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Background Active surveillance is an alternative to radical treatment for patients with low-risk prostate cancer, which could also benefit some patients with intermediate risk. We have investigated the use of miRNA in urinary extracellular vesicles to stratify these patients. Methods NGS was performed to profile the miRNAs from small urinary extracellular vesicles in a cohort of 70 patients with prostate cancer ISUP Grade 1, 2 or 3. The most promising candidates were then analysed by RT-qPCR in a new cohort of 60 patients. Results NGS analysis identified nine miRNAs differentially expressed in at least one of the comparisons. The largest differences were found with miR-1290 (Grade 3 vs. 1), miR-320a-3p (Grade 3 vs. 2) and miR-155-5p (Grade 2 vs. 1). Combinations of 2–3 miRNAs were able to differentiate between two ISUP grades with an AUC 0.79–0.88. RT-qPCR analysis showed a similar trend for miR-186-5p and miR-30e-5p to separate Grade 3 from 2, and miR-320a-3p to separate Grade 2 from 1. Conclusions Using NGS, we have identified several miRNAs that discriminate between prostate cancer patients with ISUP Grades 1, 2 and 3. Moreover, miR-186-5p, miR-320a-3p and miR-30e-5p showed a similar behaviour in an independent cohort using an alternative analytical method. Our results show that miRNAs from urinary vesicles can be potentially useful as liquid biopsies for active surveillance.

Background The association between curative treatment (CurTrt) and mortality in senior adults (≥70 years) with high‐risk prostate cancer (PCa) is poorly documented. In a population‐based cohort we report temporal trends in treatment and PCa‐specific mortality (PCSM), investigating the association between CurTrt and mortality in senior adults with high‐risk PCa, compared to findings in younger men (, Curative treatment in senior adults with high‐risk prostate cancer is associated with decreased prostate cancer‐specific and overall mortality

INTRODUCTION AND OBJECTIVE:The AUA guidelines recommend confirmatory biopsies in all patients within two years after diagnosis whereas the EAU guidelines recommend refraining from confirmatory biop...

Simple Summary Treatment decisions represent a significant dilemma for patients diagnosed with prostate cancer. The prediction of early treatment failure would inform appropriate decision making and allow the clinician and patient to consider appropriate primary treatments and adjuvant therapies. We have developed and validated a serum biomarker-based model for predicting risk of biochemical reoccurrence in prostate cancer after radical prostatectomy. This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict risk of biochemical reoccurrence. PEDF has anti-inflammatory effects impacting on cytokine production. This non-invasive tool can be employed prior to treatment and demonstrates significant benefit over current clinical practice, impacting on patients’ outcomes and quality of life. Abstract This study undertook to predict biochemical recurrence (BCR) in prostate cancer patients after radical prostatectomy using serum biomarkers and clinical features. Three radical prostatectomy cohorts were used to build and validate a model of clinical variables and serum biomarkers to predict BCR. The Cox proportional hazard model with stepwise selection technique was used to develop the model. Model evaluation was quantified by the AUC, calibration, and decision curve analysis. Cross-validation techniques were used to prevent overfitting in the Irish training cohort, and the Austrian and Norwegian independent cohorts were used as validation cohorts. The integration of serum biomarkers with the clinical variables (AUC = 0.695) improved significantly the predictive ability of BCR compared to the clinical variables (AUC = 0.604) or biomarkers alone (AUC = 0.573). This model was well calibrated and demonstrated a significant improvement in the predictive ability in the Austrian and Norwegian validation cohorts (AUC of 0.724 and 0.606), compared to the clinical model (AUC of 0.665 and 0.511). This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict BCR. This model can be employed prior to treatment and could improve clinical decision making, impacting on patients’ outcomes and quality of life.

Objectives To assess treatment response (PSA < 0.2 ng/ml), need for additional therapy and complication rate after robot assisted salvage pelvic lymph node dissection (sPLND) Material and Methods Analysis of outcomes data from radical prostatectomy (RP) patients consecutively operated with robot assisted sPLND due to biochemical recurrence and positron-emission tomography (PET)/computed tomography (CT)-detected nodal recurrence of pelvic lymph nodes. Results Sixty-nine patients underwent robotic sPLND after a median time of 47 months post- RP. Sixty-four patients (93%) had malignant lymph nodes upon histological assessment of sPLND specimen. Twenty patients (29%) achieved PSA < 0.2 ng/ml 6 weeks postoperatively. After median (IQR) follow-up of 15 months (10–27), fourteen patients (20%) still had PSA < 0.2 ng/ml without additional therapy and forty-one patients (59%) had started additional therapy. No significant predictor for treatment response was found. Postoperative complications occurred in 14 patients (20%). Eleven of these complications were classified as Clavien-Dindo grade 1 Conclusion Oncological benefit of sPLND as the only salvage procedure seems to be limited, though almost one third of patients achieved treatment response. Clinical trials are needed to determine if sPLND as part of a multimodal treatment may improve outcome.

