Explore the vast range of titles available.

Background and aim: To analyse the characteristics of and the factors associated with the development of hepatocellular carcinoma (HCC) in patients with Budd–Chiari syndrome (BCS). Patients and methods: 97 consecutive patients with BCS and a follow-up ⩾1 year were evaluated retrospectively. Liver nodules were evaluated using serum α-fetoprotein (AFP) level and imaging features (CT/MRI). Biopsy of nodules was obtained when one of the following criteria was met: number ⩽3, diameter ⩾3 cm, heterogeneity, washout on portal venous phase, increase in size on surveillance, or increase in AFP level. Results: Patients were mainly Caucasian (69%) and female (66%). Mean age at the diagnosis of BCS was 35.8 (SE 1.2 years), and median follow-up 5 years (1–20 years). The inferior vena cava (IVC) was obstructed in 13 patients. Liver nodules were found in 43 patients, 11 of whom had HCC. Cumulative incidence of HCC during follow-up was 4%. Liver parenchyma adjacent to HCC showed cirrhosis in nine patients. HCC was associated with male sex (72.7% v 29.0%, p = 0.007); factor V Leiden (54.5% v 17.5%, p = 0.01); and IVC obstruction (81.8% v 4.6%, p<0.001). Increased levels of serum AFP were highly accurate in distinguishing HCC from benign nodules: PPV = 100% and NPV = 91% for a cut-off level of 15 ng/ml. Conclusion: The incidence of HCC in this large cohort of BCS patients was similar to that reported for other chronic liver diseases. IVC obstruction was a major predictor for HCC development. Serum AFP appears to have a higher utility for HCC screening in patients with BCS than with other liver diseases.

Background: In chronic hepatitis C, it has been suggested that steatosis could accelerate progression of fibrosis. However, results of the few published studies are controversial. Aim: To determine the characteristics (epidemiological, biological, and histological) associated with steatosis and its relationship with liver lesions (grade of necroinflammation and stage of fibrosis) in patients with chronic hepatitis C. Methods: From November 2000 to July 2001, untreated consecutive adults with chronic hepatitis C admitted for liver biopsy were included in this study. On the day of liver biopsy, a questionnaire for risk factors was completed prospectively, and a blood sample was obtained for laboratory analysis. Results: Our study included 290 patients (143 men, 147 women). Mean body mass index (BMI) was 24 (3.8) kg/m2. Proportions of patients with genotypes 1 and 3 were, respectively, 48% and 18%. A total of 135 patients (46.6%) had steatosis. Liver steatosis, in multivariate analysis, was associated with hepatitis C virus genotype 3, higher grade of necroinflammation, and higher BMI. There was no significant association between stage of fibrosis and liver steatosis. In multivariate analysis, high stage of fibrosis was associated with male sex, age over 50 years, high BMI, and high grade of necroinflammation. Conclusion: In our population of patients with chronic hepatitis C, steatosis does not seem to be an important determinant of liver fibrosis. High grade of necroinflammation is associated with a high stage of fibrosis.

CIC fusions have been described in two different central nervous system (CNS) tumor entities. On one hand, fusions of CIC or ATXN1 genes belonging to the same complex of transcriptional repressors, were reported in the CIC‐rearranged, sarcoma (SARC‐CIC). The diagnosis of this tumor type, which was recently added to the World Health Organization (WHO) Classification of CNS tumors, is difficult mainly because the data concerning its histopathology (as compared to its soft tissue counterpart), immunoprofile, and clinical as well as radiological characteristics are scarce in the literature. On the other hand, a recent study, based on DNA‐methylation profiling, has identified a novel high‐grade neuroepithelial tumor characterized by recurrent CIC fusions (HGNET‐CIC). The aim of this multicentric study was to characterize a cohort of 15 primary CNS tumors harboring a CIC or ATXN1 fusion in terms of clinical, radiological, histopathological, immunophenotypical, and epigenetic characteristics. According to the integrated diagnoses, 14/15 tumors corresponded to SARC‐CIC, and only one to HGNET‐CIC. The tumors showed similar clinical (mainly pediatric), radiological (mostly supratentorial, cystic, and contrast enhancing), immunophenotypical (common expression of glioneuronal markers), and genetic (similar spectrum of fusions) profiles but their histopathological appearance was clearly distinct. Moreover, we found a novel fusion transcript (CIC::EWSR1) in a SARC‐CIC. Most DNA methylation profiles using the Heidelberg Brain Tumor Classifier (v12.8) annotated the samples to the methylation class “SARC‐CIC” (9/14 tumors with available data). By using uniform manifold approximation and projection analysis, four other samples were classified as SARC‐CIC and another clustered within the methylation class of HGNET‐CIC. Our findings confirm that CNS CIC‐fused tumors do not represent a single molecular tumor entity. Further analyses are needed to characterize HGNET‐CIC in more detail. These results may help to refine the essential diagnostic criteria for SARC‐CIC and their terminology (with a suggested consensual name of sarcoma, CIC/ATXN1‐complex rearranged). Main characteristics of sarcomas, CIC‐rearranged and HGNET, CIC‐fused.

Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses. Synopsis This study provides molecular insights into the anterior gradient 2 (AGR2) mode of action in the endoplasmic reticulum (ER) with an emphasis on the regulation of AGR2 dimers. Dysregulation of AGR2 dimer formation leads to inflammation as seen in inflammatory bowel disease (IBD) and Crohn's disease. AGR2 is a chaperone involved in the regulation of protein quality control in the ER. We have developed and used a novel cellular protein‐protein interaction screen to identify cellular regulators of AGR2 dimerization. We identify specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. Modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR2, respectively. In IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses. Graphical Abstract This study provides molecular insights into the anterior gradient 2 (AGR2) mode of action in the endoplasmic reticulum (ER) with an emphasis on the regulation of AGR2 dimers. Dysregulation of AGR2 dimer formation leads to inflammation as seen in inflammatory bowel disease (IBD) and Crohn's disease.

Background: Isolated sinusoidal dilatation is an uncommon hepatic lesion and the cause is largely unknown. Objective: To investigate whether prothrombotic disorders or perisinusoidal cell changes could be involved in pure idiopathic hepatic sinusoidal dilatation (HSD). Methods: Evaluation for associated conditions, prothrombotic disorders, and studies of hepatic perisinusoidal cell activation in consecutive patients, seen between 1993 and 2002, with isolated sinusoidal dilatation unrelated to outflow block, sinusoidal infiltration, or hepatic granulomas. Results: Among 11 patients, associated conditions were prothrombotic disorders (n = 5) and oral contraceptive use (n = 3). Prothrombotic disorders were polycythemia vera (n = 1) and anticardiolipin antibodies combined with lupus anticoagulant (n = 4). No genetic thrombophilia factor was found. Of four patients with lupus anticoagulant, three had antinuclear factors and high serum levels of anticardiolipin antibodies at repeated testing. There was no evidence of intrahepatic or extrahepatic thrombosis in any of the patients. Sinusoidal dilatation was marked in six of 11 patients (54%), including two patients with antiphospholipid antibodies. Activated perisinusoidal cells were only found around markedly dilated sinusoids. Conclusion: Idiopathic pure HSD is frequently associated with the immunological features of the antiphospholipid syndrome. Therefore, finding pure HSD in a liver biopsy specimen should prompt the search for antiphospholipid antibodies.

The purpose of this review is to illustrate the wide range of radiological abnormalities in myelofibrosis. Myelofibrosis, also called myeloid metaplasia, is a myeloproliferative disorder of unknown etiology. The common imaging findings in patients with myelofibrosis are osteosclerosis, hepatosplenomegaly, and lymphadenopathies. In addition, extramedullary hematopoiesis may develop in multiple sites such as chest, abdomen, pelvis, and central nervous system, simulating malignant disease. Selected plain-film, CT, and MR images in patients with myelofibrosis are shown as pictorial essay to allow ready recognition of the most common imaging abnormalities of the disease.

Background and aims: The rates of fibrosis progression in chronic hepatitis C are significantly different between males and females. The antifibrogenic effect of oestrogen has been proposed, possibly via inhibition of stellate cells. The aim of this study was to evaluate the severity of chronic hepatitis C in women, in relation to the menopause, steatosis and hormone replacement therapy (HRT). Methods: From November 2003 to October 2004, women with chronic hepatitis C were enrolled prospectively. A questionnaire was completed prospectively and a blood sample was obtained on the day of biopsy. We identified characteristics associated with moderate/severe fibrosis using univariate and multivariate analysis. Results: 251 women were included in the study. 122 women (52%) were menopausal and 65 were receiving HRT. 61 (24%) women with moderate/severe fibrosis (F2–F4, Metavir score) had a longer known duration of infection (>15 years), a higher body mass index and presented with steatosis more frequently than 190 (76%) women with mild fibrosis (F0–F1). Women with F2–F4 were more often menopausal (67% v 47%). The probability of fibrosis F2–F4 was lower for menopausal women receiving HRT (p = 0.012). Steatosis was more frequent and more severe in menopausal women. Conclusions: Severity of fibrosis was associated with a longer duration of infection (>15 years), a higher body mass index, advanced steatosis and the menopause. Menopausal women receiving HRT presented with a lower stage fibrosis. These results reinforce the hypothesis of a protective role of oestrogens in the progression of fibrosis. Steatosis may be implicated in the progression of fibrosis after the menopause.

