Publications by authors named "Valérie Paradis"

301 Publications

First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers.

Liver Cancer 2022 Jun 15;11(3):268-277. Epub 2022 Feb 15.

Department of Oncology, Hospital Saint Joseph, Paris, France.

Introduction: GNS561/Ezurpimtrostat is a first-in-class, orally bioavailable, small molecule that blocks cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent build-up of enlarged lysosomes by interacting with the palmitoyl-protein thioesterase 1 (PPT1).

Methods: This phase I, open-label, dose-escalation trial (3 + 3 design) explored two GNS561 dosing schedules: one single oral intake 3 times a week (Q3W) and twice daily (BID) continuous oral administration in patients with advanced hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma or colorectal adenocarcinomas with liver metastasis. The primary objective was to determine GNS561 recommended phase II dose (RP2D) and schedule. Secondary objectives included evaluation of the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of GNS561.

Results: Dose escalation ranged from 50 to 400 mg Q3W to 200-300 mg BID. Among 26 evaluable patients for safety, 20 were evaluable for efficacy and no dose-limiting toxicity was observed. Adverse events (AEs) included gastrointestinal grade 1-2 events, primarily nausea and vomiting occurred in 13 (50%) and 14 (54%) patients, respectively, and diarrhea in 11 (42%) patients. Seven grade 3 AEs were reported (diarrhea, decreased appetite, fatigue, alanine aminotransferase, and aspartate aminotransferase increased). Q3W administration was associated with limited exposure and the BID schedule was preferred. At 200 mg BID GNS561, plasma and liver concentrations were comparable to active doses in animal models. Liver trough concentrations were much higher than in plasma a median time of 28 days of administration with a mean liver to plasma ratio of 9,559 (Min 149-Max 25,759), which is in accordance with rat preclinical data observed after repeated administration. PPT1 expression in cancer tissues in the liver was reduced upon GNS561 exposure. There was no complete or partial response. Five patients experienced tumor stable diseases (25%), including one minor response (-23%).

Conclusion: Based on a favorable safety profile, exposure, and preliminary signal of activity, oral GNS561 RP2D was set at 200 mg BID. Studies to evaluate the antitumor activity of GNS561 in hepatocarcinoma cells and intrahepatic cholangiocarcinoma are to follow NCT03316222.
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http://dx.doi.org/10.1159/000522418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218623PMC
June 2022

Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation.

Biomedicines 2022 Jun 24;10(7). Epub 2022 Jun 24.

Department of Nephrology, Pasteur 1 University Hospital, 06001 Nice, France.

Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT. We also assessed the expression of four key regulators of PPi in liver tissues and established correlations between AC, and scores of liver fibrosis and liver failure in these patients. LT candidates with various liver diseases were included. AC scores were assessed in coronary arteries, abdominal aorta, and aortic valves. Liver fibrosis was evaluated on liver biopsies and from non-invasive tests (FIB-4 and APRI scores). Liver functions were assessed by measuring serum albumin, ALBI, MELD, and Pugh-Child scores. An enzymatic assay was used to dose [PPi]pl. A group of patients without liver alterations from a previous cohort provided a control group. Gene expression assays were performed with mRNA extracted from liver biopsies and compared between LT recipients and the control individuals. [PPi]pl negatively correlated with APRI (r = -0.57, = 0.001, n = 29) and FIB-4 (r = -0.47, = 0.006, n = 29) but not with interstitial fibrosis index from liver biopsies (r = 0.07, = 0.40, n = 16). Serum albumin positively correlated with [PPi]pl (r = 0.71; < 0.0001, n = 20). ALBI, MELD, and Pugh-Child scores correlated negatively with [PPi]pl (r = -0.60, = 0.0005; r = -0.56, = 0.002; r = -0.41, = 0.02, respectively, with n = 20). Liver fibrosis assessed on liver biopsies by FIB-4 and by APRI positively correlated with coronary AC (r = 0.51, = 0.02, n = 16; r = 0.58, = 0.009, n = 20; r = 0.41, = 0.04, n = 20, respectively) and with abdominal aorta AC (r = 0.50, = 0.02, n = 16; r = 0.67, = 0.002, n = 20; r = 0.61, = 0.04, n = 20, respectively). FIB-4 also positively correlated with aortic valve calcification (r = 0.40, = 0.046, n = 20). The key regulator genes of PPi production in liver were lower in patients undergoing liver transplantation as compared to controls. Three months after surgery, serum albumin levels were restored to physiological levels (40 [37-44] vs. 35 [30-40], = 0.009) and [PPi]pl was normalized (1.40 [1.07-1.86] vs. 0.68 [0.53-0.80] µmol/L, = 0.0005, n = 12). Liver failure and/or fibrosis correlated with AC in several arterial beds and were associated with low plasma PPi and dysregulation of key proteins involved in PPi homeostasis. Liver transplantation normalized these parameters.
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http://dx.doi.org/10.3390/biomedicines10071496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312703PMC
June 2022

Benign liver tumours: understanding molecular physiology to adapt clinical management.

