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This pilot study investigated the effect of sufentanil titration by 3 different analgesia monitoring devices or clinical signs during general anesthesia.Forty-eight patients undergoing radical retropubic prostatectomy with sevoflurane/sufentanil anesthesia were randomly assigned into 4 groups and received sufentanil guided either by 1 of 3 analgesia monitoring devices (Surgical Pleth Index [SPI], Pupillary Pain Index [PPI], Nociception Level [NoL]) or by clinical judgment (control). The primary end point was intraoperative sufentanil consumption. Adrenocorticotropic hormone (ACTH) and cortisol were measured at 4 time points during the day of surgery. Data were analyzed by Kruskal-Wallis and Mann-Whitney U tests and by mixed model and area under the curve (AUC) analyses for group comparisons and time effects of stress hormones.The total amount of sufentanil administration (μg·kg·minute·10) differed between the groups (median [quartiles]: control = 5.6 [4.4-6.4], SPI = 7.2 [4.8-8.4], PPI = 2.0 [1.8-2.9], NoL = 3.8 [3.3-5.1]; PPI versus SPI, -5.1 [-6.6 to -1.3], P.001; NoL versus SPI, -3.0 [-5.2 to 0.2], P = .024; control versus SPI, -1.6 [-3.7 to 1.7], P = .128; NoL versus PPI, 1.7 [0.6-3.4], P.001; control versus PPI, 3.4 [2.0-4.6], P.001; control versus NoL, 1.6 [-0.2 to 3.3], P = .017) (Hodges-Lehmann estimator [99% confidence interval {CI}], P values). The AUC analysis indicated differences among groups in cumulative ACTH levels (ng·liter·minute, natural logarithm (ln)-transformed data) of NoL versus PPI (-1.079 [-1.950 to -0.208], P = .001) and PPI versus SPI (1.192 [0.317-2.068], P= .001), as well as differences in cortisol levels (µg·liter·minute) for PPI versus SPI (46,710 [21,145-72,274], P.001), NoL versus SPI (27,645 [3163-52,126], P = .003), and control versus SPI (31,824 [6974-56,675], P = .001) (differences in means [99% CI], P value). Secondary end points (postoperative recovery, pain level, and analgesia medication) showed no differences.The type of analgesia nociception monitoring affected the total amount of sufentanil administered. Lower sufentanil doses in the PPI group were associated with an increased endocrine stress response. Titration by SPI caused no opioid reduction compared to the control but was associated with a reduced endocrine stress response.

Background Cancer patients often suffer from psychological distress. Psycho‐oncological services (POS) have been established in some health care systems in order to address such issues. This study aims to identify patient and center characteristics that elucidate the use of POS by patients in prostate cancer centers (PCCs). Methods Center‐reported certification and patient survey data from 3094 patients in 44 certified PCCs in Germany were gathered in the observational study (Prostate Cancer Outcomes). A multilevel analysis was conducted. Results Model 1 showed that utilization of POS in PCCs is associated with patients’ age (OR = 0.98; 95%‐CI = 0.96‐0.99; P, The paper identifies patient and center characteristics that account for the use of psycho‐oncological services by prostate cancer patients in certified prostate cancer centers in Germany. Multilevel analysis was conducted. The results indicate that the varying utilization of psycho‐oncological services in certified prostate cancer centers may be better explained by characteristics of the centers and the patients’ clinical characteristics, rather than by the patients’ sociodemographic features.

Purpose The self-reported functional status (sr-FS) of prostate cancer (PCa) patients varies substantially between patients and health-care providers before treatment. Information about this issue is important for evaluating comparisons between health-care providers and to assist in treatment decision-making. There have been few reports on correlates of pretherapeutic sr-FS. The objective of the article, therefore, is to describe clinical and sociodemographic correlates of pretherapeutic sr-FS, based on a subset of the TrueNTH Global Registry, a prospective cohort study. Methods A total of 3094 PCa patients receiving local treatment in 44 PCa centers in Germany were recruited between July 2016 and April 2018. Multilevel regression models were applied to predict five pretherapeutic sr-FS (EPIC-26) scores based on clinical characteristics (standard set suggested by the International Consortium for Health Outcomes Measurement), sociodemographic characteristics, and center characteristics. Results Impaired pretherapeutic sr-FS tended to be associated with lower educational level and poorer disease characteristics—except for “urinary incontinence” which was only associated with age. Notably, age was a risk factor (“urinary incontinence,” “urinary irritative/obstructive,” “sexual”) as well as a protective factor (“hormonal”) for pretherapeutic sr-FS. Pretherapeutic sr-FS varies little across centers. Conclusions Pretherapeutic sr-FS varies by clinical patient characteristics and age as well as by socioeconomic status. The findings point out the benefit of collecting and considering socioeconomic information in addition to clinical and demographic patient characteristics for treatment decision-making and fair comparisons between health-care providers.

