presence of chronic pro-statitis was identified to be an independent marker for GSU. Conclusions: Pathologists and urologists should be careful regarding the possibility of a more aggressive tumor in the presence of chronic inflammation associated with PCa because inflammation within PCa was revealed to be linked with GSU after RP. [ABSTRACT FROM AUTHOR]

High-risk prostate cancer (PCa) is associated with higher rates of biochemical recurrence, clinical recurrence, metastasis, and PCa-specific death, compared to low-and intermediate-risk disease. Herein, we review the various definitions of high-risk PCa, describe the rationale for neoadjuvant therapy prior to radical prostatectomy, and summarize the contemporary data on neoadjuvant therapies. Since the 1990s, several randomized trials of neoadjuvant androgen deprivation therapy (ADT) have consistently demonstrated improved pathological parameters, specifically tumor downstaging and reduced extraprostatic extension, seminal vesicle invasion, and positive surgical margins without improvements in cancer-specific or overall survival. These studies, however, were not exclusive to high-risk patients and were limited by suboptimal follow-up periods. Newer studies of neoadjuvant ADT in high-risk PCa show promising pathological and oncological outcomes. Recent level 1 data suggests neoadjuvant chemohormonal therapy (CHT) may improve longer-term survival in high-risk PCa. Immunologic neoadjuvant trials are in their infancy, and further study is required. Neoadjuvant therapies may be promising additions to the multimodal therapeutic landscape of high-risk and locally advanced PCa in the near future. [ABSTRACT FROM AUTHOR]

Objective: To assess the use of the cell cycle progression (CCP) score versus actual risk stratification practice in making treatment decisions for prostate cancer patients with locally adverse pathology after radical prostatectomy (RP). Patients and methods: Men with adverse pathologic features, pT3 or positive surgical margins who underwent RP in 2010–2014 at Renji hospital were retrospectively analyzed. The primary outcome was biochemical recurrence (BCR) after RP. RNA was quantified from paraffin-embedded RP specimens. The CCP score was calculated as average expression of 31 CCP genes, normalized to 15 housekeeper genes. The prognostic utility of the CCP score was assessed using Kaplan–Meier analysis and multivariable Cox proportional hazards model. Results: Among the 100 men identified, 5-year BCR-free survival for the low- (< 0), intermediate- (0–1) and high- (> 1) CCP score groups was 89.3%, 38.8%, and 12.9%, respectively. In multivariable models adjusting for clinical and pathological variables with the cancer of the prostate risk assessment post-surgical (CAPRA-S) score, both continuous CCP score [hazard ratio (HR) 1.373 per unit score, 95% confidence interval (CI) 1.006–1.874; p = 0.046) and the categorized CCP score (p < 0.001)were independent predictors of BCR. Conclusions: The present study provides insights into the role the CCP score plays in risk stratification of this cohort and in determining candidacy for deferred secondary treatment. From our perspective, the CCP score allows better stratification and can help identifying patients at lower risk of disease recurrence who could benefit from a wait-and-see policy. [ABSTRACT FROM AUTHOR]

