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Introduction: Guideline recommendations are meant to help minimize morbidity and to improve the care of nonmuscle invasive bladder cancer (NMIBC) patients but studies have suggested an underuse of guideline-recommended care. The aim of this study was to evaluate the level of adherence of German and Austrian urologists to German guideline recommendations., Methods: A survey of 27 items evaluating diagnostic and therapeutic recommendations (15 cases of strong consensus and 6 cases of consensus) for NMIBC was administered among 14 urologic training courses. Survey construction and realization followed the checklist for reporting results of internet e-surveys and was approved by an internal review board., Results: Between January 2018 and June 2019, a total of 307 urologists responded to the questionnaire, with a mean response rate of 71%. The data showed a weak role of urine cytology (54%) for initial diagnostics although it is strongly recommended by the guideline. The most frequently used supporting diagnostic tool during transurethral resection of the bladder was hexaminolevulinate (95%). Contrary to the guideline recommendation, 38% of the participants performed a second resection in the case of pTa low-grade NMIBC. Correct monitoring of Bacille Calmette-Guérin (BCG) response with cystoscopy and cytology was performed by only 34% of the urologists., Conclusions: We found a discrepancy between certain guideline recommendations and daily routine practice concerning the use of urine cytology for initial diagnostics, instillation therapy with a low monitoring rate of BCG response, and follow-up care with unnecessary second resection after pTa low-grade NMIBC in particular. Our survey showed a moderate overall adherence rate of 73%. These results demonstrate the need for sharpening awareness of German guideline recommendations by promoting more intense education of urologists to optimize NMIBC care thus decreasing morbidity and mortality rates., (© 2021 S. Karger AG, Basel.)

Background: CRP-based scoring systems were found to correlate with survival in patients with urooncologic diseases. Our retrospective single-centre study aimed to confirm CRP as a prognostic parameter in patients with bladder cancer (BCa) undergoing radical cystectomy (RC) and, based on the findings, to develop our own outcome score for muscle-invasive bladder cancer (MIBC) patients undergoing RC in order to identify patients with a high risk of mortality., Material and Methods: A total of 254 patients who underwent RC at Hanover Medical School between 1996 and 2007 were reviewed with a follow-up until autumn 2013. The clinicopathologic parameters assessed included age, co-morbidities, pre-/postoperative serum levels of CRP, leukocytes, haemoglobin, creatinine, urinary diversion, tumour grading, staging, lymph node status, lymph node density (LND), lymphovascular invasion (LVI), metastases, and resection margin status. The Chi-square test was used for univariate analyses. Kaplan-Meier estimates and the log-rank test were used for survival analyses. Regarding outcome, overall survival (OS) was assessed., Results: The multivariate analysis excluding lymph node (LN)-positive and metastatic patients at time of RC showed a significant association of R status (R; p < 0.001), LVI (L; p = 0.021) and preoperative CRP level > 5 mg/l (C; p = 0.008) with OS. Based on these parameters, the RLC score was developed. The median OS in the intermediate, high-risk and very high-risk groups according to the RLC score was 62, 22, and 6.5 months, respectively. The score had a high predictive accuracy of 0.752., Conclusion: The RLC score identifies BCa patients at a higher risk of overall mortality after RC. Overall, our study supports the role of CRP in prognostic score models for BCa., Competing Interests: Hupe MC: Vorträge für und Honorare/Reisekosten von Ipsen, Novartis, Sanofi, Solution Akademie.Struck JP: Vorträge für und Berater/Advisor für Bayer, BMS, Eusai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche.Merseburger AS: Vorträge und Berater/Advisor für Amgen, Apogepha, Astellas, Bayer, BMS, Clovis, Ferring, Hexal, Ipsen, Janssen, Merck, MSD, Novartis, Roche, Sanofi, Takeda, TEV., (Thieme. All rights reserved.)

Purpose: To date, over 4.2 million Germans and over 235 million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Uro-oncology (UO) patients are particularly vulnerable but in urgent need of life-saving systemic treatments. Our multicentric study examined the impact of the COVID-19 crisis on the medical care of UO patients in German university hospitals receiving ongoing systemic anti-cancer treatment and to detect the delay of medical care, defined as deferred medical treatment or deviation of the pre-defined follow-up assessment., Methods: Data of 162 UO patients with metastatic disease undergoing systemic cancer treatment at five university hospitals in Germany were included in our analyses. The focus of interest was any delay or change in treatment between February 2020 and May 2020 (first wave of the COVID-19 crisis in Germany). Statistical analysis of contingency tables were performed using Pearson's chi-squared and Fisher's exact tests, respectively. Effect size was determined using Cramér's V (V)., Results: Twenty-four of the 162 patients (14.8%) experienced a delay in systemic treatment of more than 2 weeks. Most of these received immuno-oncologic (IO) treatments (13/24, 54.2%, p = 0.746). Blood tests were delayed or canceled significantly more often in IO patients but with a small effect size (21.1%, p = 0.042, V = 0.230). Treatment of patients with renal cell carcinoma (12/73, 16.4%) and urothelial carcinoma (7/32, 21.9%) was affected the most., Conclusions: Our data show that the COVID-19 pandemic impacted the medical care of UO patients, but deferment remained modest. There was a tendency towards delays in IO and ADT treatments in particular., (© 2021. The Author(s).)

Objective: Osteoprotective medications are a key element not only in the management of bone metastases of castration-resistant prostate cancer (mCRPC) but also of hormone-sensitive prostate cancer (mHSPC). Additionally, osteoprotective drugs can prevent androgen deprivation-induced bone loss. The aim of this study was to illustrate the practice pattern of osteoprotection for prostate cancer patients in Germany., Material and Methods: We designed an online survey consisting of 16 questions. The survey was sent to the nation-wide working groups "Oncology" and "Uro-Oncology" as well as to colleagues from the departments of urology of University Hospital Schleswig-Holstein (Campus Lübeck), Academic Hospital Brunswick and Technical University of Munich. Furthermore, we developed flow charts for decision guidance for osteoprotection within the different stages of prostate cancer., Results: Our analysis demonstrates a routine use of osteoprotection in the management of bone metastases of mCRPC. In contrast, osteoprotective medications are less often used for the treatment of bone metastases of mHSPC and for the prevention of androgen deprivation-induced bone loss. Our flow charts depict the different dosages and intervals for the administration of osteoprotective drugs in the different stages of prostate cancer., Conclusions: Osteoprotection is not only confined to mCRPC with bone metastases. It plays a crucial role in the management of all stages of metastatic prostate cancer., Competing Interests: Hupe MC: Vorträge für und Honorare/Reisekosten von Ipsen, Novartis, Sanofi, Solution Akademie. Müller M: keine. Struck JP: Vorträge für und Berater von Novartis, Roche und Solution Akademie. Wießmeyer JR: keine. Ozimek T: keine. Steuber T: Honorare von und Berater/Advisor für Amgen, Astra Zeneca, Astellas, Bayer, Janssen, ProteoMedix, Sanofi, GSK. Gschwend JE: Vorträge für und Berater/Advisor für Amgen, Astra-Zeneca, Bayer, BMS, Janssen, Merck, MSD, Pfizer, Roche. Hammerer P: Berater/Advisor für Amgen, Apogepha, Astellas, Bayer, BMS, Ferring, Ipsen, Janssen, Merck, MSD, Roche, Sanofi, Takeda. Kramer MW: Honorare/Reisekosten von und Berater/Advisor für Bayer, BMS, Eusai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche. Merseburger AS: Vorträge und Berater/Advisor für Amgen, Apogepha, Astellas, Bayer, BMS, Clovis, Ferring, Hexal, Ipsen, Janssen, Merck, MSD, Novartis, Roche, Sanofi, Takeda, TEVA., (Thieme. All rights reserved.)

