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Purpose: The goal of this study is to address if detection rates of clinically significant prostate cancer (csPCa) can be increased by additional perilesional biopsies (PB) in magnetic resonance (MR)/ultrasound fusion prostate biopsy in biopsy-naïve men., Methods: This prospective, non-randomized, surgeon-blinded study was conducted between February 2020 and July 2022. Patients were included with PSA levels < 20 ng/ml and ≥ one PI-RADS lesion (grades 3-5) per prostate lobe. Prostate biopsy was performed by two urologists. The first performed the MR-fusion biopsy with 3-5 targeted biopsies (TB) and 6 PB in a standardized pattern. The second performed the systematic (12-fold) biopsy (SB) without knowledge of the MR images. Primary outcome of this study is absence or presence of csPCa (≥ ISUP grade 2) comparing TB, PB and SB, using McNemar test., Results: Analyses were performed for each PI-RADS lesion (n = 218). There was a statistically significant difference in csPC detection rate of TB + SB between PI-RADS 3, 4 and 5 lesions (18.0% vs. 42.5% vs. 82.6%, p < 0.001) and TB + PB (19.7% vs. 29.1% vs. 78.3%). Comparing only maximum ISUP grade per lesion, even SB plus TB plus PB did not detect more csPCa compared to SB plus TB (41.3% vs. 39.9%, p > 0.05)., Conclusion: We present prospective study data investigating the role of perilesional biopsy in detection of prostate cancer. We detected no statistically significant difference in the detection of csPCa by the addition of PB. Therefore, we recommend continuing 12-fold bilateral SB in addition to TB., (© 2024. The Author(s).)

Purpose: We evaluate differences of patient-reported outcome measurements (PROM) based urinary continence and sexual function 12 months after radical prostatectomy (RPE) based on perioperative, surgical, and patient-specific characteristics in a large European academic urology center., Materials and Methods: All men enrolled in the Prostate Cancer Outcome Study (PCO) study who were treated with RPE between 2017 and 2021 completed EPIC-26 information surveys before and 12 months after RPE. Survey data were linked to clinical data of our institution. Logistic regression analyses were performed to examine the correlation between individual surgeons, patient characteristics, patient clinical data, and their urinary continence and sexual function., Results: In total, data of 429 men were analyzed: unstratified mean (SD) EPIC-26 domain score for urinary function decreased from 93.3 (0.7) to 60.4 (1.5) one year after RPE, respectively for sexual function from 64.95 (1.6) to 23.24 (1.1). Patients with preoperative adequate urinary function (EPIC-26 score > 80) reported significantly different mean urinary function scores between 53.35 (28.88) and 66.25 (25.15), p= 0.001, stratified by surgeons experience. On binary logistic regression analyses, only nerve sparing techniques (OR: 1,83, 95% CI: 1.01;3.21; p = 0.045) and low body mass index (OR: 0.91, CI: 0.85;0.99, p= 0.032) predicted adequate postoperative urinary function., Conclusions: The results show how using provider-specific data from a larger cohort study enables to develop institution-specific analysis for functional outcomes after RPE. These models can be used for internal quality improvement as well as enhanced and provider-specific patient communication and shared decision making., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Androgen deprivation therapy (ADT) is the mainstay of the current first-line treatment concepts for patients with advanced prostate carcinoma (PCa). However, due to treatment failure and recurrence investigation of new targeted therapeutics is urgently needed. In this study, we investigated the suitability of the Cyclin K-CDK12 complex as a novel therapeutic approach in PCa using the new covalent CDK12/13 inhibitor THZ531. Here we show that THZ531 impairs cellular proliferation, induces apoptosis, and decreases the expression of selected DNA repair genes in PCa cell lines, which is associated with an increasing extent of DNA damage. Furthermore, combination of THZ531 and ADT leads to an increase in these anti-tumoral effects in androgen-sensitive PCa cells. The anti-proliferative and pro-apoptotic activity of THZ531 in combination with ADT was validated in an ex vivo PCa tissue culture model. In a retrospective immunohistochemical analysis of 300 clinical tissue samples we show that Cyclin K (CycK) but not CDK12 expression correlates with a more aggressive type of PCa. In conclusion, this study demonstrates the clinical relevance of the CycK-CDK12 complex as a promising target for combinational therapy with ADT in PCa and its importance as a prognostic biomarker for patients with PCa., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose of Review: Over the last years, there have been striking changes in the management of metastatic hormone-sensitive prostate cancer (mHSPC) based on survival advantage of combining either a new hormonal agent (NHA) or docetaxel (D) with androgen deprivation therapy (ADT). Some of these studies primarily assessing doublet treatment included men who underwent concomitant or sequential treatment with D. Most recently, prospective randomized evidence emerged on this triplet strategy too. We aimed to outline the current data and ongoing trials evaluating the usage of the triplet therapy in male individuals with mHSPC., Recent Findings: Phase III trials PEACE-1 and ARASENS showed that the upfront triplet treatment with ADT+D and either abiraterone acetate or darolutamide outperformed ADT+D in terms of survival, while severe toxicity was mainly driven by D. Importantly, prospective evidence comparing triplet vs. ADT+NHA is still lacking., Summary: Men with de novo high-volume disease benefit most from the triplet, while in cases with metachronous and/or low-volume disease, survival advantage is still disputable. As efficacy of ADT+NHA does not appear to be substantially amplified by combination with D, those men with a more favorable underlying tumor biology might mostly benefit from this doublet, also taking quality-adjusted survival into account., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Focal therapy (FT) is gaining increasing acceptance in the management of localized prostate cancer particularly due to its favorable safety. Preliminary evidence suggests advantageous utilization of local treatment in the field of oligometastatic prostate cancer (OMPC). Since data on the utilization of FT in OMPC are scarce, we sought to summarize available evidence., Methods: For this narrative comprehensive review, we employed PubMed ® , Web of Science™, Embase ® , Scopus ® , and clinicaltrial.gov databases and Google web search engine to seek peer-reviewed articles, published abstracts from international congresses, and ongoing trials in the English language using the terms "prostate cancer", "oligometastatic", "hormone-sensitive", "focal therapy", "focal treatment", "cryotherapy", "ablation", "cancer" as well as "metastasis-directed therapy. We focused on relevant publications on FT utilized in OMPC targeting the primary or metastatic sites as well as completed and ongoing clinical trials., Results: Growing evidence points to distinct differences in the biologic behavior and molecular signaling processes of OMPC as compared to polymetastatic disease (PMPC). No established biomarkers are available to accurately identify OMPC yet, while several candidates are currently under investigation. The evolution of molecular imaging is set to aid in selecting patients benefitting most from local management. Differences between OMPC and PMPC should be considered when designing the optimal therapeutic strategy. While efficacy data for FT in comparison to standard care in OMPC are scarce, longer progression-free survival and time to castration resistance have been demonstrated for bone metastatic prostate cancer with the primary tumor treated by cryosurgery followed by androgen deprivation therapy (ADT) compared to ADT alone., Conclusion: Ongoing research efforts are eagerly awaited to better characterize OMPC and establish customized strategies for patients with this condition., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Focal therapy (FT) for localized prostate cancer (PCa) is only recommended within the context of clinical trials by international guidelines. We aimed to investigate oncological follow-up and safety data of focal high-intensity focused ultrasound (HIFU) treatment., Methods: We conducted a single-center prospective study of 29 patients with PCa treated with (focal) HIFU between 2016 and 2021. Inclusion criteria were unilateral PCa detected by mpMRI-US-fusion prostate biopsy and maximum prostate specific antigen (PSA) of 15 ng/ml. Follow-up included mpMRI-US fusion-re-biopsies 12 and 24 months after HIFU. No re-treatment of HIFU was allowed. The primary endpoint was failure-free survival (FFS), defined as freedom from intervention due to cancer progression., Results: Median follow-up of all patients was 23 months, median age was 67 years and median preoperative PSA was 6.8 ng/ml. One year after HIFU treatment PCa was still detected in 13/ 29 patients histologically (44.8%). Two years after HIFU another 7/29 patients (24.1%) were diagnosed with PCa. Until now, PCa recurrence was detected in 11/29 patients (37.93%) which represents an FFS rate of 62%.One patient developed local metastatic disease 2 years after focal HIFU. Adverse events (AE) were low with 70% of patients remaining with sufficient erectile function for intercourse and 97% reporting full maintenance of urinary continence., Conclusion: HIFU treatment in carefully selected patients is feasible. However, HIFU was oncologically not as safe as expected because of progression rates of 37.93% and risk of progression towards metastatic disease. Thus, we stopped usage of HIFU in our department., (© 2023. The Author(s).)