Background/aims: Lipopolysaccharide (LPS) induces liver injury which is associated with upregulated endothelin (ET)-1 production. The aim of this study was to investigate the effects of tezosentan, a non-selective ETA and ETB receptor antagonist, in LPS challenged rats with cirrhosis. Methods: Rats with cirrhosis received LPS and then tezosentan or placebo one hour later. Four hours after LPS administration, rats were killed to measure serum transaminase activity and plasma tumour necrosis factor α (TNF-α) levels. Hepatic inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), a marker of neutrophil infiltration, and cyclooxygenase (COX)-2 expression were also measured. Results: LPS administration significantly decreased arterial pressure and significantly increased plasma endothelin levels. Following LPS and tezosentan administration, serum aspartate aminotransferase and alanine aminotransferase activities were similar to those in the control group while they were increased by more than 700% with LPS alone. Plasma TNF-α levels were significantly lower in rats receiving LPS and tezosentan (182 (38) pg/ml) compared with those receiving LPS alone (821 (212) pg/ml). Tezosentan significantly decreased hepatic MPO activity and hepatic neutrophils but had no effect on LPS induced iNOS or COX-2. Survival rate was significantly higher in rats receiving LPS plus tezosentan (80%) than in rats receiving LPS alone (50%). Conclusion: In LPS challenged cirrhotic rats, tezosentan administration prevents LPS induced liver injury by decreasing intrahepatic neutrophil infiltration. In addition, tezosentan increases survival in these rats.

Background: Budd-Chiari syndrome (BCS) is associated with parenchymal changes leading to major architecture remodelling. In order to gain further insight into the pathogenesis of BCS, we investigated expression of a set of genes involved in the course of chronic liver diseases. Methods: Quantitative expression of 35 selected genes involved in extracellular matrix regulation, growth factors, and angiogenesis was investigated in 13 cases of BCS and compared with 10 normal livers and 13 cirrhosis cases by real time reverse transcription-polymerase chain reaction. Differential gene expression was considered significant for genes showing at least a twofold variation, with p<0.05. Results: Expression of 14 genes was significantly increased in BCS versus normal liver, with the highest increase in superior cervical ganglion 10 (SCG10) gene. BCS cases were classified according to their evolution and morphological pattern as either acute or chronic in six and seven cases, respectively. Unsupervised hierarchical clustering of acute and chronic BCS cases on the basis of similarity in gene expression pattern led to distinction between the two groups. Expression of three genes was significantly different in acute versus chronic BCS (increase in matrix metalloproteinase 7 and SCG10, decrease in thrombospondin-1 for chronic BCS). Seventeen and 10 genes, mainly involved in extracellular matrix and vascular remodelling, were significantly deregulated in acute BCS versus normal liver and cirrhosis, respectively. Conclusion: These results show that BCS cases display a specific gene expression profile that is different from that of normal liver and cirrhosis; the molecular configuration of BCS can be readily distinguished by its evolution and morphological pattern.

BackgroundApproximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations).ObjectiveThe aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas.Materials and methodsWe retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas.ResultsThe median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P < 0.05). Tumours were predominantly localised in the frontal lobe regardless of the type of IDH mutation. Compared to IDH1 p.R132H-mutant gliomas, tumours with non-canonical IDH mutations were more frequently found in the infratentorial region (5.5% vs 0%; P < 0.05) and were often multicentric (4.8% vs 0.9%; P < 0.05). Compared to IDH1 P.R132H-mutant gliomas, tumours with non-canonical IDH1 mutations were more frequently astrocytomas (65.6% vs 43%, P < 0.05), while those with IDH2 mutations were more frequently oligodendrogliomas (85% vs 48.3%; P < 0.05). The median overall survival was similar in patients with IDH1 p.R132H-mutant gliomas and patients with non-canonical IDH-mutant gliomas.ConclusionGliomas with non-canonical IDH mutations have distinct radiological and histological characteristics. The presence of such tumours seems to be associated with genetic predisposition to cancer development.