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Regulation of the genes involved in WNT signaling pathway in the ALDH+ population of DU145 radioresistant (RR) cells versus ALDH- population of DU145 RR cells.

Radiotherapy is a mainstay of curative prostate cancer treatment, but risks of recurrence after treatment remain significant in locally advanced disease. Given that tumor relapse can be attributed to a population of cancer stem cells (CSC) that survives radiotherapy, analysis of this cell population might illuminate tactics to personalize treatment. However, this direction remains challenging given the plastic nature of prostate cancers following treatment. We show here that irradiating prostate cancer cells stimulates a durable upregulation of stem cell markers that epigenetically reprogram these cells. In both tumorigenic and radioresistant cell populations, a phenotypic switch occurred during a course of radiotherapy that was associated with stable genetic and epigenetic changes. Specifically, we found that irradiation triggered histone H3 methylation at the promoter of the CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), stimulating its gene transcription. Inhibiting this methylation event triggered apoptosis, promoted radiosensitization, and hindered tumorigenicity of radioresistant prostate cancer cells. Overall, our results suggest that epigenetic therapies may restore the cytotoxic effects of irradiation in radioresistant CSC populations. Cancer Res; 76(9); 2637–51. ©2016 AACR.

Irradiation-induced changes in the expression of stem cell markers (S1); Genetic alterations in the irradiated prostate cancer cells (S2); Regulation of histone methylation in response to cell irradiation (S3); Differential expression of stem cell and EMT markers in response to irradiation in the parental and radioresistant prostate cancer cells (S4); The role of ALDH1A1 expression in regulation of spherogenicity, tumorigenicity and radioresistance of the parental and radioresistant prostate cancer cells (S5); Analysis and validation of the global gene expression data (S6); Analysis of cell viability, plating efficacy and post-irradiation clonogenic survival in response to inhibition of the histone methylation activity (S7); Effect of DZNep treatment on apoptosis induction and γH2A.X level in prostate cancer cell lines (S8); Analysis of apoptosis induction and γH2A.X increase by DZNep treatment in prostate tumor tissues and primary cell cultures (S9); Co-regulation of EZH2, ALDH1A1 and CTNNB1 in cell lines and prostate tumors (S10).

Description of additional methods and procedures used in the study. Also includes Supplementary Reference.

Radiotherapy is a curative treatment option in prostate cancer. Nevertheless, patients with high-risk prostate cancer are prone to relapse. Identification of the predictive biomarkers and molecular mechanisms of radioresistance bears promise to improve cancer therapies. In this study, we show that aldehyde dehydrogenase (ALDH) activity is indicative of radioresistant prostate progenitor cells with an enhanced DNA repair capacity and activation of epithelial–mesenchymal transition (EMT). Gene expression profiling of prostate cancer cells, their radioresistant derivatives, ALDH+ and ALDH− cell populations revealed the mechanisms, which link tumor progenitors to radioresistance, including activation of the WNT/β-catenin signaling pathway. We found that expression of the ALDH1A1 gene is regulated by the WNT signaling pathway and co-occurs with expression of β-catenin in prostate tumor specimens. Inhibition of the WNT pathway led to a decrease in ALDH+ tumor progenitor population and to radiosensitization of cancer cells. Taken together, our results indicate that ALDH+ cells contribute to tumor radioresistance and their molecular targeting may enhance the effectiveness of radiotherapy. Cancer Res; 75(7); 1482–94. ©2015 AACR.

Supplementary Methods, Table 1, Figure S1-S9 (i) supplementary methods: Human tumor tissue dissociation, Immunofluorescence microscopy, Clonogenic cell survival assay, Sphere formation assay, Cell proliferation and cytotoxicity assay, Wound healing assay, Transwell migration assay, Western blot analysis, Flow cytometry analysis, Chromatin immunoprecipitation assay, siRNA-mediated gene silencing, Luciferase reporter assay, Histology, Microarray analysis of the xenograft tumors, (ii) supplementary table 1: Primary tumor tissues used in the study and (iii) supplementary figures including Figure S1 (analysis of ALDH1A1 expression in normal and tumor prostate tissues), Figure S2 (prostate cancer ALDH+ cells possess CSC properties), Figure S3 (analysis of CSC marker expression after irradiation), Figure S4 (clonogenicity and tumorigenisity of ALDH+ and ALDH- cells after irradiation), Figure S5 (characterization of the radioresistant prostate cancer cell sublines), Figure S6 (the mechanisms of prostate cancer cell radioresistance), Figure S7 (comparative gene expression profiling of ALDH+ and radioresistant DU145 cells), Figure S8 (EMT properties of ALDH+ and radioresistant prostate cancer cells), Figure S9 (WNT/β-catenin pathway regulates ALDH1A1 expression)

Background Recommendations against prostate-specific antigen (PSA) testing in 2012 have increased advanced-stage diagnosis and prostate cancer–specific mortality rates. Objective To present the position of the European Association of Urology (EAU) in 2021 and provide recommendations for the use of PSA testing as part of a risk-adapted strategy for the early detection of prostate cancer. Evidence acquisition The authors combined their review of relevant literature, including the EAU prostate cancer guidelines 2021 update, with their own knowledge to provide an expert opinion, representing the EAU’s position in 2021. Evidence synthesis The EAU has developed a risk-adapted early prostate cancer detection strategy for well-informed men based on PSA testing, risk calculators, and multiparametric magnetic resonance imaging, which can differentiate significant from insignificant prostate cancer. This approach largely avoids the overdiagnosis/overtreatment of men unlikely to experience disease-related symptoms during their lifetime and facilitates an early diagnosis of men with significant cancer to receive active treatment. It also reduces advanced-stage diagnosis, thereby potentially reducing prostate cancer–specific mortality and improving quality of life. Education is required among urologists, general practitioners, radiologists, policy makers, and healthy men, including endorsement by the European Commission to adapt the European Council’s screening recommendations in its 2022 plan and requests to individual countries for its incorporation into national cancer plans. Conclusions This risk-adapted approach for the early detection of prostate cancer will reverse current unfavourable trends and ultimately save lives. Patient summary The European Association of Urology has developed a patient information leaflet and algorithm for the early diagnosis of prostate cancer. It can identify men who do not need magnetic resonance imaging or a biopsy and those who would not show any symptoms versus those with more aggressive disease who require further tests/treatment. We need to raise awareness of this algorithm to ensure that all well-informed men at risk of significant prostate cancer are offered a prostate-specific antigen test. Take Home Message A risk-adapted early prostate cancer detection strategy, incorporating prostate-specific antigen testing, multiparametric magnetic resonance imaging, risk calculators, and biomarkers, will avoid overdiagnosis/overtreatment of insignificant cancers and ensure early detection and treatment of significant cancers, thereby improving quality of life and reducing prostate cancer–related deaths.