Background: Incidental prostate cancer (IPCa) is encountered in 10% of surgical procedures for benign prostatic obstruction (BPO). Identification of patients with underlying detrimental prostate cancer is paramount for tailored treatment decision-making, but guideline recommendations for this setting are lacking., Objective: To highlight clinical and histological characteristics related to BPO surgery that may predict IPCa with unfavorable pathology., Design, Setting, and Participants: We included men with IPCa who underwent radical prostatectomy (RP) in the short term after IPCa diagnosis. Two cohorts were built according to final pathology for the RP specimen: unfavorable pathology (International Society of Urological Pathology [ISUP] grade group [GG] ≥3 and/or ≥pT3a and/or pN1) versus favorable pathology., Outcome Measurements and Statistical Analysis: We performed multivariate regression analysis for the endpoint, which was unfavorable pathology for the RP specimen. Using the model estimates for prostate-specific antigen (PSA), ISUP GG, age, and prostate volume, we established a model for estimating the risk of unfavorable histopathology., Results and Limitations: Overall, 112 patients were included in the final assessment. On multivariate analysis, PSA (odds ratio [OR] 1.083, 95% confidence interval [CI] 1.003-1.170; p = 0.042), ISUP GG for the specimen from BPO surgery (OR 3.090; 95% CI 1.129-8.457; p = 0.028), and age (OR 1.121, 95% CI 1.026-1.225; p = 0.012) were independent predictors for unfavorable histopathology. On receiver operating characteristic analysis, the area under the curve was 0.751. A novel calculator was developed to predict adverse pathology for men with IPCa. The study is limited by its retrospective design., Conclusions: For men with IPCa, PSA before surgery for BPO, ISUP GG, and age are independent predictors of unfavorable disease. Our results might improve preoperative risk assessment for patient counseling., Patient Summary: We developed a novel calculator to estimate the risk of underlying detrimental disease in men diagnosed with prostate cancer at surgery for benign prostatic obstruction., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Several recent randomised trials have evaluated the role of combination systemic treatment using androgen deprivation therapy (ADT) plus chemotherapy or an androgen receptor signaling inhibitor (ARSI) in patients with high-risk and/or unfavourable nonmetastatic prostate cancer (nmPC)., Objective: To assess the outcomes associated with adding combination systemic treatment to primary definitive local therapy in patients with high-risk and/or unfavourable nmPC., Evidence Acquisition: We queried the PubMed, Web of Science, and Scopus databases and conference abstracts to identify prospective randomised trials examining the value of adding chemotherapy or an ARSI to ADT and primary local therapy with curative intent for nmPC. The primary endpoints were overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS), and failure-free survival (FFS). Secondary endpoints included adverse events (AEs) and pathologic outcomes., Evidence Synthesis: We identified 15 randomised studies, of which nine evaluated chemohormonal and six investigated ARSI-based treatment strategies. In both radical prostatectomy (RP) and radiation therapy (RT) settings, addition of docetaxel to ADT was associated with significantly better CSS (pooled hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49-0.95; p = 0.025), MFS (pooled HR 0.82, 95% CI 0.71-0.95; p = 0.008), and FFS (pooled HR 0.70, 95% CI 0.62-0.79; p < 0.001); the difference did not meet the conventional level of statistical significance for OS (pooled HR 0.86, 95% CI 0.73-1.01; p = 0.072). For patients treated with RT alone, docetaxel-based combination treatment did not meet the significance threshold set for OS (p = 0.3), CSS (p = 0.072), or MFS (p = 0.079), but the difference for FFS was statistically significant (pooled HR 0.72, 95% CI 0.63-0.84; p < 0.001). On network meta-analyses including RT studies, ARSI + ADT outperformed docetaxel + ADT for survival endpoints and had a more favourable AE profile., Conclusions: Intensification of systemic therapy with docetaxel or an ARSI in addition to ADT improves oncologic endpoints in high-risk and/or unfavourable nmPC treated with local definitive therapy. The highest efficacy was achieved with ARSI + ADT, specifically in patients treated with RT., Patient Summary: Our findings highlight that selected patients with high-risk nonmetastatic prostate cancer benefit from intensification of systemic therapy beyond hormonal treatment., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: MRI-guided targeted biopsy has become standard of care for diagnosis of prostate cancer, with establishment of several biopsy techniques and platforms. Augmented reality smart glasses have emerged as novel technology to support image-guided interventions. We aimed to investigate its usage while prostate biopsy., Methods: MRI with PIRADS-lesions ≥3 was uploaded to smart glasses (Vuzix Blade R ) and augmented reality smart glasses-assisted targeted biopsy (SMART-TB) of the prostate was performed using cognitive fusion technology at the point of care. Detection rates were compared to systematic biopsy. Feasibility for SMART-TB was assessed (10 domains from bad [1] to excellent [10])., Results: SMART-TB was performed for four patients. Prostate cancer detection was more likely for SMART-TB (46%; 13/28) than for systematic biopsy (27%; 13/48). Feasibility scores were high [8-10] for practicality, multitasking, execution speed, comfort and device weight and low [1-4] for handling, battery and image quality. Median execution time: 28 min; Investment cost smart glass: 1017 USD., Conclusion: First description of SMART-TB demonstrated convenient feasibility. This novel technology might enhance diagnosis of prostate cancer in future., (© 2022 The Authors. The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons Ltd.)