Objective: The aim of our study was to evaluate the impact of time until biochemical recurrence (BCR) after radical prostatectomy (RP) without neo- or adjuvant treatment on clinical progression (CP) and cancer-related death (CRD) in high-risk prostate cancer (HRPCa) patients. Materials and methods: A total of 433 men with clinically HRPCa treated between 2001 and 2017 were identified. HRPCa was defined as clinical stage ≥T2c and/or biopsy Gleason score (GS) ≥8 and/or preoperative prostate specific antigen (PSA) value ≥20 ng/ml. Exclusion criteria were neo- or adjuvant treatment and incomplete pathological or follow-up data. BCR was defined as two consecutive PSA values ≥0.2 ng/ml after RP. CP was identified as skeletal lesions, local or loco-regional recurrence. CRD was defined as death from PCa. All men were divided into two groups according to BCR. The chi-square and t -tests were used to compare baseline characteristics between groups. Biochemical progression free survival (BPFS), clinical progression free survival (CPFS), and cancer-specific survival (CSS) rates were estimated using Kaplan–Meier analysis. Patients with detected BCR were analyzed for prediction of CP and CRD with respect to time until BCR. The impact of baseline parameters on BCR, CP, and CRD was assessed by Cox regression analysis. Results: BCR, CP, and CRD rates were 47.8% (207/433), 11.3% (49/433), and 5.5% (24/433), respectively. Median (quartiles) time of follow-up after RP was 64 (40–110) months. Ten-year BPFS rate was 34.2%; CPFS, 81%; and CSS, 90.1%. Men with detected BCR were analyzed for prediction of CP and CRD with respect to time until BCR. The most informative cutoff for time from RP until CP and CRD was ≤ 1 year (p < 0.008). According to this cutoff, men were divided into two groups: BCR detected within 1 year and after a 1-year period. Ten-year CPFS was 49.8% in men with early BCR vs. 81.1% in men with late BCR; CSS was 70.9 vs. 92.8% (p = 0.001). Multivariable analysis confirmed that time until BCR within 1 year predicts CP (p = 0.005) and CRD (p = 0.03). Conclusions: Early BCR is associated with poorer oncological outcomes. The presented results may help both to improve follow-up strategy and opt for more aggressive multimodal treatment of HRPCa in men with very early BCR. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of prostate-specific antigen (PSA) fluctuation on Gleason score (GS) upgrading, disease upstaging, oncological outcomes in low-risk prostate cancer (PCa) patients who underwent robot-assisted laparoscopic radical prostatectomy (RARP) and met the inclusion criteria for active surveillance (AS). Material and methods: Data of 354 low-risk PCa patients who underwent RARP were retrospectively evaluated. Patients were divided into two groups: PSA fluctuation rate<9.5%/month (Group 1, n=192) and >9.5%/month (Group 2, n=162). Mainly compared parameters were GS upgrading, disease upstaging, biochemical recurrence (BCR) and surgical margin positivity (SMP) rates. Results: GS upgrading, disease upstaging and SMP were detected in 128 (36.2%), 56 (15.8%) and 42 (11.9%) patients, respectively. After a median follow-up of 46 months, BCR was observed in 40 (11.3%) patients. GS upgrading (41.1% vs. 30.2%, p=0.033), disease upstaging (19.8% vs. 11.1%, p=0.028), SMP (15.1% vs. 8%, p=0.035) and BCR development (15.6% vs. 6.2%, p=0.005) rates were statistically significantly higher in Group 1 than Group 2. In multivariate analysis, digital rectal examination positivity, the presence of two positive cores and low PSA fluctuation rate were found to be significant predictors of GS upgrading. Conclusion: Low PSA fluctuation rate is associated with higher GS upgrading. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the prognostic value of positive surgical margins (PSM) focality for the prediction of biochemical recurrence (BCR) in patients undergoing robotic-assisted radical prostatectomy (RARP) for prostate cancer. Methods: All men with clinically localized prostate cancer undergoing RARP in our tertiary referral centre between May 2005 and August 2016 were retrospectively identified. Patients with neoadjuvant therapy were excluded. Comparisons were made between cases with negative surgical margins (NSM), unifocal PSM (uPSM), and multifocal PSM (mPSM). Results: From a total of 973 patients available for analysis, 315 (32%) had a PSM. In these patients, 190 had uPSM and 125 had mPSM. Focality of PSM was significantly associated with tumour stage and grade, preoperative PSA, and postoperative PSA persistence (all p < 0.001), but not with nerve sparing (NS) (p = 0.15). PSA persistence was found in 120 (12%) patients, resulting in 853 patients available for survival analyses with a median follow-up of 52 months. Both uPSM and mPSM were found to be independent predictors of BCR, conferring a hazard ratio of 1.9 (95% CI 1.3–3.0; p = 0.002) and 3.4 (95% CI 2.1–5.6; p < 0.001), respectively, when compared to NSM. In subgroup analyses, PSM was particularly predictive for BCR when patients underwent unilateral or bilateral NS (p ≤ 0.003). Conclusions: Based on a large case series of RARP, we found PSM focality to be an independent predictor of BCR, with a 1.9- and 3.4-fold risk increase for BCR in case of uPSM and mPSM, respectively. PSM seems to be of particular prognostic relevance when NS has been performed. [ABSTRACT FROM AUTHOR]

Summary: Background Despite definitive local therapy, patients with high-risk prostate cancer have a significant risk for local and distant failure. To date, no systemic therapy given prior to surgery has been shown to improve outcomes. The phosphatidilinositol 3-kinase/AKT/mTOR pathway is commonly dysregulated in men with prostate cancer. We sought to determine the clinical efficacy and safety of the mTOR/TORC1 inhibitor everolimus in men with high-risk prostate cancer undergoing radical prostatectomy. Methods This is a randomized phase II study of everolimus at two different doses (5 and 10 mg daily) given orally for 8 weeks before radical prostatectomy in men with high-risk prostate cancer. The primary endpoint was the pathologic response (histologic P0, margin status, extraprostatic extension) and surgical outcomes. Secondary endpoints included changes in serum PSA level and treatment effects on levels of expression of mTOR, p4EBP1, pS6 and pAKT. Results Seventeen patients were enrolled: nine at 10 mg dose and eight at 5 mg dose. No pathologic complete responses were observed and the majority of patients (88%) had an increase in their PSA values leading to this study being terminated early due to lack of clinical efficacy. Treatment-related adverse events were similar to those previously reported with the use of everolimus in other solid tumors and no additional surgical complications were observed. A significant decrease in the expression of p4EBP1 was noted in prostatectomy samples following treatment. Conclusions Neoadjuvant everolimus given at 5 mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer. Trial registration NCT00526591. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study is to evaluate the use of androgen deprivation therapy (ADT) with post-prostatectomy radiotherapy (PPRT) in a population-based cohort of Australian men.Methods: This is a prospective cohort of men with localised prostate cancer captured in the Prostate Cancer Outcomes Registry Victoria (PCOR-Vic), who received PPRT between January 2010 and December 2015. The primary outcome was ADT use with PPRT. Multivariate logistic regressions were used to identify patient, tumour and institutional factors influencing ADT use.Results: 485 men were included in this study - 115 (24%) had pT2 disease, 231 (48%) pT3a, 134 (28%) pT3b and 5 (1%) pT4. Eighteen (4%) men had ISUP grade 1 disease, 139 (29%) ISUP grade 2, 170 (35%) ISUP grade 3 and 158 (33%) ISUP grade 4/5, while 267 (64%) men had positive surgical margins. Median time from prostatectomy to PPRT was 8.1 months (IQR = 5.3-13.9). Sixty-six (14%) patients had ADT with PPRT. In multivariate analyses, men who had increased age (OR = 1.06; 95% CI = 1.01-1.11), seminal vesicle involvement (OR = 3.81; 95% CI = 1.63-8.91) and underwent treatment in regional centres (OR = 2.17; 95% CI = 1.08-4.33) were more likely to have ADT with PPRT.Conclusion: We reported that 14% of men treated with PPRT received ADT in a population-based cohort of Australian men, which was less than half of the proportion of ADT use with PPRT in the US. It will be of interest to evaluate the uptake of ADT with PPRT in the coming years following recent publications of level 1 evidence confirming overall survival benefits of ADT with PPRT. [ABSTRACT FROM AUTHOR]