Nat Rev Gastroenterol Hepatol 2022 Jul 14. Epub 2022 Jul 14.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, team «Functional Genomics of Solid Tumors», Paris, France.

Improvements in understanding the pathophysiology of the different benign liver nodules have refined their nosological classification. New criteria have been identified using imaging, histology and molecular analyses for a precise diagnosis of these tumours. Improvement in the classification of liver tumours provides a more accurate prediction of disease progression and has modified patient management. Haemangioma and focal nodular hyperplasia, the most common benign liver tumours that develop in the absence of chronic liver disease, are usually easy to diagnose on imaging and do not require specific treatment. However, hepatocellular adenomas and cirrhotic macronodules can be difficult to discriminate from hepatocellular carcinoma. The molecular subtyping of hepatocellular adenomas in five major subgroups defined by HNF1A inactivation, β-catenin mutation in exon 3 or exon 7/8, and activation of inflammatory or Hedgehog pathways helps to identify the tumours at risk of malignant transformation or bleeding. New clinical, biological and molecular tools have gradually been included in diagnostic and treatment algorithms to classify benign liver tumours and improve patient management. This Review aims to explain the main pathogenic mechanisms of benign liver tumours and how this knowledge could influence clinical practice.
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http://dx.doi.org/10.1038/s41575-022-00643-5DOI Listing
July 2022

Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD.

Dev Cell 2022 Jul 28;57(14):1728-1741.e6. Epub 2022 Jun 28.

Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France. Electronic address:

Non-alcoholic steatotic liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD has a major effect on the intrinsic proliferative properties of hepatocytes. Here, we investigated the mechanisms underlying the activation of DNA damage response during NAFLD. Proliferating mouse NAFLD hepatocytes harbor replication stress (RS) with an alteration of the replication fork's speed and activation of ATR pathway, which is sufficient to cause DNA breaks. Nucleotide pool imbalance occurring during NAFLD is the key driver of RS. Remarkably, DNA lesions drive cGAS/STING pathway activation, a major component of cells' intrinsic immune response. The translational significance of this study was reiterated by showing that lipid overload in proliferating HepaRG was sufficient to induce RS and nucleotide pool imbalance. Moreover, livers from NAFLD patients displayed nucleotide pathway deregulation and cGAS/STING gene alteration. Altogether, our findings shed light on the mechanisms by which damaged NAFLD hepatocytes might promote disease progression.
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http://dx.doi.org/10.1016/j.devcel.2022.06.003DOI Listing
July 2022

Immunophenotypic and molecular characterization of pancreatic neuroendocrine tumors producing serotonin.

Mod Pathol 2022 Jun 23. Epub 2022 Jun 23.

Université Paris Cité - APHP Hôpital Beaujon/Bichat, Department of Pathology, FHU MOSAIC, 100 Boulevard du Général Leclerc, 92110, Clichy, France.

Serotonin producing pancreatic neuroendocrine tumors (SP-PanNET) account for 0.58-1.4% of all pancreatic neuroendocrine tumors (PanNET). They may present with atypical symptoms, such as acute pancreatitis and are often radiologically characterized by main pancreatic duct dilatation. SP-PanNET are well differentiated neuroendocrine tumors (NET) distinct from classical PanNET by atypical serotonin secretion and abundant dense stroma deposition, like serotonin producing ileal NET leading in some cases to difficulties to reliably distinguish SP-PanNET from ileal NET metastases. The biology and molecular profile of SP-PanNET remain poorly characterized and the cell of origin within the pancreas is unclear. To address these questions, we analyzed a large cohort of SP-PanNET by immunohistochemistry (n = 29; ATRX, DAXX, MENIN, Islet1, PAX6, PDX1, ARX, CDX2), whole genome copy number array (Oncoscan™) and a large NGS panel (NovoPM™) (n = 10), FISH (n = 13) and RNA sequencing (n = 24) together with 21 ileal NET and 29 nonfunctioning PanNET (NF-PanNET). These analyses revealed a unique genomic profile with frequent isolated loss of chromosome 1 (14 cases-61%) and few pathogenic mutations (KMT2C in 2 cases, ARID1A in 1 case). Unsupervised RNAseq-based clustering showed that SP-PanNET were closer to NF-PanNET than ileal NET with an exclusive beta cell-like signature. SP-PanNET showed TGF-β pathway activation signatures associated with extracellular matrix remodeling and similar signature were reproduced in vitro when pancreatic stellate cells were exposed to serotonin. SP-PanNET immunohistochemical profile resemble that of ileal NET except for PDX1 and PAX6 expression to a lesser extend suggesting that these two markers may be useful to diagnose SP-PanNET. Taken together, this suggests that SP-PanNET are a very specific PanNET entity with a peculiar biology leading to the characteristic fibrotic aspect.
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http://dx.doi.org/10.1038/s41379-022-01110-xDOI Listing
June 2022

Reply to: Correspondence regarding "Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies".