Purpose of Review: To investigate the features and optimal management of pN+ cM0 prostate cancer (PCa) according to registry-based studies., Recent Findings: Up to 15% of PCa patients harbor lymph node invasion (pN+) at radical prostatectomy plus lymph node dissection. Nonetheless, the optimal management strategy in this setting is not well characterized., Summary: We performed a systematic review including n = 13 studies. Management strategies comprised 13 536 men undergoing observation, 11 149 adjuvant androgen deprivation therapy (aADT), 7,075 adjuvant radiotherapy (aRT) +aADT and 705 aRT. Baseline features showed aggressive PCa in the majority of men. At a median follow-up ranging 48-134months, Cancer-related death was 5% and overall-mortality 16.6%. aADT and aRT alone had no cancer-specific survival or overall survival advantages over observation only and over not performing aRT, respectively. aADT plus aRT yielded a survival benefit compared to observation and aADT, which in one study, were limited to certain intermediate-risk categories. Age, Gleason, Charlson score, positive surgical margins, pathological stage, and positive nodes number, but not prostate specific antigen, were most relevant prognostic factors. Our work further confirmed pN+ PCa is a multifaceted disease and will help future research in defining its optimal management based on different risk categories to maximize survival and patient's quality of life., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To access the feasibility of palliative cystoprostatectomy/pelvic exenteration in patients with bladder/rectal invasion due to prostate cancer (PC)., Patients and Methods: Twenty-five men with cT4 PC were retrospectively identified in the institutional databases of six tertiary referral centers in the last decade. Local invasion was documented by CT or MRI scans and was confirmed by urethrocystoscopy. Oncological therapies, local symptoms, previous local treatments, time from diagnosis to intervention and type of surgical procedure were recorded. Patients were divided into groups: ADT group (12 pts) and 13 pts without any history of previous local/systemic treatments for PCa (nonADT groups). Perioperative complications were classified using the Clavien-Dindo system. Overall survival (OS) was defined as the time from surgery to death from any cause. A Cox regression analysis, stratified for ISUP score and previous hormonal treatment (ADT) was also performed for survival analysis., Results: Ileal conduit was the main urinary diversion in both cohorts. For the entire cohort, complication rate was 44%. No significant differences regarding perioperative complications and complication severity between both subgroups were observed (p = 0.2). Median follow-up was 15 months (range 3-41) for the entire cohort with a median survival of 15 months (95% CI 10.1-19.9). In Cox regression analysis stratified for ISUP score, no statistically significant differences in OS in patients with and without previous ADT before cystectomy or exenteration were observed (HR 3.26, 95% CI 0.62-17.23, p = 0.164)., Conclusion: Palliative cystoprostatectomy and pelvic exenteration represent viable treatment options associated with acceptable morbidity and good short-term survival outcome., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Prostate cancer (PCa) is the most common malignancy in men and the cause for the second most common cancer-related death in the western world. Despite ongoing development of novel approaches such as second generation androgen receptor targeted therapies, metastatic disease is still fatal. In PCa, immunotherapy (IT) has not reached a therapeutic breakthrough as compared to several other solid tumors yet. We aimed at highlighting the underlying cellular mechanisms crucial for IT in PCa and giving an update of the most essential past and ongoing clinical trials in the field., Methods: We searched for relevant publications on molecular and cellular mechanisms involved in the PCa tumor microenvironment and response to IT as well as completed and ongoing IT studies and screened appropriate abstracts of international congresses., Results: Tumor progression and patient outcomes depend on complex cellular and molecular interactions of the tumor with the host immune system, driven rather dormant in case of PCa. Sipuleucel-T and pembrolizumab are the only registered immune-oncology drugs to treat this malignancy. A plethora of studies assess combination of immunotherapy with other agents or treatment modalities like radiation therapy which might increase its antineoplastic activity. No robust and clinically relevant prognostic or predictive biomarkers have been established yet., Conclusion: Despite immunosuppressive functional status of PCa microenvironment, current evidence, based on cellular and molecular conditions, encourages further research in this field.

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.

Context: Optimal management of prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy and pelvic lymph node dissection still remains unclear., Objective: To assess the effectiveness of postoperative treatment strategies for pathologically node-positive PCa patients. The secondary aim was to identify the most relevant prognostic factors to guide the management of pN1 patients., Evidence Acquisition: A systematic review was performed in January 2020 using Medline, Embase, and other databases. A total of 5063 articles were screened, and 26 studies including 12 537 men were selected for data synthesis and included in the current review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) recommendations., Evidence Synthesis: Ten-year biochemical recurrence (BCR)-free, clinical recurrence-free, cancer-specific (CSS), and overall (OS) survival rates ranged from 28% to 56%, 70% to 92%, 72% to 98%, and 60% to 87.6%, respectively. A total of seven, five, and six studies assessed the oncological outcomes of observation, adjuvant radiotherapy (aRT), or adjuvant androgen deprivation therapy (ADT), respectively. Initial observation followed by salvage therapies at the time of recurrence represents a safe option in selected patients with a low disease burden. The use of aRT with or without ADT might improve survival in men with locally advanced disease and a higher number of positive nodes. Risk stratification according to pathological Gleason score, number of positive nodes, pathological stage, and surgical margins status is the key to risk stratification and selection of the optimal postoperative therapy. Limitations of this systematic review are the retrospective design of the studies included and the lack of data on adverse events., Conclusions: While the majority of men with pN1 disease would experience BCR after surgery, long-term disease-free survival has been reported in selected patients. Management options to improve oncological outcomes include observation versus adjuvant therapies such as aRT and/or ADT. Disease characteristics should be used to select the optimal postoperative management for pN1 PCa patients., Patient Summary: Finding node-positive prostate cancer after a radical prostatectomy often leads to high postoperative prostate-specific antigen levels and is overall a poor prognostic factor. However, this does not necessarily translate into poor survival for all men. Management can be tailored to the severity of disease and options include observation, androgen deprivation therapy, and/or radiotherapy., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Despite enzalutamide's efficacy in delaying the progression of metastatic castration-resistant prostate cancer (CRPC), resistance to this anti-androgen inevitably occurs. Several studies have revealed that the signal transducer and activator of transcription (STAT) 5 plays a role in tumour progression and development of drug resistance such as enzalutamide. Data mining revealed heterogeneous expression of STAT5 in enzalutamide-treated mCRPC patients and enzalutamide-resistant prostate cancer (PCa). Isobologram analysis revealed that the STAT5 inhibitor pimozide combined with enzalutamide has? additive and synergistic inhibitory effects on cell viability in the used models. Functional analysis with siRNA-mediated STAT5 knockdown yielded divergent results. The LNCaP-derived cell line MR49F could be resensitised to enzalutamide by siRNA-mediated STAT5b-knock-down. In contrast, neither STAT5a nor STAT5b knockdown resensitised enzalutamide-resistant LAPC4-EnzaR cells to enzalutamide. In conclusion, our results indicate that STAT5 may be a possible target in a subgroup of enzalutamide-resistant PCa. However, based on the data presented here, a general role of STAT5 in enzalutamide-resistance and its potential as a therapeutic target could not be shown., Competing Interests: The authors have read the journal's policy and have the following competing interests: This study was funded by Astellas Pharma. CT and ZC have received the research grant DE72-RG36. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

