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Background: Magnetic resonance imaging (MRI)-targeted prostate biopsy (MRI-biopsy) detects high-Grade Group (GG) prostate cancers not identified by systematic biopsy (S-biopsy). However, questions have been raised whether cancers detected by MRI-biopsy and S-biopsy, grade-for-grade, are of equivalent oncologic risk. The authors evaluated the relative oncologic risk of GG diagnosed by S-biopsy and MRI-biopsy., Methods: This was a retrospective analysis of all patients who had both MRI-biopsy and S-biopsy and underwent with prostatectomy (2014-2022) at Memorial Sloan Kettering Cancer Center. Three logistic regression models were used with adverse pathology as the primary outcome (primary pattern 4, any pattern 5, seminal vesicle invasion, or lymph node involvement). The first model included the presurgery prostate-specific antigen level, the number of positive and negative S-biopsy cores, S-biopsy GG, and MRI-biopsy GG. The second model excluded MRI-biopsy GG to obtain the average risk based on S-biopsy GG. The third model excluded S-biopsy GG to obtain the risk based on MRI-biopsy GG. A secondary analysis using Cox regression evaluated the 12-month risk of biochemical recurrence., Results: In total, 991 patients were identified, including 359 (36%) who had adverse pathology. MRI-biopsy GG influenced oncologic risk compared with S-biopsy GG alone (p < .001). However, if grade was discordant between biopsies, then the risk was intermediate between grades. For example, the average risk of advanced pathology for patients who had GG2 and GG3 on S-biopsy was 19% and 66%, respectively, but the average risk was 47% for patients who had GG2 on S-biopsy and patients who had GG3 on MRI-biopsy. The equivalent estimates for 12-month biochemical recurrence were 5.8%, 15%, and 10%, respectively., Conclusions: The current findings cast doubt on the practice of defining risk group based on the highest GG. Because treatment algorithms depend fundamentally on GG, further research is urgently required to assess the oncologic risk of prostate tumors depending on detection technique., Plain Language Summary: Using magnetic resonance imaging (MRI) to help diagnose prostate cancer can help identify more high-grade cancers than using a systematic template biopsy alone. However, we do not know if high-grade cancers diagnosed with the help of an MRI are as dangerous to the patient as high-grade cancers diagnosed with a systematic biopsy. We examined all of our patients who had an MRI biopsy and a systematic biopsy and then had their prostates removed to find out if these patients had risk factors and signs of aggressive cancer (cancer that spread outside the prostate or was very high grade). We found that, if there was a difference in grade between the systematic biopsy and the MRI-targeted biopsy, the risk of aggressive cancer was between the two grades., (© 2023 American Cancer Society.)

Purpose: Prophylactic antibiotics are routinely given at the time of catheter removal post-radical prostatectomy (RP). The low rate of infectious complications entails that large sample sizes are required for randomized controlled trials, a challenge given the cost of standard randomized controlled trials. We evaluated infectious complications associated with 1 vs 3 days of prophylactic antibiotics at the time of catheter removal post-RP using a novel, clinically integrated trial with randomization at the surgeon level., Materials and Methods: Surgeons were cluster randomized for periods of 3 months to prescribe 1-day vs 3-day regimen of prophylactic antibiotics at the time of catheter removal. The primary end point was an infectious complication as routinely captured by nursing phone call within 10 days of catheter removal and defined as positive urine cultures (≥10 5 CFU) and at least 1 of the following symptoms: fever (>38°C), urgency, frequency, dysuria or suprapubic tenderness., Results: A total of 824 patients were consented and underwent RP with, respectively, 389 and 435 allocated to 1-day and 3-day antibiotics, predominantly ciprofloxacin. Accrual was achieved within 3 years: 95% vs 88% of patients received the allocated 3-day vs 1-day antibiotic regimen. There were 0 urinary tract infections (0%) in the 1-day regimen and 3 urinary tract infections (0.7%) in the 3-day regimen, meeting our prespecified criterion for declaring the 1-day regimen to be noninferior., Conclusions: A clinically integrated trial using cluster randomization accrued rapidly with no important logistical problems and negligible burden on surgeons. If surgeons choose to prescribe empiric prophylactic antibiotics after catheter removal following RP, then the duration should not exceed 1 day.

Purpose: We investigated whether T2-weighted magnetic resonance imaging findings could improve upon established prognostic indicators of metastatic disease and prostate cancer specific survival., Materials and Methods: For a cohort of 3,406 consecutive men who underwent prostate magnetic resonance imaging before prostatectomy (2,160) or radiotherapy (1,246) between 2001 and 2006, T2-weighted magnetic resonance imaging exams were retrospectively interpreted and categorized as I) no focal suspicious lesion, II) organ confined focal lesion, III) focal lesion with extraprostatic extension or IV) focal lesion with seminal vesicle invasion. Clinical risk was recorded based on European Association of Urology (EAU) guidelines and the Cancer of the Prostate Risk Assessment (CAPRA) scoring system. Survival probabilities and c-indices were estimated using Cox models and inverse probability censoring weights, respectively., Results: The median followup was 10.8 years (IQR 8.6-13.0). Higher magnetic resonance imaging categories were associated with a higher likelihood of developing metastases (HR 3.5-18.1, p <0.001 for all magnetic resonance imaging categories) and prostate cancer death (HR 3.1-29.7, p <0.001-0.025); these associations were statistically independent of EAU risk categories, CAPRA scores and treatment type (surgery vs radiation). Combining EAU risk or CAPRA scores with magnetic resonance imaging categories significantly improved prognostication of metastases (c-indices: EAU: 0.798, EAU + magnetic resonance imaging: 0.872; CAPRA: 0.808, CAPRA + magnetic resonance imaging: 0.877) and prostate cancer death (c-indices: EAU 0.813, EAU + magnetic resonance imaging: 0.889; CAPRA: 0.814, CAPRA + magnetic resonance imaging: 0.892; p <0.001 for all)., Conclusion: Magnetic resonance imaging findings of localized prostate cancer are associated with clinically relevant long-term oncologic outcomes. Combining magnetic resonance imaging and clinicopathological data results in more accurate prognostication, which could facilitate individualized patient management.

Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA ( KLK3 )., Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3 &#95;Hi- Myc transgenic mice were imaged with 89 Zr- or treated with 90 Y- or 225 Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [ 225 Ac]hu5A10 and [ 90 Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [ 89 Zr]hu5A10 in nonhuman primates (NHP) were determined using PET., Results: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [ 90 Y]/[ 225 Ac]hu5A10 effectively reduced tumor burden and prolonged survival ( P ≤ 0.0054). Effects of [ 90 Y]hu5A10 were more immediate than [ 225 Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [ 225 Ac]hu5A10 and 1 of 9 mice [ 90 Y]hu5A10. Pharmacokinetics of [ 89 Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [ 89 Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period., Conclusions: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer., (©2021 American Association for Cancer Research.)

Minimally invasive operative techniques and enhanced recovery after surgery (ERAS) protocols have transformed clinical practice and made it possible to perform increasingly complex oncologic procedures in the ambulatory setting, with recovery at home after a single overnight stay. Capitalizing on these changes, Memorial Sloan Kettering Cancer Center's Josie Robertson Surgery Center (JRSC), a freestanding ambulatory surgery facility, was established to provide both outpatient procedures and several surgeries that had previously been performed in the inpatient setting, newly transitioned to this ambulatory extended recovery (AXR) model. However, the JRSC core mission goes beyond rapid recovery, aiming to be an innovation center with a focus on superlative patient experience and engagement, efficiency, and data-driven continuous improvement. Here, we describe the JRSC genesis, design, care model, and outcome tracking and quality improvement efforts to provide an example of successful, patient-centered surgical care for select patients undergoing relatively complex procedures in an ambulatory setting.