Background: Men with locally advanced prostate cancer (LAPCa) or regionally advanced prostate cancer (RAPCa) are at high risk for death from their disease. Clinical guidelines support multimodal approaches, which include radical prostatectomy (RP) followed by radiotherapy (XRT) and XRT plus androgen deprivation therapy (ADT). However, there are limited data comparing these substantially different treatment approaches. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, this study compared survival outcomes and adverse effects associated with RP plus XRT versus XRT plus ADT in these men.Methods: SEER-Medicare data were queried for men with cT3-T4N0M0 (LAPCa) or cT3-T4N1M0 (RAPCa) prostate cancer. Propensity score methods were used to balance cohort characteristics between the treatment arms. Survival analyses were analyzed with the Kaplan-Meier method and Cox proportional hazards models.Results: From 1992 to 2009, 13,856 men (≥65 years old) were diagnosed with LAPCa or RAPCa: 6.1% received RP plus XRT, and 23.6% received XRT plus ADT. At a median follow-up of 14.6 years, there were 2189 deaths in the cohort, of which 702 were secondary to prostate cancer. Regardless of the tumor stage or the Gleason score, the adjusted 10-year prostate cancer-specific survival and 10-year overall survival favored men who underwent RP plus XRT over men who underwent XRT plus ADT. However, RP plus XRT versus XRT plus ADT was associated with higher rates of erectile dysfunction (28% vs 20%; P = .0212) and urinary incontinence (49% vs 19%; P < .001).Conclusions: Men with LAPCa or RAPCa treated initially with RP plus XRT had a lower risk of prostate cancer-specific death and improved overall survival in comparison with those men treated with XRT plus ADT, but they experienced higher rates of erectile dysfunction and urinary incontinence. [ABSTRACT FROM AUTHOR]

Objective: To describe study design and procedures for a prospective randomized trial investigating whether radical prostatectomy (RP) ± radiation improves cause-specific survival in comparison with primary radiation treatment (RT) and androgen deprivation treatment (ADT) in patients with locally advanced prostate cancer (LAPC). Materials and methods: SPCG-15 is a prospective, multi-centre, open randomized phase III trial. Patients are randomized to either standard (RT + ADT) or experimental (RP with extended pelvic lymph-node dissection and with addition of adjuvant or salvage RT and/or ADT if deemed necessary) treatment. Each centre follows guidelines regarding the timing and dosing of postoperative RT and adjuvant treatment such as ADT The primary endpoint is cause-specific survival. Secondary endpoints include metastasis-free and overall survival, quality-of-life, functional outcomes and health-services requirements. Each subject will be followed up for a minimum of 10 years. Results: Twenty-three centres in Denmark, Finland, Norway and Sweden, well established in performing RP and RT for prostate cancer participated. Each country's sites were coordinated by national coordinating investigators and sub-investigators for urology and oncology. Almost 400 men have been randomized of the stipulated 1200, with an increasing rate of accrual. Conclusions: The SPCG-15 trial aims to compare the two curatively intended techniques supplying new knowledge to support future decisions in treatment strategies for patients with LAPC The Scandinavian healthcare context is well suited for performing multi-centre long-term prospective randomized clinical trials. Similar care protocols and a history of entirely tax-funded healthcare facilitate joint trials. [ABSTRACT FROM AUTHOR]

