TACE with degradable starch microspheres (DSM-TACE) as second-line treatment in HCC patients dismissing or ineligible for sorafenib.

OBJECTIVES: To date, there is no approved second-line treatment for patients dismissing sorafenib or ineligible for this treatment, so it would be useful to find an effective alternative treatment option. The aim of our study was to evaluate safety, feasibility and effectiveness of transarterial chemoembolisation with degradable starch microspheres (DSM-TACE) in the treatment of patients with advanced hepatocellular carcinoma (HCC) dismissing or ineligible for multikinase-inhibitor chemotherapy administration (sorafenib) due to unbearable side effects or clinical contraindications. METHODS: Forty consecutive BCLC stage B or C patients (31 male; age, 70.6 ± 13.6 years), with intermediate or locally advanced HCC dismissing or ineligible for sorafenib administration, who underwent DSM-TACE treatment cycle via lobar approach were prospectively enrolled. Tumour response was evaluated on multidetector computed tomography based on mRECIST criteria. Primary endpoints were safety, tolerance and overall disease control (ODC); secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Technical success was achieved in all patients. No intra/peri-procedural death/major complications occurred. No signs of liver failure or systemic toxicity were detected. At 1-year follow-up, ODC of 52.5% was registered. PFS was 6.4 months with a median OS of 11.3 months. CONCLUSIONS: DSM-TACE is safe and effective as a second-line treatment in HCC patients dismissing or ineligible for sorafenib. KEY POINTS: • DSM-TACE is safe and effective as second-line treatment in HCC patients dismissing or ineligible for sorafenib • DSM-TACE allows the temporary occlusion of the smaller arterial vessels, improving overall therapeutic effectiveness by reducing the immediate wash-out of the cytostatic agent • DSM-TACE also decreases the risk of systemic toxicity and post-embolic syndrome.

Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.

UNLABELLED: The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut-derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy-proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of (51)Cr-ethylene diamine tetraacetate ((51)Cr-EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 (ZO-1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. CONCLUSIONS: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition.

Diabetes and Insulin Therapy, but Not Metformin, Are Related to Hepatocellular Cancer Risk.

Introduction. Metabolic conditions, including type 2 diabetes, have been related to hepatocellular carcinoma (HCC) risk. We have further analyzed the role of diabetes and antidiabetic treatments on HCC. Methods. Data derived from a hospital-based case-control study (Italy, 2005-2012) on 224 HCC patients and 389 controls. Odds ratios (ORs) were estimated using multiple logistic regression models. Results. Sixty-nine (30.9%) cases versus 52 (13.5%) controls reported a diabetes diagnosis, corresponding to a multivariate OR of 2.25 (95% confidence interval, CI = 1.42-3.56). A stronger excess risk emerged for a longer time since diabetes diagnosis (OR = 2.96 for <10 years and 5.33 for ≥10 years). Oral therapies were inversely, though not significantly, related to HCC risk, OR being 0.44 for metformin and 0.88 for sulfonylureas; conversely, insulin was nonsignificantly directly associated (OR = 1.90). Compared to nondiabetic subjects who were never smokers, those who were diabetics and ever smokers had an OR of 6.61 (95% CI 3.31-13.25). Conclusion. Our study confirms an over 2-fold excess HCC risk in diabetics, with a stronger excess risk in diabetic subjects who are also tobacco smokers. Metformin may decrease the risk of HCC, whereas insulin may increase the risk.

The effect of CYP, GST, and SULT polymorphisms and their interaction with smoking on the risk of hepatocellular carcinoma.

Aim. The aim of our study was to assess whether selected single nucleotide polymorphisms of CYP1A1 and 2E1, GSTM1, GSTT1, and SULT1A1 influence susceptibility towards HCC, considering their interaction with cigarette smoking. Methods. We recruited HCC cases and controls among patients admitted to the hospital "Agostino Gemelli," from January 2005 until July 2010. Odds ratios (OR) of HCC were derived from unconditional multiple logistic regression. Gene-gene and gene-smoking interaction were quantified by computing the attributable proportion (AP) due to biological interaction. Results. The presence of any CYP2E1 (*) 5B variant allele (OR: 0.23; 95% CI: 0.06-0.71) and CYP2E1 (*) 6 variant allele (OR: 0.08; 95% CI: 0.01-0.33) was inversely related to HCC. There was a borderline increased risk among carriers of combined CYP1A1 (*) 2A and SULT1A1 variant alleles (OR: 1.67; 95% CI: 0.97-3.24). A significant biological interaction was observed between GSTT1 and smoking (AP = 0.48; 95% CI: 0.001-0.815), with an OR of 3.13 (95% CI: 1.69-5.82), and borderline significant interaction was observed for SULT1A1 and smoking (AP = 0.36; 95% CI: -0.021-0.747), with an OR of 3.05 (95% CI: 1.73-5.40). Conclusion. CYP2E1 (*) 5B and CYP2E1 (*) 6 polymorphisms have a favourable effect on the development of HCC, while polymorphisms of GSTT1 and SULT1A1 might play role in increasing the susceptibility among smokers.