Purpose: We studied the risk of metastatic prostate cancer development in men with Grade Group 2 disease managed with active surveillance at Memorial Sloan Kettering Cancer Center., Materials and Methods: A total of 219 men with Grade Group 2 prostate cancer had disease managed with active surveillance between 2000 and 2017. Biopsy was performed every 2 to 3 years, or upon changes in magnetic resonance imaging, prostate specific antigen level or digital rectal examination. The primary outcome was development of distant metastasis. The Kaplan-Meier method was used to estimate treatment-free survival., Results: Median age at diagnosis was 67 years (IQR 61-72), median prostate specific antigen was 5 ng/ml (IQR 4-7) and most patients (69%) had nonpalpable disease. During followup 64 men received treatment, including radical prostatectomy in 36 (56%), radiotherapy in 20 (31%), hormone therapy in 3 (5%) and focal therapy in 5 (8%). Of the 36 patients who underwent radical prostatectomy 32 (89%) had Grade Group 2 disease on pathology and 4 (11%) had Grade Group 3 disease. Treatment-free survival was 61% (95% CI 52-70) at 5 years and 49% (95% CI 37-60) at 10 years. Three men experienced biochemical recurrence, no men had distant metastasis and no men died of prostate cancer during the followup. Median followup was 3.1 years (IQR 1.9-4.9)., Conclusions: Active surveillance appears to be a safe initial management strategy in the short term for carefully selected and closely monitored men with Grade Group 2 prostate cancer treated at a tertiary cancer center. Definitive conclusions await further followup.

Purpose: We report oncologic outcomes for men with Grade Group 1 prostate cancer managed with active surveillance at a tertiary cancer center., Materials and Methods: A total of 2,907 patients were managed with active surveillance between 2000 and 2017, of whom 2,664 had Grade Group 1 disease. Patients were recommended confirmatory biopsy to verify eligibility and were followed semiannually with prostate specific antigen, digital rectal examination and review of symptoms. Magnetic resonance imaging was increasingly used in recent years. Biopsy was repeated every 2 to 3 years or after a sustained prostate specific antigen increase or changes in magnetic resonance imaging/digital rectal examination. The Kaplan-Meier method was used to estimate probabilities of treatment, progression and development of metastasis., Results: Median patient age at diagnosis was 62 years. For men with Grade Group 1 prostate cancer the treatment-free probability at 5, 10 and 15 years was 76% (95% CI 74-78), 64% (95% CI 61-68) and 58% (95% CI 51-64), respectively. At 5, 10 and 15 years there were 1,146, 220 and 25 men at risk for metastasis, respectively. Median followup for those without metastasis was 4.3 years (95% CI 2.3-6.9). Distant metastasis developed in 5 men. Upon case note review only 2 of these men were deemed to have disease that could have been cured on immediate treatment. The risk of distant metastasis was 0.6% (95% CI 0.2-2.0) at 10 years., Conclusions: Active surveillance is a safe strategy over longer followup for appropriately selected patients with Grade Group 1 disease following a well-defined monitoring plan.

Background: Active surveillance (AS) protocols rely on rectal examination, prostate-specific antigen, imaging, and biopsy to identify disease progression., Objective: To evaluate whether an AS regimen based on magnetic resonance imaging (MRI) or clinical stage changes can detect reclassification to grade group (GG) ≥2 disease compared with scheduled systematic biopsies., Design, Setting, and Participants: We identified a cohort of men initiated on AS between January 2013 and April 2016 at a single tertiary-care center. Patients completed confirmatory testing and prostate MRI prior to enrollment, then underwent laboratory and physical evaluation every 6 mo, MRI every 18 mo, and biopsy every 3yr., Outcome Measurements and Statistical Analysis: MRI results were evaluated using composite Likert/Prostate Imaging Reporting and Data System v2 scoring. MRI and clinical changes were assessed for association with disease progression. Univariable and multivariable regression models were used to predict upgrading on 3-yr biopsy., Results and Limitations: At 3yr, of 207 men, 66 (32%) had≥GG2 at biopsy: 55 (83%) with GG2, 10 (15%) with GG3, and one (1.5%) with GG4. Among patients with a 3-yr MRI score of ≥3, 41% had≥GG2 disease, compared with 15% with an MRI score of <3 (p=0.0002). The MRI score increased in 48 men (23%), decreased in 27 (13%), and was unchanged in 132 (64%) men. Increases in MRI score were not associated with reclassification after adjusting for the 3-yr MRI score (p=0.9). Biopsying only for an increased MRI score or clinical stage would avoid 681 biopsies per 1000 men, at the cost of missing ≥GG2 disease in 169 patients., Conclusions: An AS strategy that uses MRI or clinical changes to trigger prostate biopsy avoids many biopsies but misses an unacceptable amount of clinically significant disease. Prostate biopsy for men on AS should be performed at scheduled intervals, regardless of stable imaging or examination findings., Patient Summary: An active surveillance strategy for biopsy based only on increases in magnetic resonance imaging score or clinical stage will avoid many biopsies; however, it will miss many patients with clinically significant prostate cancer., (Published by Elsevier B.V.)

Aims: It has been recommended that the percentage of high-grade (HG) Gleason patterns 4 and 5 should be quantified in prostate cancer. However, this has not been assessed in a cohort using prostate cancer death as an outcome, and there is debate as to whether the biopsy with the 'worst' percentage of HG disease or an 'overall' percentage of HG disease should be reported. Such data may assist in active surveillance decisions., Methods and Results: Men with clinically localised prostate cancer diagnosed by needle biopsy from 1990 to 2003 were included. The endpoint was prostate cancer death. Clinical variables included Gleason score (GS), prostate-specific antigen level, age, clinical stage, and disease extent. Deaths were divided into those from prostate cancer and those from other causes, according to World Health Organization criteria. Nine hundred and eighty-eight biopsy cases were centrally reviewed according to criteria agreed at the Chicago International Society of Urological Pathology conference in 2014. Cores were given individual GSs and Grade Groups (GGs), and a percentage of each grade was given for each core. Both the worst percentage of HG disease seen in a biopsy series and overall percentage of HG disease were calculated. The overall percentage of HG disease was highly significant, with a hazard ratio of 4.45 for the interquartile range (95% confidence interval 3.30-6.01, P < 2.2 × 10 -16 ), and was similar to the percentage of HG disease seen in the worst core. In multivariate analysis, both were highly significant. GG2 cases with ≤5% Gleason pattern 4 showed similar survival to GG1 cases., Conclusions: These data validate the use of percentage of HG disease to predict prostate cancer death. As both worst and overall percentage of HG disease are powerful predictors of outcome, either could be chosen to provide prognostic information., (© 2019 The Authors. Histopathology Published by John Wiley & Sons Ltd.)

Standard clinical parameters fail to accurately differentiate indolent from aggressive prostate cancer. Our previous studies showed that immunohistochemical testing for Ki-67 improved prediction of prostate cancer death in a previous cohort of conservatively treated clinically localized prostate cancer. However there is a need for validation of usage with whole biopsy sections rather than tissue micro-arrays for use in routine diagnostics. Prostate cancer biopsy cases were identified in the UK, between 1990 and 2003, treated conservatively. Tumor extent and prostate-specific antigen (PSA) serum measurements were available. Biopsy cases were centrally reviewed by three uropathologists and Gleason conformed to contemporary ISUP 2014 criteria. Follow-up was through cancer registries up until 2012. Deaths were divided into those from prostate cancer and those from other causes. The percentage of Ki-67 in tumor cells was evaluated by immunohistochemistry on whole biopsy sections and was available for 756 patients. This percentage was used in analysis of cancer specific survival using a Cox proportional hazards model. In univariate analysis, the interquartile hazard ratio (HR) (95% confidence intervals) for continuous Ki-67 was 1.68 (1.49, 1.89), χ 1  = 47.975, P < 0.001. In grade groups 1 and 2, continuous Ki-67 was a statistically significant predictor of time to death from prostate cancer, HR (95% CI) = 1.97 (1.34, 2.88), χ 2  = 9.017, p = 0.003. In multivariate analysis, continuous Ki-67 added significant predictive information to that provided by grade groups, extent of disease and serum PSA, HR (95% CI) = 1.34 (1.16, 1.54), Δχ 1  = 13.703, P < 0.001. We now advocate the introduction of Ki-67 as a viable and practicable prognostic biomarker in clinical practice. The association of Ki-67 with mortality was highest in grade groups 1 and 2, showing that Ki-67 can be used as a routine biomarker in patients being considered for active surveillance.2  = 9.017, p = 0.003. In multivariate analysis, continuous Ki-67 added significant predictive information to that provided by grade groups, extent of disease and serum PSA, HR (95% CI) = 1.34 (1.16, 1.54), Δχ 1 2  = 13.703, P < 0.001. We now advocate the introduction of Ki-67 as a viable and practicable prognostic biomarker in clinical practice. The association of Ki-67 with mortality was highest in grade groups 1 and 2, showing that Ki-67 can be used as a routine biomarker in patients being considered for active surveillance.