The extent of variation in urinary and sexual functional outcomes after radical prostatectomy (RPE) between prostate cancer (PC) operating sites remains unknown. Therefore, this analysis aims to compare casemix-adjusted functional outcomes (EPIC-26 scores incontinence, irritative/obstructive function and sexual function) between operating sites 12 months after RPE.Analysis of a cohort of 7065 men treated with RPE at 88 operating sites (prostate cancer centers, "PCCs") between 2016 and 2019. Patients completed EPIC-26 and sociodemographic information surveys at baseline and 12 months after RPE. Survey data were linked to clinical data. EPIC-26 domain scores at 12 months after RPE were adjusted for relevant confounders (including baseline domain score, clinical and sociodemographic information) using regression analysis. Differences between sites were described using minimal important differences (MIDs) and interquartile ranges (IQR). The effects of casemix adjustment on the score results were described using Cohen's d and MIDs.Adjusted domain scores at 12 months varied between sites, with IQRs of 66-78 (incontinence), 89-92 (irritative/obstructive function), and 20-29 (sexual function). Changes in domain scores after casemix adjustment for sites ≥ 1 MID were noted for the incontinence domain (six sites). Cohen's d ranged between - 0.07 (incontinence) and - 0.2 (sexual function), indicating a small to medium effect of casemix adjustment.Variation between sites was greatest in the incontinence and sexual function domains for RPE patients. Future research will need to identify the factors contributing to this variation.The study is registered at the German Clinical Trial Registry ( https://www.drks.de/drks_web/ ) with the following ID: DRKS00010774.

BACKGROUNDTransrectal ultrasound-guided prostate biopsy (TRUS) is a standard procedure for prostate cancer diagnosis. Because prostate cancer is a multifocal disease in many patients, multiple sampling (n ≥ 10) is required, which may bear the risk of systemic spread of cancer cells.DESIGNUsing the standardized CellSearch® system that allows for the detection of single epithelial cell adhesion molecule-positive circulating tumor cells (CTCs) in blood, we investigated whether prostate biopsy is associated with release of prostatic tumor cells into the circulation. Peripheral blood was obtained before and within 30 min after performing prostate biopsy from 115 men with increased serum prostate-specific antigen.RESULTSThe number of CTCs significantly increased after biopsy in men with histologically confirmed prostate cancer (odds ratio, 7.8; 95% CI, 4.8–12.8), whereas no biopsy-related changes could be detected in men without confirmed prostate cancer. Multivariable analysis showed that biopsy-related increase of CTCs was significantly correlated with a worse progression-free survival (hazard ratio, 12.4; 95% CI, 3.2–48.6) within the median follow-up of 41 months.CONCLUSIONSProstate biopsies may lead to a tumor-associated release of CTCs into the blood circulation. Larger confirmatory trials with longer follow-up periods are required before any change in clinical practice can be recommended.

For patients with prostate cancer, validated and reliable instruments are essential for measuring patient-reported outcomes. The aim of this study was to validate the German version of the widely established Expanded Prostate Cancer Index Composite with 26 items (EPIC-26). A German translation of the original questionnaire was tested in 3094 patients with localized or locally advanced (any T, any N and M0) prostate cancer with treatment intent (including radical prostatectomy, brachytherapy, active surveillance, watchful waiting). They completed the EPIC-26 questionnaire before treatment. A total of 521 of them also completed a questionnaire 12 months afterward. Internal consistency, sensitivity to change, and construct validity were assessed. The internal consistency of all domains was sufficient (Cronbach’s alpha between 0.64 and 0.93). Item-to-scale correlation coefficients showed acceptable associations between items and their domain score (all > 0.30), with the lowest scores for “bloody stools” (r = 0.37) and “breast problems” (r = 0.32). Confirmatory and exploratory factor analysis confirmed the five-dimension structure of the EPIC-26 (comparative fit index 0.95). Psychometric evaluation suggests that the German version of the EPIC-26 is a well-constructed instrument for measuring patient-reported health-related symptoms in patients with prostate cancer.

