ABSTRACT
BACKGROUND: To obtain a prognostic stratification model for resected gastric cancer patients. PATIENTS AND METHODS: Clinicopathological and molecular data (expression of Cdx2, Apc, ß-catenin, E-cadherin, Fhit, p53, and human epidermal growth factor receptor-2 (Her2); HER2 and TOPO2A gene copy number; PIK3CA mutations; microsatellite instability) were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Individual patient probability (IPP) was estimated by logistic equation. A continuous score to identify risk-classes was derived according to the model ratios. RESULTS: Two-hundred eight patients were studied (median follow-up 20 months). At multivariate analysis, sex, stage, margins, location, nodes, Apc, and Fhit were independent predictors for CSS; the same factors (and age and Her2, except Fhit) predicted OS. Multivariate model predicted IPP with high prognostic accuracy (0.90 for CSS; 0.91 for OS). A two-class model significantly separated low- and high-risk patients for CSS (23.4% and 85.6%, P < 0.0001) and OS (21.4% and 82.0%, P < 0.0001). A three-class model differentiated low-, intermediate-, and high-risk patients for CSS (6.3%, 35.3%, and 88.0%, P < 0.0001) and OS (6.1%, 34.6%, and 86.5%, P < 0.0001). CONCLUSIONS: A risk classification system comprising the immunohistochemical expression of three proteins (Apc, Fhit, and Her2) and five clinicopathological parameters (stage, resected nodes, margins, location, and sex) accurately separates the resected gastric cancer patients into three classes of risk.
Subject(s)
Acid Anhydride Hydrolases/metabolism , Adenomatous Polyposis Coli Protein/metabolism , Carcinoma/metabolism , Neoplasm Proteins/metabolism , Receptor, ErbB-2/metabolism , Stomach Neoplasms/metabolism , Adenomatous Polyposis Coli Protein/genetics , Adult , Aged , Aged, 80 and over , Area Under Curve , Carcinoma/mortality , Carcinoma/secondary , Carcinoma/surgery , DNA Mutational Analysis , Female , Gene Expression , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Middle Aged , Multivariate Analysis , Prognosis , Proportional Hazards Models , ROC Curve , Receptor, ErbB-2/genetics , Retrospective Studies , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Stomach Neoplasms/surgeryABSTRACT
BACKGROUND: Kinases represent potential therapeutic targets in pancreatic endocrine tumours (PETs). PATIENTS AND METHODS: Thirty-five kinase genes were sequenced in 36 primary PETs and three PET cell lines: (i) 4 receptor tyrosine kinases (RTK), epithelial growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), tyrosine-protein kinase KIT (KIT), platelet-derived growth factor receptor alpha (PDGFRalpha); (ii) 6 belonging to the Akt/mTOR pathway; and (iii) 25 frequently mutated in cancers. The immunohistochemical expression of the four RTKs and the copy number of EGFR and HER2 were assessed in 140 PETs. RESULTS: Somatic mutations were found in KIT in one and ATM in two primary neoplasms. Among 140 PETs, EGFR was immunopositive in 18 (13%), HER2 in 3 (2%), KIT in 16 (11%), and PDGFRalpha in 135 (96%). HER2 amplification was found in 2/130 (1.5%) PETs. KIT membrane immunostaining was significantly associated with tumour aggressiveness and shorter patient survival. PET cell lines QGP1, CM and BON harboured mutations in FGFR3, FLT1/VEGFR1 and PIK3CA, respectively. CONCLUSIONS: Only rare PET cases, harbouring either HER2 amplification or KIT mutation, might benefit from targeted drugs. KIT membrane expression deserves further attention as a prognostic marker. ATM mutation is involved in a proportion of PET. The finding of specific mutations in PET cell lines renders these models useful for preclinical studies involving pathway-specific therapies.
Subject(s)
Endocrine Gland Neoplasms/enzymology , Endocrine Gland Neoplasms/genetics , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/genetics , Protein Kinases/genetics , Cell Line, Tumor , DNA Mutational Analysis , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Mutation , Protein Kinases/metabolism , Tissue Array AnalysisABSTRACT
In order to find out whether there is any relationship between blood pressure, body mass index, weight, heart rate in youth and arterial hypertension later on in life, 212 subjects (16-26 years of age) were re-examined 2 years later. Previous blood pressure level were very significantly associated with present blood pressure levels A relationship was also discovered with the other parameters measured 2 years earlier: weight, body mass index and heart rate. These findings confirm the fact that it is possible to detect future hypertensives early in life and to take effective preventive measures.