The level of copy number alteration (CNA), termed CNA burden, in the tumor genome is associated with recurrence of primary prostate cancer. Whether CNA burden is associated with prostate cancer survival or outcomes in other cancers is unknown. We analyzed the CNA landscape of conservatively treated prostate cancer in a biopsy and transurethral resection cohort, reflecting an increasingly common treatment approach. We find that CNA burden is prognostic for cancer-specific death, independent of standard clinical prognosticators. More broadly, we find CNA burden is significantly associated with disease-free and overall survival in primary breast, endometrial, renal clear cell, thyroid, and colorectal cancer in TCGA cohorts. To assess clinical applicability, we validated these findings in an independent pan-cancer cohort of patients whose tumors were sequenced using a clinically-certified next generation sequencing assay (MSK-IMPACT), where prognostic value varied based on cancer type. This prognostic association was affected by incorporating tumor purity in some cohorts. Overall, CNA burden of primary and metastatic tumors is a prognostic factor, potentially modulated by sample purity and measurable by current clinical sequencing., Competing Interests: HH, RM, AT, KY, WA, HM, DB, HS, BC, PS, NS, BT, AV, JC No competing interests declared, CS Senior Editor, eLife, (© 2018, Hieronymus et al.)

Background: A combined clinical cell-cycle risk (CCR) score that incorporates prognostic molecular and clinical information has been recently developed and validated to improve prostate cancer mortality (PCM) risk stratification over clinical features alone. As clinical features are currently used to select men for active surveillance (AS), we developed and validated a CCR score threshold to improve the identification of men with low-risk disease who are appropriate for AS., Methods: The score threshold was selected based on the 90th percentile of CCR scores among men who might typically be considered for AS based on NCCN low/favorable-intermediate risk criteria (CCR = 0.8). The threshold was validated using 10-year PCM in an unselected, conservatively managed cohort and in the subset of the same cohort after excluding men with high-risk features. The clinical effect was evaluated in a contemporary clinical cohort., Results: In the unselected validation cohort, men with CCR scores below the threshold had a predicted mean 10-year PCM of 2.7%, and the threshold significantly dichotomized low- and high-risk disease (P = 1.2 × 10 -5 ). After excluding high-risk men from the validation cohort, men with CCR scores below the threshold had a predicted mean 10-year PCM of 2.3%, and the threshold significantly dichotomized low- and high-risk disease (P = 0.020). There were no prostate cancer-specific deaths in men with CCR scores below the threshold in either analysis. The proportion of men in the clinical testing cohort identified as candidates for AS was substantially higher using the threshold (68.8%) compared to clinicopathologic features alone (42.6%), while mean 10-year predicted PCM risks remained essentially identical (1.9% vs. 2.0%, respectively)., Conclusions: The CCR score threshold appropriately dichotomized patients into low- and high-risk groups for 10-year PCM, and may enable more appropriate selection of patients for AS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To describe the salvage radical prostatectomy (sRP) experience in patients presenting with recurrent, clinically localized prostate cancer after multiple failed local treatments., Materials and Methods: Among the 251 sRP performed during 2000-2016, 11 patients had failed multiple local therapies. We describe baseline clinical characteristics at primary cancer diagnosis and prior to sRP, surgical information, complications and oncological outcomes., Results: The mean±standard deviation age at sRP was 65±5 years and the median (interquartile range) serum prostate-specific antigen (PSA) level was 2 (1.3) ng/mL. The most common first and subsequent treatments were radiotherapy and cryotherapy, respectively, with median time of 24 months from the last local treatment. The median operative time was 180 minutes and median estimated blood loss was 750 mL. Five (45.5%) patients underwent additional procedures during sRP for pre-operative morbidity from prior treatments (rectourethral fistula, urethral stricture, incontinence). Post-operative complications requiring invasive intervention occurred in 7 (63.6%) patients. Over a median follow-up of 29 (12-96) months, 10 of the 11 men (90.9%) achieved an undetectable PSA in after sRP. Three of these men with an initially undetectable PSA level experienced biochemical recurrence; the remaining 7 are without evidence of disease. Overall, no local recurrence or systemic metastasis was identified at last follow-up., Conclusions: sRP is technically feasible and offers durable cancer control in patients with recurrent prostate cancer despite having undergone multiple prior attempts at cure. These patients experience higher rates of post-operative complications and such patients must be appropriately counseled regarding the potential risks and benefits., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

The identification of perineural invasion (PNI) and extraprostatic extension (ECE) in prostate cancer (PC) biopsies is time consuming and can be difficult. Although this is required information in many datasets, there is little evidence on their effect on outcome in patients treated conservatively. Cases of PC were identified from three cancer registries in the UK from men with clinically localized prostate cancer diagnosed by needle biopsy from 1990-2003. The endpoint was prostate cancer death (DOD). Patients treated radically within 6 months, those with objective evidence of metastases or who had prior hormone therapy were excluded. Follow-up was through cancer registries up until 2012. Deaths were divided into those from PC and those from other causes, according to WHO criteria. 988 biopsy cases (6522 biopsy cores) were centrally reviewed by three uropathologists and assigned a Gleason score and Grade Group (GG). The presence of both PNI and ECE was recorded. Of 988 patients, PNI was present in 288 (DOD = 75) and ECE in 23 (DOD = 5). On univariable analysis PNI was highly significantly associated with DOD (hazard ratio [HR] 2.28, 95% CI: 1.68, 3.1, log-rank test p -value = 4.8 × 10 -8 ), but ECE was not (log-rank test p -value = 0.334). On multivariable analysis with GG, serum PSA (per 10%), clinical stage and extent of disease (per 10%), PNI lost significance (HR 1.16, 95% CI: 0.83, 1.63, likelihood ratio test p -value = 0.371). The utility of routinely examining prostate biopsies for ECE and PNI is doubtful as it is not independently associated with higher grade, stage or prognosis., Competing Interests: CONFLICTS OF INTEREST There are no conflicts of interest to disclose.