Background: Oral chemolitholysis is a noninvasive therapy for uric acid (UA) stones. Proper patient selection is crucial for success of the therapy., Objective: To develop a nomogram for prediction of UA stones using parameters gathered during emergency work-up for flank pain., Design, Setting, and Participants: A single-center cohort (459 patients) with singular ureteral stones and available stone analysis was retrospectively reviewed for radiological, urinary, and serological findings indicating UA stones., Outcome Measurements and Statistical Analysis: A Mann-Whitney U test or Kruskal-Wallis test was applied for univariate analysis. Categorical variables were compared using a χ 2 test. Binary logistic regression of significant parameters was performed to design the nomogram., Results and Limitations: Univariate analysis revealed statistically significant differences in parameters between predominantly UA and non-UA groups, including median age (60 yr, interquartile range [IQR] 51.5-70.5 vs 51 yr, IQR 39-62; p < 0.001), body mass index (30.0 kg/m 2 , IQR 27.25-35.0 vs 26.6 kg/m 2 , IQR 24.0-30.467; p < 0.001), stone density (435.0 HU, IQR 329.0-528.0 vs 750.0 HU, IQR 548.0-995.0; p < 0.001), serum UA (437.5 μmol/l, IQR 374.25-478.0 vs 321.0 μmol/l, IQR 273.0-377.0; p < 0.001), and urine pH (5.5, IQR 5.0-5.5 vs 6.0, IQR 5.5-6.5; p < 0.001). Radiolucency was more frequent in the predominantly UA group (88.60% vs 32.70%; p < 0.001). Multivariate binary logistic regression confirmed age, body mass index, stone density, serum UA, urine pH, and radiolucency as independent predictors of UA stones and these parameters were used to design the nomogram., Conclusions: We present a nomogram for the prediction of uric acid stones., Patient Summary: We developed a nomogram as a simple tool with potential to be useful in patient counseling regarding chemolitholysis as a tailored stone treatment for uric acid urinary stones., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Tripartite motif (TRIM) family proteins are post-translational protein modifiers with E3-ubiquitin ligase activity, thereby involved in various biological processes. The molecular mechanisms driving prostate cancer (PCa) bone metastasis (BM) are incompletely understood, and targetable genetic alterations are lacking in the majority of cases. Therefore, we aimed to explore the expression and potential functional relevance of 71 TRIM members in bone metastatic PCa. We performed transcriptome analysis of all human TRIM family members and 770 cancer-related genes in 29 localized PCa and 30 PCa BM using Nanostring. KEGG, STRING and Ubibrowser were used for further bioinformatic gene correlation and pathway enrichment analyses. Compared to localized tumors, six TRIMs are under-expressed while nine TRIMs are over-expressed in BM. The differentially expressed TRIM proteins are linked to TNF-, TGFβ-, PI3K/AKT- and HIF-1-signaling, and to features such as proteoglycans, platelet activation, adhesion and ECM-interaction based on correlation to cancer-related genes. The identification of TRIM-specific E3-ligase-substrates revealed insight into functional connections to oncogenes, tumor suppressors and cancer-related pathways including androgen receptor- and TGFβ signaling, cell cycle regulation and splicing. In summary, this is the first study that comprehensively and systematically characterizes the expression of all TRIM members in PCa BM. Our results describe post-translational protein modification as an important regulatory mechanism of oncogenes, tumor suppressors, and pathway molecules in PCa progression. Therefore, this study may provide evidence for novel therapeutic targets, in particular for the treatment or prevention of BM., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

High-grade prostatic intraepithelial neoplasia (HGPIN) is a facultative precursor lesion of prostate cancer (PCa). Multifocal HGPIN in needle biopsies in the absence of PCa indicates a higher risk of cancer detection in subsequent biopsies. Therefore, a reliable diagnosis of HGPIN is of high clinical relevance guiding the management of patients with cancer-negative biopsies. Detection of HGPIN is merely based on morphological features while biomarkers aiding in the diagnosis of HGPIN and its differentiation from benign glands and other glandular lesions are lacking yet. Here, we investigated the expression of cyclin-dependent kinase 19 (CDK19) by immunohistochemistry on prostate needle biopsies of 140 patients who were all diagnosed with PCa using whole-tissue sections and compared CDK19 levels between HGPIN, PCa, and adjacent benign glands. In addition, CDK19 was compared with AMACR expression in a subset of intraductal carcinomas (IDCs) on radical prostatectomy (RP) specimens. HGPIN was present in 65.7% of biopsies and in 88% associated to adjacent PCa. CDK19 overexpression defined as moderate to high CDK19 expression visible at low magnification was found in 82.6% of HGPIN. In contrast, 89.3% of benign glands were CDK19-negative or demonstrated only low CDK19 expression highlighting a high sensitivity and specificity to accurately detect HGPIN based on CDK19 expression levels. CDK19 was overexpressed in 59% of PCa but did not correlate significantly with the expression of intermingled HGPIN. On RP, CDK19 and AMACR showed no significant difference in the detection rate of IDC. In summary, assessment of CDK19 facilitates accurate and simplified diagnosis of HGPIN with high sensitivity and specificity and aides the differentiation to non-neoplastic glandular alterations. Considering the high clinical significance of diagnosis HGPIN that still has a limited reproducibility among pathologists, we suggest CDK19 as diagnostic biomarker for HGPIN., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cancer diagnostics can be supplemented by disease-related biomarkers. In the course of modern patient-tailored cancer treatment, the importance of correct risk stratification, prognosis and monitoring has significantly increased. In recent years, a multitude of biomarkers and related test procedures have emerged to fulfil this purpose. The following review article summarizes the most recent developments with respect to the use of biomarkers in the diagnostics of urological cancers., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance., Experimental Design: V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models., Results: V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25-50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity., Conclusions: V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance., (©2021 American Association for Cancer Research.)

Purpose: Radiological parameters predicting a postoperative stone-free status (SFS) or a complicated perioperative course of mini-PNL, are scarce. Our aim was to identify such factors for prone 17.5F mini-PNL., Methods: A monocentric cohort of 103 cases was retrospectively analysed for factors predicting SFS and relevant complications, i.e. Clavien-Dindo (CD) ≥ 2. Parameters measured on preoperative supine CT included maximal stone diameter, skin-to-stone distance (SSD), ideal tract length (ITL), access angle, minimal T12-Lower Kidney Pole distance (T12LP) and minimal Iliac Crest-Lower Kidney Pole distance (ICLP). Infundibulopelvic angle (IPA) was measured on intraoperative pyelography., Results: The median maximal stone diameter was lower in cases with postoperative SFS [16 mm (Min. 10; Max. 35) vs. 20 mm (Min. 6; Max. 85), p = 0.0052]. CD ≥ 2 was more frequent in cases with a bigger stone burden [19 mm (Min. 13; Max. 85) vs. 16 mm (Min. 6; Max. 49), p = 0.0056] and with the ribs in the access angle [7/23 (30.43%) vs. 8/76 (10.53%); p = 0.0454]. T12LP significantly differed in cases with and without CD ≥ 2 [80.48 mm (± 21.31) vs. 90.43 mm (± 19.42), p = 0.0397]; however, it had no influence on SFS (p > 0.05). SSD, ITL, IPA and ICLP were significant regarding neither SFS nor CD ≥ 2 prevalence (p > 0.05). Using multivariate logistic regression, T12LP was confirmed as an independent predictor on CD ≥ 2 prevalence., Conclusions: Preoperative computed tomographic factors indicating elevated kidney position influence perioperative course of mini-PNL. T12LP and the presence of ribs in the access angle are, apart from stone diameter, the most useful indicators for cases at risk of CD ≥ 2.

Introduction: Partial nephrectomy (PN) has evolved into the surgical standard of care for localized renal lesions. Hemostatic agents (HA) support the surgeon in achieving local hemostasis during PN. We previously reported initial results with the HA Hemopatch ® in PN. We now report our experiences with Hemopatch ® in a larger and more challenging single-surgeon PN cohort., Methods: Our study included 45 patients who underwent PN due to suspicious renal lesions between December 2013 and March 2018. All surgeries were performed by a single surgeon using the HA Hemopatch ® . Preoperative, intraoperative, and postoperative parameters were assessed., Results: Preoperative median tumor diameter was 27 mm. Median PADUA and RENAL nephrometry scores were 7 and 6, respectively. In 13.3% of the cases an additional HA was applied. Intraoperative and postoperative bleeding occurred in 2.2% and 8.9%, respectively. Median total blood loss was 200 ml. Urgent pedicle clamping due to bleeding was necessary in 2 (4.4%) patients. The transfusion rate was 8.9%. There were no conversions., Conclusion: We confirmed our initial results demonstrating feasibility and reliability of Hemopatch ® during PN. Notably, the cohort consists of selected patients. Prospective randomized studies are needed for comparison of different types of HA with regard to perioperative outcome.