The 2019 Briganti nomogram was developed to calculate the risk of lymph node invasion (LNI) and identify prostate cancer (PCa) patients diagnosed with magnetic resonance imaging (MRI)-targeted biopsy who should be considered for an extended pelvic lymph node dissection (ePLND). Since its implementation is still limited by lack of a formal external validation, we aimed to validate this tool in a large contemporary cohort. We identified 487 patients diagnosed using MRI-targeted with concomitant systematic biopsy who underwent radical prostatectomy (RP) and an anatomically defined ePLND at six centers. The external validity of the 2019 Briganti nomogram for estimating LNI risk was assessed via calibration, discrimination, and decision curve analyses (DCAs). A total of 38 (8%) patients had LNI at final pathology. The median number of nodes removed was 18 (interquartile range 14-24). On external validation, the 2019 Briganti nomogram had an area under the receiver operating characteristic curve (AUC) of 79%. Although there was some miscalibration, this was at predicted probabilities >35% and therefore outside the clinically relevant range. DCA demonstrated that the 2019 Briganti nomogram improved clinical risk prediction against LNI threshold probabilities of ≤30%. For a 7% cutoff, 273 (56%) ePLNDs would be spared and only 2.6% LNIs would be missed. The 2019 Briganti nomogram was characterized by higher AUC compared to the 2012 and 2017 Briganti nomograms and the Memorial Sloan Kettering Cancer Center risk calculator (79% vs 75% vs 65% vs 74%) and demonstrated the highest net benefit on DCA. This first multi-institutional validation of the 2019 Briganti nomogram in predicting LNI in PCa patients diagnosed with MRI-targeted biopsy confirms the highest AUC, better calibration and the highest net benefit compared with available tools and should be adopted to identify candidates for ePLND among men diagnosed with MRI-targeted biopsy. PATIENT SUMMARY: We performed the first multi-institutional validation of the first nomogram predicting lymph node invasion specifically developed using data from prostate cancer patients diagnosed with magnetic resonance imaging (MRI)-targeted biopsy. This nomogram exhibited excellent characteristics on external validation compared with available tools and should be adopted to identify candidates for extended pelvic lymph node dissection among men diagnosed with MRI-targeted biopsy., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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 < .001), number of comorbidities (1-2 vs 0, OR = 1.27; 95%-CI = 1.00-1.60; P=.048), disease staging (localized high-risk vs localized intermediate risk, OR = 1.41; 95%-CI = 1.14-1.74; P < .001), receiving androgen deprivation therapy before study inclusion (OR = 0.19; 95%-CI = 0.10-0.34; P < .001), and hospital teaching status (university vs academic, OR = 0.09; 95%-CI = 0.02-0.55; P = .009). Model 2 additionally includes information on treatment after study inclusion and shows that after inclusion, patients who receive primary radiotherapy (OR = 0.05; 95%-CI = 0.03-0.10; P < .001) or undergo active surveillance/watchful waiting (OR = 0.06; 95%-CI = 0.02-0.15; P < .001) are less likely to utilize POS than patients who undergo radical prostatectomy. Disease staging (localized high-risk vs localized intermediate risk, OR = 1.31; 95%-CI = 1.05-1.62; P = .02) and teaching status (university vs academic, OR = 0.08; 95%-CI = 0.01-0.65; P = .02) are also significant predictors for POS use. The second model did not identify any other significant patient characteristics., Conclusions: Future research should explore the role of institutional teaching status and whether associations with therapy after study inclusion are due to treatment effects - for example, less need following radiotherapy - or because access to POS is more difficult for those receiving radiotherapy., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Incontinence (up to 20%) and erectile dysfunction (up to 70%) occur frequently after radical prostatectomy (RP) in patients with localized prostate cancer. Human amniotic membrane (HAM) can improve tissue regeneration and functional outcome after RP owing to the growth factors and unique immune tolerance. Preliminary studies showed the potential value of HAM in the reconstruction of the urinary tract and nerve protection during RP., Methods: A protocol is developed for a prospective, randomized, single-blind, single-surgeon, placebo-controlled exploration study of the efficacy and safety of dehydrated human amnion membrane placed around the neurovascular bundle (NVB) and vesicourethral anastomosis (VUA) during RP for the treatment of localized prostate cancer. Eligible for inclusion are patients with localized prostate cancer, requiring a surgical procedure and exclusion of preoperative incontinence and erectile dysfunction. The patients are randomized 1:1 to HAM vs. placebo and blinded during the study period. According to the T test with an alpha of 0.05 and a power of 80% and expecting a dropout of 20% of the patients, an adjusted sample size per arm of 164 patients is required., Planned Outcomes: The primary outcome is a postoperative continence measured as 24-h pad test up to 12 months postoperatively. Secondary outcomes are potency, time of postoperative catheter removal, postoperative complications, and biochemical recurrence. The protocol for this randomized exploration study defines the conditions to assess the efficacy and safety of HAM application during RP in order to improve the postoperative functional outcome. This trial should pave the way for future studies of tissue engineering in an effort to reduce the morbidity of RP., Trial Registration: Clinicaltrials.gov, identifier NCT03864939.

Purpose: Along with a number of other malignancies, the term "oligometastatic" prostate cancer has recently emerged. It represents an attempt to define a subtype of cancer with a limited metastatic load that might perform more favorably than a distinctly disseminated disease, or even one that may be managed in a potentially curative way. Since there is currently a knowledge gap of what imaging modalities should be utilized to classify patients as having this type of tumor, we aimed to shed light on the role of conventional and marker-based imaging in the setting of synchronous oligometastatic prostate cancer as well as summarize the available evidence for its clinical application., Methods: A literature search on December 15th 2017 was conducted using the Pubmed database., Results: Functional imaging techniques like 68 Ga PSMA. 68 Ga PSMA PET-CT has currently been shown the best detection rates for the assessment of nodal, bone and visceral metastases, especially for smaller lesions at low PSA levels., Conclusions: Functional imaging helps detect low-burden disease metastatic patients. However, these imaging modalities are not available in every center and thus clinicians may be prone to prescribe systemic treatment rather than referring patients for cytoreductive treatments. We hope that the ongoing prospective trials will help guide clinicians in making a more personalized management of synchronous metastatic patients.

Prostate cancer (PCa) remains the most common cancer in men. The proportion of all PCa attributable to high-risk hereditary factors has been estimated to 5-15%. Recent landmark discoveries in PCa genetics led to the identification of germline mutations/alterations (eg. BRCA1, BRCA2, ATM or HOXB13), single nucleotide polymorphisms or copy number variations associated with PCa incidence and progression. However, offering germline testing to men with an assumed hereditary component is currently controversial. In the present review article, we provide an overview about the epidemiology and the genetic basis of PCa predisposition and critically discuss the significance and consequence in the clinical routine. In addition, we give an overview about genetic tests and report latest findings from ongoing clinical studies. Lastly, we discuss the impact of genetic testing in personalized therapy in advanced stages of the disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Context: Identification of early nodal recurrence after primary prostate cancer (PCa) treatment by functional imaging may guide metastasis-directed therapy such as salvage lymph node dissection (SLND)., Objective: The aim of this systematic review was to assess the oncological role and the safety of SLND in the era of modern imaging in case of exclusive nodal recurrence after primary PCa treatment with curative intent., Evidence Acquisition: A systematic literature search in the PubMed and Cochrane databases was performed up to August 2018 according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Overall, 27 SLND series have been selected for synthesis., Evidence Synthesis: Prostate-specific membrane antigen or choline positron emission tomography/computed tomography was the reference detection technique. SLND was performed by open or laparoscopic approach with <10% of grade 3 or more complication rate. Mean follow-up was 29.4 mo. Complete biochemical response after SLND was achieved in 13-79.5%of cases (mean 44.3%). The 2- and 5-yr biochemical progression-free survival rates ranged from 23% to 64% and from 6% to 31%, respectively. Fiver-year overall survival was approximately 84%. Main drawbacks limiting the interpretation of the effectiveness of SLND were the retrospective design of single-center series, heterogeneity between series in terms of adjuvant treatment, endpoints, definitions of progression and study population, as well as the absence of long-term follow-up., Conclusions: A growing body of accumulated data suggests that SLND is a safe metastasis-directed therapy option in nodal recurrence after primary treatment. However, to date, high level of evidence is still missing to draw any clinically meaningful conclusion about the oncological impact of SLND on long-term endpoints., Patient Summary: When imaging identifies exclusive nodal recurrent prostate cancer, surgery directed to the positive lesions is safe and can offer at least a temporary biochemical response. The oncological role assessed by strong clinical endpoints remains uncertain., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Lymphocele formation is the most common adverse event of pelvic lymphadenectomy during radical prostatectomy for prostate cancer. Previous studies failed to favor one surgical technique over the other in terms of minimizing its rate. Data on risk factors for its development are still conflicting and warranting further research. In this mini-review, we aimed to scrutinize available evidence on these aspects and outline current achievements in lymphocele prevention approaches., (© 2019 The Japanese Urological Association.)