J Hepatol 2022 Jun 19. Epub 2022 Jun 19.

Université Paris Cité, Faculté de Médecine, 16 rue Henri Huchard, Paris, 75018, France; Department of Pathology, Hôpital Beaujon, FHU MOSAIC, AP-HP.Nord, 100 boulevard du Général Leclerc, Clichy, 92110, France; INSERM UMR 1149, Centre de Recherche sur l'Inflammation, 16 rue Henri Huchard, Paris, 75018, France. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2022.06.011DOI Listing
June 2022

Current therapies and new developments in NASH.

Gut 2022 Jun 16. Epub 2022 Jun 16.

School of Public Health, University of Haifa, Haifa, Israel.

Non-alcoholic steatohepatitis is becoming the most important aetiology for advanced liver disease. There has been important progress in the field in recent years and the complexity of the pathophysiology of NASH is better understood. Multiple non-invasive circulating and imaging biomarkers have been tested. The importance of lifestyle has been recognised and several drugs are being tested in clinical trials. This review addresses the challenges that healthcare professionals face in the management of NASH patients.
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http://dx.doi.org/10.1136/gutjnl-2021-326874DOI Listing
June 2022

Laparoscopic-assisted liver transplantation: A realistic perspective.

Am J Transplant 2022 Jun 15. Epub 2022 Jun 15.

Department of HPB surgery and liver transplantation, AP-HP, Beaujon Hospital, DMU DIGEST, Clichy, France.

Laparoscopic approach was rarely described in recipients for liver transplantation (LT). We report the feasibility and safety of laparoscopic-assisted LT (LA-LT) in patients with unresectable liver metastases of neuroendocrine tumors. Total hepatectomy was performed laparoscopically with graft implantation through an upper midline incision. Liver grafts were retrieved from deceased donors. From July 2019 to July 2021, six patients (4 women, 2 men) underwent LA-LT. Median age and BMI were 46 (29-54) and 24 (19-35) kg/m , respectively. Implanted grafts were reduced (n = 3), full (n = 2), and a right split liver (n = 1). Median surgical time was 405 min (390-450) and median blood loss was 425 ml (250-600). Median cold and warm ischemia times were 438 min (360-575) and 35 min (30-40), respectively. Median anhepatic phase was 51 min (40-67) and midline incision was 14 cm (13-20) long. On postoperative day 5, median prothrombin index and serum bilirubin levels were 95% (70-117) and 11 (10-37) μmol/L, respectively. No Clavien-Dindo > III complications were encountered. Median hospital stay was 12 days (10-14). After a median follow-up of 8 (8-32) months, all patients were alive without tumor recurrence or adverse event. This preliminary series suggests that in selected patients, LA-LT is a safe and effective option.
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http://dx.doi.org/10.1111/ajt.17118DOI Listing
June 2022

Molecular deciphering of primary liver neuroendocrine neoplasms confirms their distinct existence with foregut-like profile.

J Pathol 2022 Sep 11;258(1):58-68. Epub 2022 Jul 11.

Université de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP), Clichy, France.

Isolated hepatic localizations of neuroendocrine tumors (NETs) are generally considered as metastatic NETs of unknown primary but could correspond to primary hepatic NETs (PHNETs), a poorly explored entity. We aimed to describe the clinicopathological and molecular features of PHNETs and compare them with other primary NETs. We assembled a retrospective cohort of patients managed for hepatic localization of NET without extra-hepatic primary tumor after exhaustive clinical, imaging, and immunohistochemical characterization. We performed whole-exome sequencing with mutational and copy number analysis. Transcriptomic profiles were compared with pancreatic (n = 31), small-bowel (n = 22), and lung (n = 15) NETs using principal component analysis, unsupervised clustering, and gene set enrichment analysis. Among 27 screened patients, 16 had PHNET (solitary tumor in 63%, median size 11 cm, G2 NETs in 81%) following clinical and pathological review. DNA analyses showed 'foregut-like' genomic profiles with frequent alterations in pathways of Fanconi DNA repair (75%), histone modifiers (58%), adherens junctions (58%), and cell cycle control (50%). The most frequently involved genes were KMT2A (58%), ATM (42%), CDH1, CDKN2C, FANCF, and MEN1 (33% each). Transcriptomic analyses showed that PHNETs clustered closer to foregut (pancreatic, lung) NETs than to midgut (small-bowel) NETs, while remaining a distinct entity with a specific profile. Assessment of potentially predictive biomarkers suggested efficacy of treatments usually active in foregut NETs. In conclusion, PHNETs display a foregut-like molecular profile distinct from other types of NETs, with recurrent molecular alterations. Upon exhaustive work-up to exclude an unrecognized primary tumor, PHNETs should not be considered metastatic NETs from an unknown primary. © 2022 The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5977DOI Listing
September 2022

Characterization and Pharmacological Validation of a Preclinical Model of NASH in Göttingen Minipigs.