// Till Eichenauer 1, 2, * , Mohammad Hussein 1, * , Claudia Hube-Magg 1 , Martina Kluth 1 , Franziska Buscheck 1 , Doris Hoflmayer 1 , Maria Christina Tsourlakis 1 , Stefan Steurer 1 , Till S. Clauditz 1 , Andreas M. Luebke 1 , Eike Burandt 1 , Waldemar Wilczak 1 , Andrea Hinsch 1 , David Dum 1 , Burkhard Beyer 3 , Thomas Steuber 3 , Hartwig Huland 3 , Markus Graefen 3 , Ronald Simon 1 , Guido Sauter 1 , Nathaniel Melling 4 , Thorsten Schlomm 5 and Sarah Minner 1 1 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 Department of Urology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany 3 Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 5 Department of Urology, Charite-Universitatsmedizin Berlin, Berlin, Germany * These authors contributed equally to this work Correspondence to: Ronald Simon, email: R.Simon@uke.de Keywords: GSK3beta; prostate cancer; prognosis; immunohistochemistry Received: January 16, 2019 Accepted: February 15, 2019 Published: March 01, 2019 ABSTRACT Glycogen synthase kinase 3s (GSK3s) regulates many cancer relevant cellular processes and represents a potential therapeutic target. GSK3s overexpression has been linked to adverse tumor features in many cancers, but its role in prostate cancer remains uncertain. We employed immunohistochemical GSK3s expression analysis on a tissue microarray with 12,427 prostate cancers. Cytoplasmic and nuclear GSK3s staining was separately analyzed. GSK3s staining was absent in normal prostate epithelium, whereas 57% of 9,164 interpretable cancers showed detectable GSK3s expression. Cytoplasmic staining was considered weak, moderate, and strong in 36%, 19.5% and 1.5% of tumors and was accompanied by nuclear GSK3s staining in 47% of cases. Cytoplasmic GSK3s staining as well as nuclear GSK3s accumulation was associated with advanced tumor stage, high Gleason grade, presence of lymph node metastasis and early biochemical recurrence ( p < 0.0001 each for cytoplasmic staining and nu-clear accumulation). Prognosis of GSK3s positive cancers became particularly poor if nuclear GSK3s staining was also seen ( p < 0.0001). The prognostic impact of nuclear GSK3s accumu-lation was independent of established preoperative and postoperative parameters in multivari-ate analyses ( p < 0.0001). The significant association of GSK3s expression with deletions of PTEN , 3p13 ( p < 0.0001 each), 5q21 ( p = 0.0014) and 6q15 ( p = 0.0026) suggest a role of GSK3s in the development of genomic instability. In summary, the results of our study identify GSK3s as an independent prognostic marker in prostate cancer.

Purpose Social service counseling (SSC) is an important instrument to support cancer patients, for example, regarding legal support, or rehabilitation. Several countries have established on-site SSC in routine care. Previous analyses have shown that SSC utilization varies across cancer centers. This analysis investigates patient and center-level predictors that explain variations in SSC utilization between centers. Methods Logistic multilevel analysis was performed with data from 19,865 prostate cancer patients from 102 prostate cancer centers in Germany and Switzerland. Data was collected within an observational study between July 2016 and June 2020 using survey (online and paper) and tumor documentation. Results The intraclass correlation coefficient for the null model implies that 51% of variance in SSC utilization is attributable to the center a patient is treated in. Patients aged 80 years and older, with higher education, private insurance, without comorbidities, localized intermediate risk, and undergoing androgen deprivation therapy before study inclusion were less likely to utilize SSC. Undergoing primary radiotherapy, active surveillance, or watchful waiting as compared to prostatectomy was associated with a lower likelihood of SSC utilization. Significant negative predictors at the center level were university hospital, center’s location in Switzerland, and a short period of certification. Conclusion The results show that patient and center characteristics contribute to explaining the variance in SSC utilization in prostate cancer centers to a large extent. The findings may indicate different organizational processes in the countries included and barriers in the sectoral structure of the healthcare system. In-depth analyses of processes within cancer centers may provide further insights into the reasons for variance in SSC utilization.

Burkhard Beyer, Praktische Tipps für die Edition landesgeschichtlicher Quellen (Materialien der Historischen Kommission für Westfalen, Bd. 15), Historische Kommission für Westfalen, Landschaftsverband Westfalen-Lippe 2018. 80 S.; https://www.lwl.org/hiko-download/HiKo-Materialien_015_(2018 – 03).pdf (letzter Abruf: 04.12.2018)

Purpose To give an overview of the multicenter Prostate Cancer Outcomes (PCO) study, involving paper-based and web-based collection of patient-reported outcome measures (PROM) in patients undergoing local treatment for prostate cancer in certified centers in Germany. The PCO study is part of the larger Movember-funded TrueNTH Global Registry. The article reports on the study’s design and provides a brief progress report after the first 2 years of data collection. Methods Prostate cancer centers (PCCs) certified according to German Cancer Society requirements were invited to participate in collecting patient-reported information on symptoms and function before and at least once (at 12 months) after treatment. The data were matched with disease and treatment information. This report describes progress in patient inclusion, response rate, and variations between centers relative to online/paper use, and also data quality, including recruitment variations relative to treatment in the first participating PCCs. Results PCC participation increased over time; 44 centers had transferred data for 3094 patients at the time of this report. Patient recruitment varied widely across centers. Recruitment was highest among patients undergoing radical prostatectomy. The completeness of the data was good, except for comorbidity information. Conclusions The PCO study benefits from a quality improvement system first established over 10 years ago, requiring collection and harmonization of a predefined clinical dataset across centers. Nevertheless, establishing a PROM routine requires substantial effort on the part of providers and constant monitoring in order to achieve high-quality data. The findings reported here may be useful for guiding implementation in similar initiatives.

