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PDF - 305K, Correlation between the expression of OGT and candidate transcription factors in localized prostate cancer.

XLSX - 10K, Primer sequences and Taqman probes used in this study.

PDF - 277K, A) Inhibition of OGT expression with siRNA reduces the growth rate of LNCaP cells. B) Knockdown of OGT induces a compensating downregulation of MGEA5.

XLSX - 9K, Clinical parameters for prostate cancer samples used for transcript profiling.

XLSX - 460K, Expression profiles induced by targeting OGT and ontology enrichment analysis of the genes downregulated by OGT inhibitor.

XLSX- 16K, Transcripts up-regulated during transition from normal prostate tissue to localized prostate cancer.

Purpose To assess if cancer-specific survival (CSS) following curative intent treatment (CIT) for muscle-invasive bladder cancer (MIBC) differs between patients presenting with MIBC (primary) and patients presenting with non-muscle-invasive bladder cancer who progress to MIBC (secondary). Methods This study uses data from the Cancer Registry of Norway on patients initially diagnosed with bladder cancer in 2008–2012 and treated with radical cystectomy (RC) or radiotherapy (RT). To ensure a clinically relevant population, we selected patients with a pre-treatment histology confirming muscle-invasion. Survival models were applied to evaluate differences in observed and adjusted CSS by type of MIBC and stratified by type of CIT. Adjustment was made for age group, sex, previous cancer, diagnostic hospital’s academic status and geographical region, and type of CIT. Results We identified 650 eligible patients: 589 (91%) primary MIBC and 61 (9%) secondary MIBC. A total of 556 (86%) patients underwent RC and 94 (14%) RT. The 5-year CSS for primary MIBC was 56% and 59% for secondary MIBC (p = 0.68). The type of MIBC did not impact the risk of bladder cancer death (HR = 0.85, CI = 0.55–1.33, p = 0.48), nor when stratified for CIT (RC: HR = 0.93, CI = 0.57–1.53, p = 0.78); RT: HR = 0.71, CI = 0.24–2.16, p = 0.55). Conclusion This first nation-wide population-based study comparing CSS between primary and secondary MIBC showed no significant difference in survival regardless of type of CIT. Continued surveillance of patients with non-muscle-invasive bladder cancer is necessary to detect early progression to MIBC. Future studies should include molecular and genetic characteristics in addition to detailed clinicopathologic information.

Publisher Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved. BACKGROUND: There is ongoing discussion whether a multivariable approach including magnetic resonance imaging (MRI) can safely prevent unnecessary protocol-advised repeat biopsy during active surveillance (AS). OBJECTIVE: To determine predictors for grade group (GG) reclassification in patients undergoing an MRI-informed prostate biopsy (MRI-Bx) during AS and to evaluate whether a confirmatory biopsy can be omitted in patients diagnosed with upfront MRI. DESIGN, SETTING, AND PARTICIPANTS: The Prostate cancer Research International: Active Surveillance (PRIAS) study is a multicenter prospective study of patients on AS (www.prias-project.org). We selected all patients undergoing MRI-Bx (targeted ± systematic biopsy) during AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A time-dependent Cox regression analysis was used to determine the predictors of GG progression/reclassification in patients undergoing MRI-Bx. A sensitivity analysis and a multivariable logistic regression analysis were also performed. RESULTS AND LIMITATIONS: A total of 1185 patients underwent 1488 MRI-Bx sessions. The time-dependent Cox regression analysis showed that age (per 10 yr, hazard ratio [HR] 0.84 [95% confidence interval {CI} 0.71-0.99]), MRI outcome (Prostate Imaging Reporting and Data System [PIRADS] 3 vs negative HR 2.46 [95% CI 1.56-3.88], PIRADS 4 vs negative HR 3.39 [95% CI 2.28-5.05], and PIRADS 5 vs negative HR 4.95 [95% CI 3.25-7.56]), prostate-specific antigen (PSA) density (per 0.1 ng/ml cm3, HR 1.20 [95% CI 1.12-1.30]), and percentage positive cores on the last systematic biopsy (per 10%, HR 1.16 [95% CI 1.10-1.23]) were significant predictors of GG reclassification. Of the patients with negative MRI and a PSA density of

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.

