Aggressive gastric carcinoma producing alpha-fetoprotein: a case report and review of the literature.

A 65-year-old man presented to our hospital with abdominal pain, dyspepsia and anorexia. Laboratory tests showed an altered liver function and abdomen ultrasonography revealed multiple liver nodules, suspected to be metastatic lesions. Serous tumor markers were elevated and a very high level of alpha-fetoprotein was found. Computer tomography confirmed the hepatic lesions and disclosed a thickening of the lesser curvature of the gastric wall. A subsequent endoscopy showed an ulcer on the lesser curvature. Biopsies taken from the gastric ulcer and the liver nodule revealed an adenocarcinoma, both of gastric origin. Shortly after the diagnosis, the patient's condition worsened and he died only 15 days later. This case report illustrates how alpha-fetoprotein-producing gastric adenocarcinomas have a high incidence of venous and lymphatic invasion and a rapid hepatic spread with a very poor prognosis

Non-invasive assessment of fibrosis in non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries, and its prevalence is increasing worldwide. It currently affects approximately 30% of adults and 10% of children and adolescents. The resulting increase in the number of patients with NAFLD is expected to translate into increased numbers of patients with liver cirrhosis, and hepatocellular carcinoma. In this context, it is particularly important to identify patients at risk for progressive chronic liver disease. Currently, liver biopsy is the gold standard to diagnose non-alcoholic steatohepatitis (NASH) and to establish the presence and stage of fibrosis. Due to the remarkable increase in the prevalence of NAFLD and the concomitant efforts in developing novel therapies for patients with NASH, non-invasive, simple, reproducible, and reliable noninvasive methodologies are needed. This paper provides a concise overview of the role of non-invasive diagnostic tools for the determination of presence and extent of fibrosis in NAFLD patients, with particular emphasis on the methods currently available in clinical practice

Assessment of liver stiffness in patients with HCV and mixed cryoglobulinemia undergoing rituximab treatment.

INTRODUCTION: Mixed cryoglobulinemia (MC) is a HCV-related lymphoproliferative disorder generally associated with advanced liver disease. Liver stiffness has been significantly correlated with histopathological stage of fibrosis. Moreover, it was influenced by necroinflammatory activity. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody inducing transient B lymphocytes depletion that was shown to be useful and safe in the majority of HCV MC patients, leading also to improvement of cirrhotic syndrome. Aim of this study was to evaluate the modifications of liver stiffness following RTX treatment in HCV-related MC patients. MATERIALS AND METHODS: Fourteen consecutive patients (10 F, 4 M; mean age 60.43 ± 43) with HCV-related chronic hepatitis (n = 10) or cirrhosis (n = 4) and MC, eligible for RTX treatment, were prospectively enrolled. Intravenous injection of 1 g of RTX was performed at day 0 and at day 15. Assessment of stiffness was carried out by Fibroscan(®) (Echosens, Paris-France) at baseline, 15 days after the first infusion, and at month 1, 3 and 6 after therapy. RESULTS: MC symptoms significantly improved during the study, especially during the first 3 months. Liver stiffness observed 3 months after treatment was significantly reduced when compared with pre-treatment values (p = 0.01). This difference disappeared after 6 months of follow-up. Cytofluorimetric analysis showed a decrease of CD19+ peripheral blood cells, with the nadir at month 3 after therapy and B cell compartment reconstitution after 6 months. CONCLUSION: This study, for the first time showed that RTX-treatment in HCV-related MC induces a reduction of liver stiffness that is strictly associated with the B-cell depletion

Non-invasive assessment of liver fibrosis in patients with HBV-related chronic liver disease undergoing antiviral treatment: A preliminary study

In chronic hepatitis B (CHB) patients, fibrosis assessment during antiviral treatment is a key step in the clinical management. Aim of this study was to evaluate the performance of elastography in assessing fibrosis stage in CHB before and after two years of nucleoside/nucleotide analogues (NUC) treatment in comparison with indirect serum markers. CHB diagnosis was made according to standard criteria. A clinical and virological evaluation was performed at baseline and again at 3, 6, 9, 12 18, and 24 months during treatment. Fibrosis was evaluated by liver biopsy, elastography and indirect serum markers. Of 75 patients, 50 had CHB, HBeAg negative and were deemed eligible for this study. Of these, 22 underwent liver biopsy. Mean histo-morphometric values of fibrotic tissue differed significantly in the stage < S3 vs. stage ≥S3: 2.01±2.62% vs. 12.85±7.31% (p=0.03), respectively. At 18 and 24 months, stiffness values were statistically reduced from those previously observed (P=0.03 and P<0.001). At 24 months the values of APRI, FIB-4 and LOK were not different from baseline values, while the value of FORNS score at 24 months was the only one statistically reduced. In two patients with fibrosis stage S3 and S6, respectively, fibrosis regressed to stage S2 and S5. In conclusion, the results of the present study show that liver histology, stiffness and FORNS score improve significantly during a long-term follow-up of HBV patients successfully treated with NUC. These results strongly suggest that the non-invasive evaluation of liver fibrosis represents a key step in the management and treatment of chronic HBV hepatitis

