Topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy

<p>Abstract</p> <p>Background</p> <p>Thymidylate synthase (TS) and Topoisomerase I (Topo I) are significant biomarkers in colorectal cancer (CRC). We aimed to study the expression of TS and Topo I in patients with resected CRC who received adjuvant chemotherapy and correlated it with clinical outcome.</p> <p>Methods</p> <p>All patients diagnosed with CRC between 1989 and 2007 and treated with adjuvant chemotherapy within Hellenic Cooperative Oncology Group's (HeCOG) protocols, were identified. Archival paraffin-embedded tumor tissues were used for immunohistochemical detection of TS and Topo I. Immunohistochemistry was performed on tissue microarray slides using monoclonal antibodies against TS and Topo I. The results were correlated with survival (OS) and disease free survival (DFS).</p> <p>Results</p> <p>A cohort of 498 patients with a median age of 61 years and Dukes' stage B (49%) and C (51%) fulfilled the criteria of the study. All patients received adjuvant 5-FU-based chemotherapy, 38% irinotecan-containing. Positive TS and Topo I expression was found in 43% and 48% of cases, respectively. Five-year OS was 74% and DFS was 68%. In univariate analysis no association of TS and Topo I expression with OS and DFS was identified. In multivariate analysis however, Topo I expression was associated with a reduced risk of death (HR = 0.61, 95% CI 0.42-0.88, p = 0.009). In the irinotecan-treated subgroup, those patients who expressed Topo I had a better OS (HR = 0.47, 95% CI 0.23-0.94, p = 0.033).</p> <p>Conclusion</p> <p>Patients with resected CRC expressing Topo I seem to benefit from irinotecan-containing adjuvant chemotherapy. However randomised prospective trials are needed to confirm these results.</p

Potential value of PTEN in predicting cetuximab response in colorectal cancer: An exploratory study

<p>Abstract</p> <p>Background</p> <p>The epidermal growth factor receptor (EGFR) is over-expressed in 70–75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab.</p> <p>Methods</p> <p>CRC patients treated with cetuximab by the Hellenic Cooperative Oncology group, whose formalin-fixed paraffin-embedded tumor tissue was available, were included. Tissue was tested for EGFR and PTEN by IHC and fluorescence in situ hybridization (FISH).</p> <p>Results</p> <p>Eighty-eight patients were identified and 72 were included based on the availability of tissue blocks with adequate material for analysis on them. All patients, except one, received cetuximab in combination with chemotherapy. Median follow-up was 53 months from diagnosis and 17 months from cetuximab initiation. At the time of the analysis 53% of the patients had died. Best response was complete response in one and partial response in 23 patients. In 16 patients disease stabilized. Lack of PTEN gene amplification was associated with more responses to cetuximab and longer time to progression (p = 0.042).</p> <p>Conclusion</p> <p>PTEN could be one of the molecular determinants of cetuximab response. Due to the heterogeneity of the population and the retrospective nature of the study, our results are hypothesis generating and should be approached with caution. Further prospective studies are needed to validate this finding.</p

Intraabdominal abscess formation as a first presentation of desmoid tumor

Desmoid tumors are benign fibrous tumors, which develop usually in patients with familial adenomatous polyposis and infrequently as sporadic cases. They present rather rarely as intra-abdominal abscesses communicating with the bowel. The case is reported of a 32 year-old woman, with unremarkable previous medical history, who was admitted with high fever and left upper quadrant pain of five days' duration. Chest X-ray revealed elevation of the left hemidiaphragm, and abdominal ultrasound and computed tomography showed an intraabdominal abscess, which was treated with percutaneous drainage. She was discharged in good condition, but the abscess relapsed a few days later and a fistulous communication with the large bowel was shown radiographically. Colonoscopy was normal. The patient underwent laparotomy with left hemicolectomy and the histologic examination revealed a desmoid tumor. In conclusion, desmoid tumors may present as intra-abdominal abscesses even in the absence of a familial adenomatous polyposis

Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis

Background The prevalence of metabolic syndrome and its possible impact on the severity of liver histological lesions have not been studied prospectively in chronic liver diseases. Aim To investigate the prevalence of metabolic syndrome in patients with chronic viral hepatitis or non-alcoholic steatohepatitis, and to determine its associations with histological severity. Methods We prospectively included 317 patients (hepatitis B e antigen-negative chronic hepatitis B: 95, chronic hepatitis C: 176, non-alcoholic steatohepatitis: 46) with liver biopsy. Metabolic syndrome was defined using the Adult Treatment Panel III criteria. Histological lesions were evaluated according to Ishak’s or Brunt’s classification. Results Metabolic syndrome was present in 10.4% of patients being significantly more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis (41.3% vs. 5.1%, P &lt; 0.001). In chronic viral hepatitis, cirrhosis (stages 5-6) was independently associated with increasing age, higher aspartate aminotransferase and gamma-glutamyl-transpeptidase levels, severe necroinflammation and metabolic syndrome (P = 0.016). In non-alcoholic steatohepatitis, severe fibrosis (stages 3-4) was independently associated with severe necroinflammation and metabolic syndrome (P = 0.033). Presence of metabolic syndrome was not associated with presence or severity of steatosis both in chronic viral hepatitis and in non-alcoholic steatohepatitis. Conclusion Metabolic syndrome is more prevalent in non-alcoholic steatoliepatitis than in chronic viral hepatitis; it is associated independently with more severe fibrosis but not with the severity of steatosis, both in chronic viral hepatitis and in non-alcoholic steatoliepatitis

