Epidemiology of Bladder Cancer in 2023: A Systematic Review of Risk Factors

CONTEXT Bladder cancer (BC) is common worldwide and poses a significant public health challenge. External risk factors and the wider exposome (totality of exposure from external and internal factors) contribute significantly to the development of BC. Therefore, establishing a clear understanding of these risk factors is the key to prevention. OBJECTIVE To perform an up-to-date systematic review of BC's epidemiology and external risk factors. EVIDENCE ACQUISITION Two reviewers (I.J. and S.O.) performed a systematic review using PubMed and Embase in January 2022 and updated it in September 2022. The search was restricted to 4 yr since our previous review in 2018. EVIDENCE SYNTHESIS Our search identified 5177 articles and a total of 349 full-text manuscripts. GLOBOCAN data from 2020 revealed an incidence of 573 000 new BC cases and 213 000 deaths worldwide in 2020. The 5-yr prevalence worldwide in 2020 was 1 721 000. Tobacco smoking and occupational exposures (aromatic amines and polycyclic aromatic hydrocarbons) are the most substantial risk factors. In addition, correlative evidence exists for several risk factors, including specific dietary factors, imbalanced microbiome, gene-environment risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy. CONCLUSIONS We present a contemporary overview of the epidemiology of BC and the current evidence for BC risk factors. Smoking and specific occupational exposures are the most established risk factors. There is emerging evidence for specific dietary factors, imbalanced microbiome, gene-external risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy. Further high-quality evidence is required to confirm initial findings and further understand cancer prevention. PATIENT SUMMARY Bladder cancer is common, and the most substantial risk factors are smoking and workplace exposure to suspected carcinogens. On-going research to identify avoidable risk factors could reduce the number of people who get bladder cancer

Developing a Novel Transgenic Zebrafish Model of Urinary Tract Cancer

Urinary tract cancers encompass cancers of the kidneys, ureters, bladder and urethra. These cancers are common and associated with substantial morbidity and mortality worldwide. The most common of these cancers overall are urothelial carcinomas which arise from the specialised epithelium (termed the urothelium) lining the urinary tract from the renal pelvis down to the urethra, but most commonly affect the bladder. The second most common of these cancers is renal cell carcinoma, an adenocarcinoma, which accounts for approximately 90% of kidney cancers and arises from renal tubular epithelial cells. Large scale sequencing projects have led to important insights on common genomic and transcriptomic alterations in these cancers. However, there is a lack of high volume in-vivo transgenic models of urinary tract cancers available for rigorous mechanistic testing of the roles of these genetic alterations. Zebrafish transgenic models of cancers have demonstrated advantages with respect to ease of genetic manipulation, in-vivo imaging and high-throughput approaches. I performed a characterisation of the zebrafish excretory urinary tract with respect to histological characteristics and anatomical structure and demonstrate several similarities to the human system. The zebrafish kidneys converge onto two mesonephric ducts (homologous to ureters) which drain into a single saccular epithelium lined urinary bladder. The urinary bladder, in turn, drains externally via a single distinct urethra that is separate from the rectum. The zebrafish urinary epithelium expresses similar proteins to the human system. In addition, I demonstrate the development of the zebrafish urinary bladder with respect to morphological change during the larval and juvenile stages from a tubular structure that develops into a saccular expansile structure at around 6 weeks post fertilisation. I outline my work on developing a novel transgenic zebrafish urinary tract cancer model using genomic alterations associated with bladder cancer (combination of oncogenic tissue specific HRAS G12V overexpression and a global tp53 DNA binding domain mutation). This model utilises the bipartite Gal4/UAS system and generates cancers in the F0 generation. The cancers are generated by one cell stage microinjection of a plasmid containing the coding sequence for a GFP- HRAS G12V fusion protein (p-UAS: GFP-HRAS_G12V) into a Gal4 enhancer trap zebrafish line (with and without a global tp53 DNA binding domain mutation). We show that this pipeline results in abdominal cancers as early as 3 weeks post-fertilisation (7.1% to 14.6% abdominal tumours between 2 weeks and 3 months for HRASG12V only and combination of tp53 mutation and HRASG12V genomic alterations, respectively). Histological characterisation of these cancers demonstrated them to be situated in the retroperitoneal region of the urinary tract and immunohistochemistry demonstrated them to be a combination of epithelial and non-epithelial in nature. Subsequent attempts at optimisation of this urinary tract cancer model with a more tissue specific zebrafish promoter sequence (cdh17 gene promoter) without using the Gal4/UAS system does not lead to cancers up to 3 months of age suggesting that the Gal4/UAS system is important for cancer formation in zebrafish