Purpose: To verify the quality of pelvic lymph node dissection (PLND) performed at radical prostatectomy (RP) and its impact on nodal recurrence in patients undergoing salvage lymph node dissection (sLND)., Materials and Methods: Retrospective review of 48 patients who underwent sLND for presumed nodal recurrence, to describe the PLND characteristics at RP and correlate the anatomical sites and number of suspicious nodes reported in radiological imaging and final pathology of sLND., Results: Overall, at RP, 8 (16.7%) did not undergo PLND, 32 (66.7%) and 8 (16.7%) received a "limited" (between external iliac vein and obturator nerve) and an "extended" (external iliac, hypogastric, and obturator) dissection, respectively. Median nodes removed during limited and extended dissection were 2 and 24, respectively. At sLND, the mean age was 61.3 years and median prostate specific antigen (PSA) was 1.07 ng/mL. Median nodes removed at sLND were 17 with a median of 2 positive nodes. Recurrent nodes were identified within the template of an extended PLND in 62.5%, 50.0% and 12.5% patients, respectively, following prior no, limited and extended dissection at RP. Recurrence outside the expected lymphatic drainage pathway was noted in 37.5% patients with prior extended dissection at RP. There was a correlation between imaging and pathology specimen in 83% for node location and 58.3% for number of anatomical sites involved., Conclusions: In prostate cancer patients undergoing sLND, most had inadequate PLND at the original RP. Pattern of nodal recurrence may be influenced by the prior dissection and pre sLND imaging appears to underestimate the nodal recurrence., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Background: Obesity, a cause of subclinical inflammation, is associated with increased risk of high-grade prostate cancer (PC) and poor outcomes. Whether inflammation occurs in periprostatic white adipose tissue (WAT), and contributes to the negative impact of obesity on PC aggressiveness, is unknown., Methods: In a single-center, cross-sectional design, men with newly diagnosed PC undergoing radical prostatectomy were eligible for study participation. The primary objective was to examine the prevalence of periprostatic WAT inflammation defined by the presence of crown-like structures (CLS-P) as detected by CD68 immunohistochemistry. Secondary objectives were to explore the clinical and systemic correlates of periprostatic WAT inflammation. Tumor characteristics and host factors including BMI, adipocyte diameter, and circulating levels of lipids, adipokines, and other metabolic factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher's exact tests, and generalized linear regression were used to examine the association between WAT inflammation and tumor and host characteristics., Results: Periprostatic fat was collected from 169 men (median age 62 years; median BMI 28.3). Periprostatic WAT inflammation was identified in 49.7% of patients and associated with higher BMI (P=0.02), larger adipocyte size (P=0.004) and Gleason grade groups IV/V tumors (P=0.02). The relationship between WAT inflammation and high Gleason grade remained significant after adjusting for BMI (P=0.04). WAT inflammation correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to those without WAT inflammation (P's <0.05)., Conclusion: Periprostatic WAT inflammation is common in this cohort of men with PC and is associated with high-grade PC.

Prostate cancer is the most common cancer among western men, with a significant mortality and morbidity reported for advanced metastatic disease. Current understanding of metastatic disease is limited due to difficulty of sampling as prostate cancer mainly metastasizes to bone. By analysing prostate cancer bone metastases using high density microarrays, we found a common genomic copy number loss at 6q16.1-16.2, containing the FBXL4 gene, which was confirmed in larger series of bone metastases by fluorescence in situ hybridisation (FISH). Loss of FBXL4 was also detected in primary tumours and it was highly associated with prognostic factors including high Gleason score, clinical stage, prostate-specific antigen (PSA) and extent of disease, as well as poor patient survival, suggesting that FBXL4 loss contributes to prostate cancer progression. We also demonstrated that FBXL4 deletion is detectable in circulating tumour cells (CTCs), making it a potential prognostic biomarker by 'liquid biopsy'. In vitro analysis showed that FBXL4 plays a role in regulating the migration and invasion of prostate cancer cells. FBXL4 potentially controls cancer metastasis through regulation of ERLEC1 levels. Therefore, FBXL4 could be a potential novel prostate cancer suppressor gene, which may prevent cancer progression and metastasis through controlling cell invasion.

Purpose: We report our initial experience with whole body and dedicated prostate magnetic resonance imaging as a single examination to assess local recurrence and metastatic disease in patients with suspected recurrent prostate cancer after radical prostatectomy., Materials and Methods: In this institutional review board approved, retrospective, single center study 76 consecutive patients with clinically suspected recurrent prostate cancer following radical prostatectomy underwent combined whole body and dedicated prostate magnetic resonance imaging at a single session from October 2014 to January 2016. Scans were evaluated to detect disease in the prostate bed and regional nodes, and at distant sites. Comparison was made to other imaging tests, and prostate bed, node and bone biopsies performed within 90 days., Results: Whole body and dedicated prostate magnetic resonance imaging was completed successfully in all patients. Median prostate specific antigen was 0.36 ng/ml (range less than 0.05 to 56.12). Whole body and dedicated prostate magnetic resonance imaging identified suspected disease recurrence in 16 of 76 patients (21%), including local recurrence in the radical prostatectomy bed in 6, nodal metastases in 3, osseous metastases in 4 and multifocal metastatic disease in 3. In 43 patients at least 1 standard staging scan was done in addition to whole body and dedicated prostate magnetic resonance imaging. Concordance was demonstrated between the imaging modalities in 36 of 43 cases (84%). All metastatic lesions detected by other imaging tests were detected on magnetic resonance imaging. In addition, the magnetic resonance imaging modality detected osseous metastases in 4 patients with false-negative findings on other imaging tests, including 2 bone scans and 3 computerized tomography scans. It also excluded osseous disease in 1 patient with positive 18 F-fluorodeoxyglucose positron emission tomography/computerized tomography and subsequent negative bone biopsy., Conclusions: Combined whole body and dedicated prostate magnetic resonance imaging is feasible in a clinical practice setting. It can provide incremental information compared to standard imaging in men with suspected prostate cancer recurrence after radical prostatectomy., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: A significant number of patients with minimal lymph node disease at radical prostatectomy (RP) and pelvic lymph node dissection (PLND) have better than expected long-term outcomes. We explored whether stratification by number of positive nodes enhances our institutional prediction model for biochemical recurrence after RP., Methods: A total of 7789 patients underwent RP and pelvic lymph node dissection from 1995 to 2012 at a tertiary referral center. We compared two recurrence prediction models: one incorporated lymph node invasion and the other tracked the number of positive nodes. Existing and updated models' discrimination was assessed using Harrell's c-index and calibration. The 10-fold cross-validation was performed to correct for model overfitting., Results: Of the 491 patients (6.3%) harboring nodal disease, 387 (5.0%) had 1-2 positive nodes and 104 (1.3%) had ⩾3 positive nodes. Data on number of positive nodes did not improve the c-index for the cohort as a whole. When we assessed discrimination for node-positive patients only, c-index for the model with number of positive nodes was 0.01 (95% confidence interval 0.001-0.024) higher than the model with lymph node invasion. Illustrative examples were provided by reclassification tables using number of positive lymph nodes. For instance, 40 of 7789 patients would be reclassified with a cutoff point of 50% for biochemical recurrence at 1 year, and 36 of 7789 patients would be reclassified with a cutoff point of 40% for biochemical recurrence at 10 years., Conclusions: Stratification by number of positive lymph nodes provided additional discriminative ability for evaluating risk in node-positive patients. Pending external validation, this model could be used for patient counseling and clinical trial stratification in this subpopulation.