Introduction: We analyzed the biochemical recurrence-free survival (BRFS) of patients with high-risk prostate cancer (HRCaP) as per the D'Amico classification undergoing radical prostatectomy (RP) at our center. We aimed to determine whether the number and type of risk factors (cT2c-T3b, prostate-specific antigen >20 ng/ml, Gleason score >7) are associated with biochemical recurrence (BCR) in HRCaP patients undergoing RP in the Indian population. Methods: Between 2006 and 2017, 192 patients underwent RP (open RP [ORP], laparoscopic RP [LRP], and robotic RP [RRP]) at our center, of which 109 had D'Amico HR disease. Preoperative, postoperative, and pathological outcome data were analyzed for patients with HR disease as per the D'Amico classification. Subgroups were formed to determine whether an increasing number of risk factors (1, 2, or 3) were associated with poorer oncological results and early BCR. The Kaplan–Meier method with log-rank test was used to test the difference in BRFS between the groups. Univariate and multivariate analyses were done to find significant variable against BCR. Results: According to the D'Amico criteria, 109 patients had HR, 63 patients had intermediate-risk, and 19 patients had low-risk disease. These 109 patients with HR disease were analyzed in our study (50 RRP, 33 ORP, and 26 LRP). A total of 59 (54.1%) patients had one HR factor (1HR), 44 (40%) had two HR factors (2HR), and 6 (5.5%) had three HR factors (3HR). The mean follow-up for our patient population was 21.5 ± 19 months (median 18 months; range, 0–108). Overall, the 2-year and 5-year BRFS was 45% and 35%, respectively (mean BRFS 46 ± 6 months). Two-year BRFS was 63%, 23%, and 22%, respectively, for 1HR, 2HR, and 3HR (logrank, P < 0.0001). The prognostic substratification based on the three risk factors was significantly predictive for adverse pathologic features and oncologic outcomes. Conclusion: Substratification based on the three well-defined criteria leads to a better identification of the more aggressive cancers and prediction of need for additional treatment modalities. Localized HRCaP includes a heterogeneous population of patients with variable oncological outcomes. [ABSTRACT FROM AUTHOR]

Background: Prostate Stem Cell Antigen (PSCA) is frequently expressed in prostate cancer but its exact function is unclear.Methods: To clarify contradictory findings on the prognostic role of PSCA expression, a tissue microarray containing 13,665 prostate cancers was analyzed by immunohistochemistry.Results: PSCA staining was absent in normal epithelial and stromal cells of the prostate. Membranous and cytoplasmic PSCA staining was seen in 53.7% of 9642 interpretable tumors. Staining was weak in 22.4%, moderate in 24.5% and strong in 6.8% of tumors. PSCA expression was associated with favorable pathological and clinical tumor features: Early pathological tumor stage (p < 0.0001), low Gleason grade (p < 0.0001), absence of lymph node metastasis (p < 0.0001), low pre-operative PSA level (p = 0.0118), negative surgical margin (p < 0.0001) and reduced PSA recurrence (p < 0.0001). PSCA expression was an independent predictor of prognosis in multivariate analysis (hazard ratio 0.84, p < 0.0001).Conclusions: The absence of statistical relationship to TMPRSS2:ERG fusion status, chromosomal deletion or high tumor cell proliferation argues against a major role of PSCA for regulation of cell cycle or genomic integrity. PSCA expression is linked to favorable prognosis. PSCA measurement is a candidate for inclusion in multi-parametric prognostic prostate cancer tests. [ABSTRACT FROM AUTHOR]

Purpose: To validate a previously characterized 10-gene signature in prostate cancer with implication to distinguish aggressive and indolent disease within low and intermediate patients’ risk groups.Methods: A case-control study design used to select 545 patients from the Mayo clinic tumor registry who underwent radical prostatectomy. A training set from this cohort (n = 359) was used to build a 10-gene model, based on high-dimensional discriminant analysis (HDDA10) to predict several endpoints of clinical patients’ outcome. An independent set (n = 219) from the same institution was used as validation set.Results: HDDA10 showed significant performance for predicting metastasis (Mets) (AUC 0.68, p = 6.4E - 6) and biochemical recurrence (BCR) (AUC = 0.65, p = 0.003) in the validation set outperforming Gleason grade grouping (GG) for BCR (AUC 0.57, p = 0.03) and with comparable performance for Mets endpoint (GG AUC 0.66, p = 8.1E - 5). HDDA10 prognostic significance was superior to any clinical-pathological parameter within GG2 + 3 (GS7) patients achieving an AUC of 0.74 (p = 0.0037) for BCR compared to Gleason pattern 4 (AUC 0.64) (p = 0.015) and AUC for Mets of 0.68 versus AUC of 0.65 for Gleason pattern 4 (p = 0.01). HDDA10 remained significant for both BCR and Mets in multivariate analysis, suggesting that it can be used to increase accuracy in stratifying patients eligible for active surveillance.Conclusion: HDDA10 is of added value to GG and other clinical-pathological parameters in predicting BCR and Mets endpoint, especially in the low to intermediate patients’ risk groups. HDDA10 prognostic value should be further validated prospectively in stratifying patients specifically in low to intermediate GS (GG1-2), such as active surveillance programs. [ABSTRACT FROM AUTHOR]

How to manage patients with prostate cancer (PCa) with biochemical recurrence (BCR) following primary curative treatment is a controversial issue. Importantly, this prostate-specific antigen (PSA)-only recurrence is a surrogate neither of PCa-specific survival nor of overall survival. Physicians are therefore challenged with preventing or delaying the onset of clinical progression in those deemed at risk, while avoiding over-treating patients whose disease may never progress beyond PSA-only recurrence. Adjuvant therapy for radical prostatectomy (RP) or local radiotherapy (RT) has a role in certain at-risk patients, although it is not recommended in low-risk PCa owing to the significant side-effects associated with RT and androgen deprivation therapy (ADT). The recommendations for salvage therapy differ depending on whether BCR occurs after RP or primary RT, and in either case, definitive evidence regarding the best strategy is lacking. Options for treatment of BCR after RP are RT at least to the prostatic bed, complete or intermittent ADT, or observation; for BCR after RT, salvage RP, cryotherapy, complete or intermittent ADT, brachytherapy, high-intensity focused ultrasound (HIFU), or observation can be considered. Many patient- and cancer-specific factors need to be taken into account when deciding on the best strategy, and optimal management depends on the involvement of a multidisciplinary team, consultation with the patient themselves, and the adoption of an individualised approach. Improvements in imaging techniques may enable earlier detection of metastases, which will hopefully refine future management decisions. [ABSTRACT FROM AUTHOR]

