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The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials., Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identified four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provided independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations were significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration was associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirmed the higher infiltration of class 2b tumors and demonstrated an association between higher immune cell infiltration and lower recurrence rates. Finally, a single-sample classification tool was built and the independent prognostic value of the transcriptomic classes was documented in 1306 validation samples. The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

Cytokeratin 20 (CK20) and insulin-like growth factor 2 (IGF2) were previously proposed to be elevated in clinical samples from patients with bladder cancer (BCa). A two cohort design validation study was used to assess the relevance for BCa detection by transcript quantitation of both markers in urine samples. Their diagnostic value was assessed in comparison with voided urine cytology (VUC). RNA isolation was carried out using cellular sediments of urine samples from 196/103 histologically positive BCa patients, as well as 97/50 control subjects for the test (TC) and validation cohort (VC), respectively. Urinary transcript levels of CK20 and IGF2 were determined by qPCR. Relative transcript levels were significantly elevated 3.4/11-fold for CK20 and 188/64-fold for IGF2 (p

Routine second transurethral resection (TUR) for non-muscle-invasive bladder cancer (NMIBC) is common practice in Germany. Applicability of European Organization for Research and Treatment of Cancer (EORTC) and Spanish Urological Club for Oncological Treatment (CUETO) models in NMIBC patients is still controversial. Aim of the study was to assess the performance of EORTC and CUETO predictive models in NMIBC patients treated with second TUR. 479 NMIBC patients with routine second TUR were analyzed retrospectively between 2003 and 2011, and investigated with clinical and pathological variables in regard to tumor recurrence and progression. Furthermore, recurrencefree survival (RFS) and progression-free survival (PFS) were evaluated according to EORTC and CUETO, and the discrimination of the models assessed. With a median follow-up of 60 months, prior recurrence rate, grade, and second TUR pathology were independent prognostic factors for the risk of disease recurrence and progression. The concordance index of the EORTC and the CUETO model was 0.563 and 0.516 for recurrence and 0.681 and 0.702 for progression, respectively. The positive pathology after second TUR was significantly associated with risk of disease recurrence and progression. EORTC and CUETO risk models estimated progression better than recurrence, especially with higherscore groups. Improved predictive tools should be developed for optimal treatment selection.

BACKGROUND: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed.OBJECTIVE: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study.DESIGN, SETTING, AND PARTICIPANTS: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions.RESULTS AND LIMITATIONS: The progression score was significantly (pCONCLUSIONS: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens.PATIENT SUMMARY: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.

The aim of the study was to investigate whether combinations of urine-based tumour markers including urinary cytology (Cytology or Cyt) increase the sensitivity in the detection of bladder cancer recurrence.Urinary cytology, NMP22, UroVysion (FISH) and ImmunoCyt (uCyt+) were determined in 221 patients during the follow-up of non-muscle-invasive transitional cell carcinoma (NMI TCC) before cystoscopy (n = 49) or with the suspicion of TCC recurrence before transurethral resection of the bladder (n = 173). For all markers alone as well as in all possible combinations (multimarker panels, MPs) sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were evaluated. MPs were considered positive if at least one marker was positive.No malignancy was found in 108 patients, whereas recurrent TCC was confirmed in 113 patients. Sensitivity and specificity for Cytology were 84% and 62%, for NMP22 68% and 49%, for FISH 72% and 63%, and for uCyt+ 73% and 62%, respectively. The NPV was below 80% for all markers alone. Combinations of two and three markers increased the sensitivity as well as the NPV to over 90 and 80%, by reducing specificity to an average of 44% and 35%, respectively. The most sensitive combinations were NMP22, uCyt+ together with Cytology and FISH, and uCyt+ together with NMP22 (sensitivity for both combinations 98%). There was no further improvement when all four markers were combined.Combinations of tumour markers increased the sensitivity and NPV in the detection of recurrence of NMI TCC. A stepwise approach of tumour marker determination may be used to reduce the frequency of follow-up cystoscopies at a reasonable risk.