Background: Presence of lymph node metástasis (LNM) at salvage radical prostatectomy (sRP) is associated with poor outcome. Predictors of outcome in this context remain undetermined. ThE objective was to assess the role of number of positive lymph node on outcome of patients with LNM after sRP and for radio-recurrent prostate cancer., Material and Methods: We analyzed data from a consecutive cohort of 215 men treated with sRP at a single institution. We used univariate Cox proportional hazard regression models for biochemical recurrence (BCR) and metastatic outcomes, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, time between radiation therapy and sRP, and number of positive nodes as predictors., Results: Of the 47 patients with LNM, 37 developed BCR, 11 developed distant metastasis and 4 died with a median follow-up of 2.3 years for survivors. The risk of metastases increased with higher pre-operative PSA levels (HR 1.19 per 1ng/ml; 95% CI: 1.06-1.34; P=.003). The remaining predictors did not reach conventional levels of significance. However, removal of 3 or more positive lymph nodes demonstrated a positive association, as expected, with metastatic disease (HR 3.44; 95% CI: 0.91-13.05; P=.069) compared to one or 2 positive nodes. Similarly, the presence of extraprostatic extension, seminal vesicle invasion and Gleason grade greater than 7 also demonstrated a positive association with higher risk of metástasis, with hazard ratios of 3.97 (95% CI: 0.50, 31.4; P=.2), 3.72 (95% CI: 0.80-17.26; P=.1), and 1.45 (95% CI: 0.44-4.76; P=.5), respectively., Conclusions: In patients with LNM after sRP for radio-recurrent prostate cancer, the risk of distant metástasis is likely to be influenced by the number of positive nodes (3 or more), high preoperative PSA, Gleason grade and advanced pathologic stage. These results are consistent with the findings of number of nodes (1 to 2 vs. 3 or more nodes positive) as a prognostic indicator after primary radical prostatectomy and strengthen the plea for a revision of the nodal staging for prostate cancer., (Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Gleason scoring (GS) has major deficiencies and a novel system of five grade groups (GS⩽6; 3+4; 4+3; 8; ⩾9) has been recently agreed and included in the WHO 2016 classification. Although verified in radical prostatectomies using PSA relapse for outcome, it has not been validated using prostate cancer death as an outcome in biopsy series. There is debate whether an 'overall' or 'worst' GS in biopsies series should be used., Methods: Nine hundred and eighty-eight prostate cancer biopsy cases were identified between 1990 and 2003, and treated conservatively. Diagnosis and grade was assigned to each core as well as an overall grade. Follow-up for prostate cancer death was until 31 December 2012. A log-rank test assessed univariable differences between the five grade groups based on overall and worst grade seen, and using univariable and multivariable Cox proportional hazards. Regression was used to quantify differences in outcome., Results: Using both 'worst' and 'overall' GS yielded highly significant results on univariate and multivariate analysis with overall GS slightly but insignificantly outperforming worst GS. There was a strong correlation with the five grade groups and prostate cancer death., Conclusions: This is the largest conservatively treated prostate cancer cohort with long-term follow-up and contemporary assessment of grade. It validates the formation of five grade groups and suggests that the 'worst' grade is a valid prognostic measure.

Background: Previous studies of prostate cancer (PCa) risk and anthropometrics (ie, body measurements) were based on single measurements or obtained over limited time spans., Objective: To study the association between anthropometrics measured at multiple time points in life and their relation to later diagnosis, metastasis, or death from PCa., Design, Setting, and Participants: This case-control study includes 27 167 Swedish men enrolled in two population-based projects from 1974 to 1996. PCa diagnosis up to December 31, 2006, disease information, gestation time, and anthropometrics at birth, military conscript testing, and adulthood were collected. A total of 1355 PCa cases were matched with 5271 controls., Outcome Measurements and Statistical Analysis: Univariate conditional logistic regression was used to determine whether clinical diagnosis, metastasis, or PCa death was associated with low birth weight (weight <2500 g); with small size for gestational age; or with weight, length, or body mass index (BMI) at birth, adolescence (aged 16-22 yr), or early middle age (aged 44-50 yr)., Results and Limitations: Apart from weight at adolescence, which was associated with an increased risk of PCa diagnosis (odds ratio [OR] per 5 kg: 1.05; 95% confidence interval [CI], 1.01-1.09; p=0.026), preadulthood measurements were not associated with any PCa end point. Adulthood parameters were not associated with diagnosis. In contrast, weight and BMI at early middle age were significantly associated with metastasis (OR per 5 kg: 1.13; 95% CI, 1.06-1.20; p<0.0001, and OR: 1.09; 95% CI, 1.05-1.14; p<0.0001) and death (OR per 5 kg: 1.11 (95% CI, 1.03-1.19; p=0.005, and OR: 1.08; 95% CI, 1.03-1.13; p=0.003), respectively. It remains unclear whether these results apply to men of nonwhite origin, to populations with active PCa screening programs, or to countries without socialized health care., Conclusions: The analyses of these large data sets demonstrate that significant effects of body characteristics (with links to metabolic syndrome) measured at early middle age are associated with PCa disease severity, metastatic progression, and outcome. Conversely, measurements at birth and adolescence are not associated with PCa prevalence or outcome., Patient Summary: Increased weight and body mass index in adults is associated with a higher risk of prostate cancer metastasis and death., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell-cycle-risk (CCR) score., Methods: Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort., Results: In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10(-13)) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10(-6)). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), χ(2)=89.0, P<10(-20)) and captured virtually all available prognostic information., Conclusions: The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment.

Background: Genome-wide association studies have identified multiple single-nucleotide polymorphsims (SNPs) associated with prostate cancer (PCa). Although these SNPs have been clearly associated with disease risk, their relationship with clinical outcomes is less clear. Our aim was to assess the frequency of known PCa susceptibility alleles within a single institution ascertainment and to correlate risk alleles with disease-specific outcomes., Methods: We genotyped 1354 individuals treated for localised PCa between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to phenotypic data. We investigated associations between 61 SNPs and disease-specific end points using multivariable analysis and also determined if SNPs were associated with PSA at diagnosis., Results: Seven SNPs showed associations on multivariable analysis (P<0.05), rs13385191 with both biochemical recurrence (BR) and castrate metastasis (CM), rs339331 (BR), rs1894292, rs17178655 and rs11067228 (CM), and rs11902236 and rs4857841 PCa-specific mortality. After applying a Bonferroni correction for number of SNPs (P<0.0008), the only persistent significant association was between rs17632542 (KLK3) and PSA levels at diagnosis (P=1.4 × 10(-5))., Conclusions: We confirmed that rs17632542 in KLK3 is associated with PSA at diagnosis. No significant association was seen between loci and disease-specific end points when accounting for multiple testing. This provides further evidence that known PCa risk SNPs do not predict likelihood of disease progression.

Background: Studying surgical secondary events is an evolving effort with no current established system for database design, standard reporting, or definitions. Using the Clavien-Dindo classification as a guide, in 2001 we developed a Surgical Secondary Events database based on grade of event and required intervention to begin prospectively recording and analyzing all surgical secondary events (SSE)., Methods: Events are prospectively entered into the database by attending surgeons, house staff, and research staff. In 2008 we performed a blinded external audit of 1,498 operations that were randomly selected to examine the quality and reliability of the data., Results: Of 4,284 operations, 1,498 were audited during the third quarter of 2008. Of these operations, 79 % (N = 1,180) did not have a secondary event while 21 % (N = 318) had an identified event; 91 % of operations (1,365) were correctly entered into the SSE database. Also 97 % (129 of 133) of missed secondary events were grades I and II. There were 3 grade III (2 %) and 1 grade IV (1 %) secondary event that were missed. There were no missed grade 5 secondary events., Conclusions: Grade III-IV events are more accurately collected than grade I-II events. Robust and accurate secondary events data can be collected by clinicians and research staff, and these data can safely be used for quality improvement projects and research.

Background: The diffusion of minimally invasive radical prostatectomy (MIRP) in the United States may have led to adverse patient outcomes due to rapid surgeon adoption and collective inexperience. We hypothesized that throughout the early period of minimally invasive surgery, MIRP patients had inferior outcomes as compared with those who had open radical prostatectomy (ORP)., Methods: We used the Surveillance, Epidemiology and End RESULTS-Medicare dataset and identified men who had ORP and MIRP for prostate cancer from 2003-2009. Study endpoints were receipt of subsequent cancer treatment, and evidence of postoperative voiding dysfunction, erectile dysfunction (ED) and bladder outlet obstruction. We used proportional hazards regression to estimate the impact of surgical approach on each endpoint, and included an interaction term to test for modification of the effect of surgical approach by year of surgery., Results: ORP (n=5362) and MIRP (n=1852) patients differed in their clinical and demographic characteristics. Controlling for patient characteristics and surgeon volume, there was no difference in subsequent cancer treatments (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76-1.05), although MIRP was associated with a higher risk of voiding dysfunction (HR 1.31, 95% CI 1.20-1.43) and ED (HR 1.43, 95% CI 1.31-1.56), but a lower risk of bladder outlet obstruction (HR 0.86, 95% CI 0.75-0.97). There was no interaction between approach and year for any outcome. When stratifying the analysis by year, MIRP consistently had higher rates of ED and voiding dysfunction with no substantial improvement over time., Conclusions: MIRP patients had adverse urinary and sexual outcomes throughout the diffusion of minimally invasive surgery. This may have been a result of the rapid adoption of robotic surgery with inadequate surgeon preparedness.

