Cyclin D1 contributes to regulate G1 progression by forming a complex with different cyclin-dependent kinases. It has oncogenic properties and is frequently overexpressed in several human tumor types. In our study, expression of cyclin D1 and Ki67, a proliferation marker, was evaluated by immunohistochemistry in human papillary superficial (pTa-pT1) bladder cancers and was correlated with p27 Kip1 , p21 Waf1 and c-erbB-2 expression, with p53 gene status and protein expression, ploidy and cancer progression. Cyclin D1 expression was neither associated with tumor stage nor with tumor grade but high cyclin D1 expression (>25% positive nuclei) was significantly associated with p53 gene mutation (p ‫؍‬ 0.012), low p21 Waf1 (p ‫؍‬ 0.015) and high p27 Kip1 (p ‫؍‬ 0.016) protein expression. Ki67 expression was not associated with tumor stage but a high proliferation index (>10% positive nuclei) was significantly associated with high tumor grade (p ‫؍‬ 0.001) and with DNA aneuploidy (p ‫؍‬ 0.005). There was no significant difference in proliferative activity between high and low cyclin D1 expressor tumors. Patients whose tumors showed high expression of cyclin D1 displayed a significantly longer disease-free survival (p < 0.001 by log-rank test). Increased Ki67 expression was significantly associated with shorter disease-free survival (p ‫؍‬ 0.003). Both cyclin D1 (p ‫؍‬ 0.027; RR ‫؍‬ 1.898) and Ki67 (p ‫؍‬ 0.047; RR ‫؍‬ 1.932) protein expressions were independent predictors of reduced diseasefree survival on a multivariate analysis that also included p27 Kip1 expression and tumor stage. The simultaneous presence of low cyclin D1, low p27 Kip1 and high Ki67 expression defined a "high-risk" group of patients who displayed a significantly increased risk of recurrence (p < 0.0001). These results suggest that evaluation of cell cycle-associated markers can help to identify high-risk patients and may affect the management of patients with papillary superficial bladder cancer.

BACKGROUND The degree of applicability of the Bethesda System 2001 (TBS 2001) for cervicovaginal cytology to a public health setting is unknown, and extrapolations from available data are unwarranted. METHODS A “before/after” study design was used to evaluate the impact of TBS 2001 on an organized, population‐based screening program in northern Italy. Between 2003–2004, 6 cytology laboratories converted from TBS 1991 to TBS 2001. A set of screening indicators based on TBS 2001 (85,012 patients) were compared with those based on TBS 1991 (199,833 patients) by means of their laboratory‐ and patient age‐standardized ratio with a 95% confidence interval (CI). RESULTS The prevalence of cervical intraepithelial neoplasm (CIN)2‐3/carcinoma was stable between the 2 populations. TBS 2001 had no effect on the unsatisfactory rate (1.99% vs. 2.03% for TBS 1991) nor on follow‐up compliance rate (93.2% vs. 92.3%). The reporting rate of atypical squamous cells (ASC) decreased from 17.1 to 14.7 per 1000 (ratio, 0.86; 95% CI, 0.81–0.91), the total positivity rate from 31.1 to 29.0 per 1000 (ratio, 0.93; 95% CI, 0.90–0.97), and the ASC:SIL (squamous intraepithelial lesion) ratio from 1.38 to 1.16. Compared with the ASCUS (ASC of undetermined significance) reports of TBS 1991, the predictive value for CIN2‐3/carcinoma decreased from 5.2 to 3.5% (ratio, 0.68; 95% CI, 0.48–0.93) among ASCUS reports, but increased from 5.1 to 17.2% (ratio, 3.41; 95% CI, 1.64–6.28) among ASC‐cannot exclude high grade lesion (ASC‐H) reports. ASC‐H had a 5.01‐fold (95% CI, 2.23–10.2) greater predictive value than ASCUS. CONCLUSIONS TBS 2001 is applicable to cervical screening in a public health setting. Cancer (Cancer Cytopathol) 2006;. © 2006 American Cancer Society.

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