J Clin Exp Hepatol 2022 Mar-Apr;12(2):293-305. Epub 2021 Sep 8.

Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France.

Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, which is associated with features of metabolic syndrome. NAFLD may progress in a subset of patients into nonalcoholic steatohepatitis (NASH) with liver injury resulting ultimately in cirrhosis and potentially hepatocellular carcinoma. Today, there is no approved treatment for NASH due to, at least in part, the lack of preclinical models recapitulating features of human disease. Here, we report the development of a dietary model of NASH in the Göttingen minipig.

Methods: First, we performed a longitudinal characterization of diet-induced NASH and fibrosis using biochemical, histological, and transcriptional analyses. We then evaluated the pharmacological response to Obeticholic acid (OCA) treatment for 8 weeks at 2.5mg/kg/d, a dose matching its active clinical exposure.

Results: Serial histological examinations revealed a rapid installation of NASH driven by massive steatosis and inflammation, including evidence of ballooning. Furthermore, we found the progressive development of both perisinusoidal and portal fibrosis reaching fibrotic septa after 6 months of diet. Histological changes were mechanistically supported by well-defined gene signatures identified by RNA Seq analysis. While treatment with OCA was well tolerated throughout the study, it did not improve liver dysfunction nor NASH progression. By contrast, OCA treatment resulted in a significant reduction in diet-induced fibrosis in this model.

Conclusions: These results, taken together, indicate that the diet-induced NASH in the Göttingen minipig recapitulates most of the features of human NASH and may be a model with improved translational value to prioritize drug candidates toward clinical development.
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http://dx.doi.org/10.1016/j.jceh.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9077241PMC
September 2021

Differentiation of hepatocellular adenoma by subtype and hepatocellular carcinoma in non-cirrhotic liver by fractal analysis of perfusion MRI.

Insights Imaging 2022 Apr 28;13(1):81. Epub 2022 Apr 28.

Université de Paris, CRI, U1149, Paris, France.

Background: To investigate whether fractal analysis of perfusion differentiates hepatocellular adenoma (HCA) subtypes and hepatocellular carcinoma (HCC) in non-cirrhotic liver by quantifying perfusion chaos using four-dimensional dynamic contrast-enhanced magnetic resonance imaging (4D-DCE-MRI).

Results: A retrospective population of 63 patients (47 female) with histopathologically characterized HCA and HCC in non-cirrhotic livers was investigated. Our population consisted of 13 hepatocyte nuclear factor (HNF)-1α-inactivated (H-HCAs), 7 β-catenin-exon-3-mutated (b-HCAs), 27 inflammatory HCAs (I-HCAs), and 16 HCCs. Four-dimensional fractal analysis was applied to arterial, portal venous, and delayed phases of 4D-DCE-MRI and was performed in lesions as well as remote liver tissue. Diagnostic accuracy of fractal analysis was compared to qualitative MRI features alone and their combination using multi-class diagnostic accuracy testing including kappa-statistics and area under the receiver operating characteristic curve (AUC). Fractal analysis allowed quantification of perfusion chaos, which was significantly different between lesion subtypes (multi-class AUC = 0.90, p < 0.001), except between I-HCA and HCC. Qualitative MRI features alone did not allow reliable differentiation between HCA subtypes and HCC (κ = 0.35). However, combining qualitative MRI features and fractal analysis reliably predicted the histopathological diagnosis (κ = 0.89) and improved differentiation of high-risk lesions (i.e., HCCs, b-HCAs) and low-risk lesions (H-HCAs, I-HCAs) from sensitivity and specificity of 43% (95% confidence interval [CI] 23-66%) and 47% (CI 32-64%) for qualitative MRI features to 96% (CI 78-100%) and 68% (CI 51-81%), respectively, when adding fractal analysis.

Conclusions: Combining qualitative MRI features with fractal analysis allows identification of HCA subtypes and HCCs in patients with non-cirrhotic livers and improves differentiation of lesions with high and low risk for malignant transformation.
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http://dx.doi.org/10.1186/s13244-022-01223-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050986PMC
April 2022

The triglycerides and glucose (TyG) index: A new marker associated with nonalcoholic steatohepatitis (NASH) in obese patients.

Diabetes Metab 2022 07 23;48(4):101345. Epub 2022 Mar 23.

Endocrinology Department, CHU Montpellier, Univ Montpellier, 371 Av du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France; Clinical Investigation Center 1411, INSERM, CHU Montpellier, Univ Montpellier, 80 Avenue Augustin Fliche, 34295 Montpellier Cedex 5, France. Electronic address:

Aim: Diagnosis of nonalcoholic steatohepatitis (NASH) relies on liver biopsy. Noninvasive tools would be useful to target patients to refer for a biopsy. We aimed to determine the diagnostic value of the triglycerides and glucose (TyG) index, an insulin-resistance indicator, to predict NASH.

