As compared with radical cystectomy alone, the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer.

SUMMARY Background Optimal management of clinically localized prostate cancer presents unique challenges because of its highly variable and often indolent natural history. To predict disease aggressiveness, clinicians combine clinical parameters to create prognostic models, but the accuracy of current models is very limited. There is significant clinical need for biomarkers that improve our ability to predict disease outcome. Methods Using quantitative RT-PCR on RNA from formalin fixed paraffin-embedded tumour samples, we measured the expression level of 31 genes involved in cell cycle progression (CCP genes), created a predefined score and evaluated its ability to predict disease outcome. The signature was tested in a retrospective cohort of 366 patients from the U.S. who had undergone radical prostatectomy, and in a retrospective cohort of 337 men with clinically localized prostate cancer diagnosed by a transurethral resection (TURP) in the UK and managed conservatively. Findings The cell cycle progression signature was a highly significant predictor of outcome in both cohorts. After prostatectomy the CCP score predicted biochemical recurrence in univariate (Hazard ratio (HR) for a one unit change in CCP (doubling) = 1.89; 95% CI (1.54, 2.31) χ2 = 34·0, 1df, p = 5·6 × 10−9) and multivariate analysis (HR = 1.74; 95% CI (1.39, 2.17) χ2 = 21·65, 1df, p = 3·3 ×10−6). The CCP score and PSA were the dominant variables in the best predictive model and were much more significant than any other clinical measure. In the TURP cohort, the CCP score was the dominant variable for predicting death from prostate cancer in both univariate (HR= 2.92; 95% CI (2.38, 3.57) χ2 = 92·7, 1df, p = 6.1 × 10−22) and multivariate analyses (χ2 = 42·2, p = 8·2 × 10−11), where it was much stronger than all other prognostic factors. In no case 4 was there significant evidence for heterogeneity in the hazard ratio for the CCP score across any clinical parameter. Interpretation The CCP score provides a substantial amount of independent information about the risk of recurrence after radical prostatectomy and the risk of death in conservatively managed prostate cancer diagnosed by TURP. Taken together, these studies provide strong evidence that the CCP score is a highly robust prognostic marker which, after additional validation, could have a central role in determining appropriate treatment for prostate cancer patients. Funding Study funded by Cancer Research UK, the Orchid Appeal, US National Institutes of Health (SPORE CA92629), and the Koch Foundation. Molecular testing performed at Myriad Genetics.

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Endometriosis is a debilitating disease characterized by the presence of functional endometrial glandular epithelium and stroma outside the uterine cavity that affects up to 20% of women of child-bearing age. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandin E(2) (PGE(2)), is highly expressed in endometriotic tissues and results in increased concentrations of peritoneal PGE(2) in women. In this study, we determined the expression of COX-2 protein in ectopic and eutopic endometria in humans and the role of COX-2 in endometriotic cell survival, migration, and invasion in humans. Our results indicate that COX-2 protein is abundantly expressed in ectopic endometria compared with eutopic endometria. Comparatively, expression of COX-2 protein is higher in eutopic endometria from women with endometriosis compared with women without endometriosis. Inhibition of COX-2 decreases survival, migration, and invasion of endometriotic cells that are associated with decreased production of PGE(2). Cell growth inhibitory effects of COX-2 inhibition/silencing are mediated through nuclear poly (ADP-ribose) polymerase-mediated apoptosis. Cell motility and invasion inhibitory effects of COX-2 inhibition/silencing are mediated through matrix metalloproteinase-2 and -9 activities. Interestingly, effects of COX-2 inhibition is more profound in endometriotic epithelial than in stromal cells. Furthermore, inhibition of COX-2 affects invasion rather than migration of endometriotic epithelial and stromal cells. It is the first evidence showing that inhibition of COX-2 decreases endometriotic epithelial and stromal cell survival, migration, and invasion in humans. Our results support the emerging concept that COX-2/PGE(2) promotes the pathophysiology and pathogenesis of endometriosis in humans.

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