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Objective To determine the prevalence and clinical correlates of the G84E mutation in the homeobox transcription factor, or HOXB13, gene using DNA samples from 9559 men with prostate cancer undergoing radical prostatectomy. Patients and Methods DNA samples from men treated with radical prostatectomy at the University of Michigan and John Hopkins University were genotyped for G84E and this was confirmed by Sanger sequencing. The frequency and distribution of this allele was determined according to specific patient characteristics (family history, age at diagnosis, pathological Gleason grade and stage). Results Of 9559 patients, 128 (1.3%) were heterozygous carriers of G84E. Patients who possessed the variant were more likely to have a family history of prostate cancer than those who did not (46.0 vs 35.4%; P = 0.006). G84E carriers were also more likely to be diagnosed at a younger age than non-carriers (55.2 years vs 58.1 years; P < 0.001). No difference in the proportion of patients diagnosed with high grade or advanced stage tumours according to carrier status was observed. Conclusions In the present study, carriers of the rare G84E variant in HOXB13 were both younger at the time of diagnosis and more likely to have a family history of prostate cancer compared with homozygotes for the wild-type allele. No significant differences in allele frequency were detected according to selected clinical characteristics of prostate cancer. Further investigation is required to evaluate the role of HOXB13 in prostate carcinogenesis.

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 Gleason scoring system is a well-established predictor of pathological stage and oncological outcomes for men with prostate cancer. Modifications throughout the last few decades – most recently by the International Society of Urological Pathology (ISUP) in 2005 – have attempted to improve the correlation between biopsy and radical prostatectomy Gleason sum and better stratify patients to predict clinical outcomes. Based on these clinical outcomes and the excellent prognosis for patients with low Gleason scores, we recommend Gleason grades incorporating a prognostic grade grouping which accurately reflect prognosis and are clearly understood by physicians and patients alike. Objective To investigate pathological and short-term outcomes since the most recent Gleason system modifications by the International Society of Urological Pathology (ISUP) in an attempt to divide the current Gleason grading system into prognostically accurate Gleason grade groups. Patients and Methods We queried the Johns Hopkins Radical Prostatectomy Database (1982–2011), approved by the institutional review board, for men undergoing radical prostatectomy (RP) without a tertiary pattern since 2004 and identified 7869 men. Multivariable models were created using preoperative and postoperative variables; prognostic grade group (Gleason grade ≤6; 3 + 4; 4 + 3; 8; 9–10) was among the strongest predictors of biochemical recurrence-free (BFS) survival. Results Significant differences were noted among the Gleason grade groups at biopsy; differences were noted in the race, PSA level, clinical stage, number of positive cores at biopsy and the maximum percentage of positive cores among the Gleason grade groups at RP. With a median (range) follow-up of 2 (1–7) years, 5-year BFS rates for men with Gleason grade ≤6, 3 + 4, 4 + 3, 8 and 9–10 tumours at biopsy were 94.6, 82.7, 65.1, 63.1 and 34.5%, respectively (P < 0.001 for trend); and 96.6, 88.1, 69.7, 63.7 and 34.5%, respectively (P < 0.001), based on RP pathology. Conclusions The 2005 ISUP modifications to the Gleason grading system for prostate carcinoma accurately categorize patients by pathological findings and short-term biochemical outcomes but, while retaining the essence of the Gleason system, there is a need for a change in its reporting to more closely reflect tumour behaviour. We propose reporting Gleason grades, including prognostic grade groups which accurately reflect prognosis as follows: Gleason score ≤6 (prognostic grade group I); Gleason score 3+4=7 (prognostic grade group II); Gleason score 4+3=7 (prognostic grade group III); Gleason score 4+4=8 (prognostic grade group (IV); and Gleason score 9–10 (prognostic grade group (V).

What's known on the subject? and What does the study add? Previous studies have reported variable outcomes at radical prostatectomy (RP) with Gleason score 6 (GS6) on biopsy. It has been shown that a significant proportion of patients with GS6 disease at biopsy are upgraded to Gleason score 7 or higher after RP, increasing the risk of an adverse outcome. However, such studies have focused on clinical parameters such as PSA, prostate volume and biopsy cancer volume, in concert with GS6, to predict clinically significant upgrading. The present study is the first to use a significant number of patients with the aim of specifically analyzing the outcome at RP (i.e. percentage organ-confined, margin status, overall grade and biochemical recurrence) and making a direct correlation with the number of positive cores to show that the overall prognosis is favourable. Objective To establish whether the good prognosis of Gleason score 6 (GS6) is maintained in the setting of multiple involved cores. Patients and Methods In total, 6156 men (from 1 April 2000 to 30 April 2007) with GS6 on biopsy underwent radical prostatectomy (RP) at our institution. The number of positive cores was correlated with the outcome at RP. Results More positive cores correlated with less organ-confined disease (P 6 cores were positive (41 men followed to 2 years) (P = 0.6). Although the predicted ‘cure rate’ of >75% probability of a tumour showing no evidence of biochemical recurrence at 10 years after RP was statistically different between cases with ≤6 vs >6 positive cores (P

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.

