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Background: Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer. Methods: The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m(2) intravenously (IV), LV 200 mg/m(2) and 5FU 450 mg/m(2) bolus (Arm A) versus LV 200 mg/m(2) and 5FU 500 mg/m(2) IV bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years. Results: The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms. Conclusions: Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity.

The diagnosis of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B indicating therapeutic intervention currently requires serum hepatitis B virus (HBV) DNA >= 2,000 IU/mL. We evaluated the severity of liver histology and the presence of histological indication for treatment in patients with HBeAg-negative chronic HBV infection focusing on those with low viremia and/or normal alanine aminotransferase (ALT). In total, 399 patients with increased ALT and detectable serum HBV DNA (chronic hepatitis B patients) and 35 cases with persistently normal ALT and HBV DNA >2,000 IU/mL (inactive carriers) were included. Histological indication for treatment (grading score >= 7 and/or stage >= 2 in Ishak’s classification) was found in 91% (185/203), 82% (75/91), 75% (47/63), and 62% (26/42) of chronic hepatitis B patients with HBV DNA >= 200,000, 20,000-199,999, 2,000-19,999, and = 20,000 IU/mL almost always require therapeutic intervention, but histological indications for treatment are also present in the majority of such cases with HBV DNA < 20,000 and even < 2,000 IU/mL. In contrast, minimal histological lesions are observed in the majority of HBeAg-negative patients with persistently normal ALT and HBV DNA > 2,000 IU/mL, who may not require immediate liver biopsy and treatment but only close follow-up. (HEPATOLOGY 2008;48:1451-1459.)

Objective. Leptin and adiponectin have been implicated in the pathogenesis and progression of non-alcoholic steatohepatitis (NASH) and chronic hepatitis C (CHC), but little is known about the role of resistin in chronic liver diseases. The objective of this study was to investigate serum levels of the above three adipokines in relation to the etiology of liver disease and to determine their associations with histological severity. Material and methods. We prospectively evaluated 146 patients (HBeAg-negative chronic hepatitis B (CHB): 52, CHC: 70, NASH: 24) who consecutively underwent liver biopsy. Detailed epidemiological, anthropometric and laboratory data were recorded. Histological lesions were evaluated blindly according to the Ishak and the Brunt classifications for CHB/CHC and NASH, respectively. Results. Serum adipokine levels were similar between CHB and CHC patients, while CHB/CHC patients had significantly lower leptin levels compared with NASH patients (8.37.3 versus 17.616.6 ng/ml, p=0.012) and higher adiponectin (10.25.1 versus 7.54 g/ml, p=0.018) and resistin levels (7.12.5 versus 5.72.8 ng/ml, p=0.016). In CHB/CHC, there was no significant association between steatosis or necroinflammation and levels of adipokines, while the presence of moderate/severe fibrosis (stages 4-6) was associated with higher leptin and adiponectin levels in male but not in female patients and with lower resistin levels irrespective of gender or other factors (adjusted odds ratio=0.788, p=0.035). Conclusions. Serum adipokine levels depend on the etiology of liver disease differing between chronic viral hepatitis and NASH, but not between CHB and CHC. In CHB/CHC, resistin levels are independently associated with fibrosis severity, whereas in the association of leptin and adiponectin levels with fibrosis, it seems to be a gender effect.

BACKGROUND/AIM: Hepatic steatosis is considered to be mostly associated with viral factors in genotype 3 and metabolic factors in genotype 1 chronic hepatitis C, while there are rather few data for genotype 4. We determined the parameters associated with steatosis in 350 chronic hepatitis C patients, focusing on genotype 4. METHODS: Histological lesions were evaluated according to Ishak’s classification and steatosis was semiquantitatively graded. Several patient characteristics on the biopsy day were also evaluated. RESULTS: Steatosis was present in 73% of patients without significant differences among genotypes. Moderate/severe steatosis was more frequent in genotype 3 than 4 (44% vs 26%, P = 0.025) and similar between genotype 4 and 1 patients. Moderate/severe steatosis was associated with body mass index (BMI) in genotype 4 (P = 0.023) and gamma-glutamyl-transpeptidase in genotype 3 patients (P = 0.044). In 150 nondiabetic patients with BMI

Background Hepatic granulomas have been reported in 2-15% of unselected liver biopsies, with a wide clinical profile responsible for their presence. To date, no series concerning the prevalence and the etiology of granulomas from Greece has been reported. Objectives To evaluate the prevalence and the etiology of hepatic granulomas and to investigate whether there has been an alteration in distribution of diagnoses in our compared with those published so far in the literature. Study The results of liver biopsy specimens performed in a Department of Medicine, between 1999 and 2004, were retrospectively reviewed and the cases revealing hepatic granulomas had their medical notes and the liver biopsies recorded. Results Over the study period, 1768 liver biopsies were performed. Hepatic granulomas were identified in 66 (3.7%). Of those, 51 were female with a mean age of 57 years (range 34-74 years) and 15 were male with a mean age of 42 years (range 18-78 years). Autoimmune liver diseases including primary biliary cirrhosis, overlap syndrome and autoimmune hepatitis accounted for the majority of cases (68%), followed by sarcoidosis (7.5%), chronic hepatitis B virus and hepatitis C virus infection (Z5%), idiopathic (6%), drugs (3%) and other miscellaneous causes (Z5%). Conclusions Our series showed that autoimmune liver diseases, mainly primary billary cirrhosis was the most common cause of granuloma formation, a finding rather similar to that stated in the studies from Western countries. A rather small number of idiopathic cases were recorded. Chronic viral hepatitis and sarcoldosis rates were equal, a finding possibly reflecting a fairly high proportion of viral hepatitis in our sample.

Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency. Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis) were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made. (c) 2006 The WJG Press. All rights reserved.

Melanoma accounts for 1-3 per cent of all malignant tumors. Except cutaneous, other less common melanomas include, among others, those in the GI tract. However, their primary or secondary nature is often difficult to establish. Referring to the stomach, scattered cases of primary melanomas have been reported in the literature. We report a case of a man with an ulcerated submucosal mass at the antrum of the stomach, manifested with dull upper abdominal pain, nausea, vomiting, fatigue and anemia. This lesion was histologically proved to be melanoma. A detailed clinical and laboratory investigation revealed no primary site elsewhere. To our knowledge, very few cases of primary gastric melanoma have been reported. Our case is the fourth ever published and the first located at the antrum of the stomach. The debate upon the primitive nature of such lesions still persists. Thus, specific diagnostic criteria have been proposed. (C) 2,006 The WJG Press. All rights reserved.

A 60-years old male was admitted to our department for investigation of constipation and hypogastric discomfort intensified during defecation of a few weeks duration. The cause proved to be a rectal carcinosarcoma that was treated by abdominoperineal resection and postoperative chemo-radiotherapy. The patient died 6 months later due to hepatic failure, showing evidence of disseminated disease. In general colonic carcinosarcomas constitute a rare category of malignant neoplasms whose nature is still incompletely understood. No specific treatment guidelines exist. Surgery is the mainstay of treatment and regardless of the addition of adjuvant therapy the prognosis is very poor. Systematic genetic analysis may be the clue for understanding the pathogenesis of these mysterious tumors. (C) 2006 The WJG Press. All rights reserved.

Objective We assessed the value of the recently developed aspartate aminotransferase to platelet ratio index (APRI) for predicting significant fibrosis or cirrhosis in patients with chronic hepatitis C or HBeAg-negative chronic hepatitis B. Methods In total, 489 patients (chronic hepatitis C, 284 patients; HBeAg-negative chronic hepatitis B, 205 patients) were included. APRI values of 0.50 or less and greater than 1.50 were evaluated for predicting significant fibrosis, and APRI values of 1.00 or less and greater than 2.00 for predicting cirrhosis. Liver biopsies were evaluated according to the Ishak’s classification. Fibrosis was considered to be significant in cases with scores 3-6, and cirrhosis to be present in cases with fibrosis scores of 5 and 6. Results Significant fibrosis was observed in 56/148 (38%) patients with APRI 1.50 (p < 10(-3)). Cirrhosis was observed in 47/311 (15%) patients with APRI 2.00 (p < 10(-3)). The areas under receiver-operating characteristic curves were 0.65 and 0.70 for prediction of significant fibrosis or cirrhosis, respectively. The combination of APRI 1.50 classified correctly 36% of patients with or without significant fibrosis, while the combination of APRI 2.00 classified correctly 62% of patients with or without cirrhosis. There was no significant difference in the predictive values of APRI between patients with chronic hepatitis C and chronic hepatitis B. Conclusions APRI is significantly associated with the extent of fibrosis, but it does not classify correctly 40-65% of patients with chronic hepatitis C or HBeAg-negative chronic hepatitis B, and thus it cannot replace liver biopsy.

Aims: The quantitative and qualitative expression of CK-7, CK-19, and c-Kit markers in various cell types were evaluated during the four stages of primary biliary cirrhosis. Methods: A total of 53 specimens were examined. Thirteen specimens were identified as Ludwig’s stage 1, 23 as stage 2, 14 as stage 3, and 2 as stage 4. Immunohistochemical stains were performed for CK-7, CK-19, c-Kit and subsequently graded. The cell types expressing the markers were qualitatively analysed. Results: In normal liver, biliary epithelial cells expressed CK-7, CK-19, whereas the Canals of Hering (CoH) were stained with c-Kit and partly CK-19, contrary to hepatocytes. The aforementioned expression patterns were detected in pathologic samples of PBC, with qualitative and quantitative differences though. CK-7 grading was found to correspond with Ludwig’s staging, in contrast to CK-19. c-Kit was absent in the early stages and focally present in the advanced stages. All biliary-type, intermediate cells and hepatocytes were CK-7 positive, particularly in samples with cholestasis, whereas CK-19 was only found in biliary-type and intermediate cells. c-Kit was expressed in CoH which appeared as clusters and strings of cuboidal cells in advanced stages. Conclusions: CK-7 can be regarded as a histological marker of progression in PBC; CK-19 cannot be assessed as a safe marker in the development of the disease. The absence of c-Kit in the early stages of PBC is related to the destruction of the CoH. CK-7 hepatocyte expression in the advanced stages is likely to be related to damaged hepatocytes’ metaplastic potential. (C) 2006 Elsevier Ireland Ltd. All rights reserved.