Faecal calprotectin assay after induction with anti-Tumour Necrosis Factor α agents in inflammatory bowel disease: Prediction of clinical response and mucosal healing at one year.

BACKGROUND: Faecal calprotectin levels correlate with inflammation in inflammatory bowel disease. We evaluated the role of faecal calprotectin after anti-Tumour Necrosis Factor α induction in inflammatory bowel disease patients to predict therapeutic effect at one year. METHODS: Faecal calprotectin levels were measured in stools of 63 patients before and after induction of anti-Tumour Necrosis Factor α therapy. Clinical activity, measured by clinical indices, was assessed before and after biologic treatment. Clinical responders after induction were included in the study and colonoscopy was performed before and after one year of treatment to assess mucosal healing. RESULTS: 63 patients (44 Crohn's disease, 19 ulcerative colitis) were prospectively included (41.2% males, mean age at diagnosis 33 years). A sustained clinical response during the first year was observed in 57% of patients; median faecal calprotectin was 106 µg/g after induction versus 308 µg/g pre-induction (p<0.0001). Post-induction faecal calprotectin was significantly lower in responders versus non-responders (p=0.0002). Post-induction faecal calprotectin had 83% sensitivity and 74% specificity (cut-off ≤ 168 µg/g) for predicting a sustained clinical response at one year (p=0.0001); also, sensitivity was 79% and specificity 57% (cut-off ≤ 121 µg/g) for predicting mucosal healing (p=0.0001). CONCLUSIONS: In inflammatory bowel disease faecal calprotectin assay after anti-Tumour Necrosis Factor α induction can be used as a marker to predict sustained clinical response and mucosal healing at one year.

A case-control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease.

The oxidative stress is a key issue in the etiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to evaluate the effect of metabolic gene polymorphisms involved in the oxidative stress (GSTT1, GSTM1, SULT1A1, CYP2E1, and 1A1), lifestyle and nutrition aspects, and their interaction, on the risk of NAFLD. We enrolled 294 cases and 359 controls, and collected demographics, anthropometric, lifestyle, and nutrition data. A subgroup of NAFLD provided additional data on nutrients and on physical activity engagement. Each patient provided a blood sample for DNA extraction and genotyping. Clinical and laboratory data were collected from cases. Multivariable analysis shows a significant protective effect of age, gender, and moderate drinking habits on the risk of NAFLD, while an increased risk for greater consumption of fruit and grilled meat or fish. Significant interactions were reported between alcohol consumption, fruit intake, grilled meat and fish, and selected genetic variants. From the subgroup analysis, a moderate/high consumption of fat and/or grilled meat/fish, and a high consumption of white meat increase the risk of NAFLD. Engaging any physical activity at least 1 time/week halves the risk of NAFLD. Besides confirming the beneficial effect of moderate alcohol intake and regular physical activity, and the increased risk associated with high fruit and fat intake, for the first time, we report a detrimental effect of grilled food on NAFLD risk. An effect modification by selected gene variants increases the risk in combination with fruit and grilled food intake.

Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux symptoms.

BACKGROUND: Gastro-oesophageal reflux symptoms are usually reported by patients with obesity and metabolic syndrome. Aim of this study was to assess the prevalence and clinical characteristics of gastro-oesophageal reflux symptoms in subjects with non-alcoholic fatty liver disease. METHODS: Cross-sectional, case-control study of 185 consecutive patients with non-alcoholic fatty liver disease and an age- and sex-matched control group of 112 healthy volunteers. Participants were interviewed with the aid of a previously validated questionnaire to assess lifestyle and reflux symptoms in the 3 months preceding enrolment. Odds ratios were determined before and after adjustment for body mass index, increased waist circumference, physical activity, metabolic syndrome and proton pump inhibitors and/or antiacid medication. RESULTS: The prevalence of heartburn and/or regurgitation and of at least one of gastro-oesophageal reflux symptoms was significantly higher in the non-alcoholic fatty liver disease group. Non-alcoholic fatty liver disease subjects were associated to higher prevalence of heartburn (adjusted odds ratios: 2.17, 95% confidence intervals: 1.16-4.04), regurgitation (adjusted odds ratios: 2.61, 95% confidence intervals: 1.24-5.48) and belching (adjusted odds ratios: 2.01, 95% confidence intervals: 1.12-3.59) and had higher prevalence of at least one GER symptom (adjusted odds ratios: 3.34, 95% confidence intervals: 1.76-6.36). CONCLUSION: Non-alcoholic fatty liver disease is associated with a higher prevalence of gastro-oesophageal reflux symptoms.