In the care for patients with urological diseases, outpatient urology secures a near-to-home treatment by specialists in urology and is located between general practitioner and urological clinic. Comparably little is known about the structure and fields of work in this area of urology. A survey of the EAU Section ESUO of outpatient and office urology ( https://uroweb.org/section/esuo/ ) shows the diversity in terms of content and organisation of this sector in Europe, in which more than 16,500 outpatient urologists and thus about half of all professional urologists work full-time. This diversity is related to the diagnostic and therapeutic methods in outpatient urology and to the working conditions of outpatient urologists. For comparison, this information about European countries is contrasted with data from the German office urology as one type of outpatient urology.

Life expectancy is increasing in many parts of the world. Using proportional hazard models for competing risks, we investigated whether this increase has changed outcomes after radical cystectomy in a sample of 1419 consecutive patients treated between 1993 and 2018. During the observation period, the mean age and the proportion of patients with American Society of Anesthesiologists physical status class 3 or 4 increased, whereas the proportion of patients with heart disease decreased. Competing mortality (causes other than bladder cancer) decreased in all subgroups (hazard ratios [HRs] per year ranged from 0.931 to 0.963) and after controlling for increasing age (HRs ranged from 1.018 to 1.081). In an optimal model resulting from an analysis including age (HR per year 1.048, 95% confidence interval [CI] 1.027–1.070; p

OBJECTIVE To investigate the relationship between increasing life expectancy and nonprostate cancer (competing) mortality after radical prostatectomy. PATIENTS AND METHODS We studied a single-center sample of 6809 consecutive patients who underwent radical prostatectomy between 1992 and 2016 with a median age of 65 years and a median follow-up of 7.9 years. Multivariate competing risk analyses were performed with competing mortality as endpoint. Linear trends over the years of surgery for 5-year competing mortality rates and for mean ages were calculated using linear regression analyses. We estimated the number of live years gained over time using a heuristic model-based calculation: (hazard ratio year of surgery) 24 calendar years × (hazard ratio age at surgery) gained life years = 1. RESULTS After controlling for age, nonprostate cancer mortality decreased significantly during the observation period. Accumulated over the 24 years, this decrease of mortality corresponded to the effect of 6.3 years of calendric age. Most of the decrease in nonprostate cancer mortality (predominantly attributable to noncancer causes of death) was seen in patients aged 65 years or older (8.1 years gained), whereas there was only a marginal decrease in patients younger than 65 years (only 1 year gained). The decrease in nonprostate cancer mortality was accompanied by a slight increase of mean age at surgery (2.7 years) that did not nearly compensate the decreasing risk. CONCLUSION Clinicians should be aware of the decreasing competing mortality risk in elderly candidates for radical prostatectomy in order to avoid undertreatment.

Background: Local ablative radiotherapy (aRT) of oligometastatic prostate cancer (PCa) is very promising and has become a focus of current clinical research. Objective: We hypothesize that aRT is safe and effective in gallium-68 prostate-specific membrane antigen targeted positron emission tomography (PSMA-PET)-staged oligometastatic PCa patients. Design, setting, and participants: A nonrandomized, prospective, investigator-initiated phase 2 trial recruited patients with oligometastatic PCa (five or fewer lymph node or osseous metastases) after local curative therapy, without significant comorbidity and androgen deprivation therapy (ADT), at two German centers from 2014 to 2018. Intervention: All PSMA-PET-positive metastases were treated with aRT. No systemic therapy was initiated. Outcome measurements and statistical analysis: The primary endpoint was treatment-related toxicity (grade ≥2) 24 mo after aRT. A one-sided single-sample test of proportions was planned to test whether the endpoint occurs in

Identification of aberrant DNA methylation is a promising tool in prostate cancer (PCa) diagnosis and treatment. In this study, we evaluated a two-step method named optimised bias-based preamplification followed by digital PCR (OBBPA-dPCR). The method was used to identify promoter hypermethylation of 2 tumour suppressor genes RASSF1A and GSTP1 in the circulating cell-free DNA (cfDNA) from serum samples of PCa patients (n = 75), benign prostatic hyperplasia (BPH, n = 58), and healthy individuals (controls, n = 155). The PCa cohort was further subdivided into subgroups comprising (I) patients with Gleason Scores (GS) ≤ 7 (n = 55), (II) GS ≥ 8 (n = 10), and (III) patients with metastatic PCa diagnosis (n = 10). We found that RASSF1A methylation levels were significantly increased in all 3 PCa subgroups compared to the controls and BPH cohorts (p &lt, 0.01 for all comparisons). Fractional abundances of methylated GSTP1 DNA fragments were significantly increased in subgroup III of metastatic PCa patients (p &lt, 0.001). RASSF1A methylation analysis was found to be beneficial as a complementary biomarker where further diagnostic validation is most crucial. In combination with free PSA, RASSF1A methylation status helps to identify PCa patients with GS ≥ 8 and grey-zone total PSA values between 2–10 ng/mL. In our study, PCR biases between 80–90% were sufficient to detect minute amounts of tumour DNA with high signal-to-noise ratios as well as high analytical sensitivity and specificity. Both RASSF1A and GSTP1 exhibited strongly increased DNA methylation levels in all metastatic PCa patients. Our data indicates a superior sensitivity of epigenetic biomarker analyses in early detection of PCa metastases that should also help to improve PCa therapy.

