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Background Pathophysiological mechanisms associated with neoplastic progression in patients with short-segment Barrett's oesophagus ( SSBO), who represent the vast majority of the Barrett population, have not been defined. Aim To evaluate pathophysiological characteristics of patients with SSBO and dysplasia detected at 3-year surveillance endoscopy (incident dysplasia). Methods Patients with SSBO underwent impedance- pH monitoring during heartburn-suppressing PPI therapy. Fifteen patients (12 males, median age 62 years) with incident dysplasia and 50 patients (43 males, median age 59 years) without dysplasia were compared. Impedance- pH parameters, including chemical clearance assessed by the post-reflux swallow-induced peristaltic wave (PSPW) index, were evaluated. Results All patients declared persisting heartburn suppression on maintenance PPI therapy at 3-year follow-up, 58/65 (89%) with standard dosages. The median gastric and oesophageal acid exposure time ( GAET and OAET) did not differ between patients with and without incident dysplasia at the time of surveillance (36% and 0.6% vs. 33% and 0.5%) or index endoscopy (33% and 0.3% vs. 41% and 0.5%) ( P > 0.05). Contrastingly, the median PSPW index was significantly lower in patients with than in patients without incident dysplasia at the time of surveillance (15%, vs. 32%) and index endoscopy (12% vs. 30%) ( P = 0.001). The PSPW index, the GAET and the OAET did not vary over time ( P > 0.05). A PSPW index <26% was predictive of incident dysplasia with a 75% accuracy. Conclusions Neoplastic progression in SSBO is associated with impairment of chemical clearance, but not inadequate acid suppression by PPI therapy. Neoplastic progression in SSBO can be predicted by a low PSPW index. [ABSTRACT FROM AUTHOR]

. Under-enrolment of women to randomized clinical trials, including chronic hepatitis C, has long been recognized. The aim of this study was to identify factors predictive of sustained virological response (SVR) to PEG IFN/Ribavirin antiviral therapy in relation to gender and reproductive status of female patients involved. Seven hundred and forty-six treatment-naïve patients (431 men, 315 women) treated with Peg-IFNα-2a (180 μg/week) or Peg-IFNα-2b (1.5 μg/kg/week) plus ribavirin (800-1400 mg/day) for 24 or 48 weeks were studied between 2006 and 2010. Differences in SVR rate, overall and by gender were assessed after adjustment and propensity score matching. SVR was obtained in 44.2% of Peg-IFNα-2a-treated patients and in 51.2% of Peg-IFNα-2b-treated patients (intention-to-treat; P = 0.139). Age, fibrosis stage and genotype 2 and 3 were independently associated with SVR by multivariate analysis. Analysing by gender, the difference in SVR between PEG-IFNα types was not significant in men but highly significant in women (Peg-IFNα-2a:39.1% vs Peg-IFNα-2b:54.4%, P = 0.007). This was attributable to a higher SVR rate with Peg-IFNα-2b in the difficult postmenopausal population (26.9% Peg-IFNα-2a vs 46.0% Peg-IFNα-2b, P = 0.040). In women, absence of menopause, genotype 2 hepatitis C virus infection and use of Peg-IFNα-2b were independently associated with SVR. In conclusion, predictive factors for SVR are different in men and women. Factors differing between genders are menopause, severe steatosis and peg-interferon used. The higher SVR rate with Peg-IFNα-2b in menopausal women is likely attributable to more favourable pharmacokinetics that allows Peg-IFNα-2b to reach visceral fat and oppose the increased cytokine production and enhanced inflammatory status in menopause. [ABSTRACT FROM AUTHOR]