Intravesical chemotherapy instillation is a unique method of treatment confined to urothelial neoplasia. Within the last decades, the substances Bacillus Calmette-Guerin (BCG) and mitomycin C (MMC) have evolved as the standard regimens for intravesical therapy. However, there are other chemotherapeutic substances, which are used less frequently, such as gemcitabine. In this article we aim to highlight the clinical relevance of intravesical gemcitabine instillations as treatment of non-muscle invasive bladder cancer.The histological subtypes of bladder tumours are as diverse as the intravesical regimens. Inverted papilloma is a rare entity in the spectrum of urological diseases. There seems to be an association with non-muscle invasive bladder cancer.We report a rare case of an inverted bladder papilloma treated with intravesical gemcitabine instillations after BCG failure and an allergic reaction to MMC., Competing Interests: Die Autoren erklären, dass keine Interessenskonflikte bestehen., (Thieme. All rights reserved.)

Introduction: For risk stratification of non-muscle invasive bladder cancer (NMIBC), the depth of stromal invasion can be further classified, where the lamina muscularis mucosae (MM) serves as a reference structure. While the overall identifiability of MM in standard transurethral specimens is low, en bloc resection may help in identification and overall orientation. The aims of this study were to report the detection rate of MM in en bloc resected bladder tumors (ERBT) and to provide real-world information on tissue stability and preservation of en bloc architecture during recovery and processing for histopathologic evaluation., Methods: Thirty-four ERBT specimens were histologically re-evaluated with regard to MM detectability and structure as well as the presence of en bloc architecture and further histologic features. Associations with tumor size and energy source and within histologic parameters were assessed by standard Pearson's chi-squared analyses and Cramér's V effect size testing (V)., Results: The first parameter assessed was MM detection rate. In 19 out of 34 samples (56%) MM was detectable: scattered in 9 cases (26%), interrupted in 8 cases (24%) and continuous in 2 cases (6%). The second parameter assessed was preservation of en bloc architecture. In 11 out of 34 samples (32%), en bloc architecture could not be confirmed, and these samples served as a reference group for the detection of MM. Preservation of en bloc architecture was associated with an increased MM detection rate (MM in en bloc preserved 16/23, 70% vs. non-preserved 3/11, 27%; p = 0.020; V = 0.398) and with tumor size (p = 0.005; V = 0.595). Medium-sized tumors (1.1-2 cm) were best preserved. The choice of energy source did not show relevant association with en bloc architecture (p = n.s.)., Conclusions: In line with recent publications, ERBT increases the MM detection rate considerably. However, a third of the ERBT specimens lost en bloc architecture during sample recovery and processing. Tumor size is a relevant factor, with optimal architecture preservation between 1 and 2 cm. Optimizing resection techniques, recovery, transport, and diagnostic processing of ERBT samples is warranted to verify the diagnostic value of MM-based substaging.

Introduction: The goal was to determine risk factors for Clavien-Dindo (CD) grade ≥2 complications, with special focus on early postoperative systemic inflammatory response syndrome (SIRS), for flexible ureteroscopy (fURS)., Materials and Methods: A retrospective monocentric statistical analysis relating to 32 factors was performed with the χ2 test, Mann-Whitney U tests, and multivariate logistic regression., Results: In total, 416 consecutive fURS performed between September 2013 and June 2017 were analyzed; 283 (68.03%) of these were for stone surgery and 133 (31.97%) for diagnostic purposes. In 43 cases (10.34%), CD ≥2 occurred; 31 cases (72.09%) of these were SIRS. On multivariate logistic regression, positive preoperative urine culture and steep pyelographic and CT-based infundibulopelvic angle (IPA) have been confirmed as independent risk factors for both CD ≥2 and SIRS. Greater maximal median stone diameter and female gender were significantly associated only with a higher CD ≥2 prevalence, but not with SIRS. The influence of ureteral access sheath (UAS) on CD ≥ 2 or SIRS occurrence could not be confirmed on multivariate analysis. Perioperative antibiotic prophylaxis for patients with negative urine culture showed no difference regarding SIRS prevalence., Conclusion: Steep CT-based IPA can be considered as a new radiologic predictor of complicated postoperative course and SIRS. The role of UAS as well as indications for perioperative antibiotic prophylaxis should be determined in prospective studies., (© 2021 S. Karger AG, Basel.)

Introduction: Penile cancer (PeCa) is an orphan disease in European countries. The current guidelines are predominantly based on retrospective studies with a low level of evidence. In our study, we aimed to identify predictors for guideline-conform treatment and hypothesize that reference centers for PeCa and physicians' experience promote guideline compliance and therefore correct local tumor therapy., Methods: This study is part of the European PROspective Penile Cancer Study (E-PROPS), an international collaboration group evaluating therapeutic management for PeCa in Central Europe. For this module, a 14-item-survey was developed and sent to 681 urologists in 45 European centers. Three questions focused on therapeutic decisions for PeCa in clinical stage Tis, Ta-T1a, and T1b. Four questions addressed potential personal confounders. Survey results were analyzed by bootstrap-adjusted stepwise multivariate linear regression analysis to identify predictors for EAU guideline-conform local treatment of PeCa., Results: For local therapy of cTis 80.4% recommended guideline-conform treatment, for cTa-cT1a 87.3% and for cT1b 59.1%. In total, 42.4% chose a correct approach in all tumor stages. The number of PeCa patients treated at the hospital, a higher level of training of the physicians, resource-based answering and the option of penile-sparing surgery offered at the hospital matched with giving guideline-conform recommendations and thus accurate local tumor treatment., Conclusion: Patients with PeCa are best treated by experienced physicians, in centers with a high number of cases, which also offer a wide range of local tumor therapy. This could be offered in reference centers.

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies, and the fifth leading cause of cancer related mortality in men. For advanced PCa, radical prostatectomy, radiotherapy, and/or long-term androgen deprivation therapy are the recommended treatment options. However, subsequent progression to metastatic disease after initial therapy results in low 5-year survival rates (29%). Omics technologies enable the acquisition of high-resolution large datasets that can provide insights into molecular mechanisms underlying PCa pathology. For the purpose of this article, a systematic literature search was conducted through the Web of Science Database to critically evaluate recent omics-driven studies that were performed towards: (a) Biomarker development and (b) characterization of novel molecular-based therapeutic targets. The results indicate that multiple omics-based biomarkers with prognostic and predictive value have been validated in the context of PCa, with several of those being also available for commercial use. At the same time, omics-driven potential drug targets have been investigated in pre-clinical settings and even in clinical trials, holding the promise for improved clinical management of advanced PCa, as part of personalized medicine pipelines.

Purpose: The increasing number of flexible ureteroscopy procedures, the fragility of devices and their repair costs are a burden for urological departments worldwide. The objective was to investigate the impact of 26 pre- and intraoperative factors on reusable flexible ureteroscope (fURS) damage., Methods: All procedures were conducted with reusable fURS: Karl Storz Flex-X2 or Olympus URF-V. Statistical analysis was performed in RStudio (1.0.136) with Chi-square test and Mann-Whitney U tests (MWU)., Results: In total, 416 flexible ureteroscopies, performed between September 2013 and June 2017, were analysed. 283 (68.03%) of these were for kidney stone surgery, and 133 (31.97%) for diagnostic purposes. In total, 39 (9.38%) devices were postoperatively deemed defective. The application of reusable laser fibre through fURS was more common in cases with documented defects [17/39 (43.59%) vs. 102/377 (27.06%), p = 0.047]. Other factors such as application of nitinol basket, biopsy via fURS, insertion of access sheath (UAS), as well as stone burden [median kidney stone maximal diameter: 6 mm (min 2.0; max 30.0) vs. 6 mm (min 1.0 vs. max 30.0)] showed no influence on fURS damage rate (p > 0.05). The infundibulopelvic angle (IPA) was steeper in cases with fURS damage as compared to cases without damage [median 44.0° (min 20.0; max 81.0) vs. 55.0 (min 7.0; max 122.0), p < 0.001]., Conclusions: Application of laser fibre via fURS can be considered as a risk factor of fURS damage. Stone burden, as well as the usage of not-sharp ended devices as nitinol baskets or forceps, is primarily not responsible for fURS damage.