Objective To update the 2007 Partin tables in a contemporary patient population. Patients and Methods The study population consisted of 5,629 consecutive men who underwent RP and staging lymphadenectomy at the Johns Hopkins Hospital between January 1, 2006 and July 30, 2011 and met inclusion criteria. Polychotomous logistic regression analysis was used to predict the probability of each pathologic stage category: organ-confined disease (OC), extraprostatic extension (EPE), seminal vesicle involvement (SV+), or lymph node involvement (LN+) based on preoperative criteria. Preoperative variables included biopsy Gleason score (6, 3+4, 4+3, 8, and 9–10), serum PSA (0–2.5, 2.6–4.0, 4.1–6.0, 6.1–10.0, greater than 10.0 ng/mL), and clinical stage (T1c, T2c, and T2b/T2c). Bootstrap re-sampling with 1000 replications was performed to estimate 95% confidence intervals for predicted probabilities of each pathologic state. Results The median PSA was 4.9 ng/mL, 63% had Gleason 6 disease, and 78% of men had T1c disease. 73% of patients had OC disease, 23% had EPE, 3% had SV+ but not LN+, and 1% had LN+ disease. Compared to the previous Partin nomogram, there was no change in the distribution of pathologic state. The risk of LN+ disease was significantly higher for tumours with biopsy Gleason 9–10 than Gleason 8 (O.R. 3.2, 95% CI 1.3–7.6). The c-indexes for EPE vs. OC, SV+ vs. OC, and LN+ vs. OC were 0.702, 0.853, and 0.917, respectively. Men with biopsy Gleason 4+3 and Gleason 8 had similar predicted probabilities for all pathologic stages. Most men presenting with Gleason 6 disease or Gleason 3+4 disease have

UNLABELLED Study Type--Diagnostic (exploratory cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Surgical margin status at radical prostatectomy (RP) has been shown to be a predictor of disease progression and the strongest predictor of benefit from adjuvant therapy, but the impact of a positive surgical margin (PSM) on long-term prostate-cancer-specific survival is unknown. The PSM rate is dependent on the pathological stage of the cancer. In a recent multicentre nomogram for 15-year prostate-cancer-specific mortality (PCSM) after RP, PSM was not significantly associated with PCSM, while Gleason score and pathological stage were the only significant predictors. This has not been validated in a single centre, and PSM has been shown to vary greatly with surgical technique. This is the first study on the impact of PSM on PCSM in a single surgeon's cohort. In other centres, the decision to administer adjuvant therapy may be influenced by surgical margin status. In this cohort, men routinely did not receive adjuvant therapy, affording the unique opportunity to study the long-term implications of a PSM. OBJECTIVE • To examine the relative impact of a positive surgical margin (PSM) and other clinicopathological variables on prostate-cancer-specific mortality (PCSM) in a large retrospective cohort of patients undergoing radical prostatectomy (RP). PATIENTS AND METHODS • Between 1982 and 2011, 4569 men underwent RP performed by a single surgeon. • Of the patient population, 4461 (97.6%) met all the inclusion criteria. • The median (range) age was 58 (33-75) years and the median prostate-specific antigen (PSA) was 5.4 ng/mL; RP Gleason score was ≤ 6 in 2834 (63.7%), 7 in 1351 (30.3%), and 8-10 in 260 (6.0%) patients; PSMs were found in 462 (10.4%) patients. • Cox proportional hazards models were used to determine the impact of a PSM on PCSM. RESULTS • At a median (range) follow-up of 10 years (1-29), 187 men (4.3%) had died from prostate cancer. • The 20-year prostate-cancer-specific survival rate was 75% for those with a PSM and 93% for those without. • Compared with those with a negative surgical margin, men with a PSM were more likely to be older (median age 60 vs 58 years) and to have undergone RP in the pre-PSA era (36.6% vs 11.8%). Additionally, they were more likely to have a higher PSA level (median 7.6 vs 5.2 ng/mL), a Gleason score of ≥ 7 (58.7% vs 33.7%), and a non-organ-confined tumour (90.9% vs 30.6% [P < 0.001 for all]). • In a univariate model for PCSM, PSM was highly significant (hazard ratio [HR] 5.0, 95% confidence interval [CI] 3.7-6.7, P < 0.001). • In a multivariable model, adjusting for pathological variables and RP year, PSM remained an independent predictor of PCSM (HR 1.4, 95% CI 1.0-1.9, P = 0.036) with a modest effect relative to RP Gleason score (HR 5.7-12.6) and pathological stage (HR 2.2-11.0 [P < 0.001]). CONCLUSION • Although a PSM has a statistically significant adverse effect on prostate-cancer-specific survival in multivariable analysis, Gleason grade and pathological stage were stronger predictors.