Background This RCT investigated the effect of opioid titration by three different nociception monitoring devices or clinical signs during general anaesthesia. Methods Ninety-six patients undergoing radical retropubic prostatectomy with propofol/remifentanil anaesthesia were randomised into one of four groups to receive remifentanil guided by one of three nociception monitoring devices (surgical pleth index [SPI], pupillary pain index [PPI], or nociception level [NOL]) or by clinical judgement (control). Intraoperative remifentanil requirement was the primary endpoint, whereas recovery parameters and stress hormone levels were secondary endpoints. Results The mean [95% confidence interval {CI}] remifentanil administration rate differed between the groups: control 0.34 (0.32–0.37), SPI 0.46 (0.38–0.55), PPI 0.07 (0.06–0.08), and NOL 0.16 (0.12–0.21) μg kg−1 min−1(P Conclusions The nociception monitoring devices and clinical signs reflect the extent of nociception differently, leading to dissimilar doses of remifentanil. Very low remifentanil doses were associated with an increase and higher remifentanil doses were accompanied by a decrease in serum cortisol concentrations. Use of nociception monitoring devices for guiding intra-operative opioid dosing needs further validation. Clinical trial registration NCT03380949.

Here, we present a functional assay to detect the repair switch to the alternative PARP1-dependent end joining (PARP1-EJ) pathway and the associated susceptibility to PARPi-mediated radiosensitization in freshly collected tumor samples from prostate cancer (PCa) patients, thereby facilitating the selection of patients who should benefit from combined PARPi plus radiotherapy (RT) treatment. Our optimized ex-vivo approach sustains tumor slices for up to 15 days under culture conditions that maintain proliferation and oxygenation rates, as measured by EdU incorporation and pimonidazole staining, respectively. We present a robust system to analyze DSB repair using, for the first time in an ex vivo tumor slice setting, two DSB-markers simultaneously i.e. γH2AX and 53BP1. A computer-based processing method (i) controls variations in DNA content and slicing on the number of repair foci and (ii) measures the PARPi-mediated enhancement ratio on DSB foci numbers to ensure inter-patient-comparability. We validated this approach using a PC3 xenograft model with its previously described repair switch to PARP1-EJ. More importantly, we show that approximately 30% of the analyzed tumor tissue samples collected from PCa patients display a switch to PARP1-EJ, as indicated by the enhanced number of residual γH2AX/53BP1 foci exclusively after PARPi+RT. Furthermore, normal prostatic tissues show no repair switch to PARP1-EJ, indicating that this repair switch and its associated radiosensitizing effect is tumor-specific. Collectively, we present here a predictive assay for the switch to PARP1-EJ that enables individualization of anti-cancer treatment using a combination of RT and radiosensitizing anticancer agents such as PARPi in PCa.

Objective Androgen deprivation therapy (ADT) enhances survival of advanced prostate cancer patients and is therefore used as a concomitant therapy. However, ADT has been reported to cause negative side effects on cognition and emotional processing. So far, research referred to the effects of short-term treatment. Since the brain may adapt to androgen deprivation, we were especially interested in the long-term effects of ADT on cognitive and socioeconomic decision making. Methods Participants underwent a battery of tests that have been associated with testosterone. We compared the results of three matched test groups: (1) prostate cancer patients with ADT up to 20 years, (2) prostate cancer controls without treatment and (3) healthy controls. We further measured the morning testosterone content in participants' saliva. Results Testosterone concentration was positively associated with visuospatial performance across and within the test groups. Patients with long-term ADT showed an overall decline in cognitive performance. Compared with untreated patients, ADT was also associated with a reduced intergroup bias during socioeconomic decision making, which was in line with previous observations in young men suggesting that testosterone may promote ingroup favoritism. Finally, depression scores were increased in ADT, while quality of life was negatively associated with the treatment. Conclusion These findings conform to results made after short-term treatment. ADT promotes negative side effects on cognitive function. We also show for the first time that testosterone deprivation may affect socioeconomic decision making. Nevertheless, it should be emphasized that these effects cannot outweigh the previously described advantages of ADT in the treatment of prostate cancer.

The A Disintegrin and Metalloproteinase (ADAM) family of endopeptidases plays a role in many solid cancers and includes promising targets for anticancer therapies. Deregulation of ADAM15 has been linked to tumor aggressiveness and cell line studies suggest that ADAM15 overexpression may also be implicated in prostate cancer. To evaluate the impact of ADAM15 expression and its relationship with key genomic alterations, a tissue microarray containing 12,427 prostate cancers was analyzed by immunohistochemistry. ADAM15 expression was compared to phenotype, prognosis and molecular features including TMPRSS2:ERG fusion and frequent deletions involving PTEN, 3p, 5q and 6q. Normal prostate epithelium did not show ADAM15 staining. In prostate cancers, negative, weak, moderate, and strong ADAM15 staining was found in 87.7%, 3.7%, 5.6%, and 3.0% of 9826 interpretable tumors. Strong ADAM15 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal stage and resection margin. ADAM15 overexpression was also associated with TMPRSS2:ERG fusions and PTEN deletions (P