Hyperthermic intravesical chemotherapy with mitomycin‐C for the treatment of high‐risk non‐muscle‐invasive bladder cancer patients

Abstract Objectives The objectives of the study are to explore tolerability, acceptability and oncological outcomes for patients with high‐risk non‐muscle‐invasive bladder cancer (NMIBC) treated with hyperthermic intravesical chemotherapy (HIVEC) and mitomycin‐C (MMC) at our institution. Patients and Methods Our single‐institution, observational study consists of consecutive high‐risk NMIBC patients treated with HIVEC and MMC. Our HIVEC protocol included six weekly instillations (induction), followed by two further cycles of three instillations (maintenance) (6 + 3 + 3) if there was cystoscopic response. Patient demographics, instillation dates and adverse events (AEs) were collected prospectively in our dedicated HIVEC clinic. Retrospective case‐note review was performed to evaluate oncological outcomes. Primary outcomes were tolerability and acceptability of HIVEC protocol; secondary outcomes were 12‐month recurrence‐free, progression‐free and overall survival. Results In total, 57 patients (median age 80.3 years) received HIVEC and MMC, with a median follow‐up of 18 months. Of these, 40 (70.2%) had recurrent tumours, and 29 (50.9%) had received prior Bacillus Calmette–Guérin (BCG). HIVEC induction was completed by 47 (82.5%) patients, but only 19 (33.3%) completed the full protocol. Disease recurrence (28.9%) and AEs (28.9%) were the most common reasons for incompletion of protocol; five (13.2%) patients stopped treatment due to logistical challenges. AEs occurred in 20 (35.1%) patients; the most frequently documented were rash (10.5%), urinary tract infection (8.8%) and bladder spasm (8.8%). Progression during treatment occurred in 11 (19.3%) patients, 4 (7.0%) of whom had muscle invasion and 5 (8.8%) subsequently required radical treatment. Patients who had received prior BCG were significantly more likely to progress (p = 0.04). 12‐month recurrence‐free, progression‐free and overall survival rates were 67.5%, 82.2%, and 94.7%, respectively. Conclusions Our single‐institution experience suggests that HIVEC and MMC are tolerable and acceptable. Oncological outcomes in this predominantly elderly, pretreated cohort are promising; however, disease progression was higher in patients pretreated with BCG. Further randomised noninferiority trials comparing HIVEC versus BCG in high‐risk NMIBC are required

Digital Tracking of Patients Undergoing Radical Cystectomy for Bladder Cancer: Daily Step Counts Before and After Surgery Within the iROC Randomised Controlled Trial

BACKGROUND: Efforts to improve recovery after radical cystectomy (RC) are needed. OBJECTIVE: To investigate wrist-worn wearable activity trackers in RC participants. DESIGN, SETTING, AND PARTICIPANTS: An observational cohort study was conducted within the iROC randomised trial. INTERVENTION: Patients undergoing RC at nine cancer centres wore wrist-based trackers for 7 days (d) at intervals before and after surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Step counts were compared with participant and operative features, and recovery outcomes. RESULTS AND LIMITATIONS: Of 308 participants, 284 (92.2%) returned digital activity data at baseline (median 17 d [interquartile range: 8-32] before RC), and postoperatively (5 [5-6] d) and at weeks 5 (43 [38-43] d), 12 (94 [87-106] d), and 26 (192 [181-205] d) after RC. Compliance was affected by the time from surgery and a coronavirus disease 2019 pandemic lockdown (return rates fell to 0-7%, chi-square p < 0.001). Step counts dropped after surgery (mean of 28% of baseline), before recovering at 5 weeks (wk) (71% of baseline) and 12 wk (95% of baseline; all analysis of variance [ANOVA] p < 0.001). Baseline step counts were not associated with postoperative recovery or death. Patients with extended hospital stays had reduced postoperative step counts, with a difference of 2.2 d (95% confidence interval: 0.856-3.482 d) between the lowest third and highest two-third tertiles (linear regression analysis; p < 0.001). Additionally, they spent less time out of the hospital within 90 d of RC (80.3 vs 74.3 d, p = 0.013). Lower step counts at 5, 12, and 26 wk were seen in those seeking medical help and needing readmission (ANOVA p ≤ 0.002). CONCLUSIONS: Baseline step counts were not associated with recovery. Lower postoperative step counts were associated with longer length of stay at the hospital and postdischarge readmissions. Studies are required to determine whether low step counts can identify patients at a risk of developing complications. PATIENT SUMMARY: Postoperative step counts appear to be a promising tool to identify patients in the community needing medical help or readmission. More work is needed to understand which measures are most useful and how best to collect these