When Nature Reviews Urology launched in 2004, the field of urology was vastly different to that which we work in today, and the past 10 years have seen the field change immensely. As a specialty on the forefront of cutting-edge innovation, urologists are often the first to embrace new technologies and ideas. In this Viewpoint, members of the Nature Reviews Urology advisory board were asked what they thought was the most important change, issue or innovation in urology in the past 10 years, and what they expected to be the most important in the next decade. Here are their opinions.

Purpose of Review: Focal therapy is gaining interest and this organ-preserving treatment is heading towards becoming an alternative for the conventional surgery and radiation. The purpose of this review is to determine what evidence is required to make focal therapy a viable option for treatment of localized prostate cancer., Recent Findings: There is still a lack of high-level evidence for the different focal treatment modalities. The early-stage focal therapy trials are conducted including a various selection of patients and different pretreatment assessment and follow-up, resulting in incomparable data. Recent literature shows it is paramount to extend the amount of biopsies and to alter the way of taking the biopsies with the template-assisted or image-guided approach. To date, multiparametric MRI is the most effective imaging technique in selecting patients for focal therapy., Summary: Focal therapy trials are at the early stage of clinical development, with the majority still being phase I studies. To make focal therapy an accepted segment of standard therapy, it needs to proceed toward phase II and III trials. These trials should be conducted with an effective trial design, which will lead to more comparable oncological, functional and quality of life outcomes. Furthermore, it is essential to improve the localization of tumor foci in order to increase the accuracy of spatial targeting of cancer.

Background: Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy., Methods: A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation., Results: Both high level gain in chromosome X (≥4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (≤ 600 nm, ≤1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival., Conclusion: Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.

Purpose: Prostate biopsy related infectious complications are associated with significant morbidity. The risk of infectious complications in patients with prostate cancer on active surveillance remains under studied., Materials and Methods: A total of 591 consecutive men who underwent prostate biopsy were prospectively enrolled in a study evaluating prostate biopsy related complications between January 2011 and January 2012. Of these men 403 were previously diagnosed with prostate cancer and were included in this study. They underwent a 14-core transrectal ultrasound guided prostate biopsy as part of an active surveillance regimen. A nurse contacted all men within 14 days of biopsy, and information was collected on potential complications, antibiotics received and bacterial culture results., Results: Fourteen patients (3.5%) had infectious complications including 13 requiring hospitalization. Five patients had positive urine cultures, and fluoroquinolone resistant isolates were identified in 4 patients, including 2 with extended spectrum beta-lactamase producing isolates. We evaluated the impact of risk factors including diabetes, benign prostatic hyperplasia and antibiotic regimen. However, only the number of previous prostate biopsies was significantly associated with an increased risk of infectious complications (p = 0.041). For every previous biopsy the odds of an infection increased 1.3 times (OR 1.33, 95% CI 1.01-1.74)., Conclusions: In men with prostate cancer on active surveillance the number of previous prostate biopsies is associated with a significant risk of infectious complications and every previous biopsy increases the risk of infectious complication. Fluoroquinolone resistant and extended spectrum beta-lactamase producing isolates represent the most commonly identified organisms. Men with prostate cancer on active surveillance should be informed of the risks associated with serial repeat prostate biopsies., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with conservatively managed prostate cancer diagnosed by transurethral resection of the prostate., Methods: The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer., Results: The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60-4.73; P=3.1 × 10(-14)). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2-24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses., Conclusion: In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease.

Background: Standard clinical parameters cannot accurately differentiate indolent from aggressive prostate cancer. Our previous work showed that immunohistochemical (IHC) Ki-67 improved prediction of prostate cancer death in a cohort of conservatively treated clinically localised prostate cancers diagnosed by transurethral resection of the prostate (TURP). Here, we present results in a more clinically relevant needle biopsy cohort., Methods: Biopsy specimens were microarrayed. The percentage of Ki-67 positively stained malignant cells per core was measured and the maximum score per individual used in analysis of time to death from prostate cancer using a Cox proportional hazards model., Results: In univariate analysis (n=293), the hazard ratio (HR) (95% confidence intervals) for dichotomous Ki-67 (≤ 10%, >10%) was 3.42 (1.76, 6.62) χ(2) (1 df)=9.8, P=0.002. In multivariate analysis, Ki-67 added significant predictive information to that provided by Gleason score and prostate-specific antigen (HR=2.78 (1.42, 5.46), χ(2) (1 df)=7.0, P=0.008)., Conclusion: The IHC Ki-67 scoring on prostate needle biopsies is practicable and yielded significant prognostic information. It was less informative than in the previous TURP cohort where tumour samples were larger and more comprehensive, but in more contemporary cohorts with larger numbers of biopsies per patient, Ki-67 may prove a more powerful biomarker.

Background: Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)-extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (CaP). The mechanism for ERK5 activation in CaP remains to be fully elucidated. Studies have recently implicated the role of microRNA (miRNA) mir143 expression in the regulation of ERK5 expression., Methods: We utilised a tissue microarray (TMA) of 530 CaP cores from 168 individual patients and stained for both mir143 and ERK5. These TMAs were scored by a combination of observer and automated methods., Results: We observed a strong inverse relation between ERK5 and mir143, which manifested itself most strongly in the subgroup of 417 cores with non-zero mir143 and ERK5 immunoreactivity, or with only one of mir143 or ERK5 being zero (cc=0.2558 and P<0.0001). Mir143 neither correlate with Gleason scores or prostate-specific antigen levels, nor was it a predictor of disease-specific survival on univariate analysis., Conclusion: Although the mechanism for ERK5 activation in CaP remains to be fully elucidated, we have further validated the potential role of mir143 in regulating ERK5 levels in the clinical context. In addition, we demonstrate that the automated counting method for nuclear ERK5 is a clinically useful alterative to observer counting method in patient stratification in the context of ERK5 targeting therapy.