Purpose: Poor prognosis of patients with muscle-invasive bladder cancer that often metastasizes drives the need for discovery of molecular determinants of bladder cancer progression. Chondroitin sulfate proteoglycans, including CD44, regulate cancer progression; however, the identity of a chondroitinase (Chase) that cleaves chondroitin sulfate from proteoglycans is unknown. HYAL-4 is an understudied gene suspected to encode a Chase, with no known biological function. We evaluated HYAL-4 expression and its role in bladder cancer., Experimental Design: In clinical specimens, HYAL-4 wild-type (Wt) and V1 expression was evaluated by RT-qPCR, IHC, and/or immunoblotting; a novel assay measured Chase activity. Wt and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for stem cell phenotype, invasive signature and tumorigenesis, and metastasis in four xenograft models, including orthotopic bladder., Results: HYAL-4 expression, specifically a novel splice variant (V1), was elevated in bladder tumors; Wt expression was barely detectable. V1 encoded a truncated 349 amino acid protein that was secreted. In bladder cancer tissues, V1 levels associated with metastasis and cancer-specific survival with high efficacy and encoded Chase activity. V1 cleaved chondroitin-6-sulfate from CD44, increasing CD44 secretion. V1 induced stem cell phenotype, motility/invasion, and an invasive signature. CD44 knockdown abrogated these phenotypes. V1-expressing urothelial cells developed angiogenic, muscle-invasive tumors. V1-expressing bladder cancer cells formed tumors at low density and formed metastatic bladder tumors when implanted orthotopically., Conclusions: Our study discovered the first naturally-occurring eukaryotic/human Chase and connected it to disease pathology, specifically cancer. V1-Chase is a driver of malignant bladder cancer and potential predictor of outcome in patients with bladder cancer., (©2020 American Association for Cancer Research.)

Introduction: Multiparametric magnetic resonance imaging (mpMRI)/ultrasound fusion-guided biopsy, in short "targeted biopsy (TB)", is becoming more attractive as it improves the detection of clinically significant prostate cancer (CaP). The accuracy of fusion-guided biopsies is limited due to false positive radiological findings as well as to histological evidence for cancer in radiologically inconspicuous regions of the prostate. We aimed to analyze histomorphological findings on mpMRI lesions highly suspicious for CaP classified as PI-RADS 4 or PI-RADS 5 (Prostate Imaging - Recording and Data System) but cancer-negative in the biopsy of this region of interest (ROI), and to compare them with findings in radiologically inconspicuous regions., Materials and Methods: We re-evaluated prostate biopsies from 57 patients who underwent TB in combination with systematic standard biopsy (SB) from June 2017 to July 2018 at the University Hospital Schleswig Holstein Campus Luebeck. Out of 143 ROIs, 34 PI-RADS 4/5 cancer-negative lesions were identified and subjected to comprehensive histomorphological reevaluation. Contralateral cancer-negative SBs were used as control. Chi-square test was used for statistical analysis., Results: The frequency of histomorphological alterations including stromal, glandular, vascular, and inflammatory alterations were 97% and 79.2% in prostatic tissues from cancer-negative TBs and SBs, respectively. Stromal, glandular, and inflammatory alterations were present in the majority of biopsies from both TBs and SBs. Statistical analysis revealed no significant difference between TBs and SBs with regard to stromal, glandular, and inflammatory alterations. However, vascular abnormalities were exclusively detected in TBs (18.2%)., Conclusion: The frequency of histomorphological alterations is slightly higher in prostate tissues from TBs compared to SB. Only vascular alterations seem to be distinct for TBs. However, it has to be assumed that additional factors influence the false-negative rate of mpMRI/ultrasound fusion-guided TB., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Androgen deprivation therapy (ADT) plays a pivotal role in the treatment of advanced or metastasised prostate cancer (PCa). The aim of this health services research was to compare real-world data on the initial use of different GnRH agonists and antagonists (GnRHa) with regard to prescription patterns, hospitalisation rates and costs., Material and Methods: Anonymised claims data from > 70 German health insurance funds between 2010 and 2015 (n = 4 205 227) were analysed (1 year pre-observation period, 1 index quarter with initial GnRHa prescription, ≥ 2 years of follow-up (FU))., Results: The study population included 2382 PCa patients (mean age 75 years). Leuprolide (Leu) was prescribed most frequently (56.6 %). At initial GnRHa administration, 70 % of patients neither had lymph node nor distant metastases. Around 11.2 % of all patients stopped GnRHa treatment after the first prescription, 17.6 % switched their initial therapy to another substance after a mean of 457 days (median: 399 days); in the hybrid (hyb) group 100 days earlier on average than in the agonist group (p = 0.016). The prevalence ranking of the most common comorbidities was consistent over time: hypertension, hyperlipidaemia, cardiovascular disease (CVD) and diabetes. The prevalence of hypertension increased significantly in the agonist group (16.4 %) compared with the antagonist (6.9 %, p = 0.022) and hyb group (11.6 %, p = 0.006). With regard to CVD, there were no significant differences in the relative growth rate between the 3 combined therapy classes. In total, 23.9 % of all patients died within the 3-year FU. The mortality rate was lowest for triptorelin (Trp, 22.1 %) and highest for goserelin (Gos, 29.4 %, n.s.). In the index quarter, 26.4 % of patients had at least one inpatient hospitalisation [min-max: Trp 22.4 %; Gos 30.3 %], with an average length of hospital stay/patient of 3 days [Trp 2.4; Gos 4.5]. The annual hospitalisation rate was between 36.2 and 40.7 %, the average length of hospital stay in the entire FU was between 17.6 (Trp) and 20.8 days (hyb). The average hospital costs in the index quarter were approx. EUR 1200 [Trp 988; Gos 1803] and per FU year approx. EUR 3000. In the Trp cohort, total costs (index quarter + 3 years) were more than EUR 1000 below the average costs of EUR 9476 [Trp 8116; Leu 9779; n.s.]., Conclusion: This comparative retrospective analysis provides real-world information on initial GnRHa treatment for advanced prostate cancer, revealing differences in treatment patterns, hospitalisation rates and hospital costs in Germany., Competing Interests: Finanzierung: Diese Arbeit wurde von der Ipsen Pharma GmbH, München, Deutschland, unterstützt. MH: Reisekosten/Honorar von Ipsen. PH: Sprecher/Berater für Janssen, Ipsen, Takeda, and Sanofi. MK: keine. NK: keine. CC: Angestellte von Ipsen Pharma GmbH, München. AM: Sprecher/Berater für Astellas, BMS, Merck, Ferring, Roche, Janssen, Ipsen, Takeda, und Sanofi, (Owner and Copyright © Georg Thieme Verlag KG 2019.)

Background: The introduction of checkpoint inhibitors is a long-awaited new option for a urothelial cancer with a poor prognosis. Apart from clinical studies, the data on real world experience is scarce. Methods: Patients for monotherapy with either Atezolizumab, Nivolumab or Pembrolizumab after chemotherapy were included. Adverse events and immune related adverse events as well as survival data and imaging analyses were recorded in a prospectively designed multi-center data base. Duration of response, progression free survival (PFS), and overall survival (OS) were estimated with the Kaplan-Meier method. Results: A total of 28 patients were included. The median follow-up was 8.0 (range, 0.7-41.7) months. Median PFS was 5.8 (95% CI, 2.3-NA) months. Median OS for all patients was 10.0 (95% CI, 8.0-NA) months. The overall response rate (ORR) was 21.4% (6 out of 28 patients). Adverse events were recorded in 20 (71.4%) of patients. Higher grade adverse events (≥Grade 3) were present in 11 (39.3%) patients. No therapy related deaths occurred during the observation period. A total of 13 (46.4%) patients had adverse events that were considered to be immune related. The most commonly affected organ was the thyroid gland with 21.4% of events. Conclusion: Our real-world clinical series confirms an objective response for about every fifth patient, promising OS and a low incidence for severe adverse events (≥Grade 3)., (Copyright © 2020 Fuhrmann, Struck, Ivanyi, Kramer, Hupe, Hensen, Fürschke, Peters, Merseburger, Kuczyk and von Klot.)

Background: The prostate biopsy report is key for risk stratification of prostate cancer patients and subsequent therapeutic decision-making. However, due to the inclusion of a multitude of additional parameters its interpretation is becoming more challenging., Objectives: We aimed to determine how urologists currently interpret prostate biopsy reports, in particular how they consider different histopathological parameters for therapy decision-making., Materials and Methods: A survey was sent to all urology practices in Germany with the help of the BDU (Berufsverband der Deutschen Urologen e. V.). In total, there were 106 complete responses that could be included for further analyses., Results: Most urologists consider the number of positive cores and relative tumor burden (%) per core as crucial for the assessment of tumor extension. In case of targeted biopsies, the majority of urologists prefers a separate statement of positive cores per random biopsy scheme and per region of interest, respectively. The core with the highest Gleason score is mostly the basis for therapy decision-making (versus the overall Gleason score). Proportion of Gleason 4 pattern also seems to be critical for prostate cancer management. Only half of the urologists demand reporting of the new ISUP/WHO (International Society of Urological Pathology/World Health Organization) grade groups. Additional parameters claimed are Ki67, prostate-specific membrane antigen status, presence of intraductal or neuroendocrine component of the tumor., Conclusions: Our survey shows that there is no standardized reporting for prostate biopsies and that the interpretation of prostate biopsy reports varies among urologists. Further studies and guideline recommendations are necessary to establish a standardized reporting scheme for prostate biopsies.