Background Several reports indicate that mesalazine (5-aminosalicylic acid, 5-ASA) is a promising candidate for the chemoprevention of colo-rectal cancer because of its ability to reach the purpose avoiding the unwanted side effects usually associated with prolonged administration of nonsteroidal anti-inflammatory drugs. This activity of 5-ASA is probably the consequence of a number of effects determined on colo-rectal cancer cells, consisting of reduced proliferation, increased apoptosis and activation of cell cycle checkpoints and DNA repair processes. A recent observation has suggested that inhibition of β-catenin signalling could induce these cellular effects. Aim To characterize better the capacity of 5-ASA to inhibit the β-catenin signalling pathway. Methods Genes belonging to the β-catenin signalling pathway were analysed in colo-rectal cancer cell lines treated with 5-ASA using a combination of laboratory assays that are able to detect their phenotypic expression and functional activity. Results The results obtained indicated that 5-ASA induces the expression of a protein called μ-protocadherin that belongs to the cadherin superfamily and is able to sequester β-catenin on the plasmatic membrane of treated cells hampering its function. Conclusion These findings suggest that μ-protocadherin might be employed as a biological marker to monitor the chemopreventive efficacy of 5-ASA. [ABSTRACT FROM AUTHOR]

A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL1 or MSH2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT25 and BAT26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC. [ABSTRACT FROM AUTHOR]

Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. Muir–Torre syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. Skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations. [ABSTRACT FROM AUTHOR]

Background: Differentiating steatosis from NASH is key in deciding treatment and follow-up schedules. We hypothesized that sonographic grading of steatosis will correlate with metabolic and pathologic changes of NASH., Methods: Fifty-three non-consecutive patients had a semi-quantitative evaluation of hepatic steatosis through ultrasonographic Fatty Liver Indicator (US-FLI) just prior to liver biopsy. All biopsies demonstrated NAFLD. US-FLI is a new scoring system ranging 2-8 based on the intensity of liver/kidney contrast, posterior attenuation of ultrasound beam, vessel blurring, difficult visualization of gallbladder wall, difficult visualization of the diaphragm and areas of focal sparing. NAFLD is diagnosed by the minimum score ≥2. Ultrasonographic findings were correlated with metabolic and histological data. Inter-observer US-FLI score agreement, evaluated by three different operators in 31 consecutive patients with steatosis, showed "almost perfect/substantial" agreement (P < 0.001)., Results: US-FLI showed a positive correlation with HOMA, insulin, uric acid, ferritin, ALT and bilirubin and was associated with steatosis extent assessed histologically and histological features of NASH, except for fibrosis. US-FLI was an independent predictor of NASH (OR 2.236; P = 0.007) and a US-FLI < 4 had a high negative predictive value (94%) in ruling out the diagnosis of severe NASH according to Kleiner's criteria., Conclusion: Data confirm the hypothesis that US-FLI significantly correlates with metabolic derangements and individual pathologic criteria for NASH and may better select patients for liver biopsy., (© 2012 John Wiley & Sons A/S.)

Background: Several reports indicate that mesalazine (5-aminosalicylic acid, 5-ASA) is a promising candidate for the chemoprevention of colo-rectal cancer because of its ability to reach the purpose avoiding the unwanted side effects usually associated with prolonged administration of nonsteroidal anti-inflammatory drugs. This activity of 5-ASA is probably the consequence of a number of effects determined on colo-rectal cancer cells, consisting of reduced proliferation, increased apoptosis and activation of cell cycle checkpoints and DNA repair processes. A recent observation has suggested that inhibition of beta-catenin signalling could induce these cellular effects., Aim: To characterize better the capacity of 5-ASA to inhibit the beta-catenin signalling pathway., Methods: Genes belonging to the beta-catenin signalling pathway were analysed in colo-rectal cancer cell lines treated with 5-ASA using a combination of laboratory assays that are able to detect their phenotypic expression and functional activity., Results: The results obtained indicated that 5-ASA induces the expression of a protein called mu-protocadherin that belongs to the cadherin superfamily and is able to sequester beta-catenin on the plasmatic membrane of treated cells hampering its function., Conclusion: These findings suggest that mu-protocadherin might be employed as a biological marker to monitor the chemopreventive efficacy of 5-ASA.