Purpose: Lymphocele (LC) is the most common adverse sequela of pelvic lymphadenectomy (PLND) during radical prostatectomy for prostate cancer. Current evidence on comparison between robotic (RARP) and open retropubic prostatectomy (RRP) in terms of the development of symptomatic LCs (SLCs) is conflicting. Moreover, no single-center assessment has illuminated the impact of the anterior vs. posterior approach of RARP on the rate of SLCs yet. We aimed to compare RRP and transperitoneal RARP for the SLC development and associated clinical risk factors., Methods: Patients treated with RRP or transperitoneal RARP (both with standard PLND) were included. Univariate comparisons and multivariate logistic regression analysis were utilized to compare the cohorts and define independent predictive variables for the development of SLCs., Results: Five hundred and ninety-five consecutive PCa patients underwent RRP and 277 ones RARP (76 anterior and 201 posterior approaches). The incidence of SLCs did not differ between both cohorts. Age and lymph node yield were independent predictors for the development of SLCs after RRP. There was a trend for a longer median time to development of SLCs after RARP as compared to RRP. Median duration of percutaneous drainage tended to be higher after RRP then after RARP. Failure rate of lymphocele drainage was comparable between both techniques., Conclusions: RRP and RARP are associated with the same risk for the development of a SLC. Posterior approach does not reduce the SLC formation compared to the anterior technique. Patients' age and LN yield are predictive for the SLC occurrence in patients treated with RRP.

Purpose: The diagnostic strategy implementing multiparametric magnet resonance tomography (mpMRI) and targeted biopsies (TB) improves the detection and characterization of significant prostate cancer (PCa). We aimed to assess the clinical usefulness of systematic biopsies (SB) in the setting of patients having a pre-biopsy positive MRI., Methods: A review of the literature was performed in March 2018. All studies investigating the performance of SB in addition to TB (all techniques) were assessed, both in the biopsy-naïve and repeat biopsy setting., Results: Evidence demonstrates that TB improves the detection of index-significant PCa compared with SB alone, in both initial and repeat biopsy settings. However, the combination of both TB and SB improved the overall (around 30%) and significant (around 10%) PCa detection rates as compared with TB alone. Significant differences between both biopsy approaches exist regarding cancer location favoring SB for the far lateral sampling, and TB for the anterior zone. Main current pitfalls of pure TB strategy are the learning curve and experience required for mpMRI reading and biopsy targeting, as well as the precision assessment in TB techniques., Conclusion: A pure TB strategy omitting SB leads to the risk of missing up to 15% of significant cancer, due to limitations of mpMRI performance/reading and of precision during lesion targeting. SB remain necessary, in addition to the TB, to obtain the most accurate assessment of the entire prostate gland in this sub-group of patients at risk of significant disease.

Prostate cancer has a heterogeneous genetic profile compared with other tumour entities. Accordingly, there are also various mutations that increase the risk of prostate cancer. Some genetic variants only have a mild impact, whereas other gene mutations (BRCA1 /2; HOXB13) may increase the risk significantly. All in all, a man with a negative family history is unlikely to be a carrier of mutations that are associated with an increased risk of PCa. However, this likelihood increases if the family history is positive for a known mutation or if there are relatives who were affected at an early age. In such cases, genetic counselling and testing should be considered, with a particular focus on BRCA1/2 mutations and HOXB13 mutations. However, genetic profiling has not had the potential to replace PSA testing, mpMRI of the prostate gland and/or prostate biopsies as part of cancer screening or the diagnostic algorithm in the general population. The presence of mutations associated with PCa merely allows patients to undergo screening earlier and in tighter intervals and possibly receive earlier definitive treatment., Competing Interests: Die Autoren geben an, dass keine Interessenkonflikte bestehen., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: The urological community's opinion over focal therapy (FT) for prostate cancer (PCa) has never been assessed. Our aim was to investigate the current opinion on FT in the European urological community., Methods: A 25-item questionnaire was devised according to the Cherries checklist and distributed through SurveyMonkey using a web link from November 2016 to October 2017. After a pilot validation (n = 40 urologists), the survey was sent through EAU and 9 other national European urological societies mailing list. Twitter was also used., Results: We received 484 replies from 51 countries. Almost half (44.8%, n = 217) stated FT would represent a step forward, and 52.0% (n = 252) would suggest FT to a patient. Almost three-quarters (70.8%, n = 343) agreed FT will become a standard option after improvements in patient selection (n = 66) or when its effectiveness will be proven (n = 78), or both (n = 199). Most frequently used definition of FT was treatment of all significant (life-threatening) cancer foci whilst leaving untreated the rest of the gland (39.3%, n = 190). FT use was considered as an alternative to whole-gland treatments by 29.7% (n = 144), and to AS by 25.0% (n = 121). On multivariate analysis, FT availability and publications were associated with a positive opinion on FT. Conversely, attending International congresses, treating high PCa volumes and high percentages of high-risk PCa was associated with a negative opinion., Conclusions: FT is considered as an attractive option for PCa treatment by the European urological community sampled by our survey. FT availability positively influences these thoughts. The present survey suggests whilst some early adopters already embraced FT, the relative majority of the urological community is prone to embrace FT in the near future, once current areas of debate are solved., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To develop a novel tool to increase the number of patients with prostate cancer eligible for active surveillance (AS) without increasing the risk of unfavourable pathological features (i.e., misclassification) at radical prostatectomy (RP)., Patients and Methods: Overall, 16 049 patients with low- or intermediate-risk prostate cancer treated with RP were identified. Misclassification was defined as non-organ confined or grade group ≥3 disease at RP. The coefficients of a logistic regression model predicting misclassification were used to develop a risk score. We then performed a systematic analysis of different thresholds to discriminate between patients with or without unfavourable disease and we compared it to available AS criteria., Results: Overall, 5289 (33.0%) patients had unfavourable disease. At multivariable analyses, PSA level, clinical stage, biopsy grade group, the number of positive cores, and PSA density were associated with the risk of unfavourable disease (all P < 0.001). The Prostate Cancer Research International: Active Surveillance (PRIAS) criteria were associated with a lower risk of misclassification (13%) compared to other criteria. Overall, 3303 (20.6%) patients were eligible according to the PRIAS protocol. The adoption of an 18% threshold according to the risk score increased the proportion of eligible patients from 20.6% to 29.4% without increasing the risk of misclassification as compared to the PRIAS criteria., Conclusions: The use of a novel risk score for AS selection would result in an absolute increase of 10% in the number of patients eligible for this approach without increasing the risk of misclassification., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Recently, a plethora of life-prolonging cytotoxic, next-generation hormonal, immunotherapeutical as well as radionuclide therapies has emerged as a standard care for metastasized castration-resistant prostate cancer. Being strikingly effective in cancer control, these novel therapies might in fact exert a beneficial impact on skeletal events. Therefore, combining anticancer drugs with osteoprotective agents might lead to additional clinical advantage but must be weighed against simultaneously exposing patients to serious toxicities. In addition, further survival prolongation by changing treatment paradigm in both metastasized hormone-sensitive and nonmetastatic castration-resistant disease might potentially increase the risk for bone density reduction complications due to a growing efficacy of androgen ablation leading to prolonged exposure. To address both possible indications of combined treatment and to draw practical conclusions, we performed a comprehensive review of the currently available evidence., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To measure the usage rate of social media (SoMe) resources in the prostate cancer community, we performed a comprehensive quantitative and qualitative assessment of SoMe activity on the topic of PCa on the four most frequented platforms., Methods: We scanned the SoMe platforms Facebook, Twitter, YouTube, and Instagram for "prostate cancer" as a cross-sectional analysis or during a defined time period. Sources were included if their communication centered on PCa by title and content. We assessed activity measurements for each SoMe source and classified the sources into six functional categories., Results: We identified 99 PCa-related Facebook groups that amassed 31,262 members and 90 Facebook pages with 283,996 "likes". On YouTube, we found 536 PCa videos accounting for 43,966,634 views, 52,655 likes, 8597 dislikes, and 12,393 comments. During a 1-year time period, 32,537 users generated 110,971 tweets on #ProstateCancer on Twitter, providing over 544 million impressions. During a 1-month time period, 638 contributors posted 1081 posts on Instagram, generating over 22,000 likes and 4,748,159 impressions. Among six functional categories, general information/support dominated the SoMe landscape on all SoMe platforms., Conclusion: SoMe activity on the topic of PCa on the four most frequented platforms is high. Facebook groups, YouTube videos, and Twitter tweets are mainly used for giving general information on PCa and education. High SoMe utilization in the PCa community underlines its future role for communication of PCa.