The demographic shift toward an older population will increase the number of prostate cancer cases. A challenge in the treatment of prostate cancer is to avoid undertreatment of patients at high risk of progression following curative treatment. These men can benefit from early salvage treatment. An explorative cohort consisting of tissue from 16 patients who underwent radical prostatectomy, and were either alive or had died from prostate cancer within 10 years postsurgery, was analyzed by mass spectrometry analysis. Following proteomic and bioinformatic analyses, major vault protein (MVP) was identified as a putative prognostic biomarker. A publicly available tissue proteomics dataset and a retrospective cohort of 368 prostate cancer patients were used for validation. The prognostic value of the MVP was verified by scoring immunohistochemical staining of a tissue microarray. High level of MVP was associated with more than 4-fold higher risk for death from prostate cancer (hazard ratio = 4.41, 95% confidence interval: 1.45–13.38; P = 0.009) in a Cox proportional hazard models, adjusted for Cancer of the Prostate Risk Assessments Post-surgical (CAPRA-S) score and perineural invasion. Decision curve analyses suggested an improved standardized net benefit, ranging from 0.06 to 0.18, of adding MVP onto CAPRA-S score. This observation was confirmed by receiver operator characteristics curve analyses for the CAPRA-S score versus CAPRA-S and MVP score (area under the curve: 0.58 versus 0.73). From these analyses, one can infer that MVP levels in combination with CAPRA-S score might add onto established risk parameters to identify patients with lethal prostate cancer., Mass spectrometry of an explorative cohort identified a promising biomarker, major vault protein. Using two independent validation cohorts, we verified an association between high MVP and adverse outcome. MVP was associated with prostate cancer-specific death independently of a composite risk model.

To study the association between time from diagnosis to radical prostatectomy (RP-interval) and prostate cancer-specific mortality (PCSM), histological findings in the RP-specimen and failure after RP (RP-failure). Patients diagnosed with non-metastatic prostate cancer (PCa) in 2001–2010 and prostatectomized within 180 days of biopsy were identified in the Cancer Registry of Norway and the Norwegian Prostate Cancer Registry. Patients were stratified according to risk groups and RP-intervals of 0–60, 61–90, 91–120 and 121–180 days. Aalen-Johansen and Kaplan–Meier methods estimated curves for PCSM, RP-failure and overall mortality. Multivariable Cox regressions and Chi-square tests were used to evaluate the impact of RP-interval on outcomes. In 5163 eligible patients, the median time from diagnosis to RP was 93 days (range 1–180). Risk group distribution was similar in all RP-interval groups. With almost eight years of observation, no association was found between RP-interval and PCSM in the intermediate-or high-risk groups. Increasing RP-interval did not increase the rate of adverse histological outcomes or incidence of RP-failure. Increasing RP-interval up to 180 days was not associated with adverse oncological outcomes at eight years follow-up. These findings should be considered when planning for prostatectomy.

Purpose: To explore whether prostatectomized men report improved post-operative erectile function and urinary control dependent on the application of intra-operative frozen section examination (NeuroSAFE) during nerve-sparing radical prostatectomies (NS-RPs). Methods: Pre- and post-RP responses to the sexual domain and the urinary incontinence subscale of EPIC-26 were analyzed in 95 and 312 men from a NeuroSAFEGroup (Martini-Klinik, Hamburg, Germany) and a Non-NeuroSAFE Group (Oslo University Hospital, Norway), respectively, undergoing NS-RPs for ≤ cT2 prostate cancer. All patients had intra-prostatic tumors as evaluated by Digital Rectal Examination. Statistical significance in bivariate and multi-variable analyses: p

To compare oncological outcomes and complication rates based on the Clavien classification between laparoscopic radical prostatectomies (LRP) and robot-assisted laparoscopic radical prostatectomies (RALP).In a prospective quality registry clinical data were consecutively entered for 544 LRP and 1081 RALP patients operated from 2003 to the end of 2012. Complications within 90 days postoperatively were assessed according to the Clavien classification and compared between LRP and RALP patients. Univariate and multivariate analyses of logistic regression were used to fit oncological outcomes and complication data.The mean operation time was 213 and 135 minutes in LRP and RALP patients, respectively. Pathological T3a stage (pT3a) in the RALP group was more frequent than in the LRP group, 32.4% versus 17.8%, respectively. For pT2 tumours, positive surgical margins (PSM) rate for LRP and RALP, was 20.3% vs 10.6%, respectively (p .001). In the LRP group 74 patients (13.6%) reported 104 and in the RALP group 141 patients (13.0%) reported 177 complications (p = .75). Seventeen (3.1%) LRP patients and 15 (1.4%) RALP patients had Clavien grade IIIb complications (p = .017). Surgical reintervention was necessary in 14 patients (2.6%) and 17 patients (1.6%) in the LRP and RALP group, respectively (p = .04).Switching from LRP to RALP resulted in a much shorter operation time without compromising oncological outcome. There was no statistically significant difference in overall complication-rates between LRP and RALP. However, LRP patients had more serious complications and increased need for surgical reintervention compared to RALP patients.

Objective To provide population-based data on 10-year prostate cancer-specific mortality (PCSM), overall mortality (OM), treatment, and prognostic factors in patients with nonmetastatic prostate cancer (PCa). Materials and Methods Based on data from the Norwegian Prostate Cancer Registry, we calculated 10-year PCSM and OM in 3449 patients diagnosed with nonmetastatic PCa in 2004-2005 who underwent radical prostatectomy (n = 913), radiotherapy (n = 1334), or no local treatment (n = 1202). Patients were stratified according to risk group, Gleason grade group (GGG), and Eastern Cooperative Oncology Group (ECOG) performance status. Aalen-Johansen and Kaplan-Meier estimates and proportional hazards regressions were used. Results The 10-year PCSM rate was 8.5% (radical prostatectomy: 1.5, radiotherapy: 6.2%, no local treatment: 16.3%) and the OM rate was 25.5%. In the low-risk group, the risk of dying from other causes was 8-fold increased compared with death from PCa, the comparable factor being approximately 2 among high-risk patients. Patients with high-risk factors seemed to benefit the most from local treatment. Within each risk group, the 5 GGGs improved the prediction of PCSM. Having an ECOG performance status of ≥1 doubled the risk of PCSM compared with patients with an ECOG performance status of 0. Conclusion For all patients, the 10-year OM was about 3 times higher than PCSM, the greatest and lowest discrepancies emerging among patients with low- and high-risk tumors, respectively. The results support increased use of local treatment in high-risk patients. GGGs should be implemented in clinical practice. The role of ECOG performance status as prognostic factor has to be validated in future studies.