The goal of this two-armed observational study was to map the clinical therapy effectiveness of radical prostatovesiculectomy (RPVE) and external beam radiation therapy (EBRT) in locally limited prostate cancer (PCA) in direct comparison over 20 years under clinical conditions. Retrospectively, the various variables and predictors for the individual therapy decision were identified, and the preference was to compared with studies on survival and recurrence characteristics. The presentation of toxicity was not the focus of this work.In all, 743 patients from a single center were enrolled according to biopsy/staging chronologically in the sequence of the initial consultation after clarification and informed consent: 494 patients were in the RPVE arm and 249 patients in the EBRT arm. We used retrospective data analysis with univariate and multivariate comparisons in the alternative therapy arms. Multivariate logical regression models were developed to objectify the allocation process. Univariate processing of survival analyses, the comparison of tumor- and comorbidity-specific mortality rates was co-founded.Predictive variables for RPVE vs. EBRT therapy decision are significantly age, Gleason score, D'Amico index, Charlson index, prostate-specific antigen (PSA), and prostate volume. There was no significance level for the biopsy score. The age gap was in the median 67 (RPVE) and 73 (EBRT) years. Overall survival (n = 734, 20 years, all risks) in the RPVE arm was 56.8% (95% confidence interval [CI] 45.1-67.0%) and in the EBRT arm 19.2% (95%CI 9.2-31.8%). Comorbid risk was highly significantly (p 0.0001) different (27.1% [95%CI 18.0-36.1%] in the RPVE arm, and 60.4% [95%CI 47.3-73.5%] in the EBRT arm). The risk of tumor-specific death at 16.2% (95%CI 8.1-24.4%) after RPVE and 20.5% (95%CI 11.7-29.3%) after EBRT was not significantly different (p = 0.2122, overlapping 95%CI). After stratification, a clear advantage can be demonstrated for the high-risk tumors after allocation to the RPVE arm.The complexity of the predictive variables of the PCA further complicates the individual therapy decision. According to our data, the higher D'Amico score, the rather low Charlson index, a high Gleason score and a higher organ volume speak for a valid therapy for RPVE.ZIELSTELLUNG: Ziel einer zweiarmigen Beobachtungsstudie war es, die klinische Therapieeffektivität der radikalen Prostatovesikulektomie (RPVE) und perkutanen Radiatio (EBRT) beim lokal begrenzten Prostatakarzinom (PCA) im direkten Vergleich über einem 20-Jahres-Intervall unter Praxisbedingungen abzubilden. Retrospektiv sollten die diversen Variablen und Prädiktoren für die individuelle Therapieentscheidung identifiziert werden und die getroffene Präferenz mit Untersuchungen zum Überleben und zur Rezidivcharakteristik kritisch abgeglichen werden. Die Präsentation der konsekutiven Toxizität stand bewusst nicht im Fokus dieser Arbeit.Enrolliert wurden 743 Patienten unizentrisch nach Biopsie/Staging chronologisch in der Abfolge der Erstkonsultation nach Aufklärung und Einverständniserklärung; davon 494 Patienten in den RPVE-Arm, 249 weitere Patienten in den EBRT-Arm. Die Datenanalyse retrospektiv univariat/multivariat in den alternativen Therapiearmen. Zur Objektivierung des Allokationsprozesses wurden multivariate logische Regressionsmodelle entwickelt. Allokations- und Confounder-adjustierte Vergleiche, tumor- und komorbiditätsspezifische Überlebens- und Rezidivraten mittels proportionaler Hazard-Modelle beschreiben das Outcome.Prädiktive Variablen für den Therapieentscheid RPVE vs. EBRT sind signifikant das Alter, der Gleason-Score, der D’Amico-Index, der Charlson-Index, das klinische Stadium, das PSA und das Prostatavolumen. Keine Erreichung des Signifikanzniveaus für den Biopsiescore. Die Allokation führte konsekutiv zu einem Altersversatz im Median von 67 Jahren (RPVE) und 73 Jahren (EBRT). Das Gesamtüberleben (n = 743, 20 Jahre, alle Risiken) betrug im EBRT-Arm 56,8 % (95 %-Konfidenzintervall [KI]: 45,1 %–67,0 %), und im EBRT-Arm 19,2 % (95 %-KI: 9,2 %–31,8 %). Die komorbiditätsspezifische Mortalität unterscheidet sich signifikant (p 0,0001) mit 27,1 % (95 %-KI: 18,0 %–36,1 %) im RPVE-Arm und 60,4 % (95 %-KI: 47,3 %–73,5 %) im EBRT-Arm. Die tumorspezifische 20-Jahres-Überlebensrate fanden wir nach der RPE zu 16,2 % (95 %-KI: 8,1 %–24,4 %) und zu 20,5 % (95 %-KI: 11,7 %–29,3 %) nach der EBRT – ohne statistische Signifikanz im Vergleich (p = 0,2122, überlappende 95 %-KI). Nach der allokations- und Confounder-adjustierten Analyse lässt sich für die Hochrisikotumoren hingegen ein deutlicher Vorteil nach der Allokation in den RPVE-Arm belegen.Die Komplexität der prädiktiven Variablen des PCA erschwert die individuelle Therapieentscheidung weiter. Für eine valide Therapieempfehlung zur RPVE sprechen nach unseren Daten der jüngere Patient, der höhere D’Amico-Score, der eher niedrige Charlson-Index, ein hoher Gleason-Score – und das relativ höheres Organvolumen.

