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Les inhibiteurs pharmacologiques de points de contrôle immunitaires (IPCI) permettent de rendre efficace la réponse antitumorale des lymphocytes T, mais sont responsables d’effets secondaires de type auto-immuns. Ces complications, fréquentes et de sévérité variable, peuvent concerner le parenchyme hépatique. La toxicité hépatique des IPCI se manifeste initialement par une perturbation du bilan biologique hépatique avec un risque secondaire de décompensation clinique. L’apparition d’une anomalie biologique hépatique doit conduire à éliminer une cause non immunomédiée d’atteinte hépatique ou un envahissement tumoral hépatique. La réalisation d’une biopsie hépatique à visée diagnostique est recommandée pour les formes sévères. En cas de toxicité hépatique des IPCI, l’examen histologique retrouve, le plus souvent, une hépatite aiguë lobulaire associée à un infiltrat lymphocytaire. La prise en charge des toxicités hépatiques des IPCI sur foie sain dépend de leur sévérité. L’arrêt des IPCI est recommandé pour les toxicités supérieures ou égales au grade 2, et une corticothérapie est recommandée pour les toxicités supérieures ou égales au grade 3 ou de grade 2 sans amélioration rapide après l’arrêt de l’IPCI. L’ajout de mycophénolate peut être indiqué en cas d’inefficacité des glucocorticoïdes. La réintroduction de l’IPCI est contre-indiquée pour les toxicités sévères. La prise en charge des perturbations du bilan biologique hépatique, survenant sur terrain d’hépatopathie chronique, ne fait pas l’objet de consensus international, mais doit tenir compte des anomalies du bilan biologique hépatique initial et du degré d’aggravation sous IPCI. La situation devient plus complexe avec les associations d’IPCI et d’autres traitements hépatotoxiques. La place de la biopsie est alors primordiale dans le bilan de causalité.

ObjectivesCounting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive ‘normal’ IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens.DesignThe study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.ResultsThe mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2–88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.ConclusionOur ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental (gluten) antigenic influence.

Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1-inactivated HCA, inflammatory HCA, -catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53 of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7 as compared with 100 on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6 as compared with 94.3 on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3 certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each “certain diagnosis” paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P<0.001). No significant difference was observed between groups A and B for FNH (P=0.714) or for HCA subtypes (P=0.750). Compared with surgical specimens, immunohistochemical analysis performed on biopsies allowed the discrimination of FNH from HCA and the identification of HCA subtypes with good performance.

Background/Aim:Fibrosis and/or cirrhosis are present in the precursor stages of most liver cancers. However, little is known about the reciprocal interactions of fibroblasts, mainly responsible for fibrosis, and the other liver cells. We report here the isolation of a new liver myofibroblast cell line from a human liver angiosarcoma and its characterization.

Previous studies have shown that a high proportion (5/6) of human liver angiosarcomas (ASL) associated with exposure to vinyl chloride (VC) contains a GC→AT mutation at the Ki-ras codon 13. This mutation, however, has not been found in 5 ASL or 2 hepatocellular carcinomas (HCC) induced in rats by VC. These 2 HCC did contain a mutation at codon 61 of the Ha-ras gene. In order to extend this study and further explore the mechanisms of tumour induction, an additional 6 ASL and 6 HCC induced in rats by VC were analysed for ras gene point mutations, as well as 10 rat and 10 murine ASL induced by vinyl fluoride (VF), and 5 ASL, 6 Kupffer cell sarcomas, 4 HCC and 2 cholangiocellular carcinomas induced by Thorotrast in rats. Tumour DNA was analysed by PCR-SSCP and direct sequencing. None of the rodent ASL contained a mutation at codon 13 of the Ki-ras gene showing that the ras gene mutational pattern is species-specific. The CAA→CTA mutation, previously found at codon 61 of the Ha-ras gene in rat HCC, was observed in 5 further VC-induced HCC but was not detected in the Thorotrast-induced HCC, suggesting carcinogen-specificity. This mutation was also absent in VC-induced ASL, which supports the cell-specificity of the ras mutational pattern in chemically induced tumours. No predominant mutation was detected in VF- and Thorotrast-induced tumours. Thus, a given mutation in a tumour may be carcinogen-specific but also depend on the species and the cell type. Int. J. Cancer 85:223–227, 2000. ©2000 Wiley-Liss, Inc.

The use of arterial or venous allografts for vascular reconstruction was first reported in 1951, but long-term results have been disappointing. Rejection and inappropriate methods of preservation are the main reasons for failure. A successful solution to this problem could be achieved by programmed cryopreservation with cryoprotectant. Our study had two aims: to define the biomechanical properties of cryopreserved arterial allografts and to study their histologic appearance. Arteries were removed as part of a protocol for multiorgan harveting for transplantation. Cryopreservation was performed within the first 24 hours after harvesting. Programmed cryopreservation with 15% dimethyl sulfoxide (cryoprotectant) was used. Mechanical testing was done immediately after thawing. Two groups were tested: a control group of fresh aortas and a group of cryopreserved aortas. Axial and circumferential strips were tested. High strain modulus and stress and strain characteristics were calculated for each strip. There was no statistically significant difference between the mechanical properties of fresh and cryopreserved human descending thoracic aortas. Biochemical tests were performed in the preservative solution at 1 and 7 days in both groups. There was no statistically significant difference between the two groups at day 1 or day 7 (p > 0.05). Histologic studies before and after arterial cryopreservation included standard and electron microscopy and showed that arteries had normal structure after cryopreservation. These results confirm that programmed cryopreservation with cryoprotectant does not alter the molecular or geometric configuration of collagen or elastic fibers. Endothelial cells were still present; however, their viability and function were not assessed. The results of our studies have encouraged us to use cryopreserved arterial allografts for clinical application, and to date 27 patients have received cryopreserved arterial allografts. Definitive results including histologic and immunologic findings will be reported in the future when the length of follow-up is adequate.

•PARPi cytotoxicity is significantly higher when combined with X-rays in liver cells•HBx expression significantly lowered this survival, probably driven by SMC5/6 loss•HCC Tumor tissues had higher PARP mRNA levels than Peri-Tumor and control livers•Increased DNA damage levels are found during liver disease progression