Study Type – Diagnostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Although non-recommended PSA testing has been reported in men younger than 40 years of age, there are few recognized data on PSA in younger American men, particularly younger African-American men, to provide age- and race-specific references. Using data from an existing large study of young, male members of the US military, aged 28–36 years, the present study provides PSA reference distributions for young Caucasian-American men (median = 0.56, 95th percentile = 1.42, range

OBJECTIVE To investigate preoperative characteristics that distinguish favourable and unfavourable pathological and clinical outcomes in men with high biopsy Gleason sum (8 – 10) prostate cancer to better select men who will most benefit from radical prostatectomy (RP). PATIENTS AND METHODS The Institutional Review Board-approved institutional RP database (1982 – 2010) was analysed for men with high-Gleason prostate cancer on biopsy; 842 men were identified. The 10-year biochemical-free (BFS), metastasis-free (MFS) and prostate cancer-specific survival (CSS) were calculated using the Kaplan – Meier method to verify favourable pathology as men with Gleason 10 ng/mL (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.38 – 3.62, P = 0.001), advanced clinical stage (≥ cT2b; OR 2.55, 95% CI 1.55 – 4.21, P 50% positive core involvement (OR 2.25, 95% CI 1.17 – 4.35, P = 0.015) were predictive of unfavourable pathology. CONCLUSIONS Men with high-Gleason sum at biopsy are at high risk for biochemical recurrence, metastasis and death after RP; men with high Gleason sum and advanced pathological stage (pT3b or N1) have the worst prognosis. Among men with high-Gleason sum at biopsy, a PSA concentration of > 10 ng/mL, clinical stage ≥ T2b, Gleason pattern 9 or 10, increasing number of cores with high-grade cancer and > 50% core involvement are predictive of unfavourable pathology. Keywords: prostate cancer, high-risk, Gleason sum, outcomes INTRODUCTION For men undergoing radical prostatectomy (RP) for prostate cancer, biopsy and pathological Gleason sum are cited as the strongest predictors of outcome in pre- and postoperative models, respectively [1-5]. Although 80% of men with Gleason 8 – 10 prostate cancer undergoing RP at our institution have biochemical recurrence by 15 years, not all patients do uniformly poorly with respect to metastases-free (MFS) and prostate cancer-specific survival (CSS). A recent multivariate evaluation of long-term surgical outcomes in men with pathological Gleason sum 8 – 10 prostate cancer determined that pathological stage at RP was the most potent indicator of mortality [6]. Men with organ-confined (pT2) or extraprostatic (pT3a,) disease at RP had a 76 – 96% CSS at 15 year compared with 37 – 73% at 15 years for men with seminal vesicle invasion (pT3b, SVI) or lymph node involvement (N1) [6]. These divergent outcomes make the ideal management of high-Gleason sum prostate cancer controversial. While recent studies suggest that inclusion of surgery in the treatment of men with Gleason sum 8 – 10 on biopsy allows for better long-term outcomes when compared with radiation [7,8], many urologists are hesitant to subject these men to the side-effects of RP when benefit may be marginal. Little data exists about the best preoperative criteria to identify men with high-Gleason sum prostate cancer who may benefit from surgery. One recent study suggests that men with a single high-risk feature (PSA concentration of > 20 ng/mL, Gleason 8 – 10 or clinical stage > cT2b [3]) have better outcomes than men with multiple high-risk features, but this work did not thoroughly explore the utility of individual preoperative parameters to predict advanced pathological stage [9]. In the present study, we evaluated the ability of preoperative characteristics, to predict favourable pathological and oncological outcomes in men found to have high Gleason sum at biopsy.