Background Prostate cancer (PCa) is among the most commonly diagnosed malignancies in men. Although 5-year survival in patients with localised disease reaches nearly 100%, metastatic disease still remains incurable. Therefore, there is a need for markers indicating metastatic dissemination. Methods EGFR overexpression (EGFRover) was tracked in 1039 primary tumours, circulating tumour cells from 39 d’Amico high-risk patients and metastatic samples from 21 castration-resistant PCa cases. EGFR status was compared to clinical parameters and multiple molecular factors were assessed using immunohistochemistry and gene ontology analysis. The functional aspect of EGFR was evaluated by plating PC-3 cells on soft and rigid matrices. Results EGFRover was found in 14% of primary tumours, where it was associated with shorter metastasis-free survival and was an independent indicator of worse overall survival. EGFRover correlated with a pro-migratory and pro-metastatic phenotype of tumour cells as well as rich collagen fibre content. All circulating tumour cells (detected in 13% of cases) were positive for EGFR, independent of their EMT-related phenotype. EGFRover was more prevalent in castration-resistant bone metastases (29% of patients) and supported growth of human PCa cells on rigid matrices mimicking bone stiffness. Conclusions EGFRover is a stable, EMT-independent marker of PCa disseminating to rigid organs, preferentially bones.

Objective: The impact of positive surgical margin (SM) on cancer control outcomes in prostate cancer patients is a subject of continuous debate. We test the hypothesis that the impact of SM on clinical recurrence (CR) rate may vary based on the other clinical/pathologic characteristics of the tumor. Materials and Methods: We focused on 5290 patients treated with robot-assisted radical prostatectomy and pelvic node dissection, between 2002 and 2013, at three tertiary care centers. Regression tree analysis stratified patients into risk groups based on their tumor characteristics and the corresponding CR rate. Kaplan-Meier log-rank and multivariable Cox regression models tested the relationship between SM status and CR rate in each tree-generated risk group. Results: Mean (median) follow-up time was 47.7 (39.0) months. Regression tree analysis that considered all available covariates, except SM status, divided patients based on their CR risk into the following risk groups: (1) high risk (any pT3b/pT4 disease); (2) intermediate risk (≤pT3a disease and pGS 8-10); (3) low risk (≤pT3a, pGS ≤7, and prostate-specific antigen [PSA] >9 ng/mL); and (4) very low risk (≤pT3a, pGS ≤7, and PSA ≤9 ng/mL). Positive SM had a significant detrimental impact on CR risk only in two groups: intermediate risk (p < 0.001) and high risk (p = 0.01). These observations were confirmed by multivariable analyses. Conclusions: Our findings show that positive SM had a detrimental impact on CR only in a minority of patients (15%), specifically in those with advanced pathologic stage and/or pathologically poorly differentiated tumor. For all the remaining patients (85%), positive SM by itself did not increase the risk of CR.

Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline PALB2 variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of RB1. We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.

The role of HistoScanning (TM) (HS) in prostate biopsy is still indeterminate. Existing literature is sparse and controversial. To provide more evidence according to that important clinical topic, we analyzed institutional data from the Martini-Clinic, Prostate Cancer Center, Hamburg. Patients who received prostate biopsy and who also received HS were included in the study cohort. A single examiner, blinded to pathological results, re-analyzed all HS data in accordance with sextants of the prostate. Each sextant was considered as an individual case. Corresponding results from biopsy and HS were analyzed. The area under the receiver-operating characteristic curve (AUC) for the prediction of a positive biopsy by HS was calculated. Furthermore, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were assessed according to different HS signal volume cutoffs (> 0, > 0.2 and > 0.5 ml). Overall, 198 men were identified and 1,188 sextants were analyzed. The AUC to predict positive biopsy results by HS was 0.58. Sensitivity, specificity, PPV and NPV for HS to predict positive biopsy results per sextant, depending on different HS signal volume cutoffs (> 0, > 0.2 and > 0.5 ml) were 84.1, 27.7, 29.5 and 82.9 %, 60.9, 50.6, 28.8 and 79.7 %, and 40.1, 73.3, 33.1 and 78.8 %, respectively. Positive HS signals do not accurately predict positive prostate biopsy results according to sextant analysis. We cannot recommend a variation of well-established random biopsy patterns or reduction of biopsy cores in accordance with HS signals at the moment.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Y-box binding protein 1 (YB-1) is an RNA and DNA binding factor with potential prognostic cancer. To evaluate the clinical impact of YB-1, a tissue microarray with 11,152 prostate cancers was analysed by immunohistochemistry. Cytoplasmic and nuclear staining was separately analysed. Cytoplasmic YB-1 was absent or weak in normal epithelium but seen in 86,3% of carcinomas. Cytoplasmic staining was weak, moderate, and strong in 29.6%, 43.7% and 13.0% of tumours and was accompanied by nuclear YB-1 staining in 32.1% of cases. Particularly nuclear staining was strongly linked to poor patient prognosis (p PTEN, 5q21 and 6q15 fits well in the protein’s role as an inhibitor of DNA damage dependent cell cycle arrest, a role that is likely to induce genomic instability. In summary, the data show, that the prognostic impact of YB-1 expression is limited to ERG negative prostate cancers.