Neuropilin-2 (NRP2) is a member of the neuropilin receptor family and known to regulate autophagy and mTORC2 signaling in prostate cancer (PCa). Our study investigated the association of immunohistochemical NRP2 expression with clinicopathological data in PCa patients. For this purpose, we generated a tissue microarray with prostate tissue specimens from 400 PCa patients treated by radical prostatectomy. We focused on patients with high-risk factors such as extraprostatic extension (pT ≥ 3), Gleason score ≥8 and/or the presence of regional lymph node metastases (pN1). Protein levels of NRP2, the vascular endothelial growth factor C (VEGFC) and oncogenic v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) gene as an indicator for TMPRSS2-ERG fusion was assessed in relation to the patients' outcome. NRP2 emerged as an independent prognostic factor for cancer-specific survival (CSS) (hazard ratio 2.360, 95% confidence interval = 1.2-4.8; p = 0.016). Moreover, the association between NRP2 expression and shorter CSS was also especially pronounced in patients at high risk for progression (log-rank test: p = 0.010). We evaluated the association between NRP2 and the TMPRSS2-ERG gene fusion status assessed by immunohistochemical nuclear ERG staining. However, ERG staining alone did not show any prognostic significance. NRP2 immunostaining is significantly associated with shorter CSS in ERG-negative tumors (log-rank test: p = 0.012). No prognostic impact of NRP2 expression on CSS was observed in ERG-positive tumors (log-rank test: p = 0.153). Our study identifies NRP2 as an important prognostic marker for a worse clinical outcome especially in patients with a high-risk PCa and in patients with ERG-negative PCa.

Based on data retrieved from a comprehensive multicenter database, we externally validated a published postoperative nomogram for the prediction of disease-specific survival (DSS) in patients with papillary renal cell carcinoma (papRCC). A multicenter database containing data of 2325 patients with surgically treated papRCC was used as validation cohort. After exclusion of patients with missing data and patients included in the development cohort, 1372 patients were included in the final analysis. DSS-probabilities according to the nomogram were calculated and compared to actual DSS-probabilities. Subsequently, calibration plots and decision curve analyses were applied. The median follow-up was 38 months (IQR 11.8–80.7). Median DSS was not reached. The c-index of the nomogram was 0.71 (95% CI 0.60–0.83). A sensitivity analysis including only patients operated after 1998 delivered a c-index of 0.84 (95% CI 0.77–0.92). Calibration plots showed slight underestimation of nomogram-predicted DSS in probability ranges below 90%: median nomogram-predicted 5-year DSS in the range below 90% was 55% (IQR 20–80), but the median actual 5-year DSS in the same group was 58% (95% CI 52–65). Decision-curve analysis showed a positive net-benefit for probability ranges between a DSS probability of 5% and 85%. The nomogram performance was satisfactory for almost all DSS probabilities; hence it can be recommended for application in clinical routine and for counseling of patients with papRCC.

Background: High-quality management of prostate cancer is needed in the fields of clinics, research, and education. Objective: The objective of this project was to develop the concept of “European Prostate Cancer Centres of Excellence” (EPCCE), with the specific aim of identifying European centres characterised by high-quality cancer care, research, and education. Design, setting, and participants: A task force of experts aimed at identifying the general criteria to define the EPCCE. Discussion took place in conference calls and by e-mail from March 2017 to November 2017, and the final consensus meeting named “European Association of Urology (EAU) Prostate Cancer Centre Consensus Meeting” was held in Barcelona on November 16, 2017. Outcome measurements and statistical analysis: The required criteria were grouped into three main steps: (1) clinics, (2) research, and (3) education. A quality control approach for the three steps was defined. Results and limitations: The definition of EPCCE consisted of the following steps: (1) clinical step—five items were identified and classified as core team, associated services, multidisciplinary approach, diagnostic pathway, and therapeutic pathway; (2) research step—internal monitoring of outcomes was required; clinical data had to be collected through a prespecified database, clinical outcomes had to be periodically assessed, and prospective trials had to be conducted; (3) educational step—it consists of structured fellowship programmes of 1 yr, including 6 mo of research and 6 mo of clinics; and (4) quality assurance and quality control procedures, related to the quality assessment of the previous three steps. A limitation of this project was that the definition of standards and items was mainly based on a consensus among experts rather than being an evidence-based process. Conclusions: The EAU Prostate Cancer Centre Consensus Meeting defined the criteria for the identification of the EPCCE in the fields of clinics, research, and education. The inclusion of a quality control approach represents the novelty that supports the excellence of these centres. Patient summary: A task force of experts defined the criteria for the identification of European Prostate Cancer Centres of Excellence, in order to certify the high-quality centres for prostate cancer management. The European Association of Urology Prostate Cancer Centre Consensus Meeting defined the criteria for the identification of European Prostate Cancer Centres of Excellence in the field of clinics, research, and education. The inclusion of a quality control approach represents the novelty that supports the excellence of these centres.

Prostate cancer (PCa) is one of the first three causes of cancer mortality in Europe. Screening in asymptomatic men (aged 55–69 yr) using prostate-specific antigen (PSA) is associated with a migration toward lower staged disease and a reduction in cancer-specific mortality. By 20 yr after testing, around 100 men need to be screened to prevent one PCa death. While this ratio is smaller than for breast and colon cancer, the long natural history of PCa means many men die from other causes. As such, the nonselective use of PSA testing and radical treatments can lead to overdiagnosis and overtreatment. The European Association of Urology (EAU) supports measures to encourage appropriate PCa detection through PSA testing, while reducing overdiagnosis and overtreatment. These goals may be achieved using personalized risk-stratified approaches. For diagnosis, the greatest benefit from early detection is likely to come in men assessed using baseline PSA levels at the age of 45 yr to individualize screening intervals. Multiparametric magnetic resonance imaging as well as risk calculators based on family history, ethnicity, digital rectal examination, and prostate volume should be considered to triage the need for biopsy, thus reducing the risk of overdiagnosis. For treatment, the EAU advocates balancing patient's life expectancy and cancer's mortality risk when deciding an approach. Active surveillance is encouraged in well-informed patients with low-risk and some intermediate-risk cancers, as it decreases the risks of overtreatment without compromising oncological outcomes. Conversely, the EAU advocates radical treatment in suitable men with more aggressive PCa. Multimodal treatment should be considered in locally advanced or high-grade cancers. Patient summary: Implementation of prostate-specific antigen (PSA)-based screening should be considered at a population level. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45 yr). The level of this test, combined with family history, ethnicity, and other factors, can be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated. The European Association of Urology supports the implementation of prostate-specific antigen (PSA)-based screening at a population level in Europe. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45 yr). This, together with family history, ethnicity, and other factors, should be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated.