Purpose: To systematically and comprehensively review and summarize the most recent literature assessing the value of the new grading system introduced by the International Society of Urological Pathology (ISUP) in 2014 and accepted by the World Health Organization (WHO) in 2016., Methods: A systematic literature search in the PubMed database was performed up to November 2018. Overall, 15 studies in the period from 2016 to 2018 evaluating the new grading system have been selected for evidence synthesis., Results: The main goals of the new ISUP 2014/WHO 2016 grading system were to establish (I) a more accurate and simplified grade stratification, (II) less overtreatment of indolent prostate cancer as well as (III) an improved patient communication. The majority of the studies chose biochemical recurrence as an endpoint for evaluation and statistically assigns the new ISUP 2014/WHO 2016 grading system a higher prognostic accuracy than the former Gleason grading. However, in only a subset of studies it was clearly evident that the historical samples were not only re-grouped according to the new grade groups but also re-graded according to the new histomorphological 2014 ISUP criteria., Conclusions: The vast majority of the studies support an improved prognostic accuracy of the ISUP 2014/WHO 2016 grade groups and endorse its worldwide application.

Background: Whether or not double J (DJ) stenting during transurethral resection of a bladder tumour (TURBT) harms patients with regard to possible metachronous upper urinary tract urothelial cancer (UUTUC) development remains controversial. This study evaluated the impact of DJ compared to nephrostomy placement during TURBT for bladder cancer (BCa) on the incidence of metachronous UUTUCs., Methods: We retrospectively analysed 637 patients who underwent TURBT in our department between 2008 and 2016. BCa, UUTUC and urinary drainage data (retrograde/anterograde DJ and percutaneous nephrostomy) were assessed, along with the prevalence of hydronephrosis, and mortality. Chi-square and Fisher's exact test was performed for univariate analyses. Survival analysis was performed by the Kaplan-Meier method and log-rank tests., Results: UUTUC was noted in 28 out of 637 patients (4.4%), whereas only eight (1.3%) developed it metachronously to BCa. Out of these, four patients received DJ stents, while four patients received no urinary drainage of the upper urinary tract. Placement of urinary drainage significantly correlated with UUTUC (50.0% vs. 17.9%; p = 0.041). DJ stenting significantly correlated with UUTUC (50.0% vs. 11%; p <  0.01), while no patient with a nephrostomy tube developed UUTUC. UUTUC-free survival rates were significantly lower for patients with DJ stents than for all other patients (p = 0.001). Patients with or without DJ stents had similar overall survival (OS) rates (p = 0.73), whereas patients with nephrostomy tubes had significantly lower OS rates than all other patients (p <  0.001)., Conclusions: Patients with DJ stenting during TURBT for BCa might have an increased risk of developing metachronous UUTUC. This study indicated advantages in placing nephrostomy tubes rather than DJ stents; however, confirmation requires investigation of a larger cohort. Even so, the increased mortality rate in the nephrostomy group reflected hydronephrosis as an unfavourable prognostic factor.

The Mediator complex is a transcriptional regulator interacting with transcription factors and RNA-polymerase-II. Recently, we identified its subunit CDK19 to be specifically expressed in prostate cancer (PCa) and to be functionally implicated in PCa aggressiveness. Aim of our study was to comprehensively characterize the protein expression of CDK19 and its paralog CDK8 in PCa. We performed immunohistochemistry (IHC) for CDK19/CDK8 on a large cohort including needle biopsies from 202 patients, 799 primary tumor foci of radical prostatectomy specimens from 415 patients, 120 locally advanced tumor foci obtained by palliative transurethral resection, 140 lymph node metastases, 67 distant metastases and 82 benigns. Primary tumors were stained for the proliferation marker Ki67, androgen receptor (AR) and ERG. For 376 patients, clinic-pathologic data were available. Primary endpoint was disease-recurrence-free survival (DFS). Nuclear CDK19 and CDK8 expression increases during progression showing the highest intensity in metastatic and castration-resistant tumors. High CDK19 expression on primary tumors correlates with DFS independently from Gleason grade and PSA. Five-year-DFS rates of patients with primary tumors expressing no, moderate and high CDK19 are 73.7, 56.9 and 30.4%, respectively. CDK19 correlates with Gleason grade, T-stage, Ki67 proliferation-index, nuclear AR expression and ERG-status. Therapeutic options for metastatic and castration-resistant PCa remain limited. In the current study, we confirmed an important role of the Mediator subunit CDK19 in advanced PCa supporting current developments to target CDK19 and its paralog CDK8. Furthermore, CDK19 protein expression has the potential to predict disease recurrence independently from established biomarkers thus contributing to individual management for PCa patients., (© 2019 UICC.)

Introduction: The aim of this study was to analyze the influence of residents' participation in flexible ureteroscopy (fURS) on intra- and postoperative outcomes., Materials and Methods: Intra- and postoperative parameters were compared in a retrospective monocentric setting between 3 groups: "resident group" (47 cases) for surgeries performed by experienced residents alone, "consultant group" (245 cases) for surgeries performed by consultants alone, "resident plus consultant group" (124 cases) for training surgeries between September 2013 and June 2017., Results: Patients operated by residents alone had a significantly smaller median kidney stone diameter (5.0 vs. 7.0 mm for "consultant group" and 6.0 mm for "resident plus consultant group," p = 0.011), shorter operating time (median 47.0 vs. 63.0 and 77.0 min, p < 0.001) and fluoroscopy time (median 39.0 vs. 69.5 and 89.0 s, p < 0.001), as well as shorter postoperative hospital stay (p = 0.013). The laser application rate was the smallest in the "resident group" (10.64 vs. 31.43 and 29.84%, p = 0.009). Univariate analysis revealed no relevant differences regarding flexible ureteroscope defect rate, postoperative stone-free rate, or ≥2 Clavien-Dindo classification complications between the groups (p > 0.05)., Conclusion: A proper case selection of less complicated cases, especially without laser application, could balance the experience deficit of the residents. fURS can be incorporated as a part of residents' training without an impact on fURS device defect rate or clinical outcomes., (© 2020 S. Karger AG, Basel.)