UNLABELLED What's known on the subject? and What does the study add? Finasteride (Proscar) and dutasteride (Avodart) are 5-α reductase inhibitors (5-ARIs) used to treat LUTS in men with benign prostatic enlargement. Because these drugs suppress androgens, the theory has been put forward that 5-ARIs might prevent the development of prostate cancer. Careful analysis of two randomized controlled trials, however, showed that, in the clinical setting, this was not the case, and that these drugs can increase the occurrence of more aggressive high-grade disease. Because of this, the U.S. Food and Drug Administration did not approve 5-ARIs for the primary prevention of prostate cancer and notified healthcare professionals about a change in the 'Warnings and Precautions' for these drugs. Interest remains among some for using 5-ARIs in men diagnosed with very low-risk prostate cancer to delay the progression from clinically indolent disease to clinically significant disease requiring treatment. The present study investigated whether 5-ARI use among men with very low-risk prostate cancer in an active surveillance (AS) programme would reduce the number of cancers reclassified to clinically significant disease on surveillance biopsy. Our results do not support the use of 5-ARIs for slowing or preventing cancer progression in men with low-risk prostate cancer, but do suggest that men with very low-risk prostate cancer who take 5-ARIs for LUTS are unlikely to be at increased risk for the development of high grade disease during AS. OBJECTIVE To determine whether 5-α reductase inhibitor (5-ARI) use delays cancer reclassification in an active surveillance (AS) cohort. PATIENTS AND METHODS We performed a retrospective study of 587 men enrolled in an AS programme, who had no history of 5-ARI use. Chi-squared and t-tests were used to compare characteristics of 5-ARI users and non-users. Univariable and multivariable proportional hazards models, treating 5-ARI use as a time-dependent covariate, were used to evaluate the influence of 5-ARIs on the risk of a subsequent biopsy no longer meeting criteria for continued AS (i.e. reclassification). RESULTS 5-ARI use was initiated in 47 men while on AS. Men using 5-ARIs had larger prostates and higher PSA levels at diagnosis. During 5-ARI use, PSA levels and prostate volume deceased by mean values of 47% and 11%, respectively. Men using 5-ARIs had a mean of 2.5 surveillance biopsies while on the drug. Reclassification occurred in 17% of 5-ARI users compared with 31% of non-users (P = 0.04). Multivariable models (adjusting for age, α-blocker use, PSA level, %free PSA, PSA density, prostate volume and number/percent biopsy core involvement at diagnosis) showed nonsignificant risk reductions for reclassification in 5-ARI users as determined by either tumour extent (hazard ratio [HR] = 0.37 (95% confidence interval [CI] 0.12 to 1.13), P = 0.08) or grade (HR = 0.8 (95% CI 0.25-2.59), P = 0.7). CONCLUSION Treatment with 5-ARIs did not significantly alter the outcome of biopsy reclassification by grade in men with very low-risk prostate cancer.

Study Type – Prognosis (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Patients with biochemical recurrence after prostatectomy often develop subsequent metastases. However, the natural history of metastatic progression in men who have not received subsequent therapies before developing metastases has been understudied. Here, we describe the largest known cohort of men with PSA-recurrent prostate cancer after prostatectomy who have not received additional treatments before metastasis. We characterize metastatic risk based on clinical variables, and we show that Gleason score and PSA doubling time are the strongest predictors of metastasis-free survival. We present tables stratifying metastatic risk by these two variables. OBJECTIVE • To describe metastasis-free survival (MFS) in men with prostate-specific antigen (PSA) recurrence following radical prostatectomy, and to define clinical prognostic factors modifying metastatic risk. PATIENTS AND METHODS • We conducted a retrospective analysis of 450 men treated with prostatectomy at a tertiary hospital between July 1981 and July 2010 who developed PSA recurrence (≥0.2 ng/mL) and never received adjuvant or salvage therapy before the development of metastatic disease. • We estimated MFS using the Kaplan–Meier method, and investigated factors influencing the risk of metastasis using Cox proportional hazards regression. RESULTS • Median follow-up after prostatectomy was 8.0 years, and after biochemical recurrence was 4.0 years. At last follow-up, 134 of 450 patients (29.8%) had developed metastases, while median MFS was 10.0 years. • Using multivariable regressions, two variables emerged as independently predictive of MFS: PSA doubling time (

Various conflicting guidelines and recommendations about prostate cancer screening and early detection have left both clinicians and their patients quite confused. At the Prostate Cancer World Congress held in Melbourne in August 2013, a multidisciplinary group of the world's leading experts in this area gathered together and generated this set of consensus statements to bring some clarity to this confusion. The five consensus statements provide clear guidance for clinicians counselling their patients about the early detection of prostate cancer.