Background: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA).Methods: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set.Results: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC. Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs.Conclusions: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement. [ABSTRACT FROM AUTHOR]

Purpose The present study aimed to re-stratify patients with high-risk prostate cancer according to the National Comprehensive Cancer Network guidelines among patients who underwent radical prostatectomy (RP). Materials and Methods This study used the Korean Prostate Cancer Database registry and identified 1,060 patients with high-risk prostate cancer who underwent RP between May 2001 and April 2013. All patients were categorized into risk groups, and subgroups were identified according to the type and number of high-risk factors. Results Of the 1,060 high-risk patients, 599 (56.5%), 408 (38.5%), and 53 (5.0%) had 1, 2, and 3 risk factors, respectively. In multivariate analysis, the Gleason score, percentage of positive biopsy cores, and number of risk factors present were identified as independent predictors of biochemical recurrence. There were significant differences in the 5-year postoperative biochemical failure-free survival (BCFFS) rate among the different high-risk factor subgroups (log-rank p < 0.001). There were no significant differences in the BCFFS rate between the subgroup of high-risk patients with a prostate-specific antigen level > 20 ng/mL alone and the intermediate-risk group with all factors (log-rank p=0.919 and p=0.781, respectively). Additionally, no significant difference was noted in the BCFFS rate between high-risk patients having all factors and those in the very-high-risk group (p=0.566). Conclusion We successfully re-stratified patients with high-risk prostate cancer and identified the combinations of high-risk criteria that will help in the selection of patients for RP. [ABSTRACT FROM AUTHOR]

Abstract: Locally advanced prostate cancer is regarded as a very high‐risk disease with a poor prognosis. Although there is no definitive consensus on the definition of locally advanced prostate cancer, radical prostatectomy for locally advanced prostate cancer as a primary treatment or part of a multimodal therapy has been reported. Robot‐assisted radical prostatectomy is currently carried out even in high‐risk prostate cancer because it provides optimal outcomes. However, limited studies have assessed the role of robot‐assisted radical prostatectomy in patients with locally advanced prostate cancer. Herein, we summarize and review the current knowledge in terms of the definition and surgical indications of locally advanced prostate cancer, and the surgical procedure and perisurgical/oncological outcomes of robot‐assisted radical prostatectomy and extended pelvic lymphadenectomy for locally advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: Oncologic outcomes of patients with pT3aN0/Nx prostate cancer (PCa) with positive surgical margins (PSM) after radical prostatectomy (RP) are heterogeneous. We investigated the impact of Gleason score (GS) on biochemical recurrence (BCR) in these patients. Methods: A retrospective, multicenter study was performed on 795 patients with pT3aN0/Nx PCa with PSM after RP between January 2006 and December 2014. Clinicopathologic characteristics of patients were examined and onset of BCR was identified. Kaplan-Meier survival analysis was used to illustrate BCR-free survival (BFS) and Cox proportional hazard models were applied to identify factors predicting BCR. Results: During the mean follow-up period of 63.9 months, BCR was identified in 274 (34.5%) patients. The 5-year BFS was 56.6% in all patients. In multivariate analysis, pathologic GS was the only significant prognostic factor for BCR in patients with pT3aN0/Nx PCa with PSM (GS 6 vs. GS 7 (3 + 4), P = 0.047; vs. GS 7 (4 + 3), P = 0.007, and vs. GS 8-10, P < 0.001). When patients were stratified according to GS, 5-year BFS was 78.6% in GS 6, 66.2% in GS 7 (3 + 4), 51.1% in GS 7 (4 + 3) and 35.5% in GS 8-10. Conclusions: In patients with pT3aN0/Nx with PSM after RP, pathologic GS is the sole independent predictor for risk stratification of BCR. These findings might be used to determine the risk and timing of BCR and to help counsel patients regarding treatment strategy and prognosis of disease on an individual basis. [ABSTRACT FROM AUTHOR]

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses. [ABSTRACT FROM AUTHOR]

Purpose of Review: We reviewed the literature to determine what role, if any, radical prostatectomy should play in the treatment of high-risk and/or node-positive prostate cancer. Recent Findings: The AUA, NCCN, and EAU all include radical prostatectomy as a treatment option for high-risk prostate cancer based on evidence that has shown improvements in biochemical-free and disease-specific survival. Lymph node-positive patients may also derive benefit from radical prostatectomy with lymph node dissection, however, only retrospective studies with high risk of selection bias have been published to date. Summary: High-risk prostate cancer is a heterogeneous disease representing a wide range of disease characteristics. Radical surgery, historically avoided in such patients, may now be considered a valid treatment option for select cases. The adverse effects of surgery using modern techniques lead to similar quality of life outcomes as radiation therapy, and treatment of the primary tumor is likely beneficial when compared to ADT alone. [ABSTRACT FROM AUTHOR]

