ABSTRACT
BACKGROUND: Human papillomavirus (HPV) is the major predictor of outcome in oropharyngeal squamous cell carcinoma (OSCC) but the disease is heterogeneous and there is limited understanding of the prognostic significance of other molecular markers in relation to HPV. This multi-institutional, retrospective study examined the prognostic significance of Ki67 expression in association with HPV status in OSCC. METHODS: The 105 patients recruited had a median follow-up of 70 months. Tumor HPV status was determined by HPV E6-targeted multiplex real-time polymerase chain reaction/p16 semiquantitative immunohistochemistry and Ki67 expression by semiquantitative immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Cox regression with censoring at dates of last follow-up. RESULTS: HPV and Ki67 positivity rates were 46 and 44 %, respectively. HPV-positive cancers were more likely to be Ki67-positive. On multivariate analysis, both HPV and Ki67 were predictors of outcome. Ki67-positive cancers were associated with a 3.13-fold increased risk of disease-related death compared with Ki67-negative cancers. Among HPV-negative patients, Ki67-positive disease was associated with 5.6-fold increased risk of oropharyngeal cancer-related death (p = 0.002), 5.5-fold increased risk of death from any cause (p = 0.001), and 2.9-fold increased risk of any event (p = 0.013). The risk of locoregional failure was lowest in patients with HPV-positive/Ki67-positive cancers. CONCLUSIONS: Ki67 predicts disease-related death in oropharyngeal cancer independent of HPV status. A combination of Ki67 and HPV status provides improved prognostic information relative to HPV status alone. Our data suggest, for the first time, that Ki67 status has prognostic value, particularly in HPV-negative oropharyngeal cancer.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Ki-67 Antigen/metabolism , Neoplasm Recurrence, Local/metabolism , Oropharyngeal Neoplasms/metabolism , Papillomaviridae/isolation & purification , Papillomavirus Infections/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/virology , DNA, Viral/genetics , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Male , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/virology , Neoplasm Staging , Oropharyngeal Neoplasms/mortality , Oropharyngeal Neoplasms/pathology , Oropharyngeal Neoplasms/virology , Papillomaviridae/genetics , Papillomavirus Infections/mortality , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Prognosis , Real-Time Polymerase Chain Reaction , Retrospective Studies , Survival RateABSTRACT
The transformation of melanocytes to melanoma cells is characterised by abnormal proliferation resulting from alterations in cell cycle regulatory mechanisms. This occurs through alterations in the two major cell cycle regulatory pathways, the retinoblastoma (Rb) and p53 tumour suppressor pathways. This review summarises the current knowledge of alterations in these two pathways at G1/S transition and specifically the role of the key cell cycle regulatory proteins pRb, p16INK4a (p16), cyclin D1, p27Kip1 (p27), p53 and p21Waf1/Cip1 (p21) in the pathogenesis of melanoma. It also considers their prognostic significance. Current data indicate that alterations of cyclin kinase inhibitor (cdki) levels are implicated in the pathogenesis of melanoma and may be useful prognostic markers. However, large validation studies linked to comprehensive clinical follow up data are necessary to clarify the prognostic significance of cell cycle regulatory proteins in individual patients.
Subject(s)
Cell Cycle Proteins/physiology , Cell Cycle/physiology , Melanoma/physiopathology , Skin Neoplasms/physiopathology , Animals , Cell Cycle/genetics , Cell Cycle Proteins/genetics , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Cyclin D1/genetics , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p27/genetics , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Disease Progression , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/physiology , Humans , Melanoma/genetics , Prognosis , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Skin Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
Cimetidine is known to have immunomodulatory effects and this study aimed to examine the effect of pre-operative cimetidine treatment on lymphocytic infiltration in n = 72 women with breast cancer randomised to 400 mg bd or placebo for five days presurgery. A combined index was devised by adding infiltrating lymphocyte percentage and lymphoid score. There were no significant differences in circumferential infiltrate and lymphoid follicles in cimetidine treated patients and control patients with breast cancer.