Methods: Our study included grade II-III obese patients aged 18-65 years undergoing bariatric surgery and included in the COMET (COllection of MEtabolic Tissues) biobank (NCT02861781). Liver biopsies performed during bariatric surgery were collected from the biobank along with blood derivatives. Biopsies were analysed according to the steatosis, activity and fibrosis (SAF) scoring system to diagnose NASH, nonalcoholic fatty liver disease (NAFLD), and fibrosis. Logistic regression models were performed to identify factors predicting NASH, NAFLD, and fibrosis.

Results: Of 238 analysed subjects (mean age 43±12 years, 33.6% men), 29% had type 2 diabetes. Steatosis was present in 67.2%, while NASH and advanced fibrosis (stage F3) were diagnosed in 18.1% and 2.9% respectively. TyG index was independently associated with NASH (odds ratio (OR): 4.7 [95% confidence interval: 2.3;9.5] P < 0.0001), NAFLD (OR: 2.0 [1.1;3.7] P = 0.03) and stages 2-3 fibrosis (OR: 4.0 [1.5;10.8] P = 0.007). NASH was also predicted by gamma-glutamyl transferase (GGT) with an area under the ROC curve: 0.79 [0.71;0.87 P = 0.04] for GGT and TyG index combined.

Conclusion: In our cohort of severely obese patients, TyG index, when associated with GGT level, exhibited high diagnostic performance to predict NASH. Although validation in larger populations is needed, this result may be of considerable clinical value to predict need for liver biopsy.
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http://dx.doi.org/10.1016/j.diabet.2022.101345DOI Listing
July 2022

Clinical Interest of Serum Alpha-2 Macroglobulin, Apolipoprotein A1, and Haptoglobin in Patients with Non-Alcoholic Fatty Liver Disease, with and without Type 2 Diabetes, before or during COVID-19.

Biomedicines 2022 Mar 17;10(3). Epub 2022 Mar 17.

Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Hepatology, Beaujon Hospital, 92110 Clichy, France.

In patients with non-alcoholic fatty liver disease (NAFLD) with or without type 2 diabetes mellitus (T2DM), alpha-2 macroglobulin (A2M), apolipoprotein A1 (ApoA1), and haptoglobin are associated with the risk of liver fibrosis, inflammation (NASH), and COVID-19. We assessed if these associations were worsened by T2DM after adjustment by age, sex, obesity, and COVID-19. Three datasets were used: the "Control Population", which enabled standardization of protein serum levels according to age and sex (N = 27,382); the "NAFLD-Biopsy" cohort for associations with liver features (N = 926); and the USA "NAFLD-Serum" cohort for protein kinetics before and during COVID-19 (N = 421,021). The impact of T2DM was assessed by comparing regression curves adjusted by age, sex, and obesity for the liver features in "NAFLD-Biopsy", and before and during COVID-19 pandemic peaks in "NAFLD-Serum". Patients with NAFLD without T2DM, compared with the values of controls, had increased A2M, decreased ApoA1, and increased haptoglobin serum levels. In patients with both NAFLD and T2DM, these significant mean differences were magnified, and even more during the COVID-19 pandemic in comparison with the year 2019 (all < 0.001), with a maximum ApoA1 decrease of 0.21 g/L in women, and a maximum haptoglobin increase of 0.17 g/L in men. In conclusion, T2DM is associated with abnormal levels of A2M, ApoA1, and haptoglobin independently of NAFLD, age, sex, obesity, and COVID-19.
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http://dx.doi.org/10.3390/biomedicines10030699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945355PMC
March 2022

Deleting the β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumor growth.

J Hepatol 2022 Aug 4;77(2):424-435. Epub 2022 Mar 4.

INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC), F-75006, France; Equipe Labellisée Ligue Nationale Contre le Cancer, France. Electronic address:

Background & Aims: One-third of hepatocellular carcinomas (HCCs) harbor mutations activating the β-catenin pathway, predominantly via mutations in the CTNNB1 gene itself. Mouse models of Apc loss-of-function are widely used to mimic β-catenin-dependent tumorigenesis. Given the low prevalence of APC mutations in human HCCs, we aimed to generate liver tumors through CTNNB1 exon 3 deletion (βcat). We then compared βcat liver tumors with liver tumors generated via frameshift in exon 15 of Apc (Apc).

Methods: We used hepatocyte-specific and inducible mouse models generated through either a Cre-Lox or a CRISPR/Cas9 approach using adeno-associated virus vectors. Tumors generated by the Cre-Lox models were phenotypically analyzed using immunohistochemistry and were selected for transcriptomic analysis by RNA-sequencing (RNAseq). Mouse RNAseq data were compared to human RNAseq data (8 normal tissues, 48 HCCs, 9 hepatoblastomas) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immuno-histochemistry.