Linnaea borealis L. (Twinflower)—a dwarf shrub in the Linnaeeae tribe of Caprifoliaceae family—is distributed across the Northern Hemisphere. By means of this study, a reliable protocol for efficient micropropagation of uniform L. borealis L. var. borealis plantlets has been provided for the first time, callus culture was also established. Different initial explants, types of cultures, media systems, and plant growth regulators in Murashige and Skoog (MS) media were tested. Agitated shoot cultures in the liquid media turned out to be the best system for the production of sustainable plant biomass. After stabilization of the callus lines, the highest growth index (c.a. 526%) was gained for callus maintained on MS enriched with picloram. TLC and UHPLC-HESI-HRMS analysis confirmed the presence of phenolic acids and flavonoids, and for the first time, the presence of iridoids and triterpenoid saponins in this species. Multiplication of L. borealis shoot culture provides renewable raw material, allowing for the assessment of the phytochemical profile, and, in the future, for the quantitative analyses and the studies of the biological activity of extracts, fractions, or isolated compounds. This is the first report on in vitro cultures of traditionally used L. borealis rare taxon and its biosynthetic potential.

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 .

Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumor-specific molecules can be found in exosomes isolated from biological fluids. We have previously analyzed the proteome of urinary exosomes by mass spectrometry, and identified proteins differentially expressed in prostate cancer patients compared to healthy males. Since mass spectrometry is so far not commonly used in clinical laboratories, we have here investigated whether antibody-based methods such as Western blot or ELISA can be used to validate the use of the identified proteins as prostate cancer biomarkers. Western blot experiments designed to detect flotillin 2, TMEM256, Rab3B and LAMTOR1 showed that the level of these proteins was higher in urinary exosomes from prostate cancer patients compared to healthy males. Furthermore, a receiver operating characteristic curve of flotillin 2 in samples from 16 controls and 16 patients showed an area under the curve of 0.91, and 88% sensitivity at a threshold set to give 94% specificity. In addition, ELISA-based detection of flotillin 2 and PARK7 showed that the combination of these proteins was able to distinguish prostate cancer patients and healthy controls with 68% sensitivity and 93% specificity. Several promising biomarkers identified by mass spectrometry could not be evaluated by Western blot or ELISA due to their low exosomal amount and/or lack of good antibodies. In conclusion, our results show that several urinary exosomal proteins identified as prostate cancer biomarkers by mass spectrometry have a high diagnostic value also when analyzed by immunology-based methods, thus bringing these biomarkers closer to a potential clinical use.

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.

There is a great need to identify new and better prognostic and predictive biomarkers to stratify prostate cancer patients for optimal treatment. The aims of this study were to characterize the exp ...

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.

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.

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

Although abnormal metabolism in metabolic syndrome and tumours has been well described, the relationship between oxoglutarate dehydrogenase (OGDH) and obesity-related diseases is still largely unknown. This study aimed to investigate whether it was possible to use transcription activator-like effector nuclease (TALEN) technology to establish OGDH−/− rats and then study the effect of a high-fat diet (HFD) on these rats. However, after OGDH+/−rats were generated, we were unable to identify any OGDH−/− rats by performing mating experiments with the OGDH+/− rats for almost one year. During the past three years, only OGDH+/− rats were stably established, and correspondingly reduced OGDH expression in the tissues of the OGDH+/− rats was verified. No significant abnormal behaviour was observed in the OGDH+/− rats compared to the wild-type (WT) control rats. However, the OGDH+/− rats were revealed to have higher body weight, and the difference was even significantly greater under the HFD condition. Furthermore, blood biochemical and tissue histological examinations uncovered no abnormalities with normal diets, but a HFD resulted in liver dysfunction with pathological alterations in the OGDH+/− rats. Our results strongly indicate that OGDH homologous knockout is lethal in rats but heterologous OGDH knockout results in vulnerable liver lesions with a HFD. Therefore, the current study may provide a useful OGDH+/− rat model for further investigations of metabolic syndrome and obesity-related hepatic carcinogenesis.

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.

Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate 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.