Study Type – Prognosis (case series) Level of Evidence 4 PURPOSE Erectile dysfunction (ED) and cardiovascular disease (CVD) share etiology and pathophysiology. The underlying pathology for preoperative ED may adversely affect survival following radical prostatectomy (RP). We examined the association between preoperative ED and survival following RP. MATERIALS AND METHODS Between 1983 and 2000, a single surgeon performed RP on 2511 men, with preoperative ED (ED group, n= 231, 9.2%) or without ED (No ED group, n= 2280, 90.8%). We retrospectively analysed their CVD-specific survival (CVDSS), prostate cancer-specific survival (PCSS), non-PCSS (NPCSS) and overall survival (OS) from time of surgery. RESULTS With median follow-up of 13 years after RP, 449 men (18%) died (140 from prostate cancer, 309 from other causes). Kaplan–Meier analyses demonstrated significant differences in CVDSS (P < 0.001), NPCSS (P < 0.001) and OS (P < 0.001), but not in PCSS (P= 0.12), between the ED group vs No ED group. In univariate proportional hazards analyses, preoperative ED was associated with a significant decrease in OS, hazard ratio (HR), 1.71 (95% CI, 1.34–2.23), P < 0.001. However, in multivariable analyses, the association of ED with survival became non-significant (HR, 1.25 (95% CI, 0.97–1.66), P= 0.111) after adjusting for other prognostic factors, such as age, preoperative prostate-specific antigen (PSA) level, Gleason score, pathologic stage, body mass index and Charlson Comorbidity Index. CONCLUSIONS Preoperative ED is associated with decreased overall survival and survival from causes other than prostate cancer following RP. However, preoperative ED was not an independent predictor of overall survival after adjusting for other predictors of survival. Urologists should carefully assess pretreatment ED status to enhance appropriate treatment recommendation for men with prostate cancer.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To examine the survival outcomes of septuagenarians and octogenarians (aged ≥80 years) who underwent radical prostatectomy (RP) at our institution, as the US Preventive Services Task Force recently released recommendations that men aged ≥75 years should not be screened for prostate cancer. PATIENTS AND METHODS Our institutional RP database (1982–2008) was queried for men aged ≥70 years at the time of surgery to evaluate actuarial survival after RP; 386 aged 70–81 years (median 71) underwent RP. The median (range) follow-up was 6.5 (1–22) years. Clinicopathological characteristics and mortality data were evaluated; mortality data were gathered through Social Security Administration Death Index and causes of death were confirmed with the Center for Disease Control National Death Index information. Kaplan-Meier analysis was used to evaluate cause-specific survival. RESULTS Ten patients (2.6%) had clinical stage T1a-b, 213 (55.3%) had T1c, and 143 (37.1%) had T2 prostate cancer. The median (range) preoperative prostate-specific antigen (PSA) level was 6.2 (0.2–49.9) ng/mL, and the biopsy and pathological Gleason sum was 6 (3–9) and 7 (4–9), respectively. Causes of death included prostate cancer (17), other malignancies (14), cardiovascular causes (14), neurological disease (four), pneumonia (two) and accident (one). The prostate cancer-specific survival rate was 97.6%, 94.0% and 90.2% at 5, 10 and 15 years after RP, respectively; the respective cardiovascular survival rate was 99.5%, 97.6% and 92.5%, and the overall survival rate was 93.1%, 82.5% and 68.9%, respectively. CONCLUSIONS If appropriately selected, older men have excellent overall and prostate-cancer specific survival after RP. The benefits of surgery should be weighed against the increased risks of surgical and anaesthetic complications.

Study Type – Prognostic (case series) Level of Evidence 4 OBJECTIVE To determine the relationship between perineural invasion (PNI) on prostate biopsy and radical prostatectomy (RP) outcomes in a contemporary RP series, as there is conflicting evidence on the prognostic significance of PNI in prostate needle biopsy specimens. PATIENTS AND METHODS From 2002 to 2007, 1256 men had RP by one surgeon. Multivariable logistic regression and Cox proportional hazards models were used to examine the relationship of PNI with pathological tumour features and biochemical progression, respectively, after adjusting for prostate-specific antigen level, clinical stage and biopsy Gleason score. Additional Cox models were used to examine the relationship between nerve-sparing and biochemical progression among men with PNI. RESULTS PNI was found in 188 (15%) patients, and was significantly associated with aggressive pathology and biochemical progression. On multivariate analysis, PNI was significantly associated with extraprostatic extension and seminal vesicle invasion (P