Results: Mice with CTNNB1 exon 3 deletion in hepatocytes developed liver tumors indistinguishable from Apc liver tumors. Both Apc and βcat mouse models induced growth of phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that differentiated mouse tumors cluster with well-differentiated human CTNNB1-mutated tumors. Conversely, undifferentiated mouse tumors cluster with human mesenchymal hepatoblastomas and harbor activated YAP signaling.

Conclusion: Apc and βcat mouse models both induce growth of tumors that are transcriptionally similar to either well-differentiated and β-catenin-activated human HCCs or mesenchymal hepatoblastomas.

Lay Summary: New and easy-to-use transgenic mouse models of primary liver cancers have been generated, with mutations in the gene encoding beta-catenin, which are frequent in both adult and pediatric primary liver cancers. The mice develop both types of cancer, constituting a strong preclinical model.
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http://dx.doi.org/10.1016/j.jhep.2022.02.023DOI Listing
August 2022

Artificial intelligence in liver diseases: Improving diagnostics, prognostics and response prediction.

JHEP Rep 2022 Apr 2;4(4):100443. Epub 2022 Feb 2.

Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.

Clinical routine in hepatology involves the diagnosis and treatment of a wide spectrum of metabolic, infectious, autoimmune and neoplastic diseases. Clinicians integrate qualitative and quantitative information from multiple data sources to make a diagnosis, prognosticate the disease course, and recommend a treatment. In the last 5 years, advances in artificial intelligence (AI), particularly in deep learning, have made it possible to extract clinically relevant information from complex and diverse clinical datasets. In particular, histopathology and radiology image data contain diagnostic, prognostic and predictive information which AI can extract. Ultimately, such AI systems could be implemented in clinical routine as decision support tools. However, in the context of hepatology, this requires further large-scale clinical validation and regulatory approval. Herein, we summarise the state of the art in AI in hepatology with a particular focus on histopathology and radiology data. We present a roadmap for the further development of novel biomarkers in hepatology and outline critical obstacles which need to be overcome.
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http://dx.doi.org/10.1016/j.jhepr.2022.100443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867112PMC
April 2022

Corrigendum to: 'Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target' [J Hepatol 2021 (74) 1155-1166].

J Hepatol 2022 May 24;76(5):1242-1243. Epub 2022 Feb 24.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors Laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2022.01.019DOI Listing
May 2022

Procollagen C-Proteinase Enhancer-1 (PCPE-1) deficiency in mice reduces liver fibrosis but not NASH progression.

PLoS One 2022 11;17(2):e0263828. Epub 2022 Feb 11.

Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France.

Background And Aims: Nonalcoholic Steatohepatitis (NASH) is a major cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma resulting ultimately in increased liver-related mortality. Fibrosis is the main driver of mortality in NASH. Procollagen C-Proteinase Enhancer-1 (PCPE-1) plays a key role in procollagen maturation and collagen fibril formation. To assess its role in liver fibrosis and NASH progression, knock-out mice were evaluated in a dietary NASH model.

Methods: Global constitutive Pcolce-/- and WT male mice were fed with a Choline Deficient Amino acid defined High Fat Diet (CDA HFD) for 8 weeks. Liver triglycerides, steatosis, inflammation and fibrosis were assessed at histological, biochemical and gene expression levels. In addition, human liver samples from control and NASH patients were used to evaluate the expression of PCPE-1 at both mRNA and protein levels.

Results: Pcolce gene deficiency prevented diet-induced liver enlargement but not liver dysfunction. Furthermore, liver triglycerides, steatosis and inflammation were not modified in Pcolce-/- male mice compared to WT under CDA HFD. However, a significant decrease in liver fibrosis was observed in Pcolce-/- mice compared to WT under NASH diet, associated with a decrease in total and insoluble collagen content without any significant modifications in the expression of genes involved in fibrosis and extracellular matrix remodeling. Finally, PCPE-1 protein expression was increased in cirrhotic liver samples from both NASH and Hepatitis C patients.

Conclusions: Pcolce deficiency limits fibrosis but not NASH progression in CDA HFD fed mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0263828PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836302PMC
February 2022

Performance of non-invasive biomarkers compared with invasive methods for risk prediction of posthepatectomy liver failure in hepatocellular carcinoma.

Br J Surg 2022 04;109(5):455-463

Université de Paris and Department of Hepatobiliary Surgery and Liver transplantation, Hôpital Beaujon, AP-HP, Clichy, France.

Background: Posthepatectomy liver failure (PHLF) is a rare but dreaded complication. The aim was to test whether a combination of non-invasive biomarkers (NIBs) and CT data could predict the risk of PHLF in patients who underwent resection of hepatocellular carcinoma (HCC).