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Introduction: The aim of the study was to identify the appropriate level of Charlson comorbidity index (CCI) in older patients (>70 years) with high-risk prostate cancer (PCa) to achieve survival benefit following radical prostatectomy (RP). Methods: We retrospectively analyzed 1008 older patients (>70 years) who underwent RP with pelvic lymph node dissection for high-risk prostate cancer (preoperative prostate-specific antigen >20 ng/mL or clinical stage ≥T2c or Gleason ≥8) from 14 tertiary institutions between 1988 and 2014. The study population was further grouped into CCI < 2 and ≥2 for analysis. Survival rate for each group was estimated with Kaplan-Meier method and competitive risk Fine-Gray regression to estimate the best explanatory multivariable model. Area under the curve (AUC) and Akaike information criterion were used to identify ideal 'Cut off' for CCI. Results: The clinical and cancer characteristics were similar between the two groups. Comparison of the survival analysis using the Kaplan-Meier curve between two groups for non-cancer death and survival estimations for 5 and 10 years shows significant worst outcomes for patients with CCI ≥ 2. In multivariate model to decide the appropriate CCI cut-off point, we found CCI 2 has better AUC and p value in log rank test. Conclusion: Older patients with fewer comorbidities harboring high-risk PCa appears to benefit from RP. Sicker patients are more likely to die due to non-prostate cancer-related causes and are less likely to benefit from RP. [ABSTRACT FROM AUTHOR]

Pleomorphic adenoma gene like-2 (PLAGL2) is a member of the PLAG gene family. Previous studies have revealed that overexpression of PLAGL2 is associated with many human cancers. However, it has been reported that PLAGL2 also plays as a tumor suppressor. The precise role of PLAGL2 in prostate cancer (PCa) is still unknown. The aim of this study was to investigate the expression and prognostic value of PLAGL2 in PCa. Data from microarray datasets demonstrated that the DNA copy number and mRNA level of PLAGL2 were significantly increased in PCa compared with normal prostate. qRT-PCR and western blot analysis from paired PCa samples and prostate cell lines confirmed upregulated mRNA and protein expression levels in PCa. Immunohistochemistry analysis showed that staining of PLAGL2 in PCa tissues was significantly higher than that in benign prostatic hyperplasia (BPH) tissues. In addition, the high expression of PLAGL2 was only involved in preoperative PSA, but was not related to age, Gleason score, seminal vesicle invasion, surgical margin status, clinical stage and positive lymph node metastasis. Moreover, our results showed that PLAGL2 was an independent prognostic factor for biochemical recurrence (BCR)-free survival and overall survival (OS) of PCa patients, and overexpressed PLAGL2 was related to early development of BCR and poor OS. In conclusion, our findings suggest that PLAGL2 is overexpressed in PCa. The increased expression of PLAGL2 correlates to PCa progression following radical prostatectomy and may serve as a novel poor prognostic marker for PCa. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the possibility of performing radical prostatectomy (RP) alone to achieve a radical cure for prostate cancer in the intermediate-risk group. Samples were collected from 638 Japanese patients who underwent antegrade RP between August 1998 and May 2013; subsequently, 157 patients were excluded. According to the D'Amico criteria, the low-, intermediate-and high-risk groups comprised 107, 222 and 152 patients, respectively. The 5-year prostate-specific antigen (PSA) failure-free survival rates in the low-, intermediate-, and high-risk groups were 96.5, 88.9 and 72.6%, respectively (P<0.001; degrees of freedom=2). In the intermediate-risk group, the difference in PSA failure-free survival between the 0

Background: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.Methods: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.Results: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.Conclusions: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa. [ABSTRACT FROM AUTHOR]