Plasma pituitary adenylate cyclase activating polypeptide (PACAP) levels in chronic hepatitis B patients under lamivudine treatment

Objective Lamivudine is a nucleoside analogue with potent antiviral activity against hepatitis B virus (HBV). Plasma pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide that is produced within the lymphoid microenvironment and induces the production of Th2-type cytokines. The aim of our study was to investigate the possible alterations of plasma PACAP-38 levels in chronic hepatitis B (CHB) patients during lamivudine treatment and to compare them with biochemical, virological and histological data. Methods Plasma PACAP-38 levels were measured using competitive radio-immune analysis (RIA) in 25 CHB patients before and after completion of a 52-week lamivudine treatment period and in 22 healthy blood donors. Biochemical evaluation was done at baseline and every three months during treatment. Virological evaluation (HBV-DNA) was performed at baseline and at weeks 24 and 52 of treatment. Baseline liver histology was assessed for all patients at the beginning and at week 52 of the study for histological comparison with the pretreatment biopsy, according to the Ishak scoring system. Statistical evaluation of data was done using analysis of variance and Student’s t-test. Results Virological breakthrough was observed in seven (28%) patients at week 52 of treatment. Histological improvement was observed in 21 (84%) CHB patients, despite the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations. Plasma PACAP-38 levels were significantly lower in CHB patients at baseline than in healthy blood donors. Significant elevation of plasma peptide levels was observed in CHB patients after the completion of lamivudine treatment period, even in the subgroup of those who exhibited YMDD variants. Conclusion The elevation of plasma PACAP-38 levels in treated CHB patients following lamivudine-induced elimination of viraemia suggests a possible alteration of T-cellular immune response, resulting in biochemical and histological remission of liver disease, even in patients who exhibited virological breakthrough. (C) 2003 Lippincott Williams Wilkins

CD56 as a useful marker in the regenerative process of the histological progression of primary biliary cirrhosis

Objective Owing to recent contradicting results in the study of the regenerative process after hepatic injury in primary biliary cirrhosis, we investigated the use of CD56 in tissue repair during the histological progression of primary biliary cirrhosis. Methods Fifty-three specimens were classified into Ludwig&apos;s stages (1-4) as follows: 14 specimens as stage 1, 23 as stage 2, 14 as stage 3, and two as stage 4. Immunohistochemical stain was performed for CD56. The cell types expressing the marker were morphologically analyzed to determine their origin. Results In normal liver biliary epithelial cells (including the epithelium of terminal bile ducts and bile ductules), hepatocytes, and intermediate cells (features between hepatocytes and biliary cells, distributed in interface between hepatic parenchyma and portal tract) were CD56-. In primary biliary cirrhosis specimens, biliary epithelial cells, hepatocytes, and intermediate cells were CD56+ distributed as 10 out of 14 cases as stage 1 (71.43%), 18 out of 23 as stage 2 (78.26%), nine out of 14 as stage 3 (64.28%), and two out of two as stage 4 (100%). The total positive cases were 39 of 53 (73.58%). CD56 was expressed equally in all three types of cells. Conclusion These findings indicate that the consistent and uniform expression of CD56 in biliary epithelial cells, hepatocytes, and intermediate cells during hepatic injury in primary biliary cirrhosis is probably related to cellular damage and may be important in tissue regeneration. Furthermore, we cannot distinguish a specific cell type from the three above mentioned ones (biliary epithelial cells, hepatocytes, intermediate cells) as a putative stem cell in primary biliary cirrhosis. © 2008 Wolters Kluwer Health | Lippincott Williams &amp; Wilkins

Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: A comparative approach with genotype 1 chronic hepatitis C

Background/aims. Hepatic steatosis has not been adequately studied in chronic hepatitis 13, while it is considered to be a cardinal feature in chronic hepatitis C and to be mainly metabolically induced in patients infected with genotype 1. We investigated the prevalence of and the parameters associated with steatosis in HBeAg-negative chronic hepatitis B. Methods. We studied 213 patients with HBeAg-negative chronic hepatitis B and compared them with 163 patients with genotype-1 chronic hepatitis C. Steatosis was semi-quantitatively graded. Results. Steatosis was significantly less frequent in chronic hepatitis B than chronic hepatitis C (60% versus 72%, P=0.016), but there was no difference in the prevalence of moderate/severe steatosis. In chronic hepatitis 13, steatosis was associated only with higher body mass index (P=0.002), while moderate/severe steatosis was associated only with higher body mass index (P=0.043) and diabetes (P=0.031). Steatosis was relatively less frequent in chronic hepatitis B than chronic hepatitis C non-diabetic, normal-weight patients (45.6% versus 62.5%, P=0.063), but it did not differ in diabetic and/or overweight/obese patients with chronic hepatitis B or chronic hepatitis C. Conclusions. Hepatic steatosis in HBeAg-negative chronic hepatitis B (a) is less frequent than in genotype-1 chronic hepatitis C, (b) is mainly associated with presence of host metabolic factors, such as high body mass index and diabetes and (c) does not seem to be associated with the severity of liver histological lesions. (C) 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved