Background Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based on specific tumor biology, are yet to be identified. Objective To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach. Design, setting, and participants Retrospective study of patients with Ta G2/3 bladder tumors at initial presentation with three distinct clinical outcomes: absence of recurrence (n = 16), recurrence without progression (n = 16), and progression to carcinoma in situ or invasive disease (n = 16). Measurements Expressions of 24 genes that feature in relevant pathways that are deregulated in bladder cancer were quantified by real-time polymerase chain reaction on tumor biopsies from the patients at initial presentation. Results and limitations CCND3 (p = 0.003) and HRAS (p = 0.01) were predictive for recurrence by univariate analysis. In a multivariable model based on CCND3 expression, sensitivity and specificity for recurrence were 97% and 63%, respectively. HRAS (p < 0.001), E2F1 (p = 0.017), BIRC5/Survivin (p = 0.038), and VEGFR2 (p = 0.047) were predictive for progression by univariate analysis. Multivariable analysis based on HRAS, VEGFR2, and VEGF identified progression with 81% sensitivity and 94% specificity. Since this is a small retrospective study using medium-throughput profiling, larger confirmatory studies are needed. Conclusions Gene expression profiling across relevant cancer pathways appears to be a promising approach for Ta bladder tumor outcome prediction at initial diagnosis. These results could help differentiate between patients who need aggressive versus expectant management.

A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma genes and pathways. Examination of the alterations in the molecules in these pathways that regulate the cell cycle and their effects on the prognosis of bladder cancer are areas of active research. While defects in the p53-Mdm2-p14 axis have been implicated in urothelial cancer, perturbations in the cyclin-dependent kinases and their inhibitors have also been extensively studied in this context. Genetic alterations of the retinoblastoma gene and aberrant post-translational modifications of its protein have also been incriminated in invasive bladder cancer. This article reviews the individual prognostic roles of alterations in these molecules in the context of bladder cancer. Additionally, we review findings from recent studies that are attempting to analyze these markers in combination in an effort to construct molecular panels that can serve as more robust outcome predictors. More importantly, alterations in these molecules are now becoming enticing targets for novel therapeutics. We also review some of these agents that can restore the tumor cells' altered homeostatic mechanisms, thereby having potential in transitional cell carcinoma therapy. Future management of bladder cancer will employ validated marker panels for outcome prediction, and novel genetic and pharmacologic agents that will be able to target molecular alterations in individual tumors based on their respective profiles.

Bladder cancer is the seventh most common malignancy worldwide, with almost 14,000 patients dying from this disease in the USA alone. Because of the need for long-term and frequent follow-up, as well as the paucity of sensitive and specific noninvasive tests, bladder cancer management has the highest cost per patient among all cancer types. Several molecular markers, especially members of the cell cycle regulation and apoptosis pathways, have been investigated. However, no individual marker has been prognostically powerful enough to change clinical management. The combined analysis of a panel of markers spanning different pathways is the most promising approach. We give an overview of the most important molecular markers functioning in crucial pathways and focus on their role in multimarker analysis.

Background Sensitivity of standard urine cytology for detecting urothelial carcinoma of the bladder (UCB) is low, attributable largely to its inability to process entire samples, paucicellularity, and presence of background cells. Objective Evaluate performance and practical applicability of a novel portable microfiltration device for capture, enumeration, and characterization of exfoliated tumor cells in urine, and compare it with standard urine cytology for UCB detection. Methods A total of 54 urine and bladder wash samples from patients undergoing surveillance for UCB were prospectively evaluated by standard and microfilter-based urine cytology. Head-to-head comparison of quality and performance metrics, and cost effectiveness was conducted for both methodologies. Results Five samples were paucicellular by standard cytology; no samples processed by microfilter cytology were paucicellular. Standard cytology had 33.3% more samples with background cells that limited evaluation (p<0.001). Microfilter cytology was more concordant (κ=50.4%) than standard cytology (κ=33.5%) with true UCB diagnosis. Sensitivity, specificity, and accuracy were higher for microfilter cytology compared to standard cytology (53.3%/100%/79.2%, versus 40%/95.8%/69.9%, respectively). Microfilter-captured cells were amenable to downstream on-chip molecular analyses. A 40ml sample was processed in under 4 minutes by microfilter cytology compared to 5.5 minutes by standard cytology. Median microfilter cytology processing and set-up costs were approximately 63% cheaper and 80 times lower than standard cytology, respectively. Conclusions The microfiltration device represents a novel non-invasive UCB detection system that is economical, rapid, versatile, and has potentially better quality and performance metrics than routine urine cytology, the current standard-of-care.