Localized prostate cancer (PCa) is a clinically heterogeneous disease, which presents with variability in patient outcomes within the same risk stratification (low, intermediate or high) and even within the same Gleason scores. Genomic tools have been developed with the purpose of stratifying patients affected by this disease to help physicians personalize therapies and follow-up schemes. This review focuses on these tissue-based tools. At present, four genomic tools are commercially available: Decipher™, Oncotype DX®, Prolaris® and ProMark®. Decipher™ is a tool based on 22 genes and evaluates the risk of adverse outcomes (metastasis) after radical prostatectomy (RP). Oncotype DX® is based on 17 genes and focuses on the ability to predict outcomes (adverse pathology) in very low-low and low-intermediate PCa patients, while Prolaris® is built on a panel of 46 genes and is validated to evaluate outcomes for patients at low risk as well as patients who are affected by high risk PCa and post-RP. Finally, ProMark® is based on a multiplexed proteomics assay and predicts PCa aggressiveness in patients found with similar features to Oncotype DX®. These biomarkers can be helpful for post-biopsy decision-making in low risk patients and post-radical prostatectomy in selected risk groups. Further studies are needed to investigate the clinical benefit of these new technologies, the financial ramifications and how they should be utilized in clinics. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the long-term prognostic impact of age-adjusted Charlson comorbidity index (ACCI) on overall mortality (OM), cancer-specific mortality (CSM), and other-cause mortality (OCM) according to risk stratification in patients with prostate cancer who underwent radical prostatectomy. Methods: Data from 542 patients who underwent radical prostatectomy between 1992 and 2006 were analyzed. The impact of preoperative variables including age, prostate-specific antigen, biopsy Gleason sum, clinical stage, and ACCI on OM, CSM, and OCM were analyzed according to risk groups, with a median follow-up of 101 months. Results: Subjects were stratified into either the high-risk group ( n = 241) or the non-high-risk group ( n = 301). Cox proportional hazards model demonstrated that the ACCI was the only significant predictor for OM in all patients (hazard ratio, HR 1.41; 95 % confidence interval, CI 1.19-1.66), non-high-risk group (HR 1.45; 95 % CI 1.09-1.91), and high-risk group (HR 1.37; 95 % CI 1.11-1.69). In competing risk analysis, CSM was not associated with the ACCI in either risk group. However, the ACCI had a significant impact on OCM in both the non-high-risk (HR 1.55; 95 % CI 1.16-2.1) and high-risk groups (HR 1.60; 95 % CI 1.23-2.08). A Bayesian model averaging approach verified that the ACCI was the most powerful predictor for OM and OCM in the both high-risk and non-high-risk groups. Conclusions: A thorough assessment of comorbidities is mandatory in establishing prognoses, even when considering invasive treatment modalities in high-risk prostate cancer patients. [ABSTRACT FROM AUTHOR]

Locally advanced prostate cancer (LAPCA) comprises about 5-10 % of all newly diagnosed prostate cancers and is associated with the highest prostate cancer specific mortality (approximately 8-20 %). LAPCA is defined by the presence of extraprostatic extension, seminal vesicle invasion, and bladder neck infiltration of pelvic lymph node metastases. It is evident that prognosis can only be improved by interdisciplinary multimodality treatment strategies. Adequate local staging by multiparametric MRI is one of the cornerstones for an individualized, risk-adapted treatment approach. This might consist of extended radical prostatectomy with an extended pelvic lymphadenectomy or intensity-modulated radiation therapy with androgen deprivation as the primary local therapeutic approach. Both treatment strategies may be combined with neoadjuvant or adjuvant radiation therapy or salvage surgery. Combination with neoadjuvant or adjuvant chemotherapy and new androgen receptor pathway inhibitors might also be possible. This article summarizes the current treatment strategies for LAPCA. [ABSTRACT FROM AUTHOR]

Purpose To identify the ability of multiple variables to predict prostate cancer specific mortality ( PCSM) in a whole of population series of all radical prostatectomies ( RP) performed in Victoria, Australia. Materials & Methods A total of 2154 open RPs were performed in Victoria between July 1995 and December 2000. Subjects without follow up data, Gleason grade, pathological stage were excluded as were those who had pT4 disease or received neoadjuvant treatment. 1967 cases (91.3% of total) met the inclusion criteria for this study. Tumour characteristics were collated via a central registry. We used competing hazards regression models to investigate associations. Results At median follow up of 10.3 years pT stage of RP ( P < 0.001) and high Gleason score of the RP specimen ( P < 0.001 for ≥8 [Subhazard ratio ( SHR) 11.19] and 4 + 3 = 7 [ SHR 7.10]) compared with Gleason score 6 disease were strong predictors of progression to PCSM. Gleason score 3 + 4 = 7 was not at this time a significant predictor of PCSM ( P = 0.08, SHR 1.84). Predictors of PCSM, independent of stage and grade, included rural residency ( P = 0.003), primary surgeon contributing less than 40 cases (low-volume) to the VRPR ( P = 0.025) and the involvement of a trainee surgeon in the operation ( P = 0.031). Conclusion The significant prediction of PCSM by pT cancer stage, Gleason score and primary Gleason pattern at RP in this whole of population study suggests a need to avoid understaging/grading in the process of cancer diagnosis and active surveillance protocols. Multi-modality therapy is likely to have a greater impact on PCSM in higher stage and Gleason grade disease. Identification of increased PCSM with rural residency and with involvement of a trainee urologist, and reduction in PCSM with higher surgeon volume all suggest potential for improved PC outcomes to be achieved with changes to surgical training and service delivery. [ABSTRACT FROM AUTHOR]

