Discrepancy between German S3 Guideline Recommendations and Daily Urologic Practice in the Management of Nonmuscle Invasive Bladder Cancer: Results of a Binational Survey.

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.

Impact of COVID-19 crisis on medical care of patients with metastasized uro-oncologic disease under systemic cancer therapy: a multicenter study in German university hospitals.

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.

Comprehensive Nomogram for Prediction of the Uric Acid Composition of Ureteral Stones as a Part of Tailored Stone Therapy.

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 χ2 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/m2, IQR 27.25-35.0 vs 26.6 kg/m2, 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.

Analysis of tripartite motif (TRIM) family gene expression in prostate cancer bone metastases.

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-, TGFß-, 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 TGFß 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.

CDK19 as a diagnostic marker for high-grade prostatic intraepithelial neoplasia.

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.

[Diagnostic markers in urology]. / Diagnostische Marker in der Urologie.

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.

HYAL4-V1/Chondroitinase (Chase) Drives Gemcitabine Resistance and Predicts Chemotherapy Failure in Patients with Bladder Cancer.

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.

Risk Factors for a Complicated Postoperative Course in Flexible Ureteroscopy.

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.

Hemopatch® as a Hemostatic Agent is Safe in Partial Nephrectomy: A Large, Single-Surgeon Retrospective Evaluation.

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.

Bicentric Retrospective Analysis of en Bloc Resection and Muscularis Mucosae Detection Rate in Non-Muscle Invasive Bladder Tumors: A Real-World Scenario.

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.

New computed tomographic predictors of complicated perioperative course of 17.5F mini-percutaneous nephrolithotomy (mini-PNL).

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.

Adherence to the EAU Guideline Recommendations for Local Tumor Treatment in Penile Cancer: Results of the European PROspective Penile Cancer Study Group Survey (E-PROPS).

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.

Omics Derived Biomarkers and Novel Drug Targets for Improved Intervention in Advanced Prostate Cancer.

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.

Checkpoint Inhibition for Metastatic Urothelial Carcinoma After Chemotherapy-Real-World Clinical Impressions and Comparative Review of the Literature.

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).

The Impact of Endourological Experience on Flexible Ureteroscopy Outcomes and Performance at Different Levels of Expertise: Retrospective Multifactorial Analysis.

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.

A Novel Splice Variant of HYAL-4 Drives Malignant Transformation and Predicts Outcome in Patients with Bladder Cancer.

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.

Impact of double J stenting or nephrostomy placement during transurethral resection of bladder tumour on the incidence of metachronous upper urinary tract urothelial cancer.

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.

Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer.

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.

Laser fibre, rather than the stone, may harm the scope: retrospective monocentric analysis of 26 pre- and intraoperative factors of flexible ureteroscope (fURS) damage.

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.