Background:  In 2014, the International Society of Urological Pathology (ISUP) introduced a new grading system for prostate cancer (PCa), which was accepted and adopted by the World Health Organisation (WHO) in 2016. The new system defined five distinct grade groups and adjusted several histomorphological criteria. Our study aimed to systematically review and summarise the most recent literature and to compare the new grading system with the former Gleason grading., Material and Methods:  We performed a literature screening in the PubMed database. A total of 15 studies evaluating the new grading system during the period from 2016 to 2018 were selected for our review., Results:  The main goals of the new ISUP 2014/WHO 2016 grading system were a more accurate and simplified grade stratification, less overtreatment of indolent PCa as well as improved patient communication. Biochemical recurrence was the most common endpoint for statistical analysis. Most studies found that the new ISUP 2014/WHO 2016 grading system provides higher prognostic accuracy than the former Gleason grading. Notably, however, only a subset of studies clearly demonstrated that the archived samples were not only re-grouped according to the new grade groups, but also re-graded according to the new histomorphological 2014 ISUP criteria., Conclusions:  The prognostic accuracy of the ISUP 2014/WHO 2016 grade groups was confirmed by the majority of the studies. Nevertheless, the interpretation of the study results should be based upon the criterion of correct re-grading., Competing Interests: Die Autoren geben an, dass keine Interessenkonflikte vorliegen., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Simply applicable biomarkers for prostate cancer patients predicting the clinical course are urgently needed. Recently, TRIM24 has been identified to promote androgen receptor signaling and to correlate with an aggressive prostate cancer phenotype. Based on these data, we proofed TRIM24 as a prognostic biomarker for risk stratification., Materials and Methods: We performed TRIM24 immunohistochemistry on 2 independent cohorts including a total of 806 primary tumors, 26 locally advanced/recurrent tumors, 30 lymph node metastases, 30 distant metastases, and 129 benign prostatic samples from 497 patients as well as on 246 prostate needle biopsies. Expression data were correlated with clinic-pathological data including biochemical recurrence-free survival (bRFS) as endpoint., Results: Benign samples show no or low TRIM24 expression in 94%, while tumor tissues demonstrate significant higher levels. Strongest expression is observed in advanced and metastatic tumors. In multivariate analyses, TRIM24 up-regulation on radical prostatectomy specimens correlates with shorter bRFS independent of other prognostic parameters. 5-(10-) year bRFS rates for TRIM24 negative, low, medium and high expressing tumors are 93.1(93.1)%, 75.4(68.5)%, 54.9(47.5)% and 43.1(32.3)%, respectively. Of interest, tumors diagnosed as indolent disease, TRIM24 expression stratifies patients into specific risk groups. Increased TRIM24 expression associates with higher grade group, positive nodal status and extraprostatic tumor growth. TRIM24 assessment on prostate needle biopsies taken prior to treatment decision at time of initial diagnosis significantly correlates with recurrence after surgery., Conclusion: Using 2 large independent radical prostatectomy specimen cohorts, we found that TRIM24 expression predicts patients' risk to develop disease recurrence with high accuracy and independent from other established biomarkers. Further, this is the first study exploring TRIM24 expression on prostate needle biopsies which represents the clinically relevant tissue type on which biomarkers guide treatment decisions. Thus, we strongly suggest introducing TRIM24 evaluation in prostate needle biopsies in clinical routine as an inexpensive and simple immunohistochemical test., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Molecular tumor boards (MTB) are becoming more common. There are several molecular alterations in urothelial cancer a molecular tumor board can potentially rely on., Objectives: The aim is to specify molecular alterations and their correlations with different clinical endpoints and to highlight potential questions addressed to a MTB for urothelial cancer., Materials and Methods: Descriptive review of the literature based on PubMed., Results: The landscape of molecular alterations in urothelial cancer is heterogeneous. Thus, recent biomarker research has been focusing on biomarker panels and classifiers instead of single biomarkers. Recently, molecular subtypes of urothelial cancer have been identified and correlated with different clinical endpoints. Furthermore, circulating tumor cells and tumor DNA are under investigation as potential biomarkers. In addition to treatment response and prognosis, molecular markers are also needed to improve clinical staging prior to radical cystectomy or for proper patient selection for neoadjuvant chemotherapy. Erdafitinib is the first targeted therapy (fibroblast growth factor receptor [FGFR] alteration) in urothelial cancer that was recently approved (in the USA)., Conclusions: Due to the lack of external validation, none of the identified biomarkers is currently established in clinical routine. In addition, there is no single driver mutation in urothelial cancer that facilitates the development of biomarkers and targeted therapies.

Objective: The bromodomain and extra-terminal (BET) family of proteins provides a scaffolding platform for the recruitment and tethering of transcription factors to acetylated chromatin, thereby modulating gene expression. In this study, we evaluated the efficacy of the BET-inhibitor PFI-1 to diminish AR/AR-V7 signaling and proliferation in castration-resistant prostate cancer cells., Methods: Prostate-specific antigen and androgen receptor (AR) protein were quantified by means of two commercial ELISAs. Transactivation of the AR, AR-V7 and Q641X was determined by reporter gene assays. Cell proliferation was measured using a colorimetric MTT-assay., Results: PFI-1 dose-dependently inhibited transactivation of full-length AR (non- mutated, i.e., wild-type or point-mutated/promiscuous forms) without affecting their cellular protein levels. Moreover, PFI-1 was active against C-terminally truncated constitutively active ARs like AR-V7 and Q641X. Prostate cancer cells exhibiting a transcriptionally active AR-signaling complex (LNCaP, 22Rv1) were more susceptible to the growth-inhibitory effects than the AR-negative PC-3 cells., Conclusion: The quinazolinone PFI-1 is a highly efficient inhibitor of AR-signaling-competent prostate cancer cells in vitro. PFI-1 could serve as a lead compound for the development of new therapeutics able to block AR/AR-V7 signaling in advanced prostate cancer.

Background: Stratifying prostate cancer (PCa) patients into risk groups at time of initial diagnosis enabling a risk-adapted disease management is still a major clinical challenge. Existing studies evaluating the prognostic potential of PSMA (prostate-specific membrane antigen) for PCa were performed on radical prostatectomy specimens (RPE), i.e., decision making for disease management was already completed at time of sample analysis. Aim of our study was to assess the prognostic value of PSMA expression for PCa patients on biopsies at time of initial diagnosis. Methods: PSMA expression was assessed by immunohistochemistry on 294 prostate biopsies with corresponding RPE, 621 primary tumor foci from 242 RPE, 43 locally advanced or recurrent tumors, 34 lymph node metastases, 78 distant metastases and 52 benign prostatic samples. PSMA expression was correlated with clinico-pathologic features. Primary endpoint was recurrence free survival. Other clinicopathologic features included WHO/ISUP grade groups, PSA serum level, TNM-stage, and R-status. Chi-square test, ANOVA-analyses, Cox-regression, and log-rank tests were performed for statistical analyses. Results: High PSMA expression on both biopsy and RPE significantly associates with a higher risk of disease recurrence following curative surgery. The 5-year-recurrence free survival rates were 88.2, 74.2, 67.7 and 26.8% for patients exhibiting no, low, medium, or high PSMA expression on biopsy, respectively. High PSMA expression on biopsy was significant in multivariate analysis predicting a 4-fold increased risk of disease recurrence independently from established prognostic markers. PSMA significantly increases during PCa progression. Conclusion: PSMA is an independent prognostic marker on biopsies at time of initial diagnosis and can predict disease recurrence following curative therapy for PCa. Our study proposes the application of the routinely used IHC marker PSMA for outcome prediction and decision making in risk-adapted PCa management on biopsies at time of initial diagnosis.

Objective: The objective of this study was to obtain real-world information on gonadotropin-releasing hormone agonist/antagonist (GnRHa) therapy in patients with advanced prostate cancer (PCa). Materials and methods: Anonymized, routine healthcare claims data from approx. 75 German statutory health insurance funds from 2010-2015 ( n = 4,205,227) were analyzed. Patients had an enrolment of 1 year before GnRHa, 1 index quarter of initial GnRHa prescription and ≥2 years of follow-up. Results: In total, 2,382 patients with PCa were eligible. The most frequent index therapy was leuprolide in 56.6%. The rank order of PCa comorbidity prevalence was consistent over time (% at index and 3-years of follow-up): hypertension (71.5; 85.0), hyperlipidemia (45.2; 60.8), cardiovascular disease ( CVD) (35.7; 54.1), and diabetes (28.3; 36.2). Comparing pooled therapy classes (agonists, hybrids, and antagonist), no significant differences in the incidence of CVD or diabetes were observed. For hypertension, there was a significant increase for agonists (16.4%) compared to antagonists (6.9%, p = 0.022) and leuprolide hybrid group (11.6%, p = 0.006). During the follow-up period 23.9% of all PCa patients died. There were no significant differences concerning mortality rate and discontinuation rates between the cohorts. In total, 11.2% of all patients discontinued GnRHa after first prescription; the mean time to first switch to another GnRHa therapy was 100 days earlier for hybrids than for agonists ( p = 0.016). Conclusion: This comparative retrospective analysis provides real-world information about healthcare characteristics and treatment patterns, highlighting the impact of different GnRHa on clinical outcomes for patients with advanced PCa in Germany.

Introduction: There is an urgent need to identify patients with bladder cancer (BC) who are at high risk of recurrence or progression. Calgranulin A is a strong marker for muscle-invasive or advanced BC and recent studies have shown its potential for identifying patients at risk even in non-muscle-invasive bladder cancer (NMIBC). The present study examines risks of recurrence and progression dependent on immunostaining with calgranulin A in NMIBC., Methods: Calgranulin A protein expression was evaluated through the immunohistochemistry of 158 randomly selected, transurethrally resected BC specimens of separate patients (pTa 89, pT1 69) using tissue microarrays. Kaplan-Meier survival analysis and Cox regression were performed to determine whether calgranulin A expression is associated with recurrence-free survival (RFS), progression-free survival (PFS), or cancer-specific survival (CSS)., Results: Calgranulin A expression is significantly different between pTa and pT1 tumors (p = 0.000, Mann-Whitney U test) and between tumor grades (p = 0.015, Kruskal-Wallis test). Kaplan-Meier estimates produced significant results for low and high calgranulin A expression concerning RFS [5y-RFS 70.4 ± 4.0% vs. 35.9 ± 12.5%, median RFS not reached (NR) vs. 12.0 ± 4.4 month, p = 0.029, log-rank test], PFS (5y-PFS 90.3 ± 2.7% vs. 51.5 ± 14.0%, median PFS NR in both groups, p = 0.000, log-rank test), and CSS (5y-CSS 92.9 ± 2.6% vs. 70.7 ± 12.4%, median CSS NR in both groups, p = 0.005, log-rank test). Calgranulin A remained an independent factor for RFS (p = 0.024, HR 2.43) and PFS (p = 0.002, HR 5.92) according to the multivariate Cox regression model., Conclusions: Calgranulin A expression in NMIBC, detected through immunohistochemistry, is a promising marker for the identification of NMIBC patients at high risk of recurrence and progression.