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Distinguishing between patients with early stage, screen detected prostate cancer who must be treated from those that can be safely watched has become a major issue in prostate cancer care. Identification of molecular subtypes of prostate cancer has opened the opportunity for testing whether biomarkers that characterize these subtypes can be used as biomarkers of prognosis. Two established molecular subtypes are identified by high expression of the ERG oncoprotein, due to structural DNA alterations that encode for fusion transcripts in approximately ½ of prostate cancers, and over-expression of SPINK1, which is purportedly found only in ERG-negative tumors. We used a multi-institutional prostate cancer tissue microarray constructed from radical prostatectomy samples with associated detailed clinical data and with rigorous selection of recurrent and non-recurrent cases to test the prognostic value of immunohistochemistry staining results for the ERG and SPINK1 proteins. In univariate analysis, ERG positive cases (419/1067; 39%) were associated with lower patient age, pre-operative serum PSA levels, lower Gleason scores (≤3+4=7) and improved recurrence free survival (RFS). On multivariate analysis, ERG status was not correlated with RFS, disease specific survival (DSS) or overall survival (OS). High-level SPINK1 protein expression (33/1067 cases; 3%) was associated with improved RFS on univariate and multivariate Cox regression analysis. Over-expression of either protein was not associated with clinical outcome. While expression of ERG and SPINK1 proteins was inversely correlated, it was not mutually exclusive since 3 (0.28%) cases showed high expression of both. While ERG and SPINK1 appear to identify discrete molecular subtypes of prostate cancer, only high expression of SPINK1 was associated with improved clinical outcome. However, by themselves, neither ERG nor SPINK1 appear to be useful biomarkers for prognostication of early stage prostate cancer. [ABSTRACT FROM AUTHOR]

Background: CD147 is an MMP-inducing protein often implicated in cancer progression. The purpose of this study was to investigate the expression of CD147 in prostate cancer (PCa) progression and the prognostic ability of CD147 in predicting biochemical recurrence after prostatectomy. Methods: Plasma membrane-localized CD147 protein expression was quantified in patient samples using immunohistochemistry and multispectral imaging, and expression was compared to clinico-pathological features (pathologic stage, Gleason score, tumor volume, preoperative PSA, lymph node status, surgical margins, biochemical recurrence status). CD147 specificity and expression were confirmed with immunoblotting of prostate cell lines, and CD147 mRNA expression was evaluated in public expression microarray datasets of patient prostate tumors. Results: Expression of CD147 protein was significantly decreased in localized tumors (pT2; p = 0.02) and aggressive PCa (≥pT3; p = 0.004), and metastases (p = 0.001) compared to benign prostatic tissue. Decreased CD147 was associated with advanced pathologic stage (p = 0.009) and high Gleason score (p = 0.02), and low CD147 expression predicted biochemical recurrence (HR 0.55; 95 % CI 0.31-0.97; p = 0.04) independent of clinico-pathologic features. Immunoblot bands were detected at 44 kDa and 66 kDa, representing non-glycosylated and glycosylated forms of CD147 protein, and CD147 expression was lower in tumorigenic T10 cells than non-tumorigenic BPH-1 cells (p = 0.02). Decreased CD147 mRNA expression was associated with increased Gleason score and pathologic stage in patient tumors but is not associated with recurrence status. Conclusions: Membrane-associated CD147 expression is significantly decreased in PCa compared to non-malignant prostate tissue and is associated with tumor progression, and low CD147 expression predicts biochemical recurrence after prostatectomy independent of pathologic stage, Gleason score, lymph node status, surgical margins, and tumor volume in multivariable analysis. [ABSTRACT FROM AUTHOR]

Introduction: We analyzed the trends of positive surgical margin (PSM) location in patients who had pT3 disease at robot-assisted radical prostatectomy (RARP). We aimed to describe our changing incidence of PSMs in the largest series to date of patients with pT3 disease who were treated by RARP. Methods: A single-institution, single-surgeon review was performed of all patients who underwent RARP from 2005 to 2011. Perioperative data were collected for all patients with pT3 prostate cancer from a prospectively maintained RARP database. The PSM incidence and rates were stratified by location. The PSM rates per location were trended over time. Results: In total, 2478 consecutive patients underwent RARP between July 2005 and December 2011. Of these patients, 555 were found to have pT3 disease. The PSM rate for patients with pT3 disease was 47%. The PSM rate for patients with pT3a and pT3B disease was 42.8% and 60.6%, respectively. Over the duration of this study, the PSM rate in patients with pT3 disease decreased significantly from 70.6% in 2005 to 32.3% in 2011 ( p=0.002). The apical PSM rate showed the greatest decrease during this period going from 52.9% in 2005 to 5.2% in 2011 ( p=0.018). Conclusion: We present the largest series to date involving the treatment of locally advanced prostate cancer initially managed with RARP. Our findings suggest that patients with locally advanced prostate cancer can be treated with RARP with acceptable positive margin rates. Overall PSM rates improved nearly 40% over the 6.5-year period of this study. [ABSTRACT FROM AUTHOR]

A significant proportion of patients present with locally advanced prostate cancer with inherent higher risk of local recurrence and systemic relapse after initial treatment. Recent literature favors combination of radiation therapy and extended hormonal therapy for this subset of patients. The effectiveness of Radical prostatectomy (RP) alone for locally advanced prostate cancer is controversial and is a focus of debate. However, it can decrease the tumor burden and allows the accurate and precise pathological staging with the need for subsequent treatment. Comparison of RP and other treatment modalities is difficult and incorrect because of inherent selection bias. RP as a part of multi-modality treatment (with neo-adjuvant hormonal therapy (HT) and with adjuvant or salvage radiation therapy (RT)/ HT) can provide long term overall and cancer specific survival. Surgical treatment (such as transurethral resection (TUR), JJ stenting and percutaneous nephrostomy (PCN) placement etc.) can also provide symptomatic improvement and palliative care to improve quality of life of patients with advanced prostate cancer. [ABSTRACT FROM AUTHOR]