// Xiaoli Li 1, 2, * , Gaoyang Han 3, * , Xiaoran Li 2 , Quancheng Kan 4 , Zhirui Fan 1 , Yaqing Li 1, 2 , Yasai Ji 1 , Jing Zhao 1 , Mingzhi Zhang 1 , Mantas Grigalavicius 2 , Viktor Berge 5 , Mariusz Adam Goscinski 6 , Jahn M. Nesland 2 and Zhenhe Suo 1, 2 1 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450000, China 2 Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0379, Norway 3 Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui City, Henan Province, 453000, China 4 Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450000, China 5 Department of Urology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway 6 Department of Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway * These authors have contributed equally to this work Correspondence to: Zhenhe Suo, email: zhenhes@medisin.uio.no , zhenhesuo@aliyun.com Keywords: MPC, OXPHOS, TCA, glycolysis, stem cell Received: November 09, 2016 Accepted: May 05, 2017 Published: May 25, 2017 ABSTRACT One of the remarkable features of cancer cells is aerobic glycolysis, a phenomenon known as the “Warburg Effect”, in which cells rely preferentially on glycolysis instead of oxidative phosphorylation (OXPHOS) as the main energy source even in the presence of high oxygen tension. Cells with dysfunctional mitochondria are unable to generate sufficient ATP from mitochondrial OXPHOS, and then are forced to rely on glycolysis for ATP generation. Here we report our results in a prostate cancer cell line in which the mitochondrial pyruvate carrier 1 (MPC1) gene was knockout. It was discovered that the MPC1 gene knockout cells revealed a metabolism reprogramming to aerobic glycolysis with reduced ATP production, and the cells became more migratory and resistant to both chemotherapy and radiotherapy. In addition, the MPC1 knockout cells expressed significantly higher levels of the stemness markers Nanog, Hif1α, Notch1, CD44 and ALDH. To further verify the correlation of MPC gene function and cell stemness/metabolic reprogramming, MPC inhibitor UK5099 was applied in two ovarian cancer cell lines and similar results were obtained. Taken together, our results reveal that functional MPC may determine the fate of metabolic program and the stemness status of cancer cells in vitro .

Background There is a clear need for assays that can predict the risk of metastatic prostate cancer following curative procedures. Importantly these assays must be analytically robust in order to provide quality data for important clinical decisions. DNA microarray based gene expression assays measure several analytes simultaneously and can present specific challenges to analytical validation. This study describes the analytical validation of one such assay designed to predict metastatic recurrence in prostate cancer using primary formalin fixed paraffin embedded tumour material. Methods Accuracy was evaluated with a method comparison study between the assay development platform (Prostate Disease Specific Array) and an alternative platform (Xcel™ microarray) using 50 formalin-fixed, paraffin-embedded prostate cancer patient samples. An additional 70 samples were used to establish the assay reportable range. Determination of assay precision and sensitivity was performed on multiple technical replicates of three prostate cancer samples across multiple variables (operators, days, runs, reagent lots, and equipment) and RNA/cDNA inputs respectively using the appropriate linear mixed model. Results The overall agreement between the development and alternative platform was 94.7% (95% confidence interval, 86.9–98.5%). The reportable range was determined to be 0.150 to 1.107 for core needle biopsy samples and − 0.214 to 0.844 for radical prostatectomy samples. From the precision study, the standard deviations for assay repeatability and reproducibility were 0.032 and 0.040 respectively. The sensitivity study demonstrated that a total RNA input and cDNA input of 50 ng and 3.5 μg respectively was conservative. Conclusion The Metastatic Assay was found to be highly reproducible and precise. In conclusion the studies demonstrated an acceptable analytical performance for the assay and support its potential use in the clinic. Electronic supplementary material The online version of this article (10.1186/s12920-018-0442-y) contains supplementary material, which is available to authorized users.

Publisher's version, source at http://doi.org/10.18632/oncotarget.6479. The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy are not fully understood. This is the first study to address whether β2-adrenergic receptor (ADRB2)- mediated signaling may affect CRPC progression in vivo. By immunohistochemical analyses, we observed that low levels of ADRB2 is associated with a more rapid development of CRPC in a Norwegian patient cohort. To elucidate mechanisms by which ADRB2 may affect CRPC development, we stably transfected LNCaP cells with shRNAs to mimic low and high expression of ADRB2. Two UDP-glucuronosyltransferases, UGT2B15 and UGT2B17, involved in phase II metabolism of androgens, were strongly downregulated in two LNCaP shADRB2 cell lines. The low-ADRB2 LNCaP cell lines displayed lowered glucuronidation activities towards androgens than high-ADRB2 cells. Furthermore, increased levels of testosterone and enhanced androgen responsiveness were observed in LNCaP cells expressing low level of ADRB2. Interestingly, these cells grew faster than high-ADRB2 LNCaP cells, and sustained their low glucuronidation activity in castrated NOD/SCID mice. ADRB2 immunohistochemical staining intensity correlated with UGT2B15 staining intensity in independent TMA studies and with UGT2B17 in one TMA study. Similar to ADRB2, we show that low levels of UGT2B15 are associated with a more rapid CRPC progression. We propose a novel mechanism by which ADRB2 may affect the development of CRPC through downregulation of UGT2B15 and UGT2B17.