OBJECTIVE To assess the biochemical outcome after radical prostatectomy (RP) specifically for men aged 30–39 years, as previous studies suggest that prostate cancer in young men might be more aggressive. PATIENTS AND METHODS From a large (15 899) database of RPs (1975–2007) we identified 42 men aged 30–39, 893 aged 40–49, 4085 aged 50–59, 3766 aged 60–69, and 182 men aged ≥70 years old. The clinical characteristics and treatment outcomes were compared between men aged 30–39 years and older men. RESULTS Among the men in their thirties, 81% had organ-confined disease in the RP specimen, vs 62% of men aged ≥40 years. At a mean follow-up of 5 years, there was biochemical progression in 4.8% of men in their thirties and 16.1% of men age ≥40 years (P = 0.055). The corresponding 5-year biochemical progression-free survival estimates were 95% for men in their thirties and 83% for men aged ≥40 years (P = 0.045). On multivariate analysis, increasing age was a significant independent predictor of biochemical progression. CONCLUSION Contrary to earlier reports, in the present study men in their thirties did not have more aggressive disease. Instead, they had more favourable pathological features and progression-free survival rates than their older counterparts. After controlling for other prognostic variables on multivariate analysis, being in the fourth decade was independently associated with a lower risk of biochemical progression. These results suggest that early aggressive treatment for these patients with a long life-expectancy is associated with favourable long-term biochemical outcomes.

Various conflicting guidelines and recommendations about prostate cancer screening and early detection have left both clinicians and their patients quite confused. At the Prostate Cancer World Congress held in Melbourne in August 2013, a multidisciplinary group of the world's leading experts in this area gathered together and generated this set of consensus statements to bring some clarity to this confusion. The five consensus statements provide clear guidance for clinicians counselling their patients about the early detection of prostate cancer.

To determine the prevalence and clinical correlates of the G84E mutation in the homeobox transcription factor, or HOXB13, gene using DNA samples from 9559 men with prostate cancer undergoing radical prostatectomy.DNA samples from men treated with radical prostatectomy at the University of Michigan and John Hopkins University were genotyped for G84E and this was confirmed by Sanger sequencing. The frequency and distribution of this allele was determined according to specific patient characteristics (family history, age at diagnosis, pathological Gleason grade and stage).Of 9559 patients, 128 (1.3%) were heterozygous carriers of G84E. Patients who possessed the variant were more likely to have a family history of prostate cancer than those who did not (46.0 vs 35.4%; P = 0.006). G84E carriers were also more likely to be diagnosed at a younger age than non-carriers (55.2 years vs 58.1 years; P0.001). No difference in the proportion of patients diagnosed with high grade or advanced stage tumours according to carrier status was observed.In the present study, carriers of the rare G84E variant in HOXB13 were both younger at the time of diagnosis and more likely to have a family history of prostate cancer compared with homozygotes for the wild-type allele. No significant differences in allele frequency were detected according to selected clinical characteristics of prostate cancer. Further investigation is required to evaluate the role of HOXB13 in prostate carcinogenesis.

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.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.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'.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 (P0.001). Ileus delayed discharge in 0.28%, 0.37% and 1.9% of patients undergoing RRP, LRP and RALRP, respectively (P0.001).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 Gleason scoring system is a well-established predictor of pathological stage and oncological outcomes for men with prostate cancer. Modifications throughout the last few decades - most recently by the International Society of Urological Pathology (ISUP) in 2005 - have attempted to improve the correlation between biopsy and radical prostatectomy Gleason sum and better stratify patients to predict clinical outcomes. Based on these clinical outcomes and the excellent prognosis for patients with low Gleason scores, we recommend Gleason grades incorporating a prognostic grade grouping which accurately reflect prognosis and are clearly understood by physicians and patients alike.To investigate pathological and short-term outcomes since the most recent Gleason system modifications by the International Society of Urological Pathology (ISUP) in an attempt to divide the current Gleason grading system into prognostically accurate Gleason grade groups.We queried the Johns Hopkins Radical Prostatectomy Database (1982-2011), approved by the institutional review board, for men undergoing radical prostatectomy (RP) without a tertiary pattern since 2004 and identified 7869 men. Multivariable models were created using preoperative and postoperative variables; prognostic grade group (Gleason grade ≤ 6; 3 + 4; 4 + 3; 8; 9-10) was among the strongest predictors of biochemical recurrence-free (BFS) survival.Significant differences were noted among the Gleason grade groups at biopsy; differences were noted in the race, PSA level, clinical stage, number of positive cores at biopsy and the maximum percentage of positive cores among the Gleason grade groups at RP. With a median (range) follow-up of 2 (1-7) years, 5-year BFS rates for men with Gleason grade ≤ 6, 3 + 4, 4 + 3, 8 and 9-10 tumours at biopsy were 94.6, 82.7, 65.1, 63.1 and 34.5%, respectively (P0.001 for trend); and 96.6, 88.1, 69.7, 63.7 and 34.5%, respectively (P0.001), based on RP pathology.The 2005 ISUP modifications to the Gleason grading system for prostate carcinoma accurately categorize patients by pathological findings and short-term biochemical outcomes but, while retaining the essence of the Gleason system, there is a need for a change in its reporting to more closely reflect tumour behaviour. We propose reporting Gleason grades, including prognostic grade groups which accurately reflect prognosis as follows: Gleason score ≤ 6 (prognostic grade group I); Gleason score 3+4=7 (prognostic grade group II); Gleason score 4+3=7 (prognostic grade group III); Gleason score 4+4=8 (prognostic grade group (IV); and Gleason score 9-10 (prognostic grade group (V).

