Prognostic Factors in Survival of Patients With Stage Ta and T1 Bladder Urothelial Tumors The Role of G<SUB>1</SUB>-S Modulators (p53, P21Waf1, p27Kip1, Cyclin D1, and Cyclin D3), Proliferation Index and Clinicopathologic Parameters

Department of Pathology, Reina Sofia University Hospital, Cordoba, Spain.
American Journal of Clinical Pathology (Impact Factor: 3.01). 10/2004; 122(3):444-52. DOI: 10.1309/LTFU-3UUM-BY09-5HUM
Source: PubMed

ABSTRACT We studied 159 cases of superficial (stage Ta or T1) bladder tumors to determine the significance on survival of a subset of regulators of transition from G1 to S phase of the cell cycle (p53, p21Waf1, p27Kip1, cyclin D1, cyclin D3) and tumor proliferation (Ki-67 [MIB-1]). Clinical findings (patient age, sex, tumor size, grade, stage [Ta or T1]) were included in the analysis. Univariate analysis revealed association of tumor size (P = .0353), grade in stage Ta tumors (P = .0074), cyclin D1 expression (P = .0182), and Ki-67 index (P = .0033) with disease-free survival and of tumor size (P = .0005), stage (P = .0494), cyclin D3 expression (P = .0105), and Ki-67 index (P = .0272) with overall survival. Cox multivariate analysis revealed cyclin D1 expression and high proliferation index (disease-free) and tumor size, cyclin D3 expression, and high proliferation index (overall survival) as independent predictors. Results suggest that alterations of the progression from the G1 to S phase of the cell cycle are common in papillary urothelial bladder tumors. High tumor proliferation, expression of cyclins D1 and D3, and tumor size at diagnosis might be relevant predictors of survival in patients with stage Ta and T1 bladder urothelial tumors.