Background: Up to a third of prostate cancer patients fail curative treatment strategiessuch as surgery and radiation therapy in the form of biochemical recurrence (BCR) whichcan be predictive of poor outcome. Recent clinical trials have shown that menexperiencing BCR might benefit from earlier intervention post-radical prostatectomy(RP). Therefore, there is an urgent need to identify earlier prognostic biomarkers whichwill guide clinicians in making accurate diagnosis and timely decisions on the nextappropriate treatment. The objective of this study was to evaluate Serum ResponseFactor (SRF) protein expression following RP and to investigate its association with BCR.Materials and Methods: SRF nuclear expression was evaluated by immunohistochemistry(IHC) in TMAs across three international radical prostatectomy cohorts for a totalof 615 patients. Log-rank test and Kaplan-Meier analyses were used for BCRcomparisons. Stepwise backwards elimination proportional hazard regression analysiswas used to explore the significance of SRF in predicting BCR in the context of otherclinical pathological variables. Area under the curve (AUC) values were generated bysimulating repeated random sub-samples.Results: Analysis of the immunohistochemical staining of benign versus cancer coresshowed higher expression of nuclear SRF protein expression in cancer cores comparedwith benign for all the three TMAs analysed (P < 0.001, n = 615). Kaplan-Meier curves ofthe three TMAs combined showed that patients with higher SRF nuclear expression hada shorter time to BCR compared with patients with lower SRF expression (P < 0.001,n = 215). Together with pathological T stage T3, SRF was identified as a predictor of BCRusing stepwise backwards elimination proportional hazard regression analysis(P = 0.0521). Moreover ROC curves and AUC values showed that SRF was betterthan T stage in predicting BCR at year 3 and 5 following radical prostatectomy, thecombination of SRF and T stage had a higher AUC value than the two taken separately.Conclusions: SRF assessment by IHC following RP could be useful in guiding cliniciansto better identify patients for appropriate follow-up and timely treatment. European Commission - Seventh Framework Programme (FP7) Health Research Board Irish Cancer Society Science Foundation Ireland Insight Research Centre

Background Magnetic resonance imaging (MRI) has the potential to help the surgeon tailor radical prostatectomy (RP) more accurately according to the location and extent of the tumour and thereby reduce the rate of positive surgical margins (PSMs). Objective To evaluate the benefit of performing MRI prior to RP. Design, setting, and participants This single-institution randomised trial included 438 patients between December 2009 and June 2012 who were scheduled for robot-assisted laparoscopic prostatectomy. The study was registered (ClinicalTrials.gov identifier NCT01347320). Intervention Patients were preoperatively randomly assigned to non-MRI or MRI groups. Outcome measurements and statistical analysis The primary end point was the difference in the PSM rates between the two groups. Secondary end points were the rates of PSMs in clinical subgroups. Summary statistics were extracted from descriptive analyses, chi-square, or Fisher exact test, and logistic regression was used to analyse the data according to the intention-to-treat principle. Results and limitations A total of 216 patients were randomised to non-MRI; 222 were randomised to MRI. There were 49 cases (23%) of PSMs in the non-MRI group and 43 cases (19%) in the MRI group ( p =0.4). The relative and absolute risk reduction was 15% and 4%, respectively. Patients with cT1 constituted 55% of the cohort, in which the rate of PSMs was 27% in the non-MRI group and 16% in the MRI group ( p =0.035). The relative and absolute risk reduction was 41% and 11%, respectively. A limitation was suboptimal communication between the radiologist and urologist. Conclusions MRI prior to RP did not reduce the overall risk for PSMs in this patient cohort. However, at subgroup analysis we observed a possible benefit of MRI in patients with cT1. Patient summary This study could not demonstrate a definite benefit of performing magnetic resonance imaging before surgery for all patients. However, there was a possible improved result in patients in which physical examination could not detect the cancer.

Background Focal therapy as a treatment option for localized prostate cancer (PCa) is an increasingly popular and rapidly evolving field. Objective To gather expert opinion on patient selection, interventions, and meaningful outcome measures for focal therapy in clinical practice and trial design. Design, setting, and participants Fifteen experts in focal therapy followed a modified two-stage RAND/University of California, Los Angeles (UCLA) Appropriateness Methodology process. All participants independently scored 246 statements prior to rescoring at a face-to-face meeting. The meeting occurred in June 2013 at the Royal Society of Medicine, London, supported by the Wellcome Trust and the UK Department of Health. Outcome measurements and statistical analysis Agreement, disagreement, or uncertainty were calculated as the median panel score. Consensus was derived from the interpercentile range adjusted for symmetry level. Results and limitations Of 246 statements, 154 (63%) reached consensus. Items of agreement included the following: patients with intermediate risk and patients with unifocal and multifocal PCa are eligible for focal treatment; magnetic resonance imaging–targeted or template-mapping biopsy should be used to plan treatment; planned treatment margins should be 5 mm from the known tumor; prostate volume or age should not be a primary determinant of eligibility; foci of indolent cancer can be left untreated when treating the dominant index lesion; histologic outcomes should be defined by targeted biopsy at 1 yr; residual disease in the treated area of ≤3 mm of Gleason 3 + 3 did not need further treatment; and focal retreatment rates of ≤20% should be considered clinically acceptable but subsequent whole-gland therapy deemed a failure of focal therapy. All statements are expert opinion and therefore constitute level 5 evidence and may not reflect wider clinical consensus. Conclusions The landscape of PCa treatment is rapidly evolving with new treatment technologies. This consensus meeting provides guidance to clinicians on current expert thinking in the field of focal therapy. Patient summary In this report we present expert opinion on patient selection, interventions, and meaningful outcomes for clinicians working in focal therapy for prostate cancer., Take Home Message Focal therapy as an active treatment for prostate cancer is rapidly evolving. Expert opinion gathered in this report using robust consensus methodology captures current thinking and can help direct future research and clinical care.