Many patients diagnosed with cancer search for health information on the Web. We aimed to assess the quality and reliability of online health information on prostate cancer. Google, Yahoo, and Bing were searched for the term "prostate cancer." After selecting the most frequented websites, quality was measured by DISCERN score, JAMA benchmark criteria, and presence of HONcode certification. Popularity was assessed by Alexa tool, while accessibility, usability, and reliability were investigated by LIDA tool. Readability was analyzed by Flesch-Kincaid Reading Grade Level and Automated Readability Index. All 13 selected websites were rated as being of high quality according to the DISCERN instrument (76.5 ± 2.6 out of 80 points). JAMA benchmark criteria were fulfilled by 87 % of websites, whereas only 37 % were certified by the HONcode. Median Alexa Traffic Rank was 2718 ranging from 7 to 679,038. Websites received 2.3 ± 0.5 daily pageviews per visitor and users spent an average of 2 min 58 s ± 39 sec on the website. Accessibility (92 ± 5 %) and usability (92 ± 3 %) scores were high and reliability (88 ± 8 %) moderate according to the LIDA tool. Flesch-Kincaid Grade Level was 7.9 ± 2.2, and Automated Readability Index was 7.5 ± 2.4, rating the websites as fairly difficult to read. In conclusion, quality, accessibility, and usability of websites on prostate cancer provided a high rating in the current analysis. These findings are encouraging in view of the growing frequency of patients' access of health information online.

Background: Many patients diagnosed with prostate cancer search for information on robotic prostatectomy (RobP) on the Web. We aimed to evaluate the qualitative characteristics of the mostly frequented Web sites on RobP with a particular emphasis on provider-dependent issues., Materials and Methods: Google was searched for the term "robotic prostatectomy" in Europe and North America. The mostly frequented Web sites were selected and classified as physician-provided and publically-provided. Quality was measured using Journal of the American Medical Association (JAMA) benchmark criteria, DISCERN score, and addressing of Trifecta surgical outcomes. Popularity was analyzed using Google PageRank and Alexa tool. Accessibility, usability, and reliability were investigated using the LIDA tool and readability was assessed using readability indices., Results: Twenty-eight Web sites were physician-provided and 15 publically-provided. For all Web sites, 88% of JAMA benchmark criteria were fulfilled, DISCERN quality score was high, and 81% of Trifecta outcome measurements were addressed. Popularity was average according to Google PageRank (mean 2.9 ± 1.5) and Alexa Traffic Rank (median, 49,109; minimum, 7; maximum, 8,582,295). Accessibility (85 ± 7%), usability (92 ± 3%), and reliability scores (88 ± 8%) were moderate to high. Automated Readability Index was 7.2 ± 2.1 and Flesch-Kincaid Grade Level was 9 ± 2, rating the Web sites as difficult to read. Physician-provided Web sites had higher quality scores and lower readability compared with publically-provided Web sites., Conclusion: Websites providing information on RobP obtained medium to high ratings in all domains of quality in the current assessment. In contrast, readability needs to be significantly improved so that this content can become available for the populace., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Despite impressive survival benefits from new agents to treat metastasized prostate cancer (PCa), progressive drug resistance hinders long-term response and restricts the efficacy of subsequent therapy. Due to reported antitumor activity of amygdalin and growing popularity for complementary and alternative medicine the potential of this natural, widely used substance to exert antineoplastic effects on prostate cancer cells has been assessed., Main Methods: LNCaP (castration-sensitive), DU-145 and PC3 cells (castration-resistant) were exposed to different concentrations of amygdalin for 24h or 2weeks. Cell growth was measured by the MTT test, clonal formation by the clonogenic assay. Flow cytometry served to investigate apoptosis and cell cycle phases. Cell cycle regulating proteins and the mTOR-akt signaling axis were analyzed by western blotting., Key Findings: Amygdalin dose-dependently diminished tumor cell growth with maximum effects at 10mg/ml. Apoptosis of PC3 and LNCaP but not of DU-145 cells was reduced, whereas colony formation was suppressed in all cell lines. A decrease in the number of G2/M- and S-phase cells along with an elevated number of G0/G1-phase cells was recorded. The cell cycle proteins cdk 1, cdk 2 and cdk 4 as well as cyclin A, cyclin B and cyclin D3 were modulated by amygdalin after both 24h and 2weeks. Distinct effects on p19 and p27 expression and on Akt, Rictor and Raptor activation became evident only after 2weeks., Significance: Amygdalin exhibits significant antitumor activity in both castration-sensitive and castration-resistant PCa cell lines and merits further evaluation for therapeutic purposes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A significant proportion of men diagnosed with prostate cancer (PCa) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase (HDAC) inhibitor valproic acid (VPA), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha (IFNα) on PCa cell growth and dissemination capacity were investigated. For that purpose, the human PCa cell lines, PC-3, DU-145 and LNCaP were treated with the combined regimen or separate single agents. Cell growth was investigated by the MTT dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin α and β subtypes were investigated by flow cytometry, western blotting and RT-PCR. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal-regulated kinases (ERK)1/2 activation were also assessed. The triple application of VPA, everolimus and low dosed IFNα blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining VPA, everolimus and low dosed IFNα might be a promising option to counteract resistance development and improve outcome in PCa patients., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Purpose: Chemokines undergo alterations during neoplasia. However, knowledge about their functional significance in prostate cancer (PCa) progression is still sparse. Since chemokine (C-C motif) ligand 2 (CCL2) is significantly up-regulated in patients with PCa, aim of the current study was to assess whether CCL2 contributes to invasive behavior of prostate cancer cells in vitro., Methods: The human PCa cell line PC3 was stimulated with CCL2. Cell growth was investigated by MTT dye reduction assay. Cell adhesion was analyzed by measuring attachment to a human endothelial cell (HUVEC) monolayer and immobilized collagen. Cell migration was assessed by a chemotactic assay. Integrin expression on the cell surface was evaluated by Western blot. Blocking studies were performed with anti-integrin α3, anti-integrin α6 and anti-integrin β4 monoclonal antibodies., Results: PC3 cell growth 72 h after CCL2 exposure was significantly increased, compared to controls. Activation of tumor cells by CCL2 significantly enhanced tumor cell adhesion to HUVEC and immobilized collagen. CCL2, added for 4 or 24 h, elevated α6 and β4 (4 > 24 h) integrin expression. α3 was enhanced after 4 h, but reduced after 24 h. Blocking either α3, α6 or β4 led to significant suppression of tumor cell binding to immobilized collagen., Conclusions: CCL2 stimulates PCa cell adhesion and induces alterations in α3-, α6- and β4-integrin expression on the cell surface. Blocking these integrins leads to a significant reduction in cell adhesion.