Background:  In 2016, the first German guideline for bladder cancer was introduced. This survey evaluates current management of bladder cancer in Germany, focusing on systemic therapies and compares this to the guidelines., Material and Methods:  More than 4000 urologists and oncologists in Germany received a questionnaire assessing surgical and systemic therapeutic management of bladder cancer. We received 278 evaluable responses., Results:  This is the largest nationwide survey evaluating current bladder cancer management in Germany. Management can be optimised of non-muscle invasive bladder cancer including intravesical instillation therapies, as well as of muscle invasive bladder cancer including (neo)adjuvant chemotherapies, particularly with respect to the numbers of chemotherapy courses. Management of metastasised bladder cancer is predominantly performed according to the guidelines., Conclusions:  Adherence to bladder cancer guidelines in Germany can be optimised and could possibly decrease cancer-specific mortality, supported by the development of novel diagnostic and therapeutic options., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: The increasing number of flexible ureterorenoscopy (fURS) procedures, the fragility of devices, and their growing repair costs represent a substantial burden for urological departments worldwide. No risk factors of flexible ureteroscope damage have been identified so far. The objective of this study was to investigate the impact of infundibulopelvic angle (IPA) on device damage and on other intraoperative and postoperative factors such as length of hospital stay, surgical complications, stone-free rate (SFR), operation, and fluoroscopy time., Materials and Methods: In a retrospective monocentric study, IPA was measured based on intraoperative retrograde pyelography images taken during fURS. All procedures were conducted with modern reusable flexible ureteroscopes: Karl Storz Flex-X2 or Olympus URF-V. Statistical analysis was performed in RStudio (version 1.0.136) with the unpaired t-test and Mann-Whitney U test. Pearson correlation coefficient (Pearson's r) was measured whenever applicable., Results: In total, 381 fURS performed between September 2013 and March 2017 were analyzed: 260 (68.24%) for kidney stone operation and 121 (31.76%) for diagnostic purposes; of these, 38 (9.97%) devices were postoperatively deemed defective. IPA values were significantly steeper in cases with flexible ureteroscope damage compared to cases without damage (median 42.5 degrees vs 56.0, p < 0.001). Steeper IPA was significantly associated with the occurrence of Clavien-Dindo ≥2 complications (median 51.0 degrees vs 55.0, p = 0.005) as well as prolonged hospital stay (median 51.0 degrees vs 55.0, p = 0.014). No influence on SFR was observed (p > 0.05). IPA did not correlate with operation or fluoroscopy time., Conclusions: Steep IPA can be considered the first risk factor predicting both flexible ureteroscope damage and an unfavorable postoperative course. A better understanding of damage mechanisms is the key for the proper indications to use costly single-use devices.

Objectives: We had previously demonstrated changes in defecation after radical cystectomy (RC). Reports addressing long-term bowel disorders following RC are rare. This cross-sectional study evaluates long-term bowel issues in a large cohort., Material and Methods: A questionnaire assessing changes in bowel function (diarrhea, constipation, urge to defecate, sensation of incomplete defecation, and flatulence) and its effect on quality of life was developed based on the gastrointestinal quality of life index and distributed in collaboration with the German bladder cancer support group. There were 431 evaluable questionnaires. For the analyses, we focused on patients that had the RC>1 year ago (n = 324)., Results: Current bowel problems were reported by 42.6% of patients. The most frequent bowel problems were flatulence (48.8%), diarrhea (29.6%), and sensation of incomplete defecation (22.5%). In cases of bowel problems, 39.7% and 59.8% of the patients indicated life restriction and dissatisfaction, respectively. Prevalence of diarrhea and flatulence were significantly higher>12 (vs. ≤12) months following RC. Both symptoms significantly correlated with younger age at RC, life restriction, lower quality of life, lower health state, and lower energy level. Additionally, diarrhea significantly correlated with pouches as urinary diversion (vs. ileal conduit or ureterocutaneostomy) and higher dissatisfaction level., Conclusions: To our knowledge this is the largest cohort evaluating long-term bowel symptoms after RC. Diarrhea is a prominent symptom after RC with a high impact on daily life that leads to dissatisfaction. A better understanding of long-term bowel symptoms could be translated into optimized surgical procedures, postoperative medication/nutrition, and patient education., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR. The following review delineates recent progress in the development of AR inhibitors that do not depend on androgen binding and represent a putative third generation of AR inhibitors.

Introduction: Laparoendoscopic single-site surgery (LESS), robot-assisted (RA), and retroperitoneoscopic (R) surgery expand the armamentarium of minimally invasive surgery (MIS). As information on the use of these surgical approaches in daily routine is limited, we conducted a survey among German urologists., Materials and Methods: In 2017, all urology departments in Germany received a questionnaire evaluating practice patterns of MIS in the retroperitoneum. Chi-Square test was performed for statistical analyses. The response rate was 51.1% (162/311) including 23 universities., Results: R adrenalectomy and (partial) nephrectomy are performed by 32.7-40.1% of all departments. Transperitoneal LESS adrenalectomy and nephrectomy are performed by 8.6-11.7%. Retroperitoneal RA adrenalectomy and (partial) nephrectomy are performed by 6.2-13.0%. There was no difference in the R and LESS approach between (non)-university departments. Retroperitoneal RA access is more frequently used in university hospitals (all p < 0.01). If performed, mean counts within the last 12 months were < 5 for R, LESS, and RA adrenalectomy; and < 20 for R, LESS, and RA (partial) nephrectomy., Conclusion: Our survey provides a detailed insight into MIS in the retroperitoneum in German urology departments. Numbers of adrenalectomies as well as R, transperitoneal LESS and retroperitoneal RA procedures are low. Retroperitoneal RA surgery is more common in universities. Comprehensively, our survey proves that these approaches are not standard approaches yet., (© 2018 S. Karger AG, Basel.)

Objective: The increasing number of flexible ureterorenoscopy (fURS) procedures, the fragility of devices, and their growing maintenance and repair costs represent a substantial burden for urologic departments. Disposable single-use fURS devices offer many advantages over reusable fURS. Among them, the LithoVue™ model shows the best clinical utility. In our study, we assessed the economic aspects of reusable fURS application compared with the potential costs and benefits of single-use fURS (LithoVue™). Indications for single-use fURS were proposed based on potential risk factors of reusable fURS damage., Materials and Methods: This single-center retrospective analysis compared the actual cost of reusable fURS procedures with the potential costs of LithoVue™ based on the price offered by the manufacturer. Consecutive case analysis of damaged fURS was performed to determine potential risk factors associated with fURS damage., Results: The study group consisted of 423 reusable fURS procedures conducted between January 2013 and December 2016. During this period, 102 (24.11%) diagnostic fURS and 321 (75.89%) fURS for kidney stone therapy were performed. In 32 of 423 (7.57%) fURS cases, devices were postoperatively deemed defective, 9 of which were used for diagnostic procedures (9/102; 8.82%), 7 for stone removal (7/148; 4.73%), and 16 for stone removal and laser (Ho:YAG) application (16/173; 9.25%). The average cost per reusable fURS procedure was found to be €503.26., Conclusions: Disposable fURS is a more expensive option for high-volume centers. Based on our case analysis, laser disintegration treatment of multiple, large stones in the lower kidney pole of recurrent stone formers, as well as a steep infundibulopelvic angle (IPA ≤50°), seems to be the main risk factor for fURS damage. For these cases, disposable fURS may be a cost-effective alternative; however, a prospective comparison of economic outcomes between disposable and reusable fURS, together with confirmation of the proposed damage risk factors, is needed.

