Showing papers by "James G. Kench published in 2002"

Aberrant p16(INK4A) and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma.

Abstract: Background and aims: Intraductal papillary mucinous tumours (IPMT) of the pancreas constitute a unique pathological entity with an overall incidence of associated invasive malignancy of 20%. The malignant potential of an individual IPMT cannot be accurately predicted. Preoperative estimation of the risk of associated invasive malignancy with IPMT would be of significant clinical benefit. As aberrations in cell cycle regulatory genes are associated with the progression of precursor pancreatic ductal lesions to invasive adenocarcinoma, we examined expression of key cell cycle regulatory genes in the cyclin D1/retinoblastoma pathway and the transforming growth factor β/Smad4 signalling pathway in a cohort of patients with surgically resected IPMT. Methods: Sections of formalin fixed paraffin embedded pancreatic tissue from a cohort of 18 patients with IPMT were examined using immunohistochemistry for protein expression of cell cycle regulatory genes p16 INK4A , p21 CIP1 , p27 KIP1 , cyclin D1, pRb, and p53, as well as the cell signalling molecule Smad4. A comparison of expression levels was made between adenoma/borderline IPMT (10 patients) and intraductal papillary mucinous carcinoma (IPMC) (eight patients, four of whom harboured invasive carcinoma). Statistical analysis was performed using the χ 2 and Fisher9s exact tests. Results: Aberrant expression of the proteins examined increased in frequency from adenoma/borderline IPMT to IPMC. Specifically, there was a significantly greater incidence of loss of p16 INK4A expression in IPMC: 8/8 lesions (100%) compared with 1/10 (10%) adenoma/borderline IPMT (p Conclusions: These data indicate that loss of p16 INK4A and Smad4 expression occur more frequently in IPMC alone, or with associated invasive carcinoma, compared with adenoma/borderline IPMT. Aberrant protein expression of these cell cycle regulatory genes in IPMT and pancreatic intraepithelial neoplasia in the current model of pancreatic cancer progression suggest similarities in their development and may also represent the subsequent risk of invasive carcinoma.

Genotype‐specific mechanisms for hepatic steatosis in chronic hepatitis C infection

Abstract: Background: Hepatic steatosis is common in hepatitis C, but the relative importance of host and viral factors is controversial. In the present prospective study, we examined metabolic factors associated with non-alcoholic fatty liver and viral genotype as predictors of steatosis and fibrosis in chronic hepatitis C infection. Methods: In 124 chronic hepatitis C patients, the association between liver histology and the following was investigated: demographic and anthropometric data, alcohol intake, alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein–cholesterol, high-density lipoprotein–cholesterol, triglyceride, transferrin saturation, ferritin, insulin, c-peptide, glucose and insulin resistance (homeostasis model). Results: By multivariate analysis, genotype 3 was associated with increased steatosis grade (P = 0.02). There were significant pairwise interactions between genotype 3 status and total cholesterol (P = 0.01), current alcohol intake (P = 0.04) and serum ALT (P = 0.01). This showed that the etiology of steatosis was different in patients with genotype 3 and those with non-genotype 3 chronic hepatitis C infection. In genotype 3 patients, the degree of steatosis was inversely associated with serum cholesterol (P = 0.005) and positively associated with serum triglyceride (P = 0.02). There was no association between body mass index (BMI) and the extent of steatosis. Among patients with other genotypes, the steatosis grade was strongly influenced by BMI (P < 0.0001) and serum ALT (P < 0.01). Independent predictors of fibrosis were age (P = 0.001), past alcohol intake (P = 0.04), ALT (P = 0.002), serum insulin (P = 0.001) and portal inflammation (P < 0.001). Conclusions: Hepatitis C genotype 3 may interfere with pathways of hepatic lipid metabolism, whereas increased BMI appears to be a more important pathogenic factor in other genotypes. Although steatosis and BMI were not associated with hepatic fibrosis, their relationship with serum insulin suggests that metabolic factors related to insulin action could influence fibrogenesis in hepatitis C.

DPC4/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma

Abstract: PURPOSE: Prognostic indicators in pancreatic cancer (PC) are poorly defined and difficult to quantify preoperatively, hence they may lead to inappropriate patient selection for treatment. We examined the protein expression of key cell-cycle regulatory and cell-signaling molecules that occur at high frequency in PC and assessed their relationship to clinicopathologic parameters, response to operative resection, and outcome. PATIENTS AND METHODS: We identified 348 patients with pancreatic ductal adenocarcinoma and assessed the influence of reported clinicopathologic prognostic factors and the expression of the cell-cycle regulatory genes p21WAF1/CIP1 (CDKN1A), cyclin D1 (CCND1), p53, and p16INK4A (CDKN2) and the cell-signaling molecule DPC4/Smad4 (MADH4) using immunohistochemistry in a subgroup of 129 patients. RESULTS: Independent prognostic factors in resected patients were tumor size greater than 45 mm (P = .0015), involvement of surgical margins (P < .0001), and perineural invasion (P = .014). Loss of D...

Gliclazide-induced acute hepatitis with hypersensitivity features.

Abstract: Gliclazide [Diamicron, Servier Laboratories, Australia] is a second generation sulfonylurea used in the treatment of type 2 diabetes mellitus. Generally well tolerated with a relatively low incidence of hypoglycemia, it may have beneficial effects beyond the reduction of serum glucose, including reduced platelet aggregation and antioxidant effects (1). Hepatotoxicity with this agent is not well recognized, with the exception of one report of acute hepatitis (2). In early clinical studies, therapy was withdrawn in 2% of patients because of adverse reactions, which included gastrointestinal symptoms and liver test abnormalities. However, the role of gliclazide in causing the latter was regarded as inconclusive (1). We report a second case of gliclazideinduced acute hepatitis. The clinical presentation in this patient was characterized by well-defined features of hypersensitivity and acute hepatitis, which were relatively severe, compared to that reported previously.