The detection rate for the HT 1 (index tumour) was 92%; HT 2, 45%; and HT 3, 37%. The MRTV 1-3 vs the HTV 1-3 were 2.8 mL vs 4.0 mL (index tumour, P < 0.001), 1.0 mL vs 0.9 mL (tumour 2, P = 0.413), and 0.6 mL vs 0.5 mL (tumour 3, P = 0.492). The rate of true-positive and -negative sectors was 50% and 88%, κ= 0.39. Conclusion A combination of T2W and DW MRI detects the index tumour in 92% of cases, although MRI underestimates both TV and tumour burden compared with histology.

The aim of this study was to identify microRNAs in urinary exosomes that are differently expressed in prostate cancer patients and healthy donors. For this purpose, RNA was extracted from urinary exosomes from 20 prostate cancer patients and 9 healthy males and the microRNAs were analyzed by next generation sequencing. Interestingly, 5 microRNAs – miR-196a-5p, miR-34a-5p, miR-143-3p, miR-501-3p and miR-92a-1-5p – were significantly downregulated in exosomes from prostate cancer patients. Furthermore, RT-qPCR analysis of an independent cohort of 28 prostate cancer patients and 19 healthy males confirmed that miR-196a-5p and miR-501-3p were downregulated in prostate cancer samples. These results suggest that specific microRNAs in urinary exosomes might serve as non-invasive biomarkers for prostate cancer. In particular, miR-196a-5p and miR-501-3p are promising biomarkers that need to be further studied in large patient cohorts. Electronic supplementary material The online version of this article (10.1186/s12943-017-0726-4) contains supplementary material, which is available to authorized users.

Background Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however,>30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR¼3.21 (1.35–7.67); P¼0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR¼2.71 (1.11–6.63); P¼0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR¼3.23 (1.22–8.59); P¼0.019] whilst CAPRA itself was not significant [HR¼1.88, (0.52–6.77); P¼0.332]. A high concordance [100% (61.5–100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

Nature Reviews Clinical Oncology 11, 482–491 (2014) In the published version of this article, the affiliation and position held by Dr Viktor Berge was incorrectly stated as Professor of Urology and Director of Research at the University Hospital Oslo. Dr Berge is a Consultant Urologist at the Department of Urology, at the Oslo University Hospital.

Background: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy.Objective: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy.Design, setting, and participants: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months.Outcome measurements and statistical analysis: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis.Results and limitations: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p = 0.0092) and metastatic recurrence (multivariable HR = 3.20 [1.76-5.80]; p = 0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR = 2.67 [1.90-3.75]; p < 0.0001 and HR = 7.53 [4.13-13.73]; p < 0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation.Conclusions: The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential.Patient summary: The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population. (C) 2017 European Association of Urology. Published by Elsevier B.V. Refereed/Peer-reviewed

Background: Robust biomarkers that identify prostate cancer patients with high risk of recurrence will improve personalised cancer care. In this study, we investigated whether tissue metabolites detectable by high-resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) were associated with recurrence following radical prostatectomy. Methods: We performed a retrospective ex vivo study using HR-MAS MRS on tissue samples from 110 radical prostatectomy specimens obtained from three different Norwegian cohorts collected between 2002 and 2010. At the time of analysis, 50 patients had experienced prostate cancer recurrence. Associations between metabolites, clinicopathological variables, and recurrence-free survival were evaluated using Cox proportional hazards regression modelling, Kaplan–Meier survival analyses and concordance index (C-index). Results: High intratumoural spermine and citrate concentrations were associated with longer recurrence-free survival, whereas high (total-choline+creatine)/spermine (tChoCre/Spm) and higher (total-choline+creatine)/citrate (tChoCre/Cit) ratios were associated with shorter time to recurrence. Spermine concentration and tChoCre/Spm were independently associated with recurrence in multivariate Cox proportional hazards modelling after adjusting for clinically relevant risk factors (C-index: 0.769; HR: 0.72; P=0.016 and C-index: 0.765; HR: 1.43; P=0.014, respectively). Conclusions: Spermine concentration and tChoCre/Spm ratio in prostatectomy specimens were independent prognostic markers of recurrence. These metabolites can be noninvasively measured in vivo and may thus offer predictive value to establish preoperative risk assessment nomograms. r 2017 Cancer Research UK. All rights reserved 0007 – 0920/17. The authors' accepted and reviewed manuscript (post-print) is locked until 3 April 2018 due to copyright restrictions. The Publisher's version will become freely available on 3 October 2018 under a Creative Commons Attribution- NonCommercial-Share Alike 4.0 Unported License.

