Prognostic value of cell cycle regulatory proteins in muscle-infiltrating bladder cancer.
OBJECTIVE
The aims of this study were to investigate the expression levels of proteins involved in cell cycle regulation in specimens of bladder cancer and to correlate them with the clinicopathological characteristics, proliferative activity and survival.


METHODS
Eighty-two specimens obtained from patients affected by muscle-invasive bladder cancer were evaluated immunohistochemically for p53, p21 and cyclin D1 expression, as well as for the tumour proliferation index, Ki-67. The statistical analysis included Kaplan-Meier curves with log-rank test and Cox proportional hazards models.


RESULTS
In univariate analyses, low Ki-67 proliferation index (P = 0.045) and negative p21 immunoreactivity (P = 0.04) were associated to patient's overall survival (OS), but in multivariate models p21 did not reach statistical significance. When the combinations of the variables were assessed in two separate multivariate models that included tumour stage, grading, lymph node status, vascular invasion and perineural invasion, the combined variables p21/Ki-67 or p21/cyclin D1 expression were independent predictors for OS; in particular, patients with positive p21/high Ki-67 (P = 0.015) or positive p21/negative cyclin D1 (P = 0.04) showed the worst survival outcome.


CONCLUSIONS
Important alterations in the cell cycle regulatory pathways occur in muscle-invasive bladder cancer and the combined use of cell cycle regulators appears to provide significant prognostic information that could be used to select the patients most suitable for multimodal therapeutic approaches.
Galmozzi
Fabia
F
Department of Medical Oncology, University of Genova, Genova, Italy.
Rubagotti
Alessandra
A
Romagnoli
Andrea
A
Carmignani
Giorgio
G
Perdelli
Luisa
L
Gatteschi
Beatrice
B
Boccardo
Francesco
F
D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D049109:Cell Proliferation; D015331:Cohort Studies; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D016213:Cyclins / Q000096:biosynthesis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D015999:Multivariate Analysis; D011379:Prognosis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53