Purpose: A barrier to the acceptance of active surveillance for men with prostate cancer is the risk of underestimating the cancer burden on initial biopsy. We assessed the value of endorectal magnetic resonance imaging in predicting upgrading on confirmatory biopsy in men with low risk prostate cancer., Materials and Methods: A total of 388 consecutive men (mean age 60.6 years, range 33 to 89) with clinically low risk prostate cancer (initial biopsy Gleason score 6 or less, prostate specific antigen less than 10 ng/ml, clinical stage T2a or less) underwent endorectal magnetic resonance imaging before confirmatory biopsy. Three radiologists independently and retrospectively scored tumor visibility on endorectal magnetic resonance imaging using a 5-point scale (1-definitely no tumor to 5-definitely tumor). Inter-reader agreement was assessed with weighted kappa statistics. Associations between magnetic resonance imaging scores and confirmatory biopsy findings were evaluated using measures of diagnostic performance and multivariate logistic regression., Results: On confirmatory biopsy, Gleason score was upgraded in 79 of 388 (20%) patients. Magnetic resonance imaging scores of 2 or less had a high negative predictive value (0.96-1.0) and specificity (0.95-1.0) for upgrading on confirmatory biopsy. A magnetic resonance imaging score of 5 was highly sensitive for upgrading on confirmatory biopsy (0.87-0.98). At multivariate analysis patients with higher magnetic resonance imaging scores were more likely to have disease upgraded on confirmatory biopsy (odds ratio 2.16-3.97). Inter-reader agreement and diagnostic performance were higher for the more experienced readers (kappa 0.41-0.61, AUC 0.76-0.79) than for the least experienced reader (kappa 0.15-0.39, AUC 0.61-0.69). Magnetic resonance imaging performed similarly in predicting low risk and very low risk (Gleason score 6, less than 3 positive cores, less than 50% involvement in all cores) prostate cancer., Conclusions: Adding endorectal magnetic resonance imaging to the initial clinical evaluation of men with clinically low risk prostate cancer helps predict findings on confirmatory biopsy and assess eligibility for active surveillance., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Unlabelled: What's known on the subject? and What does the study add? Active surveillance for prostate cancer is gaining increasing acceptance for low risk prostate cancer. Focal therapy is an emerging tissue preservation strategy that aims for treat only areas of cancer. Early phase trials have shown that side-effects can be significantly reduced using focal therapy. There is significant uncertainty in both active surveillance and focal therapy. This consensus group paper provides a road-map for clinical practice and research for both tissue-preserving strategies in the areas of patient population, tools for risk stratification and cancer localisation, treatment interventions as well as comparators and outcome measures in future comparative trials., Objective: To reach consensus on key issues for clinical practice and future research in active surveillance and focal therapy in managing localized prostate cancer., Patients and Methods: A group of expert urologists, oncologists, radiologists, pathologists and computer scientists from North America and Europe met to discuss issues in patient population, interventions, comparators and outcome measures to use in both tissue-preserving strategies of active surveillance and focal therapy. Break-out sessions were formed to provide agreement or highlight areas of disagreement on individual topics which were then collated by a writing group into statements that formed the basis of this report and agreed upon by the whole Transatlantic Consensus Group., Results: The Transatlantic group propose that emerging diagnostic tools such as precision imaging and transperineal prostate mapping biopsy can improve prostate cancer care. These tools should be integrated into prostate cancer management and research so that better risk stratification and more effective treatment allocation can be applied. The group envisaged a process of care in which active surveillance, focal therapy, and radical treatments lie on a continuum of complementary therapies for men with a range of disease grades and burdens, rather than being applied in the mutually exclusive and competitive way they are now., Conclusion: The changing landscape of prostate cancer epidemiology requires the medical community to re-evaluate the entire prostate cancer diagnostic and treatment pathway in order to minimize harms resulting from over-diagnosis and over-treatment. Precise risk stratification at every point in this pathway is required alongside paradigm shifts in our thinking about what constitutes cancer in the prostate., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Background: The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy., Methods: Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer., Results: In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10(-9)) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10(-5)), with Gleason score (P=5 × 10(-4)) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions., Conclusion: For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.

Objective: To compare the performance of a systems-based risk assessment tool with standard defined risk groups and the 10-year postoperative nomogram for predicting disease progression, including biochemical relapse and clinical (systemic) failure., Patients and Methods: Clinical variables, biometric profiles and outcome results from a training cohort comprising 373 patients in a published postoperative systems-based prognostic model were obtained. Patients were stratified according to D'Amico standard risk groups, Kattan 10-year postoperative nomogram and prognostic scores from the postoperative tissue model. The association of pathological variables and calculated risk groups with biochemical recurrence and clinical (systemic) failure was assessed using the concordance index (C-index) and hazard ratio (HR)., Results: Systems-based post-prostatectomy models to predict significant disease progression (post-treatment clinical failure) were more accurate than the D'Amico defined risk groups and the Kattan 10-year postoperative nomogram (systems model: C-index, 0.84; HR, 17.46; P < 0.001 vs D'Amico: C-index, 0.73; HR, 11; P = 0.001; 10-year nomogram: C-index, 0.79; HR, 5.06; P < 0.001). The systems models were also more accurate than standard risk groups for predicting prostate-specific antigen recurrence (systems model: C-index, 0.76; HR, 8.94; P < 0.001 vs D'Amico C- index, 0.70; HR, 4.67; P < 0.001) and showed incremental improvement over the 10-year postoperative nomogram (C-index, 0.75; HR, 5.83; P < 0.001). The postoperative tissue model provided additional risk discrimination over surgical margin status and extracapsular extension for predicting disease outcome, and was most significant for the clinical (systemic) failure endpoint (surgical margin: C-index, 0.58; HR, 1.57; P= 0.2; extracapsular extension: C-index, 0.62; HR, 2.06; P = 0.04)., Conclusions: Risk assessment models that incorporate characteristics from the patient's own tumour specimen are more accurate than clinical-only nomograms for predicting significant disease outcome. Systems-based tools should provide useful information concerning the appropriate receipt of adjuvant therapy in the post-surgical setting., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Background: Previous studies have shown that complications and biochemical recurrence rates after radical prostatectomy (RP) vary between different surgeons to a greater extent than might be expected by chance. Data on urinary and erectile outcomes, however, are lacking., Objective: In this study, we examined whether between-surgeon variation, known as heterogeneity, exists for urinary and erectile outcomes after RP., Design, Setting, and Participants: Our study consisted of 1910 RP patients who were treated by 1 of 11 surgeons between January 1999 and July 2007., Intervention: All patients underwent RP at Memorial Sloan-Kettering Cancer Center., Measurements: Patients were evaluated for functional outcome 1 yr after surgery. Multivariable random effects models were used to evaluate the heterogeneity in erectile or urinary outcome between surgeons, after adjustment for case mix (age, prostate-specific antigen, pathologic stage and grade, comorbidities) and year of surgery., Results and Limitations: We found significant heterogeneity in functional outcomes after RP (p<0.001 for both urinary and erectile function). Four surgeons had adjusted rates of full continence <75%, whereas three had rates >85%. For erectile function, two surgeons in our series had adjusted rates <20%; another two had rates >45%. We found some evidence suggesting that surgeons' erectile and urinary outcomes were correlated. Contrary to the hypothesis that surgeons "trade off" functional outcomes and cancer control, better rates of functional preservation were associated with lower biochemical recurrence rates., Conclusions: A patient's likelihood of recovering erectile and urinary function may differ depending on which of two surgeons performs his RP. Functional preservation does not appear to come at the expense of cancer control; rather, both are related to surgical quality., (Copyright © 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Optimum management of clinically localised prostate cancer presents unique challenges because of the highly variable and often indolent natural history of the disease. To predict disease aggressiveness, clinicians combine clinical variables to create prognostic models, but the models have limited accuracy. We assessed the prognostic value of a predefined cell cycle progression (CCP) score in two cohorts of patients with prostate cancer., Methods: We measured the expression of 31 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumour samples, and created a predefined score and assessed its usefulness in the prediction of disease outcome. The signature was assessed retrospectively in a cohort of patients from the USA who had undergone radical prostatectomy, and in a cohort of randomly selected men with clinically localised prostate cancer diagnosed by use of a transurethral resection of the prostate (TURP) in the UK who were managed conservatively. The primary endpoint was time to biochemical recurrence for the cohort of patients who had radical prostatectomy, and time to death from prostate cancer for the TURP cohort., Findings: After prostatectomy, the CCP score was useful for predicting biochemical recurrence in the univariate analysis (hazard ratio for a 1-unit change [doubling] in CCP 1·89; 95% CI 1·54-2·31; p=5·6×10(-9)) and the best multivariate analysis (1·77, 1·40-2·22; p=4·3×10(-6)). In the best predictive model (final multivariate analysis), the CCP score and prostate-specific antigen (PSA) concentration were the most important variables and were more significant than any other clinical variable. In the TURP cohort, the CCP score was the most important variable for prediction of time to death from prostate cancer in both univariate analysis (2·92, 2·38-3·57, p=6·1×10(-22)) and the final multivariate analysis (2·57, 1·93-3·43; p=8·2×10(-11)), and was stronger than all other prognostic factors, although PSA concentration also added useful information. Heterogeneity in the hazard ratio for the CCP score was not noted in any case for any clinical variables., Interpretation: The results of this study provide strong evidence that the CCP score is a robust prognostic marker, which, after additional validation, could have an essential role in determining the appropriate treatment for patients with prostate cancer., Funding: Cancer Research UK, Queen Mary University of London, Orchid Appeal, US National Institutes of Health, and Koch Foundation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The optimal method for measuring cancer extent in prostate biopsy specimens is unknown. Seven hundred forty-four patients diagnosed between 1990 and 1996 with prostate cancer and managed conservatively were identified. The clinical end point was death from prostate cancer. The extent of cancer was measured in terms of number of cancer cores (NCC), percentage of cores with cancer (PCC), total length of cancer (LCC) and percentage length of cancer in the cores (PLC). These were correlated with prostate cancer mortality, in univariate and multivariate analysis including Gleason score and prostate-specific antigen (PSA). All extent of cancer variables were significant predictors of prostate cancer death on univariate analysis: NCC, hazard ration (HR) = 1.15, 95% confidence interval (CI) = 1.04-1.28, P = 0.011; PPC, HR = 1.01, 95% CI = 1.01-1.02, P < 0.0001; LCC, HR = 1.02, 95% CI = 1.01-1.03, P = 0.002; PLC, HR = 1.01, 95% CI = 1.01-1.02, P = 0.0001. In multivariate analysis including Gleason score and baseline PSA, PCC and PLC were both independently significant P = 0.004 and P = 0.012, respectively, and added further information to that provided by PSA and Gleason score, whereas NNC and LCC were no longer significant (P = 0.5 and P = 0.3 respectively). In a final model, including both extent of cancer variables, PCC was the stronger, adding more value than PLC (χ² (1df) = 7.8, P = 0.005, χ² (1df) = 0.5, P = 0.48 respectively). Measurements of disease burden in needle biopsy specimens are significant predictors of prostate-cancer-related death. The percentage of positive cores appeared the strongest predictor and was stronger than percentage length of cancer in the cores.