Methods: Patients with HCC who had liver resection between 2012 and 2020 were included. A relevant combination of NIBs (NIB model) to model PHLF risk was identified using a doubly robust estimator (inverse probability weighting combined with logistic regression). The adjustment variables were body surface area, ASA fitness grade, male sex, future liver remnant (FLR) ratio, difficulty of liver resection, and blood loss. The reference invasive biomarker (IB) model comprised a combination of pathological analysis of the underlying liver and hepatic venous pressure gradient (HVPG) measurement. Various NIB and IB models for prediction of PHLF were fitted and compared. NIB model performances were validated externally. Areas under the curve (AUCs) were corrected using bootstrapping.

Results: Overall 323 patients were included. The doubly robust estimator showed that hepatitis C infection (odds ratio (OR) 4.33, 95 per cent c.i. 1.29 to 9.20; P = 0.001), MELD score (OR 1.26, 1.04 to 1.66; P = 0.001), fibrosis-4 score (OR 1.36, 1.06 to 1.85; P = 0.001), liver surface nodularity score (OR 1.55, 1.28 to 4.29; P = 0.031), and FLR volume ratio (OR 0.99, 0.97 to 1.00; P = 0.014) were associated with PHLF. Their combination (NIB model) was fitted externally (2-centre cohort, 165 patients) to model PHLF risk (AUC 0.867). Among 129 of 323 patients who underwent preoperative HVPG measurement, NIB and IB models had similar performances (AUC 0.753 versus 0.732; P = 0.940). A well calibrated nomogram was drawn based on the NIB model (AUC 0.740). The risk of grade B/C PHLF could be ruled out in patients with a cumulative score of less than 160 points.

Conclusion: The NIB model provides reliable preoperative evaluation with performance at least similar to that of invasive methods for PHLF risk prediction.
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http://dx.doi.org/10.1093/bjs/znac017DOI Listing
April 2022

Reply to: "Malignant transformation of hepatocellular adenoma".

JHEP Rep 2022 Mar 8;4(3):100429. Epub 2022 Jan 8.

Department of pathology, Assistance Publique-Hôpitaux de Paris and Université de Paris, Hôpital Beaujon, Clichy, France.

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http://dx.doi.org/10.1016/j.jhepr.2022.100429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810563PMC
March 2022

Contrast-enhanced CT and liver surface nodularity for the diagnosis of porto-sinusoidal vascular disorder: A case-control study.

Hepatology 2022 Aug 16;76(2):418-428. Epub 2022 Feb 16.

Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de Recherche sur l'inflammation, Inserm, UMR 1149, Université de Paris, AP-HP, Hôpital Beaujon, Paris, France.

Background And Aims: Porto-sinusoidal vascular disorder (PSVD) is a rare and commonly overlooked cause of portal hypertension. The interest of CT analysis, including quantification of liver surface nodularity (LSN) for PSVD diagnosis has not been established. This study aimed at assessing the performance of LSN and CT features for a PSVD diagnosis in patients with signs of portal hypertension.

Approach And Results: This retrospective case-control study included a learning cohort consisting of 50 patients with histologically proven PSVD, according to VALDIG criteria, and 100 control patients with histologically proven cirrhosis, matched on ascites. All patients and controls had at least one sign of portal hypertension and CT available within 1 year of liver biopsy. Principal component analysis of CT features separated patients with PSVD from patients with cirrhosis. Patients with PSVD had lower median LSN than those with cirrhosis (2.4 vs. 3.1, p < 0.001). Multivariate analysis identified LSN < 2.5 and normal-sized or enlarged segment IV as independently associated with PSVD. Combination of these two features had a specificity of 90% for PSVD and a diagnostic accuracy of 84%. Even better results were obtained in an independent multicenter validation cohort including 53 patients with PSVD and 106 control patients with cirrhosis (specificity 94%, diagnostic accuracy 87%).

Conclusions: This study that included a total of 103 patients with PSVD and 206 patients with cirrhosis demonstrates that LSN < 2.5 combined with normal-sized or enlarged segment IV strongly suggests PSVD in patients with signs of portal hypertension.
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http://dx.doi.org/10.1002/hep.32367DOI Listing
August 2022

Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

Lancet Oncol 2022 01 11;23(1):161-171. Epub 2021 Dec 11.

Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Service d'Hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Paris, France.

Background: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma.

Methods: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts.

Findings: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10), PNPLA3 (rs738409; p=9·29 × 10), and HSD17B13 (rs72613567; p=2·49 × 10). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10), TM6SF2 (rs58542926; p=4·06 × 10), and PNPLA3 (rs738409; p=1·17 × 10). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis.

Interpretation: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis.

Funding: Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.
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http://dx.doi.org/10.1016/S1470-2045(21)00603-3DOI Listing
January 2022

Imaging features of histological subtypes of hepatocellular carcinoma: Implication for LI-RADS.

JHEP Rep 2021 Dec 30;3(6):100380. Epub 2021 Sep 30.

Department of Radiology, Hôpital Beaujon, Clichy, France.