To establish whether the good prognosis of Gleason score 6 (GS6) is maintained in the setting of multiple involved cores.In total, 6156 men (from 1 April 2000 to 30 April 2007) with GS6 on biopsy underwent radical prostatectomy (RP) at our institution. The number of positive cores was correlated with the outcome at RP.More positive cores correlated with less organ-confined disease (P0.001), positive margins (P0.012), increasing RP grade (P0.001) and increased seminal vesicles/lymph node involvement (P = 0.012). For men with data available, the actuarial risk of being biochemically free of disease at 5 years was 93.2% when ≤6 cores were positive (812 men followed to 5 years) vs 89.1% if6 cores were positive (41 men followed to 2 years) (P = 0.6). Although the predicted 'cure rate' of75% probability of a tumour showing no evidence of biochemical recurrence at 10 years after RP was statistically different between cases with ≤6 vs6 positive cores (P0.0001), the outcome in both groups was still favourable (90.5% vs 84%). Partin-like tables were generated factoring in the number of positive cores to predict organ-confined disease as a guide for urologists to perform nerve-sparing surgery. For example, with T1c disease, there was a ≥75% probability of organ-confined disease with one to three positive cores regardless of prostate-specific antigen (PSA) level, and the same probability was present with four to six positive cores and a PSA level of 0-4 ng/mL.A low Gleason score on biopsy is a powerful prognostic finding, such that this favourable outcome is maintained even in the setting of multiple positive cores with GS6.

Study Type--Diagnostic (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Although non-recommended PSA testing has been reported in men younger than 40 years of age, there are few recognized data on PSA in younger American men, particularly younger African-American men, to provide age- and race-specific references. Using data from an existing large study of young, male members of the US military, aged 28-36 years, the present study provides PSA reference distributions for young Caucasian-American men (median = 0.56, 95th percentile = 1.42, range:0.01-3.34 ng/mL) and African-American men (median = 0.64, 95th percentile = 1.89, range: 0.12-6.45 ng/mL). Previous estimates from the literature are also summarized.• To provide race-specific prostate-specific antigen (PSA) reference distributions for young men less than 40 years of age who might have undergone non-recommended PSA testing because of their family history of prostate cancer or inadvertently as part of a standard panel of tests.• We used data from a large existing study of young, male Caucasian- and African-American members of the US military with stored serum in the Department of Defense serum repository. • As part of this previous study, we selected a random sample of 373 Caucasian- and 366 African-American men aged 28-36 years with an archived serum specimen collected for standard military purposes from 2004 to 2006. • We measured serum total PSA concentration in this specimen using the Beckman Coulter Access Hybritech PSA assay.• The PSA level ranged from0.01 to 3.34 ng/mL among Caucasian-American men, with a median of 0.56 ng/mL and a 95th percentile of 1.42 ng/mL. • The PSA level ranged from 0.12 to 6.45 ng/mL among African-American men, with a median of 0.64 ng/mL and 95th percentile of 1.89 ng/mL. • The PSA level was significantly higher in African- than in Caucasian-American men (P= 0.001).• The PSA estimates, together with those summarized from the literature, provide age- and race-specific PSA reference distributions for young men who might have undergone non-recommended PSA testing. • Comparisons by race could also begin to inform the timing of divergence of prostate cancer risk by race.