Background: Most men with elevated levels of prostate-specific antigen (PSA) do not have prostate cancer, leading to a large number of unnecessary biopsies. A statistical model based on a panel of four kallikreins has been shown to predict the outcome of a first prostate biopsy. In this study, we apply the model to an independent data set of men with previous negative biopsy but persistently elevated PSA., Methods: The study cohort consisted of 925 men with a previous negative prostate biopsy and elevated PSA (>or=3 ng ml(-1)), with 110 prostate cancers detected (12%). A previously published statistical model was applied, with recalibration to reflect the lower positive biopsy rates on rebiopsy., Results: The full-kallikrein panel had higher discriminative accuracy than PSA and DRE alone, with area under the curve (AUC) improving from 0.58 (95% confidence interval (CI): 0.52, 0.64) to 0.68 (95% CI: 0.62, 0.74), P<0.001, and high-grade cancer (Gleason >or=7) at biopsy with AUC improving from 0.76 (95% CI: 0.64, 0.89) to 0.87 (95% CI: 0.81, 0.94), P=0.003). Application of the panel to 1000 men with persistently elevated PSA after initial negative biopsy, at a 15% risk threshold would reduce the number of biopsies by 712; would miss (or delay) the diagnosis of 53 cancers, of which only 3 would be Gleason 7 and the rest Gleason 6 or less., Conclusions: Our data constitute an external validation of a previously published model. The four-kallikrein panel predicts the result of repeat prostate biopsy in men with elevated PSA while dramatically decreasing unnecessary biopsies.

Our previous work identified a chromosomal translocation t(4;6) in prostate cancer cell lines and primary tumors. Using probes located on 4q22 and 6q15, the breakpoints identified in LNCaP cells, we performed fluorescence in situ hybridization analysis to detect this translocation in a large series of clinical localized prostate cancer samples treated conservatively. We found that t(4;6)(q22;q15) occurred in 78 of 667 cases (11.7%). The t(4;6)(q22;q15) was not independently associated with patient outcome. However, it occurs more frequently in high clinical T stage, high tumor volume specimens and in those with high baseline PSA (P=0.001, 0.001 and 0.01, respectively). The t(4;6)(q22;q15) occurred more frequently in samples with two or more TMPRSS2:ERG fusion genes caused by internal deletion than in samples without these genomic alterations, but this correlation is not statistically significant (P=0.0628). The potential role of this translocation in the development of human prostate cancer is discussed.

We show protein kinase C-zeta (PKC-ζ) to be a novel predictive biomarker for survival from prostate cancer (P < 0.001). We also confirm that transcription of the PRKC-ζ gene is crucial to the malignant phenotype of human prostate cancer. Following siRNA silencing of PRKC-ζ in PC3-M prostate cancer cells, stable transfectant cell line si-PRKC-ζ-PC3-M(T1-6) is phenotypically nonmalignant in vitro and in vivo. Genome-wide expression analysis identified 373 genes to be differentially expressed in the knockdown cells and 4 key gene networks to be significantly perturbed during phenotype modulation. Functional interconnection between some of the modulated genes is revealed, although these may be within different regulatory pathways, emphasizing the complexity of their mutual interdependence. Genes with altered expression following PRKC-ζ knockdown include HSPB1, RAD51, and ID1 that we have previously described to be critical in prostatic malignancy. Because expression of PRKC-ζ is functionally involved in promoting the malignant phenotype, we propose PKC-ζ as a novel and biologically relevant target for therapeutic intervention in prostate cancer.

Purpose: Surgical margin status is commonly used as an end point for surgical learning. We examined the surgical margin learning curve and investigated whether surgical margins are a good marker for oncological outcome., Materials and Methods: The study cohort included 7,765 patients with prostate cancer treated with radical prostatectomy by 1 of 72 surgeons at a total of 4 major American academic medical centers. We calculated the learning curve for surgical margins and a concordance probability between the surgeon rates of positive surgical margins and 5-year biochemical recurrence., Results: A positive surgical margin was identified in 2,059 patients (27%). On multivariate analysis surgeon experience was strongly associated with surgical margin status (p = 0.017). The probability of a positive surgical margin was 40% for a surgeon with 10 prior cases, which decreased to 25% for a surgeon with 250 (absolute difference 15%, 95% CI 11 to 18). Learning curves differed dramatically among surgeons. For surgeon pairs the surgeon with the superior positive surgical margin rate also had the better biochemical recurrence rate only 58% of the time., Conclusions: We noted a learning curve for surgical margins after open radical prostatectomy. The poor concordance between surgeon margin and recurrence rates suggests that while margins clearly matter and efforts should be made to decrease positive margin rates, surgical margin status is not a strong surrogate for cancer control. These results have implications for using the margin rate to evaluate changes in surgical technique and as surgeon feedback., (Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The discovery of ERG/ETV1 gene rearrangements and PTEN gene loss warrants investigation in a mechanism-based prognostic classification of prostate cancer (PCa). The study objective was to evaluate the potential clinical significance and natural history of different disease categories by combining ERG/ETV1 gene rearrangements and PTEN gene loss status., Methods: We utilised fluorescence in situ hybridisation (FISH) assays to detect PTEN gene loss and ERG/ETV1 gene rearrangements in 308 conservatively managed PCa patients with survival outcome data., Results: ERG/ETV1 gene rearrangements alone and PTEN gene loss alone both failed to show a link to survival in multivariate analyses. However, there was a strong interaction between ERG/ETV1 gene rearrangements and PTEN gene loss (P<0.001). The largest subgroup of patients (54%), lacking both PTEN gene loss and ERG/ETV1 gene rearrangements comprised a 'good prognosis' population exhibiting favourable cancer-specific survival (85.5% alive at 11 years). The presence of PTEN gene loss in the absence of ERG/ETV1 gene rearrangements identified a patient population (6%) with poorer cancer-specific survival that was highly significant (HR=4.87, P<0.001 in multivariate analysis, 13.7% survival at 11 years) when compared with the 'good prognosis' group. ERG/ETV1 gene rearrangements and PTEN gene loss status should now prospectively be incorporated into a predictive model to establish whether predictive performance is improved., Conclusions: Our data suggest that FISH studies of PTEN gene loss and ERG/ETV1 gene rearrangements could be pursued for patient stratification, selection and hypothesis-generating subgroup analyses in future PCa clinical trials and potentially in patient management.