The relevance of blood-based assays to monitor minimal residual disease (MRD) in non-metastatic prostate cancer (PCa) remains unclear. Proving that clinically relevant circulating tumor cells (CTCs) can be detected with available technologies could address this. This study aimed to improve CTC detection in non-metastatic PCa patients by combining three independent CTC assays: the CellSearch system, an in vivo CellCollector and the EPISPOT. Peripheral blood samples from high-risk PCa patients were screened for CTCs before and three months after radical prostatectomy (RP). Combining the results of both time points, CTCs were detected in 37%, 54.9% and 58.7% of patients using CellSearch, CellCollector and EPISPOT, respectively. The cumulative positivity rate of the three CTC assays was 81.3% (87/107) with 21.5% (23/107) of patients harboring ≥5 CTCs/7.5 ml blood. Matched pair analysis of 30 blood samples taken before and after surgery indicated a significant decrease in CTCs captured by the CellCollector from 66% before RP to 34% after therapy (p = 0.031). CTC detection by EPISPOT before RP significantly correlated with PSA serum values (p

Deletion of chromosome 8p is the second most frequent genomic alteration in prostate cancer. To better understand its clinical significance, 8p deletion was analyzed by fluorescence in-situ hybridization on a prostate cancer tissue microarray. 8p deletion was found in 2,581 of 7,017 cancers (36.8%), and was linked to unfavorable tumor phenotype. 8p deletion increased from 29.5% in 4,456 pT2 and 47.8% in 1,598 pT3a to 53.0% in 931 pT3b-pT4 cancers (P < 0,0001). Deletions of 8p were detected in 25.5% of 1,653 Gleason ≤ 3 + 3, 36.6% of 3,880 Gleason 3 + 4, 50.2% of 1,090 Gleason 4 + 3, and 51.1% of 354 Gleason ≥ 4 + 4 tumors (P < 0,0001). 8p deletions were strongly linked to biochemical recurrence (P < 0.0001) independently from established pre- and postoperative prognostic factors (P = 0.0100). However, analysis of morphologically defined subgroups revealed, that 8p deletion lacked prognostic significance in subgroups with very good (Gleason ≤ 3 + 3, 3 + 4 with ≤ 5% Gleason 4) or very poor prognosis (pT3b, Gleason ≥ 8, pN1). 8p deletions were markedly more frequent in cancers with (53.5%) than without PTEN deletions (36.4%; P < 0,0001) and were slightly more frequent in ERG-positive (40.9%) than in ERG-negative cancers (34.7%, P < 0.0001) due to the association with the ERG-associated PTEN deletion. Cancers with 8p/PTEN co-deletions had a strikingly worse prognosis than cancers with deletion of PTEN or 8p alone (P ≤ 0.0003). In summary, 8p deletion is an independent prognostic parameter in prostate cancer that may act synergistically with PTEN deletions. Even statistically independent prognostic biomarkers like 8p may have limited clinical impact in morphologically well defined high or low risk cancers.

Altered expression of the p16 tumor suppressor is frequently found in prostate cancer, but its role for tumor development and patient prognosis is disputed. In order to clarify the prognostic role of p16 and to draw conclusions on interactions with key molecular features of prostate cancer, we studied p16 expression in a tissue microarray (TMA) with more than 12,400 prostate cancers and attached clinical, pathological, and molecular data such as ERG status and deletions of 3p13, 5q21, 6q15, and PTEN. p16 immunostaining was absent in non-neoplastic prostate cells but was found in 37 % of 9627 interpretable prostate cancers. Finding p16 expression in 58 % of ERG positive but in only 22 % of ERG negative cancers (p

