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.

Nomograms including the UBC® Rapid test to detect primary bladder cancer based on a multicentre dataset.

OBJECTIVES: To evaluate the clinical utility of the urinary bladder cancer antigen test UBC® Rapid for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high risk of primary BC. PATIENTS AND METHODS: Data from 1787 patients from 13 participating centres, who were tested between 2012 and 2020, including 763 patients with BC, were analysed. Urine samples were analysed with the UBC® Rapid test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid test was evaluated using receiver-operating characteristic curve analysis. Brier scores and calibration curves were chosen for the validation. Biopsy-proven BC was predicted using multivariate logistic regression. RESULTS: The sensitivity, specificity, and area under the curve for the UBC® Rapid test were 46.4%, 75.5% and 0.61 (95% confidence interval [CI] 0.58-0.64) for low-grade (LG) BC, and 70.5%, 75.5% and 0.73 (95% CI 0.70-0.76) for high-grade (HG) BC, respectively. Age, UBC® Rapid test results, smoking status and haematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in areas under the curve of 0.79 (95% CI 0.72-0.87) and 0.95 (95% CI: 0.92-0.98) for predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid test alone for low and medium risk levels in decision curve analysis. The R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. CONCLUSION: The UBC® Rapid test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status and haematuria provides a fast, highly accurate and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

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.

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.

BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL as urinary marker for bladder cancer: Final results of a German multicenter study.

INTRODUCTION AND OBJECTIVE: BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL are urinary-based rapid tests. This multicenter study is the first study comparing all available rapid tests on a large cohort of bladder cancer patients and healthy controls in one setting. METHODS: In total 732 urine samples (second morning urine) in a real-world assessment have been analyzed. We evaluated clinical samples from 464 patients with histologically confirmed urothelial tumors of the urinary bladder (17 solitary CIS, 189 low-grade, 187 high-grade nonmuscle invasive, 71 high-grade muscle invasive), 77 patients with No Evidence of Disease (NED), and from 191 healthy controls. Urine samples were analyzed by the BTA stat®, NMP22® BladderChek®, UBC® Rapid Test point-of-care (POC) system using the concile Omega 100 POC reader, and CancerCheck® UBC® rapid VISUAL. Sensitivities and specificities were calculated by contingency analyses. RESULTS: All investigated urinary markers detected more pathological concentrations in urine of bladder cancer patients compared to tumor-free patients. The calculated diagnostic sensitivities for BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, CancerCheck® UBC® rapid VISUAL, and cytology were 62.4%, 13.4%, 58.2%, 28.6%, 36.2% for low-grade, 83.4%, 49.5%, 84.5%, 63.1%, 71.2% for high-grade nonmuscle invasive, and 95.8%, 35.2%, 76.1%, 50.7%, 67.7% for high-grade muscle-invasive bladder cancer. The specificity was 67.9%, 95.5%, 79.4%, 94.4%, and 83.7%, respectively. The area under the curve (AUC) after receiver operating characteristics (ROC) analysis for high-grade non-muscle-invasive tumors was 0.757, 0.725, 0.819, 0.787, and 0.774, respectively. CONCLUSIONS: The analysis of more than 700 urine samples offers an objective view on urine-based rapid diagnostics. Elevated pathological concentrations of markers in urine of bladder cancer patients were detected in all investigated tests. The highest sensitivities for high-grade non-muscle-invasive tumors were calculated for BTA stat® and UBC® Rapid Test, whereas NMP22® BladderChek®, and cytology showed the highest specificities. BTA stat® and UBC® Rapid Test have the potential to be used as a clinical valuable urinary protein biomarker for the detection of high-grade non-muscle-invasive bladder cancer patients and could be included in the management of these tumors.

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.

[Potential for improvement by new resection and imaging techniques in TUR-B]. / Verbesserungspotenziale durch neue Resektions- und Bildgebungstechniken bei der TUR-B.