Signal Transduction by the Chemokine Receptor CXCR3 ACTIVATION OF Ras/ERK, Src, AND PHOSPHATIDYLINOSITOL 3-KINASE/Akt CONTROLS CELL MIGRATION AND PROLIFERATION IN HUMAN VASCULAR PERICYTES

Hepatic stellate cells (HSC) and glomerular mesangial cells (MC) are tissue-specific pericytes involved in tissue repair, a process that is regulated by members of the chemokine family. In this study, we explored the signal transduction pathways activated by the chemokine receptor CXCR3 in vascular pericytes. In HSC, interaction of CXCR3 with its ligands resulted in increased chemotaxis and activation of the Ras/ERK cascade. Activation of CXCR3 also stimulated Src phosphorylation and kinase activity and increased the activity of phosphatidylinositol 3-kinase and its downstream pathway, Akt. The increase in ERK activity was inhibited by genistein and PP1, but not by wortmannin, indicating that Src activation is necessary for the activation of the Ras/ERK pathway by CXCR3. Inhibition of ERK activation resulted in a decreased chemotactic and mitogenic effect of CXCR3 ligands. In MC, which respond to CXCR3 ligands with increased DNA synthesis, CXCR3 activation resulted in a biphasic stimulation of ERK activation, a pattern similar to the one observed in HSC exposed to platelet-derived growth factor, indicating that this type of response is related to the stimulation of cell proliferation. These data characterize CXCR3 signaling in pericytes and clarify the relevance of downstream pathways in the modulation of different biologic responses

Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy: A prospective pilot study

AIM: To evaluate the association between liver stiffness (LS) prior to the initiation of dual/triple therapy and viral response. METHODS: LS was measured in all patients before treatment was administered. The therapeutic approach was based on hepatic, virological, and immunological evaluations and considered the fact that patients with severe fibrosis (F3) or compensated cirrhosis (F4) in Child-Pugh class A are the primary candidates for triple therapy. In total, 65 hepatitis C virus (HCV) patients were treated with Peg-interferon/ribavirin (Peg-IFN/RBV); 24 patients were classified as genotypes 1/4 (36.92%), and 41 patients were classified as genotypes 2/3 (63.08%) (dual therapy). In addition, 20 HCV treatment-experienced genotype 1 patients were treated with PegIFN-RBV and boceprevir (triple therapy). Wilcoxon rank-sum tests were used to compare the groups. RESULTS: LS significantly differed between dual therapy and triple therapy (P = 0.002). The mean LS value before dual therapy treatment was 8.61 ± 5.79 kPa and was significantly different between patients achieving a sustained virologic response (SVR) 24 weeks after therapy and those who did not (7.23 ± 5.18 kPa vs 11.72 ± 5.99 kPa, respectively, P = 0.0003). The relative risk of non-response to therapy was 4.45 (95%CI: 2.32-8.55). The attributable risk of non-response to therapy was 49%. The mean LS value before triple therapy treatment was 13.29 ± 8.57 kPa and was significantly different between patients achieving and not achieving SVR24 (9.41 ± 5.05 vs 19.11 ± 9.74, respectively; P = 0.008). The relative risk of non-response to therapy was 5.57% (95%CI: 1.50-20.65). The attributable risk of non-response to therapy (70%) was increased compared with dual therapy patients. Pre-treatment stiffness > 12 kPa was significantly associated with non-SVR (P < 0.025) in both groups. CONCLUSION: Pre-treatment liver stiffness may be useful for predicting the response to treatment in patients treated with either dual or triple anti-HCV therapy

Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: A prospective, controlled, open-label, cohort study

Limited data are available about the efficacy of antiviral treatment in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC), especially concerning the long-term effects of HCV eradication. The aim of this study was to evaluate the influence of MC on the virological response and the long-term effects of viral eradication on MC. We prospectively enrolled 424 HCV+ patients belonging to the following groups: MCS-HCV (121 patients with symptomatic MC); MC-HCV (132 patients with asymptomatic MC); HCV group (158 patients without MC). Peg-IFN+RBV treatment was administered according to standard protocols. Post-treatment follow-up ranged from 35 to 124 months (mean: 92.5 months). A significant difference was observed in the rate of sustained virological response (SVR) between HCV and both MC-HCV (p=0.009) and MC-HCV+MCS-HCV (p=0.014) groups. Multivariate logistic regression analysis identified cryoglobulinemia as an independent prognostic factor of non-response. The clinical-immunological response in MCS-HCV correlated with the virological one. All patients with SVR also experienced a sustained clinical response, either complete or partial. In the majority of SVR patients all MCS symptoms persistently disappeared (36 patients, 57%); in only 2 (3%) did definite MCS persist. All virological non-responders were also clinical non-responders, in spite of a transient improvement in some cases. No evolution to lymphoma was observed. For the first time we have evaluated both the effects of IFN-based therapy on HCV patients with or without MC, and with or without symptoms, and the long-term effects of viral eradication on MC. MC was shown to be a negative prognostic factor of virological response. HCV clearance led to persistent resolution or improvement of MC syndrome, strongly suggesting the need for a next generation of highly effective antiviral drugs