A higher incidence of bladder cancer has been reported in men compared with women. Clinical gender differences have been observed but are less well described.This retrospective analysis further examines clinical differences in the development and manifestation of bladder cancer between men and women.Consecutive male and female patients with bladder cancer treated between 1969 and 1997 at a single center (University Hospital of Innsbruck, Innsbruck, Austria) were included in the study. Patient characteristics regarding age, tumor classification, localization, and recurrence were compared between male and female patients. Statistical analysis was conducted using the t test, the chi(2) test, and the Kaplan-Meier method, with the log-rank test for subgroup analysis.In the 1,269 patients (876 men, 393 women) who were examined, 1,744 tumors were found. The male-to-female bladder cancer incidence ratio was 2.2:1. Tumors were diagnosed at a significantly younger age in men than in women (mean age: 62 years vs 67 years, respectively; P0.001). No difference in the histology of tumors was observed between the sexes. Muscle-invasive tumors more frequently occurred in men than in women (39.8% vs 34.5%; P = NS). In men compared with women, primary tumors were more aggressive (grade 2, 36.6% vs 28.2%; P0.001) and tumor recurrences were more invasive (59.0% vs 57.8%; P = NS). Tumors were more often located in the urethra in men than in women (43 [3.4%] vs 9 [1.8%]; P = 0.034), the trigonum (246 [19.8%] vs 75 [14.9%]; P0.001), and the bladder dome or vault (128 [10.3%] vs 37 [7.4%]; P = 0.015). Generally, no difference in survival rate was observed between the sexes; only in the subgroup of muscle-invasive tumors (n = 455) did women have a worse overall survival rate than did men (P = 0.022).Clinical gender differences in bladder cancer appear to have a higher incidence in men than in women. In this analysis, women were older at the age of detection, but had less-invasive and less-aggressive tumors than did men. However, women with muscle-invasive disease had a worse overall survival rate than did men in the same subset.

Objective To prospectively evaluate the role of fluorescence-guided cystoscopy in a high-risk bladder cancer population undergoing screening based on a multi-marker panel of urine-tests (UroScreen-study). Patients and methods UroScreen was conducted as a validation study for tumor markers within the frame of a health surveillance program of workers with occupational exposure to aromatic amines. Voluntary annual screens were done in 1,609 men. Cytology, quantitative NMP22® assay, and UroVysion (FISH) were applied to 7091 urine samples. Subjects with at least one positive urine-based tumor marker and/or persisting microscopic hematuria were offered fluorescence-guided (PDD) instead of white light cystoscopy. In case of suspicious findings histopathological evaluation by transurethral biopsy was performed. Data were statistically summarized and compared to tumors found by the standard algorithm of the screening study. Results Twenty-two subjects with a mean age of 58 years (39–72) underwent PDD cystoscopy. Of those 3 had positive NMP22 tests, 14 positive FISH tests and 9 suspicious cytologies. Two had persisting microscopic hematuria only. PDD cystoscopy revealed enhanced unifocal fluorescence in 14. All had subsequent transurethral biopsy or resection. In total, 1 urothelial carcinoma (pTaG1, low grade) was diagnosed. In the other participants urothelial cancer of the bladder was ruled out. Chronic cystitis was revealed in 8 of 14 biopsies. No higher detection rate was found using PDD than with the standard algorithm of the UroScreen study in which 17 tumors were detected by white light cystoscopy. Conclusion The use of PDD does not lead to a higher cancer detection rate in a high-risk screening population. Larger sample sizes may be needed to ultimately asses the value of PDD for bladder cancer screening.

165 patients of whom 26 (15%) developed de novo bladder cancer following upper-tract surgery. A variety of salvage upper-tract therapies were utilized, although the majority of cases progressed to nephroureterectomy. 5-year cancer specific survival was dependent on primary tumor pathology and ranged between 50% and 100%. CONCLUSIONS: Pooled analysis of the literature highlights that approximately 15% of patients will suffer ipsilateral upper-tract or bladder recurrences after segmental resection of ureteral or renal pelvic tumors. These rates of recurrence should be discussed prior to surgery and underscore the need for vigilant post-operative surveillance.

Objectives To evaluate gender differences of initial posters in threads dealing with bladder cancer on an online discussion board. Method 529 threads opened between 09/2005 and 03/2012 were screened on the largest German speaking bladder cancer online discussion board. 366 threads fulfilled the requirements for this study. Gender, age, number, status of concern and oncological situation of initiating posters as well as their motives and language style were analyzed following a standardized protocol. Results Threads were initiated in 45% (164/366) by men and in 55% (202/366) by women. Mean age of male initiating posters was 50 years and of female posters 44 years (p Conclusion Even though women are less often affected by bladder cancer, they are more active –especially for their concerned family members - on the evaluated discussion board than men. Whereas both genders equally often ask for medical information, women more often want to share their experiences and look for emotional support.