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Purpose: To prospectively evaluate the diagnostic performance of magnetic resonance imaging (MRI), (11)C-acetate positron emission tomography/computed tomography (PET/CT) and contrast-enhanced CT for bladder cancer staging, using whole-mount pathologic review of radical cystectomy and pelvic lymph node specimens as the reference standard.Materials and Methods: The institutional review board approved this prospective study, which was compliant with the Health Insurance Portability and Accountability Act. Written informed consent was obtained from 16 patients with histologically confirmed bladder cancer who underwent MRI, (11)C-acetate PET/CT and contrast-enhanced CT before radical cystectomy and pelvic lymph node dissection. Before imaging 4/16 patients had received intravesical Bacillus Calmette-Guérin treatment, 6 had received systemic chemotherapy, 3 had received both and 3 had received neither. Measures of diagnostic performance including accuracy, sensitivity and specificity were estimated separately for each imaging modality.Results: MRI correctly staged 56% of patients (9/16), overstaged 38% (6/16) and understaged 6% (1/16). CT correctly staged 50% of patients (8/16), overstaged 44% (7/16) and understaged 6% (1/16). In 9 patients, (11)C-acetate PET/CT showed uptake within the bladder wall; the uptake was true-positive in 7 patients and false-positive in 2 patients. Of the remaining 7 patients, 5 had true-negative and 2 had false-negative PET/CT results for cancer in the bladder wall. For all modalities, staging accuracy was reduced in patients with a history of prior intravesical and/or systemic chemotherapy.Conclusion: In staging bladder cancer, MRI, (11)C-acetate PET/CT and CT displayed similar levels of accuracy. For all modalities, a history of intravesical and/or systemic chemotherapy affected staging accuracy. [ABSTRACT FROM AUTHOR]

Background: It has been demonstrated that multivariate prediction models predict cancer outcomes more accurately than cancer stage; however, the effects of these models on clinical management are unclear. The objective of the current study was to determine whether a previously published multivariate prediction model for bladder cancer ("bladder nomogram") improved medical decision making when referral for adjuvant chemotherapy was used as a model.Methods: Data were analyzed from an international cohort study of 4462 patients who underwent cystectomy without chemotherapy from 1969 to 2004. The number of patients eligible for chemotherapy was determined using pathologic stage criteria (lymph node-positive disease or pathologic T3 [pT3] or pT4 tumor classification) and for 3 cutoff levels on the bladder nomogram (10%, 25%, and 70% risk of recurrence with surgery alone). The number of recurrences was calculated by applying a relative risk reduction to the baseline risk among eligible patients. Clinical net benefit was then calculated by combining recurrences and treatments and weighting the latter by a factor related to drug tolerability.Results: A nomogram cutoff outperformed pathologic stage for chemotherapy in every scenario of drug effectiveness and tolerability. For a drug with a relative risk of 0.80, with which clinicians would treat Conclusions: The authors concluded that referring patients who undergo cystectomy to adjuvant chemotherapy on the basis of a multivariate model is likely to lead to better patient outcomes than the use of pathologic stage. Further research is warranted to evaluate the clinical effects of multivariate prediction models. [ABSTRACT FROM AUTHOR]

Background: Thrombospondin-1 (TSP) is a 430-kd glycoprotein that is an important component of the extracellular matrix and is known to be a potent inhibitor of angiogenesis (i.e., formation of new blood vessels) both in vitro and in vivo. Several reports suggest that TSP possesses tumor suppressor function, possibly through its ability to inhibit tumor neovascularization. It has recently been shown that TSP expression is enhanced by the product of the p53 gene (also known as TP53).Purpose: We examined the role of TSP expression in tumor recurrence and overall survival in patients with invasive bladder cancer. We also examined the relationship between alterations in p53 protein expression, TSP expression, and tumor angiogenesis.Methods: Tumors from 163 patients (with a median follow-up of 7.7 years) who underwent radical cystectomy for invasive transitional cell carcinoma of the bladder (63 patients with organ-confined disease and no lymph node involvement, 48 patients with extravesical extension of the disease and no lymph node involvement, and 52 patients with metastasis to regional lymph nodes) were examined for TSP expression by immunohistochemistry, utilizing monoclonal antibody MA-II, which recognizes an epitope in the amino-terminal region of TSP. For each tumor, microvessel density counts and p53 protein expression status (via immunohistochemistry) were also determined. TSP expression was graded as low, moderate, or high without knowledge of clinical outcome, p53 status, and microvessel density count; tumors with moderate and high TSP levels were considered as one group. Groups of patients were compared by Kaplan-Meier product limit estimates of overall survival, the complement of cumulative incidence curves for recurrence-free survival, and the stratified logrank test. Reported P values are two-sided.Results: TSP expression was significantly associated with disease recurrence (P = .009) and overall survival (P = .023). Patients with low TSP expression exhibited increased recurrence rates and decreased overall survival. TSP expression was an independent predictor of disease recurrence (P = .002) and overall survival (P = .01) after stratifying for tumor stage, lymph node status, and histologic grade, but it was not independent of p53 status. TSP expression was significantly associated with p53 expression status (P = .001) and microvessel density counts (P = .001). Tumors with p53 alterations were significantly more likely to demonstrate low TSP expression, and tumors with low TSP expression were significantly more likely to demonstrate high microvessel density counts. Results of an analysis of variance were compatible with the hypothesis that p53 affects tumor angiogenesis by regulating the level of TSP expression.Conclusions and Implications: These data support the concept that TSP may possess a tumor-inhibitory function. TSP may act, in part, through the regulation of tumor neovascularity. These results may also provide insight into one mechanism by which p53 exerts its tumor suppressor effects, i.e., through the control of tumor angiogenesis. [ABSTRACT FROM AUTHOR]

Purpose: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy.Experimental Design: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features.Results: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable effect on clinical outcomes.Conclusions: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment. [ABSTRACT FROM AUTHOR]