What's known on the subject? and What does the study add? Men with high-risk prostate cancer experience recurrence, metastases and death at the highest rate in the prostate cancer population. Pathological stage at radical prostatectomy (RP) is the greatest predictor of recurrence and mortality in men with high-grade disease. Preoperative models predicting outcome after RP are skewed by the large proportion of men with low- and intermediate-risk features; there is a paucity of data about preoperative criteria to identify men with high-grade cancer who may benefit from RP. The present study adds comprehensive biopsy data from a large cohort of men with high-grade prostate cancer at biopsy. By adding biopsy parameters, e.g. number of high-grade cores and50% involvement of any core, to traditional predictors of outcome (prostate-specific antigen concentration, clinical stage and Gleason sum), we can better inform men who present with high-grade prostate cancer as to their risk of favourable or unfavourable disease at RP.To investigate preoperative characteristics that distinguish favourable and unfavourable pathological and clinical outcomes in men with high biopsy Gleason sum (8-10) prostate cancer to better select men who will most benefit from radical prostatectomy (RP).The Institutional Review Board-approved institutional RP database (1982-2010) was analysed for men with high-Gleason prostate cancer on biopsy; 842 men were identified. The 10-year biochemical-free (BFS), metastasis-free (MFS) and prostate cancer-specific survival (CSS) were calculated using the Kaplan-Meier method to verify favourable pathology as men with Gleason8 at RP or ≤ pT3a compared with men with unfavourable pathology with Gleason 8-10 and pT3b or N1. Preoperative characteristics were compared using appropriate comparative tests. Logistic regression determined preoperative predictors of unfavourable pathology.There was favourable pathology in 656 (77.9%) men. The 10-year BFS, MFS and CSS were 31.0%, 60.9% and 74.8%, respectively. In contrast, men with unfavourable pathological findings had significantly worse 10-year BFS, MFS and CSS, at 4.3%, 29.1% and 52.3%, respectively (all P0.001). In multivariable logistic regression, a prostate-specific antigen (PSA) concentration of10 ng/mL (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.38-3.62, P = 0.001), advanced clinical stage (≥ cT2b; OR 2.55, 95% CI 1.55-4.21, P0.001), Gleason pattern 9 or 10 at biopsy (OR 2.55, 95% CI 1.59-4.09, P0.001), increasing number of cores positive with high-grade cancer (OR 1.16, 95% CI 1.01-1.34, P = 0.04) and50% positive core involvement (OR 2.25, 95% CI 1.17-4.35, P = 0.015) were predictive of unfavourable pathology.Men with high-Gleason sum at biopsy are at high risk for biochemical recurrence, metastasis and death after RP; men with high Gleason sum and advanced pathological stage (pT3b or N1) have the worst prognosis. Among men with high-Gleason sum at biopsy, a PSA concentration of10 ng/mL, clinical stage ≥ T2b, Gleason pattern 9 or 10, increasing number of cores with high-grade cancer and50% core involvement are predictive of unfavourable pathology.

To examine the survival outcomes of septuagenarians and octogenarians (agedor =80 years) who underwent radical prostatectomy (RP) at our institution, as the US Preventive Services Task Force recently released recommendations that men agedor =75 years should not be screened for prostate cancer.Our institutional RP database (1982-2008) was queried for men agedor =70 years at the time of surgery to evaluate actuarial survival after RP; 386 aged 70-81 years (median 71) underwent RP. The median (range) follow-up was 6.5 (1-22) years. Clinicopathological characteristics and mortality data were evaluated; mortality data were gathered through Social Security Administration Death Index and causes of death were confirmed with the Center for Disease Control National Death Index information. Kaplan-Meier analysis was used to evaluate cause-specific survival.Ten patients (2.6%) had clinical stage T1a-b, 213 (55.3%) had T1c, and 143 (37.1%) had T2 prostate cancer. The median (range) preoperative prostate-specific antigen (PSA) level was 6.2 (0.2-49.9) ng/mL, and the biopsy and pathological Gleason sum was 6 (3-9) and 7 (4-9), respectively. Causes of death included prostate cancer (17), other malignancies (14), cardiovascular causes (14), neurological disease (four), pneumonia (two) and accident (one). The prostate cancer-specific survival rate was 97.6%, 94.0% and 90.2% at 5, 10 and 15 years after RP, respectively; the respective cardiovascular survival rate was 99.5%, 97.6% and 92.5%, and the overall survival rate was 93.1%, 82.5% and 68.9%, respectively.If appropriately selected, older men have excellent overall and prostate-cancer specific survival after RP. The benefits of surgery should be weighed against the increased risks of surgical and anaesthetic complications.