High intensity focused ultrasound may have a role as an alternative to standard radical therapies for localized prostate cancer. An attribute of high intensity focused ultrasound is that it can be repeated. We determined morbidity after primary and redo high intensity focused ultrasound.We performed an academic lead analysis of United Kingdom registry data on high intensity focused ultrasound treatments at 3 centers using patient reported continence and sexual function outcomes. Validated questionnaires were completed before and after each ultrasound treatment.A total of 359 patients received 1 whole gland high intensity focused ultrasound treatment for localized prostate cancer from October 2004 to June 2012, of whom 130 (36.2%) received re-treatment. Median followup was 27 months (range 3 to 81) after re-treatment. When analyzing adverse events, 10.8% of patients experienced urinary tract infection after the first treatment compared to 3.9% after re-treatment (p=0.009). Urethral dilatation was required in 13.8% and 14.0% of patients after first and redo ultrasound treatments (p=0.7), and bladder neck incision was required in 9.2% and 11.6%, respectively (p=0.2). Before and after re-treatment 73.3% and 55.1% of patients had no leak, and 2.7% and 9.0% used daily pads (p0.001 and p=0.07, respectively). Analysis of erectile function showed that 56.2% and 56.0% of patients were potent before and after re-treatment, respectively (p=0.9).Redo high intensity focused ultrasound is associated with an increase in urinary side effects but sexual side effects do not appear to be significantly increased. The number of adverse events seems to be equivalent after first and redo treatments. Meticulous patient selection is of paramount importance when selecting men for redo high intensity focused ultrasound.

Tissue-preserving focal therapies, such as brachytherapy, cryotherapy, high-intensity focused ultrasound and photodynamic therapy, aim to target individual cancer lesions rather than the whole prostate. These treatments have emerged as potential interventions for localized prostate cancer to reduce treatment-related adverse-effects associated with whole-gland treatments, such as radical prostatectomy and radiotherapy. In this article, the Prostate Cancer RCT Consensus Group propose that a novel cohort-embedded randomized controlled trial (RCT) would provide a means to study men with clinically significant localized disease, which we defined on the basis of PSA level (≤ 15 ng/ml or ≤ 20 ng/ml), Gleason grade (Gleason pattern ≤ 4 + 4 or ≤ 4 + 3) and stage (≤ cT2cN0M0). This RCT should recruit men who stand to benefit from treatment, with the control arm being whole-gland surgery or radiotherapy. Composite outcomes measuring rates of local and systemic salvage therapies at 3-5 years might best constitute the basis of the primary outcome on which to change practice.

Objective To report the oncological and functional outcomes of hemi salvage high-intensity focused ultrasound (HSH) in patients with unilateral radiorecurrent prostate cancer. Patients and Methods Between 2009 and 2012, 48 patients were prospectively enrolled in two European centres. Inclusion criteria were biochemical recurrence (BCR) after primary radiotherapy (RT), positive magnetic resonance imaging and ≥1 positive biopsy in only one lobe. BCR was defined using Phoenix criteria (a rise by ≥2 ng/mL above the nadir prostate specific antigen [PSA] level). The following schemes and criteria for functional outcomes were used: Ingelman-Sundberg score using International Continence Society (ICS) questionnaire (A and B), International prostate symptom score (IPSS), International Index of Erectile Function-5 (IIEF-5) points, the European Organisation for the Research and Treatment of Cancer (EORTC) quality of life questionnaires (QLQ C-30). HSH was performed under spinal or general anaesthesia using the Ablatherm® Integrated Imaging device. Patients with obstructive voiding symptoms at the time of treatment underwent an endoscopic bladder neck resection or incision during the same anaesthesia to prevent the risk of postoperative obstruction. Results After HSH the mean (sd) PSA nadir was 0.69 (0.83) ng/mL at a median (interquartile range) follow-up of 16.3 (10.5–24.5) months. Disease progression occurred in 16/48 (33%). Of these, four had local recurrence in the untreated lobe and four bilaterally, six developed metastases, and two had rising PSA levels without local recurrence or radiological confirmed metastasis. Progression-free survival rates at 12, 18, and 24 months were 83%, 64%, and 52%. Severe incontinence occurred in four of the 48 patients (8%), eight (17%) required one pad a day, and 36/48 (75%) were pad-free. The ICS questionnaire showed a mean (sd) deterioration from 0.7 (2.0) to 2.3 (4.5) for scores A and 0.6 (1.4) to 1.6 (3.0) for B. The mean (sd) IPSS and erectile function (IIEF-5) scores decreased from a mean (sd) of 7.01 (5.6) to 8.6 (5.1) and from 11.2 (8.6) to 7.0 (5.8), respectively. The mean (sd) EORTC QLC-30 scores before and after HSH were 35.7 (8.6) vs 36.8 (8.6). Conclusion HSH is a feasible therapeutic option in patients with unilateral radiorecurrent prostate cancer, which offers limited urinary and rectal morbidity, and preserves health-related quality of life.

Objective To study the risk of serial prostate biopsies on complications in men on active surveillance (AS) and determine the effect of complications on receiving further biopsies. Patients and methods In the global Prostate cancer Research International: Active Surveillance (PRIAS) study, men are prospectively followed on AS and repeat prostate biopsies are scheduled at 1, 4, and 7 years after the diagnostic biopsy, or once yearly if prostate-specific antigen-doubling time is

Objective. Laparoscopic radical prostatectomy (LRP) was introduced in the Department of Urology, Oslo University Hospital, in 2002. The aim of this study was to report mid-term oncology results and survival data. Material and methods. From February 2002 to November 2007, 582 consecutive patients with localized prostate cancer underwent LRP. Data were collected prospectively into a database. Results. Mean and median follow-up after LRP was 30.3 months (± 15.5) and 36.0 months (range 3–72). Five patients (1%) were lost during follow-up. Two patients died of prostate cancer during the study period and 10 patients died of other causes. The overall positive surgical margin (PSM) rate was 29% and decreased to 13% for the last 100 patients. The overall PSA progression-free survival (PFS) was 85% at 3 years and 73% at 5 years. Gleason score in the tumour specimen, pT stage and surgical margins were statistical significant independent predictors of biochemical PFS. Conclusion. These oncology results and 5...

