Prognostic Value of Cyclooxygenase-2 Expression in Squamous Cell Carcinoma of the Bladder
ABSTRACT Inflammation is associated with the pathogenesis of carcinoma, including squamous cell carcinoma of the bladder. Cyclooxygenase-2 is an enzyme that is induced at inflammation sites. We assessed the expression pattern of cyclooxygenase-2 in patients with squamous cell carcinoma of the bladder and determined whether cyclooxygenase-2 expression is associated with clinical outcomes after radical cystectomy.
Immunohistochemical staining for cyclooxygenase-2 was done on archival bladder specimens from 152 patients treated with radical cystectomy for squamous cell carcinoma on the Autostainer (DakoCytomation, Carpinteria, California). Bright field microscopy imaging coupled with advanced color detection software was used. Cyclooxygenase-2 was defined as over expressed when greater than 20% cells were positive. We assessed the relationship of cyclooxygenase-2 expression with pathological parameters and clinical outcome.
The study included 99 male and 53 female patients with a mean age of 52 years who had squamous cell carcinoma, including 80.9% with bilharziasis. Presenting stage was T2 or greater and presenting grade was GII or less in 93.4% of patients. Median followup was 63.2 months. Cyclooxygenase-2 was over expressed in 74 cystectomy specimens (48.7%) and associated with higher pathological stage (p=0.003) and grade (p=0.049). On multivariate Cox proportional hazards regression analysis cyclooxygenase-2 over expression was associated with disease recurrence (p=0.031) and bladder cancer specific mortality (p=0.046).
Cyclooxygenase-2 over expression is associated with pathological stage, grade and worse outcomes after radical cystectomy, suggesting a role in bladder squamous cell carcinoma progression. Our findings support the need for further evaluation of cyclooxygenase-2 and inflammatory signaling pathways, and cyclooxygenase-2 targeted prevention or therapy in patients with bladder squamous cell carcinoma.
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ABSTRACT: Aberrant overexpression of cyclooxygenase-2 (COX2) is observed in urothelial carcinoma of the bladder (UCB). Studies evaluating COX2 as a prognostic marker in UCB report contradictory results. We determined the prognostic potential of COX2 expression in UCB and quantitatively summarize the results with those of the literature through a meta-analysis. Newly diagnosed UCB patients recruited between 1998-2001 in 18 Spanish hospitals were prospectively included in the study and followed-up (median, 70.7 months). Diagnostic slides were reviewed and uniformly classified by expert pathologists. Clinical data was retrieved from hospital charts. Tissue microarrays containing non-muscle invasive (n = 557) and muscle invasive (n = 216) tumours were analyzed by immunohistochemistry using quantitative image analysis. Expression was evaluated in Cox regression models to assess the risk of recurrence, progression and disease-specific mortality. Meta-hazard ratios were estimated using our results and those from 11 additional evaluable studies. COX2 expression was observed in 38% (211/557) of non-muscle invasive and 63% (137/216) of muscle invasive tumors. Expression was associated with advanced pathological stage and grade (p<0.0001). In the univariable analyses, COX2 expression - as a categorical variable - was not associated with any of the outcomes analyzed. As a continuous variable, a weak association with recurrence in non-muscle invasive tumors was observed (p-value = 0.048). In the multivariable analyses, COX2 expression did not independently predict any of the considered outcomes. The meta-analysis confirmed these results. We did not find evidence that COX2 expression is an independent prognostic marker of recurrence, progression or survival in patients with UCB.PLoS ONE 09/2012; 7(9):e45025. DOI:10.1371/journal.pone.0045025 · 3.53 Impact Factor
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ABSTRACT: Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Apoptotic pathways are important in carcinogenesis. Many studies, involving small numbers of patients, have found an association between one or two apoptotic markers and some of the pathological features of squamous cell carcinoma (SCC). This study included a large number of patients who had undergone radical cystectomy (RC) for SCC with long-term follow-up, allowing us to study biomarker alterations and their prognostic role. This is the first study on the prognostic role of a panel of apoptotic-related markers in SCC of the urinary bladder, introducing the novel concept of a prognostic marker score based on the number of altered markers. We found that apoptotic markers can improve prediction of oncological outcomes after RC for SCC and might potentially help in patient selection for adjunct therapies. • To evaluate the association of cleaved caspase-3 (CC-3), Bax, COX-2, and p53 expression with pathological features and clinical outcomes in patients with squamous cell carcinoma (SCC) of the urinary bladder. • Immunohistochemistry for CC-3, Bax, COX-2, and p53 was performed on tissue microarray sections of radical cystectomy specimens with pure SCC from 1997 to 2003. The relationship between the expression of these markers and pathological features was assessed. • A prognostic marker score (PS) was defined as favourable if ≤2 biomarkers were altered and unfavourable if >2 biomarkers were altered and the association of the PS with oncological outcomes was examined. • The study included 151 patients, of whom 98 were men and 53 were women, with a mean age of 52 years. SCC was associated with schistosomiasis (bilharziasis) in 122 (81%) patients. • Pathological stage was T2 in 50%, T3 in 38%, T1 in 6% and T4 in 6% of patients. Tumours were low grade in 53%, lymph node metastasis was found in 30.5% and lymphovascular invasion was found in 16% of patients. • Median follow-up was 63.2 months. • Advanced stage was associated with COX-2, p53 and CC-3 alterations and high grade was associated with COX-2 alterations (P < 0.05). The total number of altered markers and unfavourable PS were associated with both disease recurrence and bladder cancer-specific mortality in Kaplan-Meier analyses (P < 0.05). Unfavourable PS was an independent predictor of disease recurrence (hazard ratio [HR] 2.694, 95% confidence interval [CI] 1.386-5.235, P= 0. 003) and bladder cancer-specific mortality (HR 2.868, 95% CI 1.209-6.802, P= 0. 017) in multivariable Cox regression analysis. • Markers of apoptosis pathways may play an important role in the prognosis of SCC of the bladder. An increased number of altered markers and an unfavourable PS may identify patients who might benefit from multimodal therapies.BJU International 02/2012; 110(7):961-6. DOI:10.1111/j.1464-410X.2012.10949.x · 3.13 Impact Factor
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ABSTRACT: Patients with locally 'advanced' or muscle invasive bladder cancer have higher mortality rates than patients with nonmuscle invasive ('superficial') bladder cancer. Biomarkers can stratify clinical outcomes and thus promise to more accurately prognosticate and thus help assign patients to the appropriate treatments. The aim of this review is to summarize biomarker developments in the past year and to discuss their implications in prognosis and treatment selection in locally advanced bladder cancer. Prognostic biomarkers for bladder cancer are identified at the DNA, RNA and/or protein levels. Some are new markers, whereas others are established markers with new roles in bladder cancer. Markers can report on the risk of disease recurrence or metastasis, or treatment responsiveness and thus are useful in determining 'who to treat' and 'what to treat with'. The list of biomarkers for prognosis and treatment selection for advanced bladder cancer is growing. For most, their clinical relevance is unclear due to their lack of validation in external datasets. MicroRNAs and new techniques including next-generation sequencing offer additional opportunities for biomarker discovery, validation, and clinical applications.Current opinion in urology 09/2011; 21(5):420-7. DOI:10.1097/MOU.0b013e32834956d6 · 2.12 Impact Factor