Transurethral resection of bladder tumors (TURB) is the cornerstone in urological care of bladder cancer patients. Since the introduction of resectoscopes almost 100 years ago, little has changed in the basic resection technique. The further dissemination of the en-bloc resection (ERBT), which in contrast to fragmented removal preserves the tumor's integrity, might re-adjust the surgical landscape. Benefits attributed to ERBT are better histopathological judgment and higher detrusor muscle rate. In addition, trends for a lower rate of so-called "in-field" recurrences as well as a reduced complication rate have been described. However, randomised, controlled studies with appropriate case numbers and methodology are pending. Few innovations in improved endoscopic tumor diagnostics have been added in recent years. Worth mentioning is the multiparametric magnetic resonance imaging of the bladder, which is intended to improve the accuracy of local tumor propagation compared to conventional imaging alone, as well as techniques in the field of artificial intelligence. The intention of this article is to provide an up-to-date status on EBRT as well as the local diagnostics for urinary bladder tumors.

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.

Diarrhea and flatulence are major bowel disorders after radical cystectomy: Results from a cross-sectional study in bladder cancer patients.

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.

Molecular Characterization of Renal Cell Carcinoma: A Potential Three-MicroRNA Prognostic Signature.

Background: Aberrantly expressed miRNAs promote renal cell carcinoma (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, a consensus clinically significant miRNA signature has not been identified. To identify an miRNA signature for predicting clinical outcome in RCC patients, we used a four-pronged interconnected approach.Methods: Differentially expressed miRNAs were identified and analyzed in 113 specimens (normal kidney: 59; tumor: 54). miRNA profiling was performed in matched normal and tumor specimens from 8 patients and extended to 32 specimens. Seven aberrantly expressed miRNAs were analyzed by qPCR, and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in The Cancer Genome Atlas RCC dataset (n = 241).Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150, and miR-155 as significantly upregulated (2-4-fold) and miR-192 and miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (<4 cm) from benign oncocytomas. In univariate and multivariate analyses, miRNA combinations (miR-21+194; miR-21+142-5p+194) significantly predicted metastasis and/or disease-specific mortality; miR-21+142-5p+194 (for metastasis): P = 0.0017; OR, 0.53; 95% confidence interval (CI), 0.75-0.33; 86.7% sensitivity; 82% specificity. In the TCGA dataset, combined biomarkers associated with metastasis and overall survival (miR-21+142-5p+194: P < 0.0001; OR, 0.37; 95% CI, 0.58-0.23).Conclusions: The interconnected discovery-validation approach identified a three-miRNA signature as a potential predictor of disease outcome in RCC patients.Impact: With 10% survival at 5 years, metastatic disease presents poor prognosis for RCC patients. The three-miRNA signature discovered and validated may potentially at an early stage detect and predict metastasis, to allow early intervention for improving patient prognosis. Cancer Epidemiol Biomarkers Prev; 27(4); 464-72. ©2018 AACR.

The Role of CD44 in Disease Pathophysiology and Targeted Treatment.

The cell-surface glycoprotein CD44 is involved in a multitude of important physiological functions including cell proliferation, adhesion, migration, hematopoiesis, and lymphocyte activation. The diverse physiological activity of CD44 is manifested in the pathology of a number of diseases including cancer, arthritis, bacterial and viral infections, interstitial lung disease, vascular disease, and wound healing. This diversity in biological activity is conferred by both a variety of distinct CD44 isoforms generated through complex alternative splicing, posttranslational modifications (e.g., N- and O-glycosylation), interactions with a number of different ligands, and the abundance and spatial distribution of CD44 on the cell surface. The extracellular matrix glycosaminoglycan hyaluronic acid (HA) is the principle ligand of CD44. This review focuses both CD44-hyaluronan dependent and independent CD44 signaling and the role of CD44-HA interaction in various pathophysiologies. The review also discusses recent advances in novel treatment strategies that exploit the CD44-HA interaction either for direct targeting or for drug delivery.