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Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6-induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6-STAT3 pathway in benign hepatocellular tumorigenesis.

Purpose: To retrospectively evaluate a respiratory-triggered diffusion-weighted (DW) magnetic resonance (MR) imaging sequence combined with parallel acquisition to allow the calculation of pure molecular-based (D) and perfusion-related (D*, f) diffusion parameters, on the basis of the intravoxel incoherent motion (IVIM) theory, to determine if these parameters differ between patients with cirrhosis and patients without liver fibrosis., Materials and Methods: The institutional review board approved this retrospective study; informed consent was waived. IVIM DW imaging was tested on three alkane phantoms, on which the signal-intensity decay curves according to b factors were logarithmically plotted. Ten b factors (0, 10, 20, 30, 50, 80, 100, 200, 400, 800 sec/mm(2)) were used in patients. Patients with documented liver cirrhosis (cirrhotic liver group, n = 12) and patients without chronic liver disease (healthy liver group, n = 25) were included. The mean liver D, D*, and f values were measured and compared with the apparent diffusion coefficient (ADC) computed by using four b values (0, 200, 400, 800 sec/mm(2)). Liver ADC and D, f, and D* parameters were compared between the cirrhotic liver group and healthy liver group. Means were compared by using the Student t test., Results: Signal-intensity decay curves were monoexponential on phantoms and biexponential in patients. In vivo, mean ADC values were significantly higher than D in the healthy liver group (ADC = 1.39 x 10(-3) mm(2)/sec +/- 0.2 [standard deviation] vs D = 1.10 x 10(-3) mm(2)/sec +/- 0.7) and in the cirrhotic liver group (ADC = 1.23 x 10(-3) mm(2)/sec +/- 0.4 vs D = 1.19 x 10(-3) mm(2)/sec +/- 0.5) (P = .03). ADC and D* were significantly reduced in the cirrhotic liver group compared with those in the healthy liver group (respective P values of .03 and .008)., Conclusion: Restricted diffusion observed in patients with cirrhosis may be related to D* variations, which reflect decreased perfusion, as well as alterations in pure molecular water diffusion in cirrhotic livers., (RSNA, 2008)

Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1alpha (HNF1alpha) and beta-catenin were sequenced. No tumors were mutated in both HNF1alpha and beta-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1alpha mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10(-4)), lack of cytological abnormalities (P < 10(-6)), and no inflammatory infiltrates (P < 10(-4)). In contrast, the group of tumors defined by beta-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10(-5)). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P = 10(-3)), ductular reaction (P < 10(-2)), and dystrophic vessels (P = .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the beta-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1alpha mutated tumors (P = .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with beta-catenin activation have a higher risk of malignant transformation.

Objective: In patients with ankylosing spondylitis (AS), inflammatory processes have been detected in the ileal and colonic mucosa. The inducible isoform of nitric oxide synthase (iNOS) may be expressed early in the inflammatory process. We investigated iNOS activity and lymphocytic infiltration in the duodenum and colon in patients with AS and ulcerative colitis compared with controls., Methods: Gastroscopy with duodenal biopsies and/or colonoscopy with biopsies were conducted in 42 patients with AS treated or not treated with nonsteroidal antiinflammatory drugs (NSAID), in 15 with ulcerative colitis, and in 46 controls. Lymphocytic infiltration in the lamina propria and intraepithelial infiltration were quantified by histological score. iNOS expression was assessed by immunohistochemistry with monoclonal antibodies, and iNOS activity was determined by radiochemical assay., Results: Endoscopic examination of the gastroduodenal or colonic mucosa did not reveal macroscopic lesions in the AS patients. In the duodenum, mucosal lymphocytic infiltration was found in 83.3% of the AS group compared to 48.6% of controls (p = 0.02), and was independent of the NSAID intake. Intraepithelial lymphocyte infiltration was increased in both duodenum and colon in AS patients compared to controls. iNOS activity in duodenum and colon and expression of iNOS protein in lamina propria inflammatory cells was increased in AS patients compared to controls., Conclusion: Lymphocytic infiltration and iNOS expression and activity were detected in duodenal and colonic mucosa from patients with AS. Such findings may indicate an inflammatory process in the small intestine and colon of patients with AS.

Background & Aims: Hepatic myofibroblasts play a key role in the development of liver fibrosis associated with chronic liver diseases. We have shown that oxidative stress is a messenger of 15-deoxy-delta-12,14-prostaglandin J2 (15-d-PGJ2) in human hepatic myofibroblasts. The aim of the present study was to investigate the role of a stress-inducible protein, heme oxygenase-1 (HO-1), in the action of 15-d-PGJ2., Methods: Expression of HO-1 was characterized in biopsy specimens of normal human liver and active cirrhosis by immunohistochemistry, and in cultured human hepatic myofibroblasts by Northern and Western blot analysis. Functional studies also were performed in cultured human hepatic myofibroblasts., Results: Immunohistochemistry showed that in biopsy specimens from normal livers, HO-1 protein expression was restricted to Kupffer cells. Biopsy specimens from cirrhotic patients displayed HO-1 protein both in macrophages and in myofibroblasts within fibrotic septa. HO-1 messenger RNA (mRNA) and protein also were detected in cultured human hepatic myofibroblasts and increased in response to 15-d-PGJ2 in a time- and dose-dependent manner. Induction of HO-1 in human hepatic myofibroblasts mediated 2 major antifibrogenic properties of 15-d-PGJ2, namely, inhibition of proliferation and of procollagen I mRNA expression. These effects were ascribed to bilirubin, one of the products of HO-1-mediated heme degradation., Conclusions: This study shows that HO-1 is expressed in human hepatic myofibroblasts and induced during chronic liver injury. Moreover, these data unravel HO-1 as a major antifibrogenic pathway.