Gleason grading is the best independent predictor for prostate cancer (PCa) progression. Recently, a new PCa grading system has been introduced by the International Society of Urological Pathology (ISUP) and is recommended by the World Health Organization (WHO). Following studies observed more accurate and simplified grade stratification of the new system. Aim of this study was to compare the prognostic value of the new grade groups compared to the former Gleason Grading and to determine whether re-definition of Gleason Pattern 4 might reduce upgrading from prostate biopsy to radical prostatectomy (RP) specimen. A cohort of men undergoing RP from 2002 to 2015 at the Hospital of Goeppingen (Goeppingen, Germany) was used for this study. In total, 339 pre-operative prostatic biopsies and corresponding RP specimens, as well as additional 203 RP specimens were re-reviewed for Grade Groups according to the ISUP. Biochemical recurrence-free survival (BFS) after surgery was used as endpoint to analyze prognostic significance. Other clinicopathological data included TNM-stage and pre-operative PSA level. Kaplan-Meier analysis revealed risk stratification of patients based on both former Gleason Grading and ISUP Grade Groups, and was statistically significant using the log-rank test ( p  < 0.001). Both grading systems significantly correlated with TNM-stage and pre-operative PSA level ( p  < 0.001). Higher tumor grade in RP specimen compared to corresponding pre-operative biopsy was observed in 44 and 34.5% of cases considering former Gleason Grading and ISUP Grade Groups, respectively. Both, former Gleason Grading and ISUP Grade Groups predict survival when applied on tumors in prostatic biopsies as well as RP specimens. This is the first validation study on a large representative German community-based cohort to compare the former Gleason Grading with the recently introduced ISUP Grade Groups. Our data indicate that the ISUP Grade Groups do not improve predictive value of PCa grading and might be less sensitive in deciphering tumors with 3 + 4 and 4 + 3 pattern on RP specimen. However, the Grade Group system results less frequently in an upgrading from biopsy to the corresponding RP specimens, indicating a lower risk to miss potentially aggressive tumors not represented on biopsies.

Patients with advanced bladder cancer have poor outcomes, indicating a need for more efficient therapeutic approaches. This study characterizes proteomic changes underlying bladder cancer invasion aiming for the better understanding of disease pathophysiology and identification of drug targets. High resolution liquid chromatography coupled to tandem mass spectrometry analysis of tissue specimens from patients with non-muscle invasive (NMIBC, stage pTa) and muscle invasive bladder cancer (MIBC, stages pT2+) was conducted. Comparative analysis identified 144 differentially expressed proteins between analyzed groups. These included proteins previously associated with bladder cancer and also additional novel such as PGRMC1, FUCA1, BROX and PSMD12, which were further confirmed by immunohistochemistry. Pathway and interactome analysis predicted strong activation in muscle invasive bladder cancer of pathways associated with protein synthesis e.g. eIF2 and mTOR signaling. Knock-down of eukaryotic translation initiation factor 3 subunit D (EIF3D) (overexpressed in muscle invasive disease) in metastatic T24M bladder cancer cells inhibited cell proliferation, migration, and colony formation in vitro and decreased tumor growth in xenograft models. By contrast, knocking down GTP-binding protein Rheb (which is upstream of EIF3D) recapitulated the effects of EIF3D knockdown in vitro , but not in vivo . Collectively, this study represents a comprehensive analysis of NMIBC and MIBC providing a resource for future studies. The results highlight EIF3D as a potential therapeutic target., Competing Interests: CONFLICTS OF INTEREST Harald Mischak is the founder and co-owner of Mosaiques Diagnostics. Dr. Maria Frantzi is employed by Mosaiques Diagnostics. Dr. Agnieszka Latosinska is also currently employed by Mosaiques Diagnostics.

Tumor cell-derived hyaluronidase HYAL-1 degrades hyaluronic acid (HA) into angiogenic fragments (AGF: 10-12 disaccharides). AGF support tumor growth and progression. Urine and tissue HAase/HYAL-1 levels are sensitive markers for high-grade bladder cancer (BCa) and its metastasis. In preclinical models of BCa, we evaluated whether o-sulfated AGF (sHA-F) inhibits HAase activity and has antitumor activity. At IC50 for HAase activity inhibition (5-20 μg/ml [0.4-1.7 μM]), sHA-F significantly inhibited proliferation, motility and invasion of HYAL-1 expressing BCa cells (253J-Lung, HT1376, UMUC-3), P<0.001. sHA-F did not affect the growth of HYAL-1 non-expressing BCa (5637, RT4, T24, TCCSUP) and normal urothelial (Urotsa, SV-HUC1) cells. sHA-F treatment induced apoptosis by death receptor pathway. sHA-F downregulated transcript and/or protein levels of HA receptors (CD44, RHAMM), p-AKT, β-catenin, pβ-Catenin(S552), Snail and Twist but increased levels of pβ-Catenin(T41/S45), pGSK-3α/β(S21/S9) and E-cadherin. sHA-F also inhibited CD44/Phosphoinositide 3-kinase (PI-3K) complex formation and PI-3K activity. AGF addition or myristoylated-AKT overexpression attenuated sHA-F effects. Contrarily, HYAL-1 expression sensitized RT4 cells to sHA-F treatment. In the 253J-L and HT1376 xenograft models, sHA-F treatment significantly inhibited tumor growth (P<0.001), plausibly by inhibiting angiogenesis and HA receptor-PI-3K/AKT signaling. This study delineates that sHA-F targets tumor-associated HA-HAase system and could be potentially useful in BCa treatment.

Purpose of Review: There are multiple minimal invasive approaches to remove the adrenal gland. The purpose of this review is to summarize the most up-to-date findings about laparoscopic, retroperitoneoscopic, robot-assisted, and single-site adrenalectomy, and to define the most common approaches to the adrenal gland., Recent Findings: Laparoscopic adrenalectomy is the gold standard to remove adrenal tumors. New approaches are being explored to outperform the advantages of laparoscopic adrenalectomy., Summary: Retroperitoneoscopic adrenalectomy, when performed by skilled surgeons, offers an alternative to the conventional laparoscopic approach, with better outcome. The robot-assisted and single-site approaches still need further studies to fully identify their roles in adrenalectomy.

Androgen deprivation therapy (ADT) is the mainstay palliative treatment for men with locally advanced and metastatic prostate cancer, and aims to reduce testosterone to levels obtained by surgical castration. Use of gonadotropin-releasing hormone (GnRH) agonists predominates among the ADT options. The GnRH agonist, triptorelin is a first-line hormonal therapy that has demonstrated efficacy and safety in clinical trials of patients with locally advanced non-metastatic or metastatic disease. Sustained-release 1-, 3- and 6-month formulations of triptorelin, administered intramuscularly or subcutaneously, have been developed to provide improved flexibility and convenience for the patient. Head-to-head studies of GnRH agonists are lacking in the field of prostate cancer. Despite the inevitable progression to castration-resistant prostate cancer (CRPC) in most patients receiving ADT, monitoring of testosterone levels needs to improve in routine practice and physicians should not overlook the benefits of continued ADT in their patients when introducing one of the various new treatment options for CRPC. For improved survival outcomes, there remains a need to tailor ADT treatment regimens, novel hormonal agents and chemotherapy according to the individual patient with advanced prostate cancer.

We report a successful pregnancy and birth subsequent to fertility-preserving cystectomy and neobladder formation in a muscle-invasive sarcomatoid urothelial carcinoma., (© 2015 S. Karger AG, Basel.)

Purpose: To determine whether implementation of the 2004 WHO/ISUP bladder cancer (BCa) grading system caused a grade migration, i.e., more tumors being graded as high grade (HG)., Methods: Data on 1040 BCa cases from 668 patients treated at our institution between 2000 and 2013 and reviewed by six pathologists were evaluated: low grade (LG): 249; HG: 791; Ta: 389; T1: 214; CIS: 95; ≥T2: 342. Differences in LG or HG cases (expressed as %BCa cases/year) were analyzed by Mann-Whitney test. Correlation between the year of diagnosis and clinical/pathological parameters was evaluated by logistic regression analyses., Results: During the study period, BCa cases diagnosed as LG significantly decreased with a corresponding increase in HG cases. Nonlinear regression analysis indicated that ~2008 was the crossover point for grade migration; %LG: 31.8 ± 4.8 (2000-2007); 14.1 ± 7.0 (2008-2013); %HG: 68.2 ± 4.8 (2000-2007); 85.9 ± 6.9 (2008-2013), P = 0.004. The grade migration was confined to Ta cases with %LG Ta cases diagnosed decreasing by 3.6-fold from 2000-2007 to 2008-2013 (P = 0.004). Univariate and multivariate analyses confirmed the grade migration following the adoption of the 2004 system (P < 0.0001). Kaplan-Meier curves showed no significant differences between the two time intervals in terms of disease progression (P > 0.05)., Conclusions: Implementation of the 2004 WHO/ISUP system caused a significant increase in pathologists grading Ta cases as HG; however, this increase did not seem to correlate with disease progression. Since LG and HG Ta tumors are treated differently, grade migration may impact the clinical management of BCa patients.