Background Current trials are investigating radical intervention in men with metastatic prostate cancer. However, there is a lack of safety data for radical prostatectomy as therapy in this setting. Objective To examine perioperative outcomes and short-term complications after radical prostatectomy for locally resectable, distant metastatic prostate cancer. Design, setting, and participants A retrospective case series from 2007 to 2014 comprising 106 patients with newly diagnosed metastatic (M1) prostate cancer from the USA, Germany, Italy, and Sweden. Intervention Radical prostatectomy and extended pelvic lymphadenectomy. Outcome measurements and statistical analysis Descriptive statistics were used to present margin status, continence, and readmission, reoperation, and overall complication rates at 90 d, as well as for 21 specific complications. Kaplan-Meier plots were used to estimate survival function. Intercenter variability and M1a/ M1b subgroups were examined. Results and limitations Some 79.2% of patients did not suffer any complications; positive-margin (53.8%), lymphocele (8.5%), and wound infection (4.7%) rates were higher in our cohort than in a meta-analysis of open radical prostatectomy performed for standard indications. At a median follow-up of 22.8 mo, 94/106 (88.7%) men were still alive. The study is limited by its retrospective design, differing selection criteria, and short follow-up. Conclusions Radical prostatectomy for men with locally resectable, distant metastatic prostate cancer appears safe in expert hands for meticulously selected patients. Overall and specific complication rates related to the surgical extirpation are not more frequent than when radical prostatectomy is performed for standard indications, and the use of extended pelvic lymphadenectomy in all of this cohort compared to its selective use in localized/locally advanced prostate cancer accounts for any extra morbidity. Patient summary Men presenting with advanced prostate cancer that has spread beyond the prostate are increasingly being considered for treatments directed at the prostate itself. On the basis of results for our international series of 106 men, surgery appears reasonably safe in this setting for certain patients.

Cancer control outcomes following robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa) remain inadequately addressed over intermediate-term (≥5-year) follow-up. We examined biochemical recurrence-free survival (BCRFS), clinical recurrence-free survival (CRFS), and cancer-specific survival (CSS) in a multi-institutional cohort of men undergoing RARP for localized PCa. A total of 5670 PCa patients undergoing RARP ± pelvic lymph node dissection as primary treatment modality at three tertiary care centers between 2001 and 2010 were analyzed. BCRFS, CRFS, and CSS were estimated using the Kaplan–Meier method. Cox proportional hazards model tested their association with available preoperative and postoperative parameters. 43.6 and 15.1 % of patients had D’Amico intermediate- and high-risk disease, respectively. Over a mean (median) follow-up of 56 (50.4) months, 797 men had a BCR, 78 men had CR, and 32 men died of PCa. Actuarial BCRFS, CRFS, and CSS, respectively, were 83.3, 98.6, and 99.5 % at 5-year; 76.5, 97.5, and 98.7 % at 8-year; and 73.3, 96.7, and 98.4 % at 10-year follow-ups. Only 1.7 % of patients received any adjuvant treatment. Preoperative prostate-specific antigen (PSA) and biopsy Gleason score (GS) were independent clinical predictors of BCRFS, CRFS, and CSS, while postoperatively positive surgical margin, pathological GS, pathological stage, and lymph node invasion were significantly associated with BCR and CR (all p

Background Long-term cancer control outcomes in clinically high-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP) remain unknown. Objective To report on long-term biochemical recurrence (BCR)-free survival, clinical recurrence (CR)-free survival, and salvage therapy rates in these patients. Given the heterogeneity of high-risk patients, a second objective was to stratify them according to their BCR risk (using preoperative parameters), in an effort to counsel them better preoperatively regarding their cancer control outcomes. Design, setting, and participants We evaluated 1100 D'Amico high-risk PCa patients who underwent RARP between 2002 and 2013 at three tertiary care centers. Outcome measures and statistical analyses Outcomes consisted of BCR-free survival, CR-free survival, and salvage therapy rates. Regression tree analysis stratified patients into novel risk groups based on preoperative characteristics and corresponding BCR risk. Kaplan-Meier curves estimated BCR-free survival, CR-free survival, and salvage therapy rates in the entire cohort and after stratification according to the novel risk groups (RGs). Results and limitations Median age and prostate-specific antigen (PSA) were 63 yr and 6.5 ng/ml, respectively. Biopsy Gleason score (GS) was ≥8 in 57.7%. Mean follow-up was 53 mo (median: 49 mo). At 10 yr, BCR-free survival, CR-free survival, and salvage therapy rates were 50%, 87%, and 37%, respectively. Regression tree analysis stratified patients into five novel RGs): RG1, very low risk (GS ≤6); RG2, low risk (PSA ≤10 ng/ml; GS: 7); RG3, intermediate risk (PSA ≤10 ng/ml; GS ≥8); RG4, high risk (PSA >10 ng/ml; GS: 7); RG5, very high risk (PSA >10 ng/ml; GS ≥8). In these RGs, the 10-yr BCR-free survival rates were 86%, 70%, 36%, 31%, and 26% (p < 0.001), respectively; the 10-yr CR-free survival rates were 99%, 96%, 85%, 67%, and 55% (p < 0.001), respectively; and the 10-yr salvage therapy rates were 9.8%, 16%, 42%, 47%, and 64% (p < 0.001), respectively. Conclusions Most patients with clinically high-risk PCa treated with RARP alone remain CR free at long term. Nonetheless, almost 37% of the patients at 10 yr require salvage therapy. Our novel tool allows accurate stratification of these heterogeneous patients according to their BCR, CR, and salvage therapy risks. This may help inform patients preoperatively about their cancer control outcomes postoperatively. Patient summary Robot-assisted radical prostatectomy confers lasting long-term oncologic control in most high-risk prostate cancer patients. Our novel risk grouping might serve as a useful tool for setting expectations and counseling patients regarding their cancer control outcomes.