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    • "These patients could potentially benefit from early aggressive therapy. Ki-67 has been reported as a prognostic marker for disease and progression-free survival in pTa and pT1 UCC [18] [26]. In the 203 pTa and pT1 tumours across all grades investigated in this study, we were able to confirm its relation to disease progression ( p < 0.03). "
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    ABSTRACT: The clinical management of non-muscle-invasive urothelial cell carcinoma of the bladder (UCC) is challenging, as it has a marked tendency to recur and to progress. Aim of this study was to investigate the prognostic value of the WHO 1973 and 2004 grading systems and biomarkers FGFR3, CK20 and Ki-67. In a prospective study, tumours from 221 patients were studied for the expression of CK20 and Ki-67 by immunohistochemistry, and FGFR3 status by SNaPshot mutation detection. Staging and grading were performed according to the WHO classification systems of 1973 and 2004. : Median follow-up was 35 mo. Recurrence occurred in 72 of 221 patients. None of the parameters was able to predict disease recurrence. CK20, Ki-67, FGFR3 mutation, molecular grade using FGFR3 mutation analysis and Ki-67, and histological grading and staging were significantly associated with disease progression in stage. In multivariable analyses, WHO 1973 and 2004 grading systems remained statistically significant and independent predictors of progression, with p=0.005 for WHO 1973 and p=0.004 for 2004. FGFR3 status was able to discriminate progressors from nonprogressors in a subset of patients with high-grade UCC (p=0.009). This is the first prospective study comparing the WHO 1973 and 2004 grading systems. We show that both grading systems contribute valuable independent information. Therefore, it should be considered whether a better grading system could be developed that incorporates essential elements from both. The combination of WHO 2004 grading with FGFR3 status allows a better risk stratification for patients with high-grade non-muscle-invasive UCC.
    European Urology 10/2008; 54(4):835-43. DOI:10.1016/j.eururo.2007.12.026 · 12.48 Impact Factor
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    • "The results presented in this manuscript clearly demonstrate a correlation between p53 levels and cyclin D1 expression. To the best of our knowledge, this is one of the few reports, which directly correlates p53 status with cyclin D1 since both are regulators of G1 to S phase transition [31]. p53 overexpression downregulates Akt which is constitutively active in MCF-7As53 cells Akt activation which is downstream of PI3-K pathway is known to be involved in cell growth and survival [32]. "
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    ABSTRACT: The p53 protein has been a subject of intense research interest since its discovery as about 50% of human cancers carry p53 mutations. Mutations in the p53 gene are the most frequent genetic lesions in breast cancers suggesting a critical role of p53 in breast cancer development, growth and chemosensitivity. This report describes the derivation and characterization of MCF-7As53, an isogenic cell line derived from MCF-7 breast carcinoma cells in which p53 was abrogated by antisense p53 cDNA. Similar to MCF-7 and simultaneously selected hygromycin resistant MCF-7H cells, MCF-7As53 cells have consistent basal epithelial phenotype, morphology, and estrogen receptor expression levels at normal growth conditions. Present work documents investigation of molecular variations, growth kinetics, and cell cycle related studies in relation to absence of wild-type p53 protein and its transactivation potential as well. Even though wild-type tumor suppressor p53 is an activator of cell growth arrest and apoptosis-mediator genes such as p21, Bax, and GADD45 in MCF-7As53 cells, no alterations in expression levels of these genes were detected. The doubling time of these cells decreased due to depletion of G0/G1 cell phase because of constitutive activation of Akt and increase in cyclin D1 protein levels. This proliferative property was abrogated by wortmannin, an inhibitor of PI3-K/Akt signaling pathway. Therefore this p53 null cell line indicates that p53 is an indispensable component of cellular signaling system which is regulated by caveolin-1 expression, involving Akt activation and increase in cyclin D1, thereby promoting proliferation of breast cancer cells.
    Experimental Cell Research 11/2007; 313(19):3945-3958. DOI:10.1016/j.yexcr.2007.08.022 · 3.37 Impact Factor
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    • "Two well-established markers are CK20 (Harnden et al, 1999) and Ki67 (van Rhijn et al, 2003; Lopez-Beltran et al, 2004). Ki67 is a commonly applied prognostic and diagnostic tool (van Rhijn et al, 2003; Lopez-Beltran et al, 2004), as the Ki67 protein is present in the nuclei of cells in the G 1 , S, and G 2 phases of the cell cycle in dividing cells as well as in mitosis but not in the G 0 phase of quiescent cells. Nevertheless it is unlikely that Ki67 reliably labels the entire proliferative cell fraction. "
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    ABSTRACT: Stage Ta/T1 urothelial carcinoma of the bladder (Ta/T1 BC) has a marked tendency to recur. Besides histopathology, markers such as CK20 expression and proliferation index (Ki67) have been shown to predict its clinical course. The replication-licensing factor minichromosome maintenance protein 2 (Mcm2) is a marker of proliferative potential shown to be a promising prognostic marker in various malignancies. The aim of the present study was to evaluate the prognostic value of Mcm2 in comparison to stage, grade, CK20 and Ki67. Initial sporadic Ta/T1 BC (n=71) were evaluated for their expression of CK20, Ki67 and Mcm2 by immunohistochemistry and tissue microarray technology. Prognostic power was analysed by univariate and multivariate Cox regression model for tumour recurrence rate. Median follow-up period was 39 months. A total of 35% patients experienced recurrence. While CK20 was not predictive, grade, Ki67 and Mcm2 were significantly related to recurrence rate in univariate Cox regression model. Only grade (HR 2.37; 95% CI 1.24-4.51; P=0.009) and Mcm2 expression with a cutoff > or = 40% (HR 5.81; 95% CI 2.41-14.00; P<0.001) were independent predictors of recurrence rate in multivariate Cox regression analysis. In addition to grade, expression of Mcm2 is an independent predictor of recurrence in Ta/T1 BC.
    British Journal of Cancer 06/2007; 96(11):1711-5. DOI:10.1038/sj.bjc.6603784 · 4.82 Impact Factor
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