Background: Measurement of prostate-specific antigen (PSA) advanced the diagnostic and prognostic potential for prostate cancer (PCa). However, due to PSA's lack of specificity, novel biomarkers are needed to improve risk assessment and ensure optimal personalized therapy. A set of protein molecules as potential biomarkers was therefore evaluated in serum of PCa patients., Methods: Serum samples from patients undergoing radical prostatectomy (RPE) for biopsy-proven PCa without neoadjuvant treatment were compared to serum samples from healthy subjects. Preliminary screening of 119 proteins in 10 PCa patients and 10 controls was carried out by the Proteome Profiler Antibody Array. Those markers showing distinct differences between patients and controls were then further evaluated by ELISA in the serum of 165 PCa patients and 19 controls. Uni- and multivariate as well as correlation analysis were performed to test the capability of these molecules to detect disease and predict pathological outcome., Results: Screening showed that soluble (s)E-cadherin, E-selectin, MMP2, MMP9, TIMP1, TIMP2, Galectin and Clusterin warranted further evaluation. sE-Cadherin, TIMP1, Galectin and Clusterin were significantly over- and MMP9 under-expressed in PCa compared to controls. The concentration of sE-cadherin, MMP2 and Clusterin correlated negatively and that of MMP9 and TIMP1 positively with the Gleason Sum at prostatectomy. Only sE-cadherin significantly correlated with the highest Gleason pattern. Compared to serum PSA, sE-cadherin provided an independent and better matching predictive ability for discriminating PCas with an upgrade at RPE and aggressive tumors with a Gleason Sum ≥7., Conclusions: sE-cadherin performed most favorably from a large panel of serum proteins in terms of diagnostic and predictive potential in curatively treatable PCa. sE-cadherin merits further investigation as a biomarker for PCa.

Background: Extent of pelvic lymph node (LN) dissemination is a critical prognostic feature for patients with prostate cancer (PCa) maintaining extended pelvic lymphadenectomy (LAD) as the gold standard for LN-staging. Unfortunately, conventional histopathological assessment may miss micrometastasis and recently presented immunocytochemical approach of the single cell analysis is still intricate., Objective: To comparatively assess the potential of Prostate cancer gene 3 (PCA3) and prostate specific antigene (PSA) to perform as markers for tumor cell load., Methods: Patients with high risk PCa for LN metastasis undergoing either a sentinel LN-guided staging LAD or retropubic radical prostatectomy with sentinel-guided pelvic LN dissection were included. LNs were investigated by routine histopathology. Tumor cell load was quantified by %immunocytochemistry. immunocytochemical single cell analysis. Gene activity was determined by qRT-PCR., Results: Twenty four out of 226 LNs were positive in routine histopathology and 51 in single cell analysis. PSA mRNA level correlated with tumor cell density in patients with a positive immunocytochemistry. Gene activity of PCA3 was upregulated in metastatic LNs and correlated with tumor cell density in patients with tumor-invaded LNs as detected by immunocytochemistry., Conclusions: PCA3 gene expression discriminates LN metastasis and might outperform PSA gene activity in reflecting tumor cell burden in pelvic LNs of PCa patients.

Molecular tumour targeting has significantly improved anti-cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of Rapamycin (mTOR) and histone deacetylase (HDAC) inhibition has been shown not only to enhance anti-tumour potential, but also to prevent resistance development seen under mono-drug therapy. This investigation was designed to evaluate whether cross-communication exists between mTOR signalling and epigenetic events regulated by HDAC. DU-145 prostate cancer cells were treated with insulin-like growth factor (IGF) to activate the Akt-mTOR cascade or with the HDAC-inhibitor valproic acid (VPA) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, mTOR, Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between mTOR and the epigenetic machinery. IGF activated mTOR, Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGFr blockade and knock-down blocked the Akt-mTOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up-regulated histone acetylation, but also activated mTOR-Akt signalling. HDAC1 and 2 knock-down revealed that the interaction with the mTOR system is initiated by histone H3 acetylation. HDAC-mTOR communication, therefore, is apparent whereby tumour-promoting (Akt/mTOR(high), aH3/aH4(low)) and tumour-suppressing signals (Akt/mTOR(low) , aH3/aH4(high)) are activated in parallel. Combined use of an HDAC- and mTOR inhibitor might then diminish pro-tumour effects triggered by the HDAC- (Akt/mTOR(high)) or mTOR inhibitor (aH3/aH4(low)) alone., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: To reliably compare the results of gene expression studies, the expression of the target gene should be normalized to the expression of a reference gene. For lymph node metastases of prostate cancer, no data on polymerase chain reaction (PCR) normalization have yet been reported. We aimed to determine the most reliable reference gene combination for this purpose in patients with prostate cancer., Materials and Methods: Ten histologically- positive and ten negative lymph nodes of patients with prostate cancer were analyzed respectively. Expression of six candidate reference genes was comparatively assessed with quantitative Real-time PCR. The most stably-expressed gene combination was determined with geNorm software version 3.4., Results: Hypoxanthine phosphoribosyltransferase-1 (HPRT1) and TATA box binding protein (TPB) were found to be the most stably expressed genes, with their combination having an expression stability value of M=0.17., Conclusion: Gene combination HPRT1 and TPB has the potential to be utilized for normalization in gene profiling assessment of metastatic and non-metastatic pelvic lymph node tissue from patients with prostate cancer.

Multiparametric magnetic resonance imaging (MRI) represents the most accurate imaging modality for prostate cancer imaging to date. Transrectal ultrasound (TRUS) is easily applied and therefore remains the gold standard for systematic prostate biopsies. However, the advantages of both modalities can be combined by image fusion. Currently, several image fusion devices are being implemented into clinical routine. First data show an increased detection rate of prostate cancer compared to systematic TRUS biopsies. At present prostatic deformation and intracorporeal movement represent technical challenges yet to be overcome. The present article gives an overview about the status of MRI-based biopsy techniques and highlights the current studies on the topic.