// Prashant Kumar 1,* , Sayantani Nandi 1,* , Tuan Zea Tan 2,* , Siok Ghee Ler 3 , Kee Seng Chia 4 , Wei-Yen Lim 5 , Zentia Butow 6 , Dimitrios Vordos 6 , Alexandre De laTaille 6 , Muthafar Al-Haddawi 1 , Manfred Raida 7 , Burkhard Beyer 8 , Estelle Ricci 9 , Marc Colombel 9 , Tsung Wen Chong 10 , Edmund Chiong 11 , Ross Soo 12 , Mi Kyoung Park 13 , Hong Koo Ha 14,** , Jayantha Gunaratne 3,4,** and Jean Paul Thiery 1,2,7,** 1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 2 Cancer Science Institute, National University of Singapore, Singapore 3 Quantitative Proteomics Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 4 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 6 CHU Hopital Henri Mondor, Department of Urology, Creteil, France 7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 8 Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 9 Service d’Urologie et Chirurgie de la Transplantation, Hopital Edouard Herriot, Lyon, France 10 Department of Urology, Singapore General Hospital, Singapore 11 Department of Urology, University Surgical Cluster, National University Health System (NUHS), Singapore 12 Haematology-Oncology Research Group, Department of Haematology-Oncology, National University Cancer Institute (NCIS), National University Hospital, Singapore 13 Institute of Microelectronics (IME), A*STAR, Singapore 14 Department of Urology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea * These authors are co-first authors ** These authors are co-senior authors Correspondence to: Jean Paul Thiery, email: // Keywords : transitional bladder carcinoma, urine biomarkers, receiving operating characteristics, combination model Received : December 08, 2014 Accepted : March 19, 2015 Published : April 15, 2015 Abstract Transitional bladder carcinoma (BCa) is prevalent in developed countries, particularly among men. Given that these tumors frequently recur or progress, the early detection and subsequent monitoring of BCa at different stages is critical. Current BCa diagnostic biomarkers are not sufficiently sensitive for substituting or complementing invasive cystoscopy. Here, we sought to identify a robust set of urine biomarkers for BCa detection. Using a high-resolution, mass spectrometry-based, quantitative proteomics approach, we measured, compared and validated protein variations in 451 voided urine samples from healthy subjects, non-bladder cancer patients and patients with non-invasive and invasive BCa. We identified five robust biomarkers: Coronin-1A, Apolipoprotein A4, Semenogelin-2, Gamma synuclein and DJ-1/PARK7. In diagnosing Ta/T1 BCa, these biomarkers achieved an AUC of 0.92 and 0.98, respectively, using ELISA and western blot data (sensitivity, 79.2% and 93.9%; specificity, 100% and 96.7%, respectively). In diagnosing T2/T3 BCa, an AUC of 0.94 and 1.0 was attained (sensitivity, 86.4% and 100%; specificity, 100%) using the same methods. Thus, our multiplex biomarker panel offers unprecedented accuracy for the diagnosis of BCa patients and provides the prospect for a non-invasive way to detect bladder cancer.

Zinc-binding Alpha-2-Glycoprotein 1 (AZGP1) is a soluble protein that is known to stimulate lipid degradation in adipocytes. AZGP1 is physiologically expressed in various normal tissues including several types of secretory epithelial cells like breast cells, prostate cells and liver cells, and deregulated expression has been reported from several tumor types including breast, uterine cervix, and prostate cancers. In prostate cancer, AZGP1 was suggested as a candidate prognostic biomarker. To thoroughly evaluate the clinical impact of AZGP1 alteration in prostate cancer, we analyzed immunohistochemical AZGP1 expression in a tissue microarray containing 11,152 prostate cancers with attached clinical and molecular data. In addition, we estimated the relationship of AZGP1 expression with key genomic alterations in prostate cancer. For that purpose, we used data on ERG status and PTEN, 3p13, 5q21 and 6q15 deletions from our earlier studies. AZGP1 expression was strong in benign prostatic glands but absent in 38.0% of 8,510 interpretable prostate cancers. Reduced AZGP1 expression was associated with TMPRSS2:ERG fusion detected by FISH and immunohistochemical analysis (p In conclusion, reduced expression of AZGP1 is strongly related to adverse prognostic features in prostate cancer - independent of clinico-pathological findings and PTEN deletions. Citation Format: Maria Christina Tsourlakis, Martina Kluth, Sandra Kleinhaus, Sawinee Masser, Christoph Burdelski, Hartwig Huland, Hans Heinzer, Markus Graefen, Burkhard Beyer, Stefan Steurer, Ronald Simon, Christina Koop, Thorsten Schlomm, Guido Sauter, Sarah Minner. Reduced AZGP1 expression is an independent predictor of early PSA recurrence and associated with ERG fusion positive, PTEN deleted prostate cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 572. doi:10.1158/1538-7445.AM2014-572