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 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.

Trial Registration: trial registry, ClinicalTrials.gov; registration number, NCT00412971; http://www.clinicaltrials.gov/ct2/show/ NCT00412971?spons=%22PhotoCure%22&spons_ex=Y&rank=15• Patients were randomized to cystoscopy and WL TURB (118 patients) or WL TURB followed immediately by HAL TURB (115 patients). Cystoscopy/TURB and bladder biopsies were performed under general anaesthesia. No patients had intravesical chemotherapy immediately after TURB.• Recurrences were verified histologically. RESULTS• The two groups were similar regarding age and previous bladder cancer history.• In all, 90 patients from the HAL TURB group had bladder tumour. Fluorescenceguided cystoscopy after complete WL TURB identified residual tumour tissue in 44 of 90 patients (49%). In 37 of 83 (45%) residual Ta tumour was found; in three of seven residual T1 was found and in four cases carcinoma in situ .• True (and false) positive detection rate of photodynamic diagnosis was 64% (25%) and of white light 83% (16%).• In all, 145 patients were eligible for analysis of tumour recurrence. Twelve patients had their last follow-up after 4 months. The recurrence rate in patients followed for 12 months was 47.3% (35/74) after WL TURB and 30.5% (18/59) after HAL TURB ( P = 0.05).• Kaplan-Meier analyses comprising data from all 145 patients showed that the recurrence-free period was significantly longer in the HAL TURB group than in the WL TURB group ( P = 0.02). CONCLUSION• WL TURB often leaves residual tumour in the bladder. HAL TURB improves the detection of Ta/T1 tumours of the bladder resulting in more complete TURB procedures and thus a reduced recurrence rate. KEYWORDSHexvix®, bladder cancer, fluorescence cystoscopy, recurrence, non-muscleinvasive, residual tumour What's known on the subject? and What does the study add? Photodynamic diagnosis (PDD) improves the diagnostic sensitivity of non-invasive bladder cancer as compared to TURB without PDD.TURB in white light leaves residual tumour in the bladder in up to 49% of the patients. PDD-guided TURB improves the detection of Ta/T1 tumours of the bladder resulting in more complete TURB procedures and thus a reduced tumour recurrence rate. Study Type -Therapy (RCT) Level of Evidence 1b OBJECTIVES• To compare the bladder tumour recurrence rate in stage Ta and T1 tumours after conventional transurethral resection of the bladder in white light (WL TURB) and after fluorescence-guided TURB (HAL TURB) using hexaminolaevulinate (HAL: Hexvix®, Photocure, Norway) for photodynamic diagnosis during 12 months of follow-up.• As secondary objectives, to relate the tumour recurrence rate to fluorescencedetected residual tumour after WL TURB and to assess the false positive rate. PATIENTS AND METHODS• This was a prospective, comparative, randomized, open-label study carried out in hospital outpatient urology clinics and the operating theatre. A total of 233 patients presenting with suspected superficial bladder tumour were recruited. Both patients with new tumours and patients with recurrent tumours were inclu...

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The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC. We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for , and methylation and , and mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups. In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type and methylation of and were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of mutation status and methylation of , this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%). We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. .