In the Prostate Cancer Intervention Versus Observation Trial (PIVOT), surgery was not associated with lower mortality compared with observation. However, the high competing mortality rate of approximately 33% after 10 yr among the PIVOT study population has raised concerns on the generalizability of these results. We investigated 4282 patients who underwent radical prostatectomy at our institution between 1992 and 2010 to determine which subgroups harbored a competing (non-prostate cancer) mortality risk comparable to that of PIVOT and tested several combinations of higher age and comorbidities ("worst case scenarios") to identify subgroups reaching or even superseding the competing mortality rate of the PIVOT population. The competing mortality rate of PIVOT was not reached till an age-adjusted Charlson score of 5 or higher (corresponding to an age of 70-79 yr with diabetes with end-organ damage). Only 8.9% of patients belonged to this high-risk subgroup, and only small subgroups comprising 1-5% patients superseded the competing mortality rate among the PIVOT study population. This data underline that the results of PIVOT should be used with great caution to exclude candidates for radical prostatectomy with comorbidities from curative treatment. PATIENT SUMMARY: Only10% of patients selected for radical prostatectomy reached the competing mortality rate of approximately 33% observed in the Prostate Cancer Intervention Versus Observation Trial (PIVOT). The results of PIVOT should be used with great caution to exclude patients with concomitant diseases who seem otherwise fit for radical prostatectomy from curative treatment.

Standardized prediction of perioperative mortality risk is of major clinical concern in the radical cystectomy setting. We validated the recently developed Preoperative Score to Predict Postoperative Mortality (POSPOM) in a sample of 1083 consecutive cystectomy patients treated between 1993 and 2014. POSPOM was calculated as originally described based on age and 13 further parameters; three parameters which were not available in our database were ignored. Thirty-day and 90-d mortality were 1.0% and 4.1%, respectively. The areas under the receiver operator characteristic curves were 0.86 for 30-d mortality and 0.78 for 90-d mortality. Below the median of 27 POSPOM risk points, 30-d mortality was 0% and 90-d mortality was 0.5%. Above this level, the corresponding figures were 1.7% and 6.5%, respectively. The 30-d (p

Contains fulltext : 233937.pdf (Publisher’s version ) (Closed access) BACKGROUND: Owing to the large variation in treatment response among patients with high-risk prostate cancer, it would be of value to use objective tools to monitor the status of bone metastases during clinical trials. Automated Bone Scan Index (aBSI) based on artificial intelligence has been proposed as an imaging biomarker for the quantification of skeletal metastases from bone scintigraphy. OBJECTIVE: To investigate how an increase in aBSI during treatment may predict clinical outcome in a randomised controlled clinical trial including patients with high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively selected all patients from the Zometa European Study (ZEUS)/SPCG11 study with image data of sufficient quality to allow for aBSI assessment at baseline and at 48-mo follow-up. Data on aBSI were obtained using EXINIbone(BSI) software, blinded for clinical data and randomisation of zoledronic acid treatment. Data on age, overall survival (OS), and prostate-specific antigen (PSA) at baseline and upon follow-up were available from the study database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association between clinical parameters and aBSI increase during treatment was evaluated using Cox proportional-hazards regression models, Kaplan-Meier estimates, and log-rank test. Discrimination between prognostic variables was assessed using the concordance index (C-index). RESULTS AND LIMITATIONS: In this cohort, 176 patients with bone metastases and a change in aBSI from baseline to follow-up of ≤0.3 had a significantly longer median survival time than patients with an aBSI change of >0.3 (p

Objectives: The aim of this study was to assess penile cancer incidence, clinical characteristics, treatment options, transparency of clinical quality, and relative survival based on data from the clinical cancer registry. Subjects and Methods: A total of 898 patients with tumours of the penis were diagnosed and analysed in the period from 2000 to 2018; they were documented in the 4 regional clinical cancer registries and summarized in the Command Office of these 4 registries. Results: The standardized incidence rate increased from 0.86 in 2000 to 2.67 in 2018. Most tumours were located at the glans (42.9%) followed by the prepuce (19.5%) and corpus penis (6.9%); they were classified into pT1a/pT1b (20.0%/7.0%), pT2 (23.5%), pT3 (12.4%), and pT4 (0.8%). In only 32.0% of all documented cases, a stage-related lymphadenectomy (LND) was carried out. Negative surgical margins were found in only 70% and the Rx status in 15.1%. Primary metastasis was detected in pN1 (5.1%), pN2 (3.9%), pN3 (3.1%), and M1 status in 3.0%, respectively. The predominant therapy was surgery in 78.3%. The proportion of penile partial resections was significantly (p = 0.0045) regredient over the control period. Adjuvant chemotherapy was performed in 4.7%, adjuvant external-beam radiotherapy in 3.0%. The 5-year relative overall survival rate was 74.7% and ranged from 108.0% (stage 0) to 17.1% (stage IV). A total of 29 hospitals performed tumour operations. Conclusions: The multitude of clinical and epidemiological variables available in clinical cancer registries allows a safe assessment of tumour dynamics themselves, as well as good quality of transparency and broadly acceptable guideline adherence. Deviations from the accepted level of evidence were found in the grading definition, in the high quota of positive surgical margins, in the defensive indication position to the glans resurfacing/reconstruction and diagnostical LND. Based on these relevant findings in the database combined with the low frequency of the tumour in area/clinics/year, we recommended establishing SCCP reference clinics. This work is the first time that European standardized rate-based cancer registry data on penile cancer from Germany has been communicated.