After radical external beam radiation therapy (EBRT), local recurrence may benefit from definitive local therapy. The objective of this study was to evaluate the safety and short-term biochemical results and morbidity after salvage high-intensity focused ultrasound (HIFU) treatment in patients with biopsy-proven local prostate cancer recurrence after EBRT.From October 2006 46 patients were treated with HIFU. Bone scan and abdominal CT/MRI scan were negative. Median follow-up was 9 months (range 3-24 months).The median prostate-specific antigen (PSA) nadir was 0.3 ng/ml (range 0-24 ng/ml). Eighteen patients (39.1%) were classified as failures. In addition, there were four patients (8.7%) with post-HIFU PSA nadir0.5 ng/ml. No patients died during follow-up. One patient developed urethrorectal fistulae and was successfully treated conservatively. Two patients developed urethrocutaneous fistulae. Seven patients (15.2%) and one patient (2.1%) developed grade 2 and grade 3 incontinence, respectively. Seven men (15.2%) had erectile function sufficient for intercourse pre-HIFU and only two men (4.3%) post-HIFU.Early results of salvage HIFU in patients with local recurrence of prostate cancer after radical EBRT indicate the procedure to be a reasonable treatment option, but better patient selection criteria are needed. The side-effects are not negligible.

Objectives The amount of additional surgical procedures that cancer patients undergo following their initial treatment is one means of measuring the impact that cancer and cancer treatment has on their quality of life. In this study we looked for treatment-related differences in the need for additional surgical intervention among men with nonmetastatic prostate cancer within 66 mo of their initial treatment. Methods Data for this study were from the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) program and from the Medicare claims database. We searched the claims database for procedure codes indicating artificial urinary sphincter procedures, cystoscopy, urethral dilation, transurethral resection of the prostate (TURP) and bladder-neck incision, bladder irrigation/cystotomy, or nephrostomy. Results Of the 12,711 patients in our study, 3940 (31.0%) were initially treated by radical prostatectomy (RP), 3950 (31.1%) by radiation therapy (RT), 1209 (9.5%) by androgen-deprivation therapy (ADT), and 3612 (28.4%) by watchful waiting (WW). The percentage of patients who underwent cystoscopy 6–66 mo after their initial treatment ranged narrowly from 22% to 24% among members of the four treatment groups. In the RP group, 5.2% had artificial urinary sphincter procedures; 6.8% of the RT group, 8.2% of the ADT group, and 10.1% of the WW group had TURP/bladder-neck procedures compared with 3.7% of the RP group; and 12.5–16.2% of members in the four groups had urethral dilation procedures. Conclusions Over one third of prostate cancer patients needed surgical intervention within 66 mo of their initial treatment despite the type of initial treatment.

Aims of this chapter are to highlight the following: The concept of significant and insignificant cancer The importance of identifying the index tumor Benefits and limitations of MRI Optimal biopsy strategy

Methods for quantification of bladder outlet obstruction (BOO) are still controversial. Parameters such as detrusor opening pressure (p(det.open)), maximum detrusor pressure (p(det.max)), minimum voiding pressure (p(det.min.void)), and detrusor pressure at maximum flow rate (P(det.Qmax)) separate obstructed from nonobstructed patients to some extent, but two nomograms, the Abrams-Griffiths nomogram and the linearized passive urethral resistance relation (LinPURR), are more accepted for this purpose, along with the urethral resistance algorithm. In this retrospective, methodologic study, we evaluated the properties of these parameters with regard to test-retest reproducibility and ability to detect a moderate (pharmacologic) and a pronounced (surgical) relief of bladder outlet obstruction. We studied the pressure-flow charts of 42 patients who underwent 24 weeks of androgen suppressive therapy, 42 corresponding patients who received placebo, and 30 patients who had prostate surgery. The patients performed repeat void pressure-flow examinations before and after treatment or placebo. The various parameters were compared. Among the bladder pressure parameters, P(det.Qmax) seemed to have some advantages, supporting the belief that it is the most relevant detrusor pressure parameter to include in nomograms to quantify BOO. In assessment of a large decrease in urethral resistance, such as after TURp, resistance parameters that are based on maximum flow rate as well as detrusor pressure are preferable.

