Search

Background Aberrant DNA hypomethylation of the long interspersed nuclear elements (LINE-1 or L1) has been recognized as an early event of colorectal transformation. Simultaneous genetic and epigenetic analysis of colorectal adenomas may be an effective and rapid strategy to identify key biological features leading to accelerated colorectal tumorigenesis. In particular, global and/or intragenic LINE-1 hypomethylation of adenomas may represent a helpful tool for improving colorectal cancer (CRC) risk stratification of patients after surgical removal of polyps. To verify this hypothesis, we analyzed a cohort of 102 adenomas derived from 40 high-risk patients (who developed CRC in a post-polypectomy of at least one year) and 43 low-risk patients (who did not develop CRC in a post-polypectomy of at least 5 years) for their main pathological features, the presence of hotspot variants in driver oncogenes (KRAS, NRAS, BRAF and PIK3CA), global (LINE-1) and intragenic (L1-MET) methylation status. Results In addition to a significantly higher adenoma size and an older patients’ age, adenomas from high-risk patients were more hypomethylated than those from low-risk patients for both global and intragenic LINE-1 assays. DNA hypomethylation, measured by pyrosequencing, was independent from other parameters, including the presence of oncogenic hotspot variants detected by mass spectrometry. Combining LINE-1 and L1-MET analyses and profiling the samples according to the presence of at least one hypomethylated assay improved the discrimination between high and low risk lesions (p = 0.005). Remarkably, adenomas with at least one hypomethylated assay identified the patients with a significantly (p p = 0.02). Conclusions LINE-1 and L1-MET hypomethylation in colorectal adenomas are associated with a higher risk of developing CRC. DNA global and intragenic hypomethylation are independent markers that could be used in combination to successfully improve the stratification of patients who enter a colonoscopy surveillance program. Graphic abstract

Background/Aims : To evaluate the efficacy and tolerance of amantadine in combination with interferon in the treatment of chronic hepatitis C. Methods : Multi-centre trial including 180 chronic hepatitis C patients without cirrhosis, randomly enrolled to receive interferon 6 MU every other day for 6 months followed by 3 MU for further 6 months (group A, 90 patients), or the same schedule plus amantadine 200 mg/day (group B, 90 patients). Primary end-point was a sustained virological and biochemical response, secondary end-points were on-treatment (third month) and end-of-treatment response rates. Results : The two groups had similar demographic, biochemical and virological characteristics. A sustained response after 6 months follow-up was observed in 17% of group A and 24% of group B patients ( P not significant), an end-of-treatment response was observed in 37% in group A and 47% in group B ( P not significant), an on-treatment response was observed in 46% in group A and 61% in group B patients ( P Conclusions : Adding amantadine to interferon did not improve the sustained treatment efficacy. However, the rate of early response at the third month of therapy was significantly higher in the combination therapy group.

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic diseases of unknown etiology. Much effort has been made in the last years to clarify the pathogenesis of inflammatory bowel disease (IBD). Data are not conclusive at the moment, but the most important known risk factor for developing IBD is a positive familial history. Genetic analyses have shown a linkage between loci on several chromosomes and IBD (IBD1 gene on chromosome 16 for CD and on chromosome 12 for UC). The association of genotype to specific phenotypes of disease could be hypothesized by the concordance of clinical characteristics in familial IBD, by the association of specific HLA haplotypes to clinically different groups of patients, and by different responses to treatment related to different polymorphisms of other chromosome 6 genes. The clinical heterogeneity of IBD has led to classifications of patients with Crohn’s disease based upon clinical features (e.g. Rome and Vienna classifications) that allow the identification of subgroups of patients with similar clinical behavior. The possible drawbacks of these classifications are the lack of validation of intra–interobserver concordance, the absence of prospective evaluations, and stratification into too many subgroups. Furthermore, in our experience, clinical presentation (surgical or medical) seems to have a good correlation with prognosis, is easy identifiable, and can be applied at the time of diagnosis. In UC, extension of disease and clinical behavior correlate with prognosis. For these reasons, studies correlating genotype to phenotype should be performed to improve our knowledge of the diseases and possibly to stratify patients into different subgroups for more personalized treatments, in clinical trials and for research purposes.

Abdominal bowel ultrasound (US) is widely used in the management of Crohn's disease (CD). The aim of this study was to evaluate the prognostic role of bowel-wall US morphology on the short-term risk of surgery.The 147 CD patients recruited in a case-control study comprised 49 cases operated on within 30 days after US examination and 98 matched non-operated controls. Clinical and US characteristics were analysed. Bowel-wall thickness was recorded, bowel-wall patterns were grouped into five types, but for final analysis they were grouped as "preserved" or "disrupted stratification".Wall thickness and US patterns were significantly different between cases and controls (p0.0001). A wall thickness4.5 mm was observed in 45/49 cases and 47/98 controls (OR = 12.21), while "disrupted stratification" was observed in 34/49 cases and 12/98 controls (OR = 16.24). Among the clinical and US characteristics recorded, only 4 US variables were independently associated with surgery (pattern, thickness, presence of fistulae/abscesses and stenoses) and considered for the US score=(2.5*US pattern)+(1.5*Bowel thickness)+(3*Presence of fistulae/abscesses)+(1.5*Presence of stenoses). Based on this score, up to 84% of patients were correctly classified according to actual status (operated/non-operated).Although it needs further prospective validation, the score we propose seems to be a reliable prognostic marker for the short-term risk of surgery in CD. In particular, the score points out those patients with an impending risk of surgery who need careful and frequent control in order to decide on the right time for surgery.

Quantitative determination of pancreatic elastase-1 (E1) in stools has been proposed as a novel, noninvasive test of pancreatic function. The aim of the study was to verify its role in the differential diagnosis of chronic diarrhea.E1 was measured in spot stool samples of 50 patients with pancreatic disease (PD), 62 with inflammatory bowel disease (IBD), 45 with chronic diarrhea (CD), 34 with other gastroduodenal and liver disease (gastrointestinal; GI), and in 18 normal controls, by a commercial kit (Schebo-Tech., Wettemburg, Germany).In PD, patients with severe damage and diarrhea displayed E1 levels below 100 microg/g; normal values were found in mild-moderate disease. Abnormal values were detected in 4 CD and in 14 IBD patients, either in the presence of severe protein malnutrition or in patients with previous ileo-anal pouch anastomosis and pouchitis. In nine cases, values reverted to normal after adequate treatment. Diagnostic accuracy of E1 in discriminating diarrhea of pancreatic and nonpancreatic origin was: SS, 97%; SP, 84%; VP+, 66%; VP-, 100%.1) The finding of a normal E1 value rules out a malabsorption of pancreatic origin. 2) in CD and IBD, decreased E1 might be owing to bacterial elastase degradation (pouchitis) or transient defective pancreatic enzyme secretion.