Background: A catheter allowing a release of antibacterial substances such as antiseptics into the bladder could be a new way of preventing biofilm formation and subsequent catheter-associated urinary tract infections. Methods: Minimal inhibitory and bactericidal concentration (MIC/MBC) determinations in cation-adjusted Mueller-Hinton broth and artificial urine were performed for 4 antiseptics against 3 uropathogenic biofilm producers, Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis. Furthermore, effects of octenidine and polyhexanide against catheter biofilm formation were determined by quantification of biofilm-producing bacteria. Results: Sodium hypochlorite showed MIC/MBC values between 200 and 800 mg/L for all strains tested. Triclosan was efficient against E. coli and P. mirabilis (MIC ≤2.98 mg/L) but ineffective against P. aeruginosa. Octenidine and polyhexanide showed antibacterial activity against all 3 species tested (MIC 1.95–7.8 and 3.9–31.25 mg/L). Both octenidine and polyhexanide were able to prevent biofilm formation on catheter segments in a concentration dependent manner. Furthermore, adding 250 mg/L of each biocide disrupted biofilms formed by E. coli and P. mirabilis, whereas even 500 mg/L was not sufficient to completely destroy P. aeruginosa biofilms. Conclusion: Octenidine- and polyhexanide-containing antiseptics showed a broad effect against typical uropathogenic biofilm producers even in high dilutions. This study provides a basis for further investigation of the potential of octenidine and polyhexanide as prophylaxis or treatment of catheter biofilms.

Currently used tumor markers for early diagnosis of prostate cancer (PCa) are often lacking sufficient specificity and sensitivity. Therefore, the diagnostic potential of selected microRNAs in comparison to serum PSA levels and PSA density (PSAD) was explored. A panel of 12 PCa-associated microRNAs was quantified by qPCR in urinary sediments from 50 patients with suspected PCa undergoing prostate biopsy, whereupon PCa was detected in 26 patients. Receiver operating characteristic (ROC) curve analyses revealed a potential for non-invasive urine-based PCa detection for miR-16 (AUC = 0.744, p = 0.012, accuracy = 76%) and miR-195 (AUC = 0.729, p = 0.017, accuracy = 70%). While serum PSA showed an insufficient diagnostic value (AUC = 0.564, p = 0.656, accuracy = 50%) in the present cohort, PSAD displayed an adequate diagnostic performance (AUC = 0.708, p = 0.031, accuracy = 70%). Noteworthy, the combination of PSAD with the best candidates miR-16 and miR-195 either individually or simultaneously improved the diagnostic power (AUC = 0.801&ndash, 0.849, p &lt, 0.05, accuracy = 76&ndash, 90%). In the sub-group of patients with PSA &le, 10 ng/mL (n = 34), an inadequate diagnostic power of PSAD alone (AUC = 0.595, p = 0.524, accuracy = 68%) was markedly surpassed by miR-16 and miR-195 individually as well as by their combination with PSAD (AUC = 0.772&ndash, 0.882, p &lt, accuracy = 74&ndash, 85%). These findings further highlight the potential of urinary microRNAs as molecular markers with high clinical performance. Overall, these results need to be validated in a larger patient cohort.

Context Genomic testing is becoming increasingly important in patients with advanced prostate cancer (PC) and is being incorporated in clinical practice to guide treatment. Objective To review the current understanding of genomic alterations and the status of genomic testing in patients with metastatic castration-resistant PC (mCRPC), and the potential use of genomic tests in clinical practice. Evidence acquisition We reviewed recent publications (past 15 yr) from PubMed, proceedings of scientific conferences, and published guidelines. Reports on mCRPC in the following areas were selected: development, testing, and validation of techniques for identifying genomic alterations; molecular characterization; and trials of genetically targeted therapies. Evidence synthesis mCRPC tumors harbor molecular alterations that are possible targets for treatment, and a number of therapies are in development to exploit these alterations (eg, PD-1 inhibitors, PARP inhibitors, tyrosine kinase inhibitors). Next-generation sequencing of DNA from tumor tissue can identify somatic alterations that would not be identified by germline testing. Work is ongoing to evaluate the use of less invasive somatic testing methods (eg, sequencing of cell-free circulating tumor DNA). Current international guidelines recommend germline and/or somatic testing for men with advanced and/or high-risk PC regardless of family history to identify those with homologous recombination repair gene mutations or mismatch repair defects/microsatellite instability who may be eligible for treatment with a PARP inhibitor or pembrolizumab, respectively. Conclusions Genomic testing for mCRPC may provide information on prognostic, predictive, and resistance biomarkers. Although the incorporation of testing into clinical practice remains challenging, routine genomic testing of men with advanced PC is recommended to guide management and treatment decisions. Patient summary Similar to many cancers, prostate cancer is caused by defects in the cancer’s DNA, which are called genetic or genomic defects. New treatments targeting these defects are approved for metastatic castration-resistant prostate cancer. Specific new tests are under development to detect these potentially treatable genetic defects.

Contains fulltext : 220648.pdf (Publisher’s version ) (Closed access) The coronavirus disease 2019 (COVID-19) pandemic is unlike anything seen before by modern science-based medicine. Health systems across the world are struggling to manage it. Added to this struggle are the effects of social confinement and isolation. This brings into question whether the latest guidelines are relevant in this crisis. We aim to support urologists in this difficult situation by providing tools that can facilitate decision making, and to minimise the impact and risks for both patients and health professionals delivering urological care, whenever possible. We hope that the revised recommendations will assist urologist surgeons across the globe to guide the management of urological conditions during the current COVID-19 pandemic.

Objectives: To compare oncological outcomes of open (ORNU) and laparoscopic radical nephroureterectomy (LRNU) after controlling for preoperative patient-derived factors. Patients and methods: We evaluated a multi-institutional collaborative database composed of 3984 patients diagnosed with upper tract urothelial carcinoma (UTUC) treated with RNU between 2006 and 2018. To adjust for potential selection bias, propensity score matching adjusted for age, gender and American society Anesthesiology (ASA) score was performed with one ORNU patient matched to one LRNU patient. Uni- and multivariable Cox regression evaluating the risk of overall recurrence, cancer-specific mortality (CSM) and overall mortality (OM) in the overall population and after propensity matching were performed. Results: In total, 3984 patients underwent RNU, of these 3227 (81%) patients were treated with ORNU and 757 (19%) patients with LRNU. Within a median follow-up of 62months, 1276 recurrences, 844 CSMs and 1128 OMs were recorded. On multivariable analyses, the LRNU approach was associated with an increased risk of overall recurrence (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.03–1.54; P =0.02), but on the other hand LRNU was associated with a protective effect on CSM (HR 0.74, 95% CI 0.56–0.98; P =0.04). After propensity matching analyses adjusted for age, gender and ASA score, 757 patients treated with LRNU and 757 patients treated with ORNU were available for the analyses. On multivariable Cox regression, LRNU vs ORNU was not associated with any difference in overall recurrence (P =0.08), CSM (P =0.1) or OM (P =0.9). Conclusion: Our present data suggest that even if the type of approach to RNU was associated with different survival outcomes considering the overall population, this difference vanished when adjusted for potential confounders in propensity matching analyses. Therefore, we found that LRNU is not inferior to the ORNU approach for the treatment of UTUC. Abbreviations: ASA: American Society of Anesthesiology; CIS: carcinoma in situ; CSM: cancer-specific mortality; HR: hazard ratio; IQR: interquartile range; LN: lymph node; LNI: lymph node invasion; LVI: lymphovascular invasion; OM: overall mortality; pT: pathological tumour stage; RCT: randomised controlled trial; (L)(O)RNU: (laparoscopic) (open) radical nephroureterectomy; UTUC: upper tract urothelial carcinoma.

Bladder cancer is one of the more common malignancies in humans and the most expensive tumor for treating in the Unites States (US) and Europe due to the need for lifelong surveillance. Non-invasive tests approved by the FDA have not been widely adopted in routine diagnosis so far. Therefore, we aimed to characterize the two putative tumor suppressor genes ECRG4 and ITIH5 as novel urinary DNA methylation biomarkers that are suitable for non-invasive detection of bladder cancer. While assessing the analytical performance, a spiking experiment was performed by determining the limit of RT112 tumor cell detection (range: 100&ndash, 10,000 cells) in the urine of healthy donors in dependency of the processing protocols of the RWTH cBMB. Clinically, urine sediments of 474 patients were analyzed by using quantitative methylation-specific PCR (qMSP) and Methylation Sensitive Restriction Enzyme (MSRE) qPCR techniques. Overall, ECRG4-ITIH5 showed a sensitivity of 64% to 70% with a specificity ranging between 80% and 92%, i.e., discriminating healthy, benign lesions, and/or inflammatory diseases from bladder tumors. When comparing single biomarkers, ECRG4 achieved a sensitivity of 73%, which was increased by combination with the known biomarker candidate NID2 up to 76% at a specificity of 97%. Hence, ITIH5 and, in particular, ECRG4 might be promising candidates for further optimizing current bladder cancer biomarker panels and platforms.

Background Prostate cancer (PCa) is the most prevalent solid cancer among men in Western Countries. The clinical behavior of localized PCa is highly variable. Some cancers are aggressive leading to death, while others can even be monitored safely. Hence, there is a high clinical need for precise biomarkers for identification of aggressive disease in addition to established clinical parameters. Objective To develop an RNA expression-based score for the prediction of PCa prognosis that facilitates clinical decision making. Design, setting, and participants We assessed 233 tissue specimens of PCa patients with long-term follow-up data from fresh-frozen radical prostatectomies (RPs), from formalin-fixed and paraffin-embedded RP specimens and biopsies by transcriptome-wide next-generation sequencing and customized expression microarrays. Outcome measurements and statistical analysis We applied Cox proportional hazard models to the cohorts from different platforms and specimen types. Evidence from these models was combined by fixed-effect meta-analysis to identify genes predictive of the time to death of disease (DoD). Genes were combined by a weighted median approach into a prognostic score called ProstaTrend and transferred for the prediction of biochemical recurrence (BCR) after RP in an independent cohort of The Cancer Genome Atlas (TCGA). Results and limitations ProstaTrend comprising ∼1400 genes was significantly associated with DoD in the training cohort of PCa patients treated by RP (leave-one-out cross-validation, Cox regression: p = 2e-09) and with BCR in the TCGA validation cohort (Cox regression: p = 3e-06). The prognostic impact persisted after multivariable Cox regression analysis adjusting for Gleason grading group (GG) ≥3 and resection status (p = 0.001; DoD, training cohort) and for GG ≥ 3, pathological stage ≥T3, and resection state (p = 0.037; BCR, validation cohort). Conclusions ProstaTrend is a transcriptome-based score that predicts DoD and BCR in cohorts of PCa patients treated with RP. Patient summary ProstaTrend provides molecular patient risk stratification after radical prostatectomy.

Contains fulltext : 220533pub.pdf (Publisher’s version ) (Closed access) Contains fulltext : 220533pos.pdf (Author’s version postprint ) (Open Access) CONTEXT: There is a lack of accepted consensus on what should constitute appropriate quality-of-care indicators for bladder cancer. OBJECTIVE: To evaluate the optimal management of bladder cancer and propose quality indicators (QIs). EVIDENCE ACQUISITION: A systematic review was performed to identify literature on current optimal management and potential quality indicators for both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer. A panel of experts was convened to select a recommended list of QIs. EVIDENCE SYNTHESIS: For NMIBC, preoperative QIs include tobacco cessation counselling and appropriate imaging before initial transurethral resection of bladder tumour (TURBT). Intraoperative QIs include administration of antibiotics, proper safe conduct of TURBT using a checklist, and performing restaging TURBT with biopsy of the prostatic urethra in appropriate cases. Postoperative QIs include appropriate receipt of perioperative adjuvant therapy, risk-stratified surveillance, and appropriate decision to change therapy when indicated (eg, bacillus Calmette-Guerin [BCG] unresponsive). For MIBC, preoperative QIs include multidisciplinary care, selection for candidates for continent urinary diversion, receipt of neoadjuvant cisplatin-based chemotherapy, time to commencing radical treatment, consideration of trimodal therapy as a bladder-sparing alternative in select patients, preoperative counselling with stoma marking, surgical volume of radical cystectomy, and enhanced recovery after surgery protocols. Intraoperative QIs include adequacy of lymphadenectomy, blood loss, and operative time. Postoperative QIs include prospective standardised monitoring of morbidity and mortality, negative surgical margins for pT2 disease, appropriate surveillance after primary treatment, and adjuvant cisplatin-based chemotherapy in appropriate cases. Participation in clinical trials was highlighted as an important component indicating high quality of care. CONCLUSIONS: We propose a set of QIs for both NMIBC and MIBC based on established clinical guidelines and the available literature. Although there is currently a lack of level 1 evidence for the benefit of implementing these QIs, we believe that the measurement of these QIs could aid in the improvement and benchmarking of optimal care for bladder cancer. PATIENT SUMMARY: After a systematic review of existing guidelines and literature, a panel of experts has recommended a set of quality indicators that can help providers and patients measure and strive towards optimal outcomes for bladder cancer care.