11 Background: Approximately 20% of patients with organ confined prostate cancer (PCa) will develop disease recurrence following radical treatment (surgery or external beam radiotherapy (EBRT)). We hypothesized that a molecular subgroup of early PCa may have metastatic potential at presentation, resulting in disease recurrence. Methods: Using unsupervised hierarchical clustering of gene expression from a PCa dataset we identified a novel molecular subgroup with a transcriptional profile similar to metastatic disease. We developed a 70 gene expression assay to prospectively identify patients within the subgroup from formalin fixed and paraffin embedded tissue (FFPE). Initial assessment found the assay to be prognostic in three independent publicly available prostatectomy datasets. We therefore assessed the prognostic value of the assay in FFPE clinical samples collected from multiple international sites. FFPE tumor resections and tumor biopsy specimens were obtained from 322 surgical patients and 248 patients treated with EBRT. Regions of highest Gleason grade were identified for macrodissection, RNA extraction and gene expression analysis. Samples were dichotomized as metastatic biology assay positive or negative using a pre-specified cut-off. The association of assay results with biochemical failure (BF) and distant metastases (DM) was tested on multivariate (MVA). Results: The assay was significantly associated with BF on MVA (HR 1.67 [1.16-2.38]; p = 0.0059), (HR 2.26 [1.26-4.04]; p = 0.0062) and DM on MVA (HR 3.39 [1.88-6.12]; p = 0.0001), (HR 3.26 [1.27-8.30]; p = 0.0137) for surgery and EBRT cohorts respectively. Importantly, in a combined model, the assay demonstrated additional information to the commonly used CAPRA clinical tool for prediction of DM, HR 2.72 [2.10-3.51]; p < 0.0001, and HR 2.72 [1.42-5.20]; p = 0.0026 (Prostate Metastatic Assay combined with CAPRA-S and CAPRA respectively). Conclusions: The metastatic biology assay predicts BF and DM in PCa patients treated with surgery or EBRT. The assay may help to select patients at risk of metastatic disease for additional treatment aimed at preventing disease recurrence.

The purpose of this study is to study the influence of radical prostatectomy (RP) for prostate cancer on work status and working life in men 3 years after surgery. In a prospective, questionnaire-based study on adverse effects after RP, 330 prostate cancer (PCa) patients who had been active in the workforce before RP described their work status 3 years after having surgery. We dichotomized their postoperative work status into “unchanged or increased” versus “reduced.” The participants also reported whether their working life was influenced by the PCa trajectory to no, some, or a great extent. Univariate and multiple logistic regression models were established with sociodemographic and clinical characteristics as independent variables and “work status” or “influence of PCa trajectory on working life” as dependent variables. Twenty-five percent of the participants had retired. Of the remaining participants, approximately 20 % had a reduced work status, which in the multivariate analyses was significantly associated with increasing age. One third of the men still active in the workforce considered the PCa to negatively influence their working life. This was independently associated with bother related to urinary leakage, fatigue, and having undergone additional oncological therapy (pelvic radiotherapy and/or hormone treatment). Though RP does not affect work status in most men, approximately one third of them experience problems in their working life due to adverse effects related to RP and/or additional post-RP anti-cancer therapy. Most PCa survivors can expect to remain in the workforce for at least 3 years after RP, but for some, persistent adverse effects after RP and /or additional anti-cancer treatment negatively affect their working life. Pre-RP counseling of men within the workforce should cover possible post-RP changes concerning work status and working life.

Objective: To evaluate health-related quality of life (HRQOL) after salvage high-intensity focused ultrasound (HIFU) for locally radiorecurrent prostate cancer (PCa). Methods: Since June 2006 we have treated 61 patients consecutively by salvage HIFU. All patients were offered the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI) questionnaire at baseline and at follow-up. Scores ranged from 0 (worst) to 100 (best). Clinically significant changes were defined as a minimum difference of 10 points between the baseline score and the score at follow-up. Results: Fifty-seven patients (93%) had evaluable data at baseline, compared with 46 (75%) after treatment. The mean time lapse between HIFU treatment and questionnaire response was 17.5 months (range 6–29 months). The mean score for urinary function decreased from 79.7 ± 12.1 prior to HIFU to 67.4 ± 17.8 after HIFU (P

In 1325 open heart operated (OHO) patients with a perioperative mortality of 5.8% the incidence of septicemia and perioperative myocardial infarction (PMI) were much higher in a cohort of 110 patients given intra-aortic balloon pump (IABP) support during the operative course. Analysis of this cohort showed that peri/postoperative insertion of the pump, the presence of disease in the descending branch of left coronary artery (LAD) and the need of more than one saphenous vein graft were risk factors for PMI. The presence of LAD disease was the only independent risk factor for PMI with an odds ratio (OR) of 4.62. Well known risk factors such as NYHA functional class, emergency, low left ventricular ejection fraction (EF) or elevated end diastolic pressure (EDP) were not prognostic of PMI. Thus, the intraoperative seemed to be more important than the preoperative risk profile for the development of PMI. Independent risk factors for the development of septicemia were the duration of IABP with an OR of 1.5 for each pump day and implantation of a valve prosthesis with an OR of 6.3. To avoid septic complications, this study suggests pump removal as soon as possible.

To examine how the use of additional treatment for prostate cancer differs as a function of the initial therapy (radical prostatectomy [RP], radiation therapy [RT], androgen deprivation therapy [ADT], or watchful waiting [WW]) for men with non-metastatic prostate cancer.A dataset was created that combined information from the Surveillance, Epidemiology, and End Results program and Medicare claims for hospital and physician services. To identify patients receiving additional cancer treatment, we searched the claims for the presence of RP, RT (palliative radiation not included), or ADT.The study population consisted of 12 711 patients: as initial treatment, 3940 (31.0%) had RP, 3950 (31.1%) RT, 1209 (9.5%) ADT, and 3612 (28.4%) WW. The RP group had a less favorable distribution of tumor differentiation than the RT group. Only 54.6% of men who had initial RP had localized cancer. In men who had initial RP, 8.1% had RT and 12.4% ADT during the follow-up period, which was 6-66 months after the initial therapy ended. Among patients who had initial RT or WW, 22.8% and 22.1%, respectively had ADT during the follow-up period.Older American men with prostate cancer who are initially treated with RT or simply observed (WW) are more likely than men who undergo RP to receive ADT as a follow-up treatment.