A Step Closer to Predicting Progression After Bacillus Calmette-Guérin Immunotherapy in High-risk Non-muscle-invasive Bladder Cancer.

Treatment-naïve tumors from patients who then experience recurrence or progression after bacillus Calmette-Guérin (BCG) therapy exhibit elevated expression of genes associated with basal differentiation and immune suppression. Three tumor molecular subtypes have been associates with distinct clinical outcomes and will allow early identification of patients unlikely to respond to BCG immunotherapy.

Sex differences in the aging murine urinary bladder and influence on the tumor immune microenvironment of a carcinogen-induced model of bladder cancer.

Sex and age associated differences in the tumor immune microenvironment of non-muscle invasive bladder (NMIBC) cancer and associated clinical outcomes are emerging indicators of treatment outcomes. The incidence of urothelial carcinoma of the bladder is four times higher in males than females; however, females tend to present with a more aggressive disease, a poorer response to immunotherapy and suffer worse clinical outcomes. Recent findings have demonstrated sex differences in the tumor immune microenvironment of non-muscle invasive and muscle invasive bladder cancer and associated clinical outcomes. However, a significant gap in knowledge remains with respect to the current pre-clinical modeling approaches to more precisely recapitulate these differences towards improved therapeutic design. Given the similarities in mucosal immune physiology between humans and mice, we evaluated the sex and age-related immune alterations in healthy murine bladders. Bulk-RNA sequencing and multiplex immunofluorescence-based spatial immune profiling of healthy murine bladders from male and female mice of age groups spanning young to old showed a highly altered immune landscape that exhibited sex and age associated differences, particularly in the context of B cell mediated responses. Spatial profiling of healthy bladders, using markers specific to macrophages, T cells, B cells, activated dendritic cells, high endothelial venules, myeloid cells and the PD-L1 immune checkpoint showed sex and age associated differences. Bladders from healthy older female mice also showed a higher presence of tertiary lymphoid structures (TLSs) compared to both young female and male equivalents. Spatial immune profiling of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen exposed male and female bladders from young and old mice revealed a similar frequency of TLS formation, sex differences in the bladder immune microenvironment and, age associated differences in latency of tumor induction. These findings support the incorporation of sex and age as factors in pre-clinical modeling of bladder cancer and will potentially advance the field of immunotherapeutic drug development to improve clinical outcomes.

Sex and Gender Differences in Cancers of the Genitourinary Tract: The Need to Consider Immune Divergence.

Delineating the processes of immune response underlying sexual dimorphism in cancers of the genitourinary tract will improve outcomes from immunotherapy treatment.

Is there a measurable association of epidural use at cystectomy and postoperative outcomes? A population-based study.

INTRODUCTION: Thoracic epidural analgesia (TEA) is commonly used to manage postoperative pain and facilitate early mobilization after major intra-abdominal surgery. Evidence also suggests that regional anesthesia/analgesia may be associated with improved survival after cancer surgery. Here, we describe factors associated with TEA at the time of radical cystectomy (RC) for bladder cancer and its association with both short- and long-term outcomes in routine clinical practice. METHODS: All patients undergoing RC in the province of Ontario between 2004 and 2008 were identified using the Ontario Cancer Registry (OCR). Modified Poisson regression was used to describe factors associated with epidural use, while a Cox proportional hazards model describes associations between survival and TEA use. RESULTS: Over the five-year study period, 1628 patients were identified as receiving RC, 54% (n=887) of whom received TEA. Greater anesthesiologist volume (lowest volume providers relative risk [RR] 0.85, 95% confidence interval [CI] 0.75-0.96) and male sex (female sex RR 0.89, 95% CI 0.79-0.99) were independently associated with greater use of TEA. TEA use was not associated with improved short-term outcomes. In multivariable analysis, TEA was not associated with cancer-specific survival (hazard ratio [HR] 1.02, 95% CI 0.87-1.19; p=0.804) or overall survival (HR 0.91, 95% CI 0.80-1.03; p=0.136). CONCLUSIONS: In routine clinical practice, 54% of RC patients received TEA and its use was associated with anesthesiologist provider volume. After controlling for patient, disease and provider variables, we were unable to demonstrate any effect on either short- or long-term outcomes at the time of RC.

