We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression.

Background Hematuria is a common clinical finding and represents the most frequent presenting sign of bladder cancer. The American Urological Association recommends cystoscopy and abdomino-pelvic imaging for patients over 35 years. Nonetheless, fewer than half of patients presenting with hematuria undergo proper evaluation. We sought to identify clinical and non-clinical factors associated with evaluation of persons with newly diagnosed hematuria. Methods Retrospective cohort study, using claims data and laboratory values. The primary exposure was practice site, as a surrogate for non-clinical, potentially modifiable sources of variation. Primary outcomes were cystoscopy and/or abdomino-pelvic imaging within 180 days following hematuria diagnosis. We modeled the association between clinical and non-clinical factors and appropriate hematuria evaluation. Results We identified 2,455 primary care patients 40 years of age or older diagnosed with hematuria between 2004 and 2012 in the absence of other explanatory diagnosis. 13.7% of patients underwent cystoscopy within 180 days. Multivariate logistic regression revealed significant variation between those who did and did not undergo evaluation in age, gender and anti-coagulant use (p<0.001, p=0.036, p=0.028). Addition of practice site improved the predictive discrimination of each model (p<0.001). Evaluation was associated with higher rates of genitourinary neoplasia diagnosis. Conclusions Patients with hematuria rarely underwent complete evaluation. While established risk factors for malignancy were associated with increasing use of diagnostic testing, factors unassociated with risk, such as practice site, also accounted for significant variation. Inconsistency across practice sites is undesirable and may be amenable to quality improvement interventions.

Summary Objective To evaluate predictors of understaging in patients with presumed non-muscle invasive bladder cancer (NMIBC) identified on transurethral resection of bladder tumor (TURBT) who underwent radical cystectomy (RC) with attention to the role of a restaging TURBT. Materials and Methods We retrospectively evaluated 279 consecutive patients with clinically staged T1 (cT1) disease following TURBT who underwent RC at our institution from April 2000 to July 2011. 60 of these cT1 patients had undergone a restaging TURBT prior to RC. The primary outcome measure was pathological staging of T2 or greater disease at the time of RC. Results 134 (48.0%) patients were understaged. Of the 60 patients who remained cT1 after a restaging TURBT, 28 (46.7%) were understaged. Solitary tumor (OR 0.43, 95% CI 0.25–0.76, p = 0.004) and fewer prior TURBTs (OR 0.84, 95% CI 0.71–1.00, p = 0.05) were independent risk factors for understaging. Conclusions Despite the overall improvement in staging accuracy linked to restaging TURBTs, the risk of clinical understaging remains high in restaged patients found to have persistent T1 urothelial carcinoma who undergo RC. Solitary tumor and fewer prior TURBTs are independent risk factors for being understaged. Incorporating these predictors into preoperative risk stratification may allow for augmented identification of those patients with clinical NMIBC who stand to benefit most from RC.

BACKGROUNDSOX2 is a member of SOX (SRY-related HMG box) family of transcription factors.METHODSin this study, we examined the expression of SOX2 in murine and human prostatic specimens by immunohistochemistry.RESULTSwe found that SOX2 was expressed in murine prostates during budding morphogenesis and in neuroendocrine (NE) prostate cancer (PCa) murine models. Expression of SOX2 was also examined in human prostatic tissue. We found that SOX2 was expressed in 26 of 30 benign prostate hyperplasia (BPH) specimens. In these BPH samples, expression of SOX2 was limited to basal epithelial cells. In contrast, 24 of 25 primary PCa specimens were negative for SOX2. The only positive primary PCa was the prostatic NE tumor, which also showed co-expression of synaptophysin. Additionally, the expression of SOX2 was detected in all prostatic NE tumor xenograft lines. Furthermore, we have examined the expression of SOX2 on a set of tissue microarrays consisting of metastatic PCa tissues. Expression of SOX2 was detected in at least one metastatic site in 15 of 24 patients with metastatic castration-resistant PCa; and the expression of SOX2 was correlated with synaptophysin.CONCLUSIONSSOX2 was expressed in developing prostates, basal cells of BPH, as well as prostatic NE tumors.

Introduction Differences in quality of care (QOC) may contribute to racial variation in outcomes of bladder cancer (BCa). Quality indicators in patients undergoing surgery for BCa include use of high-volume surgeons (HVSs) and hospitals (HVHs), and, when clinically indicated, receipt of pelvic lymphadenectomy (PLND), use of continent urinary diversion and undergoing radical cystectomy (RC) instead of partial cystectomy (PC). We compared these quality indicators, as well as adverse perioperative outcomes in Black and White patients with BCa. Methods We used the Healthcare Cost and Utilization Project’s State Inpatient Databases, selecting NY, FL, and MD (1996–2009), because they consistently included race, surgeon and hospital identifiers. Quality indicators were compared across racial groups using regression models adjusting for age, sex, Elixhauser comorbidity sum, insurance, state, and year of surgery, accounting for clustering within hospital. Results Black patients were more often treated by lower volume surgeons and hospitals; had significantly lower utilization of PLND and continent diversion; and experienced higher rates of adverse outcomes compared to White patients. These associations remained significant for Black patients receiving treatment by surgeons and hospitals in the top volume decile. Conclusion Black BCa patients had lower utilization of experienced providers and institutions for BCa surgery. In addition, QOC for Black patients was lower than for Whites even if treated in a high-volume setting. This gap in QOC requires further investigation.

Purpose-To determine whether race, gender, and number of bladder cancer risk factors are significant predictors of hematuria evaluation.Methods-We used self-reported data from the Southern Community Cohort Study linked to Medicare claims data. Evaluation of subjects diagnosed with incident hematuria was considered complete if both imaging and cystoscopy were performed within 180 days of diagnosis. Exposures of interest were race, gender, and risk factors for bladder cancer.Results-Among 1412 patients, evaluation was complete in 261 (18%). In our adjusted analyses, black patients were less likely than white patients to undergo any aspect of evaluation: urology referral (OR 0.72; 95%CI 0.56, 0.93), cystoscopy (OR 0.67; 95%CI 0.50, 0.89) and imaging (OR 0.75; 95%CI 0.59, 0.95). Women were less likely than men to be referred to a urologist (OR 0.59; 95%CI 0.46, 0.76). And although all patients with 2-3 risk factors had 31% higher odds of urology referral (OR 1.31; 95%CI 1.02, 1.69), adjusted analyses indicated that effect was only apparent among men.Conclusions-Only 18% of incident hematuria diagnoses had a complete hematuria evaluation. Gender had a substantial effect on referral to urology when controlling for socioeconomic factors but otherwise had an unclear role on quality of evaluation. Black patients had markedly lower rates of thorough evaluation than white patients. Number of risk factors predicted referral to urology among men but was otherwise a poor predictor of evaluation. There is opportunity for improvement by increasing the completion of hematuria evaluations, particularly in high-risk and vulnerable patients. KeywordsUrinary bladder neoplasm; hematuria; cystoscopy; outcome and process assessment (healthcare); urinary bladder HHS Public Access

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