Pharmacologic options for patients with castration-resistant prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow tumor growth. Therefore, the growth-blocking potential of the histone deacetylase-inhibitor LBH589 and the multiple tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of LBH589 and/or TKI258. Tumor cell growth, cell cycle regulating proteins, HDAC3- and HDAC4-expression and histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting. LBH589 dose-dependently blocked prostate cancer cell growth. In contrast, TKI258 did not down-regulate tumor cell growth up to a 1,000 nM dosage. LBH589 elevated histone H3 and H4 acetylation. The cell cycle regulators cyclin B, cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor proteins p21 and p27 were up-regulated in LNCaP by LBH589. TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated cyclin B, cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in cyclin and cdk caused by TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in TKI258 non-responsiveness. The LBH589/TKI258-combination was not superior to the LBH589 single-drug use in terms of growth reduction. Obviously, TKI258 did not enhance the sensitivity of prostate cancer cells towards an HDAC based regimen. Therefore, the LBH589/TKI258-combination probably does not provide an optimum strategy in fighting advanced prostate cancer.

We evaluated whether low-dosed interferon alpha (IFNa) may augment the anti-tumor potential of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer cells in vitro and in vivo. PC-3, DU-145, or LNCaP prostate cancer cells were treated with VPA (1 mM), IFNa (200 U/ml), or with the VPA-IFNa combination. Tumor cell growth, cell cycle progression, and cell cycle regulating proteins were then investigated by the MTT assay, flow cytometry, and western blotting. Tumor cell adhesion to endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, were evaluated. Integrin α and β adhesion molecules and alterations of cell signaling pathways were analyzed. Finally, effects of the drug treatment on prostate cancer growth in vivo were determined in the NOD/SCID mouse model. VPA reduced tumor cell adhesion, migration, and growth in vitro. A much stronger anti-cancer potential was evoked by the VPA-IFNa combination, although IFNa in itself did not block growth or adhesion. The same effect was seen when tumor growth was evaluated in vivo. Molecular analysis revealed distinct elevation of histone H3 acetylation caused by VPA which was further up-regulated by VPA-IFNa, whereas IFNa alone did not alter H3 acetylation. The combinatorial benefit became obvious in Akt phosphorylation, p21 and p27 and integrin α1, α3, and β1 expression. Application of low-dosed IFNa to a VPA based regimen profoundly boosts the anti-tumor properties of VPA. The combined use of VPA and low-dosed IFNa may therefore be an innovative option in treating advanced prostate cancer., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Inhibitors of the mammalian target of rapamycin (mTOR) might become a novel tool to treat advanced prostate cancer. However, chronic drug exposure may trigger resistance, limiting the utility of mTOR inhibitors., Methods: Metastatic potential of PC3 prostate cancer cells, susceptible (PC3(par)) or resistant (PC3(res)) to the mTOR-inhibitor RAD001 was investigated. Adhesion to vascular endothelium or immobilised collagen, fibronectin and laminin was quantified. Motility, migration and invasion were explored by modified Boyden chamber assay. Integrin α and β subtypes were analysed by flow cytometry, western blotting and real-time PCR. Integrin-related signalling, EGFr, Akt, p70S6kinase and ERK1/2 activation were determined., Results: Adhesion was reduced, whereas motility, migration and invasion were enhanced in PC3(res). The α2 and β1 integrin subtypes were dramatically elevated, integrins α1 and α6 were lowered, whereas α5 was nearly lost in PC3(res). Activation of the Akt signalling pathway was strongly upregulated in these cells. Treating PC3(par) cells with RAD001 reduced motility, migration and invasion and deactivated Akt signalling. Blocking studies revealed that α2 and β1 integrins significantly trigger the motile behaviour of the tumour cells., Conclusion: Chronic RAD001 treatment caused resistance development characterised by distinct modification of the integrin-expression profile, driving prostate cancer cells towards high motility.

Background: Single drug use has not achieved satisfactory results in the treatment of prostate cancer, despite application of increasingly widespread targeted therapeutics. In the present study, the combined impact of the mammalian target of rapamycin (mTOR)-inhibitor RAD001, the dual EGFr and VGEFr tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer growth and adhesion in vitro was investigated., Methods: PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin α and β subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined., Results: All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anti-cancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin α and β subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination., Conclusions: Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer.

The concept of molecular tumor targeting might provide new hope in the treatment of advanced prostate cancer. We evaluated metastasis blocking properties of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell lines. RAD001 or VPA were applied to PC-3 or LNCaP cells, either separately or in combination. Adhesion to vascular endothelium or to immobilized collagen, fibronectin or laminin was quantified. Migration and invasion were explored by a modified Boyden chamber assay. Integrin α and β subtypes were analyzed by flow cytometry, western blotting and RT-PCR. Effects of drug treatment on integrin related signaling, Akt and p70S6kinase activation, histone H3 and H4 acetylation were also determined. Separate application of RAD001 or VPA distinctly reduced tumor cell adhesion, migration and invasion, accompanied by elevated Akt activation and p70S6kinase de-activation. Integrin subtype expression was altered significantly by both compounds (VPA > RAD001). When both drugs were used in concert additive effects were observed on the migratory and invasive behavior but not on tumor-endothelium and tumor-matrix interaction. Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA monotreatment with particular respect to migration and invasion. Ongoing studies are required to assess the relevance of VPA monotherapy versus VPA-RAD001 combination on tumor cell motility.

Aims: To analyze the combined impact of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell growth., Main Methods: PC-3, DU-145 and LNCaP cells were treated with RAD001, VPA or with an RAD001-VPA combination for 3 or 5 days. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT assay, flow cytometry and Western blotting, respectively. Effects of drug treatment on cell signaling pathways were determined., Key Findings: Separate application of RAD001 or VPA distinctly reduced tumor cell growth and impaired cell cycle progression. Significant additive effects were evoked when both drugs were used in concert. Particularly, the cell cycle regulating proteins cdk1, cdk2, cdk4 and cyclin B were reduced, whereas p21 and p27 were enhanced by the RAD001-VPA combination. Signaling analysis revealed deactivation of EGFr, ERK1/2 and p70S6k. Phosphorylation of Akt was diminished in DU-145 but elevated in PC-3 and LNCaP cells., Significance: The RAD001-VPA combination exerted profound antitumor properties on a panel of prostate cancer cell lines. Therefore, simultaneous blockage of HDAC and mTOR related pathways should be considered when designing novel therapeutic strategies for treating prostate carcinoma., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The impact of the mTOR inhibitor RAD001 combined with the EGFr/VEGFr tyrosine kinase inhibitor AEE788 on prostate tumor cell growth, adhesion and migration was analyzed in vitro. The RAD001-AEE788 combination profoundly reduced tumor-endothelium and tumor-matrix contacts, suppressing cell growth and cell cycle progression. The underlying molecular mode of action depended on the cell phenotype, since cell cycle proteins, integrin subtype expression and integrin dependent signaling were altered in a different manner in PC-3 and DU-145 versus LNCaP prostate cancer cells. Simultaneous targeting of mTOR and VEGFr/EGFr related pathways may offer a novel therapeutic strategy for prostate cancer treatment., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)