Is there a gender effect in bladder cancer? A population-based study of practice and outcomes.

INTRODUCTION: The incidence of bladder cancer varies by gender. Whether differences exist between women and men in extent of disease, treatment, and outcome is not well-described. We evaluate gender differences in bladder cancer using a population-based cohort. METHODS: Electronic records of treatment were linked to the population-based Ontario Cancer Registry to identify all patients with bladder cancer treated with cystectomy or radical radiotherapy (RT) in Ontario between 1994 and 2008. We compare extent of disease at time of cystectomy, treatment, and outcomes between women and men. RESULTS: In total, 5259 patients with bladder cancer were treated with cystectomy or radical RT; of these, 25% (n = 1296) were women. There was no gender difference in the proportion of patients treated with cystectomy (75% of women [974/1296], 73% of men [2905/3963], p = 0.189). At the time of cystectomy, women were more likely to have muscle-invasive disease (86% [836/974] vs. 80% [2335/2905], p < 0.001), but less likely to have lymph nodes dissected (68% [664/974] vs. 76% [2210/2905], p < 0.001]. Among the 2944 patients with muscle-invasive urothelial carcinoma treated with cystectomy, use of neoadjuvant (5% vs. 4%, p = 0.419) and adjuvant chemotherapy (18% vs. 20%, p = 0.190) did not differ significantly between genders. Five-year cancer-specific survival and overall survival of the full cohort did not differ between women and men (38% vs. 39%, p = 0.522; 33% vs. 33%, p = 0.795). CONCLUSIONS: This population-based cohort did not demonstrate any substantial differences in extent of disease, treatment, or outcome between women and men treated with cystectomy or radical RT for bladder cancer.

Serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer.

INTRODUCTION: Treatment of advancing prostate cancer focuses on blocking the activation of the androgen receptor with resultant prolonged perturbation of the hypothalamic-pituitary-gonadal axis. Androgen deprivation therapy (ADT) is marked, however, by eventual progression to castration- resistant prostate cancer (CRPC). Emerging evidence has postulated that follicle-stimulating hormone (FSH) may lead to proliferative and mutagenic responses of prostate cancer. We investigated the association of serum FSH and time to castration resistance. METHODS: This was a single-centre retrospective study assessing serum FSH levels of patients undergoing ADT for advancing prostate cancer. The primary outcome was time of ADT initiation to the development of CRPC. For each patient on treatment and with castrate levels of testosterone, the maximum FSH value between ADT commencement and CRPC was identified and recorded. FSH was analyzed as a continuous and categorical variable. Cox multivariate regression in a step-wise fashion was used to explore the association between FSH levels and time to CRPC. RESULTS: From a database of 323 prostate cancer patients actively managed with ADT, 103 men had a documented FSH value while castrate, with 45 men progressing to CRPC. The mean ± standard deviation maximum FSH value of these patients was 6.66 ± 4.22 mIU/mL (range: 1.5-28.1). The mean duration from ADT commencement to CRPC was 3.03 ± 0.34 years (range: 0.36-9.71). Univariate analysis suggested a trend of a negative correlation between FSH values and time to castrate resistance. A FSH value of less than or equal to the lowest tertile (4.8 mIU/mL) was associated with a longer time to CRPC (hazard ratio 0.46; p = 0.006). In the Cox regression analysis, elevated FSH was associated with a shorter duration time to CRPC (p = 0.03). CONCLUSIONS: This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated palliatively with ADT for advancing prostate cancer. Further clinical investigation in a larger cohort of men is required to determine any clinical utility of FSH as a biomarker of progression or target for therapy.