UNLABELLED: Active surveillance (AS) represents a well-recognized management option for many patients with low- and very low-risk prostate cancer (PCa). AS aims to reduce overtreatment whilst ensuring curative treatment for those in whom it is needed, without losing the window of curability. While long-term series have confirmed the safety of AS in carefully selected patients, this has resulted in new clinical questions. Can the inclusion criteria be expanded? Is there a role for biomarkers and multiparametric magnetic resonance imaging at diagnosis or during AS? What is the optimal follow-up schedule as well as the most meaningful trigger for definitive treatment? These questions, together with increasingly adopted heterogeneous protocols in AS, have prompted the European Association of Urology to produce a position paper corroborated by a summary of the scientific background on AS. PATIENT SUMMARY: Active surveillance (AS) is becoming a widely adopted strategy for patients affected by low-risk prostate cancer. While a formal systematic review on the topic will soon be available, the European Association of Urology has produced specific statements for different open questions on AS. ispartof: EUROPEAN UROLOGY vol:74 issue:3 pages:357-368 ispartof: location:Switzerland status: published

Context Radical cystectomy continues to be associated with a significant risk of morbidity and all-cause mortality (ACM). Practice pattern data demonstrating underuse of surgery for patients with muscle-invasive and high-risk non–muscle invasive bladder cancer (BC) have been linked to the advanced age and higher comorbidity status of such patients, which suggests that rates of ACM as well as cancer-specific mortality should be incorporated into patient counseling and guideline recommendations. Objective To review the literature on risk assessment tools for preoperative comorbidity in BC that may aid in treatment decision-making. Evidence acquisition A systematic search was conducted using Ovid and Medline according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2017 reporting on comorbidity risk assessment (CRA) tools for BC. Prospective and retrospective studies were included. Evidence synthesis There are no published randomized control trials comparing CRA tools for BC. Patients undergoing radical cystectomy with combined high-risk comorbidity and performance scores may face up to a sevenfold greater risk of other-cause mortality compared to those with low scores. The Charlson Comorbidity Index is one of the most widely studied indices for 90-d perioperative mortality and overall and cancer-specific survival, with an area under the receiver operating characteristic curve of up to 0.810. Prospective studies of CRA tools for BC have consistently shown that patients with higher comorbidity have worse outcomes. While not specific for BC, comorbidity indices provide useful assessment of competing risks. Competing-risks assessment tools are lacking, with limited studies assessing the impact of these tools on treatment decision-making by patients and providers. We provide the impetus for incorporation of comorbidity risks into practice guidelines when discussing treatment options with patients. Conclusions CRA tools should be incorporated into preoperative treatment counseling and the assessment of postoperative outcomes. While retrospective evidence supports the use of CRA tools for BC, further comparative studies evaluating the effectiveness of these tools and identifying the patients most likely to benefit from a treatment according to competing-risks assessment are needed. Patient summary In this review we explored the clinical evidence for comorbidity risk assessment tools in bladder cancer. We found evidence to support incorporation of comorbidity risks into practice guidelines when discussing treatment options with patients.

The impact of smoking on mortality among patients with bladder cancer is subject to controversy. We investigated 1000 patients who consecutively underwent radical cystectomy between 1993 and 2013. Proportional hazards models for competing risks were used to study the combined effects of variables on mortality. Compared to nonsmokers, current smokers were more frequently male (35.7% vs 12.0%, p p 2 , p p =0.0129). Among current smokers there was a trend towards lower bladder cancer mortality and higher competing mortality in comparison to nonsmokers. On multivariable analysis, current smoking was not a predictor of bladder cancer mortality (hazard ratio [HR] in the full model 0.76; p =0.0687) but was a predictor of competing mortality (HR in the optimal model 1.62; p =0.0044). In conclusion, this study did not confirm adverse bladder cancer–related outcome among current smokers after radical cystectomy. With a younger mean age and a male predominance, there was a trend towards lower bladder cancer mortality current smokers that was eventually neutralized by higher competing mortality, illustrating that selection effects may explain some smoking-related outcome differences after radical cystectomy. The single-center design is a study limitation. Patient summary Current smokers are not at higher risk of bladder cancer after radical cystectomy but have a higher risk of competing mortality.

Die adjuvante Therapie des NMBIC vermittels variater BCG-Praparationen ist klinisch etabliert. In unserer Beobachtungsstudie fand sich bezogen auf den onkologischen Outcome eine Gleichwertigkeit zwischen dem BCG- und MMC-Arm. Gravierende Unterschiede in der Toxizitat zu Ungunsten des BCG-Arms wurden dokumentiert. Das potentielle Nebenwirkungsspektrum in Gestalt der BCGitis-Erkrankung wird in der Haufigkeit des Auftretens jedoch kontrovers diskutiert. Wir stellen in diesem Kontext die Ergebnisse einer retrospektiven Registerstudie mit 106 Patienten vor. Im BCG-Arm resultierten zu 78,4 % Minor-Komplikationen; anteilig koinzident mit den variaten Major-Komplikationen (lokal-urogenital/systemisch) in 43,3 %. Im parallel laufenden Vergleichsarm mit MMC lag der Anteil der komplizierenden Events mit 34,7 % bzw. 1,4 % erwartungsgemas deutlich niedriger. Auf dem Boden der aktuellen klinischen Diskussion wird auf alternative Konzepte verwiesen. Unsere Daten weisen auf eine hohe klinische Relevanz der primaren Komorbiditat hin.