Background & Aims: The histopathological subtypes of hepatocellular carcinoma (HCC) are associated with distinct clinical features and prognoses. This study aims to report Liver Imaging Reporting and Data System (LI-RADS)-defined imaging features of different HCC subtypes in a cohort of resected tumours and to assess the influence of HCC subtypes on computed tomography (CT)/magnetic resonance imaging (MRI) LI-RADS categorisation in the subgroup of high-risk patients.

Methods: This retrospective institutional review board-approved study included patients with resected HCCs and available histopathological classification. Three radiologists independently reviewed preoperative CT and MRI exams. The readers evaluated the presence of imaging features according to LI-RADS v2018 definitions and provided a LI-RADS category in patients at high risk of HCC. Differences in LI-RADS features and categorisations were assessed for not otherwise specified (NOS-HCC), steatohepatitic (SH-HCC), and macrotrabecular-massive (MTM-HCC) types of HCCs.

Results: Two hundred and seventy-seven patients (median age 64.0 years, 215 [77.6%] men) were analysed, which involved 295 HCCs. There were 197 (66.7%) NOS-HCCs, 62 (21.0%) SH-HCCs, 23 (7.8%) MTM-HCCs, and 13 (4.5%) other rare subtypes. The following features were more frequent in MTM-HCC: elevated α-foetoprotein serum levels ( <0.001), tumour-in-vein ( <0.001 on CT, ≤0.052 on MRI), presence of at least 1 LR-M feature ( ≤0.010 on CT), infiltrative appearance ( ≤0.032 on CT), necrosis or severe ischaemia ( ≤0.038 on CT), and larger size ( ≤0.006 on CT, ≤0.011 on MRI). SH-HCC was associated with fat in mass ( <0.001 on CT, ≤0.002 on MRI). The distribution of the LI-RADS major features and categories in high-risk patients did not significantly differ among the 3 main HCC subtypes.

Conclusions: The distribution of LI-RADS major features and categories is not different among the HCC subtypes. Nevertheless, careful analysis of tumour-in-vein, LR-M, and ancillary features as well as clinico-biological data can provide information for the non-invasive diagnosis of HCC subtypes.

Lay Summary: In high-risk patients, the overall distribution of LI-RADS major features and categories is not different among the histological subtypes of hepatocellular carcinoma, but tumour-in-vein, presence of LR-M features, and ancillary features can provide information for the non-invasive diagnosis of hepatocellular carcinoma subtypes.
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http://dx.doi.org/10.1016/j.jhepr.2021.100380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603197PMC
December 2021

Immune Profiling of Combined Hepatocellular- Cholangiocarcinoma Reveals Distinct Subtypes and Activation of Gene Signatures Predictive of Response to Immunotherapy.

Clin Cancer Res 2022 02 16;28(3):540-551. Epub 2021 Nov 16.

Université Paris Est Créteil, INSERM, IMRB, Créteil, France.

Purpose: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare malignancy associated with an overall poor prognosis. We aimed to investigate the immune profile of cHCC-CCA and determine its impact on disease outcome.

Experimental Design: We performed a multicenter study of 96 patients with cHCC-CCA. Gene expression profile was analyzed using nCounter PanCancer IO 360 Panel. Densities of main immune cells subsets were quantified from digital slides of IHC stainings. Genetic alterations were investigated using targeted next-generation sequencing.

Results: Two main immune subtypes of cHCC-CCA were identified by clustering analysis: an "immune-high" (IH) subtype (57% of the cases) and an "immune-low" (IL) subtype (43% of the cases). Tumors classified as IH showed overexpression of genes related to immune cells recruitment, adaptive and innate immunity, antigen presentation, cytotoxicity, immune suppression, and inflammation ( < 0.0001). IH cHCC-CCAs also displayed activation of gene signatures recently shown to be associated with response to immunotherapy in patients with HCC. Quantification of immunostainings confirmed that IH tumors were also characterized by higher densities of immune cells. Immune subtypes were not associated with any genetic alterations. Finally, multivariate analysis showed that the IH subtype was an independent predictor of improved overall survival.

Conclusions: We have identified a subgroup of cHCC-CCA that displays features of an ongoing intratumor immune response, along with an activation of gene signatures predictive of response to immunotherapy in HCC. This tumor subclass is associated with an improved clinical outcome. These findings suggest that a subset of patients with cHCC-CCA may benefit from immunomodulating therapeutic approaches.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1219DOI Listing
February 2022

Autofluorescence imaging within the liver: a promising tool for the detection and characterization of primary liver tumors.

Eur Radiol 2022 Apr 25;32(4):2481-2491. Epub 2021 Oct 25.

INSERM IMRB U955, Equipe 18, Créteil, France.

Objectives: To assess the performance of 405 nm-induced autofluorescence for the characterization of primary liver nodules on ex vivo resected specimens.

Materials And Methods: Forty resected liver specimens bearing 53 primary liver nodules were included in this IRB-approved prospective study. Intratissular spectroscopic measurements were performed using a 25-G fibered-needle on all ex vivo specimens: 5 autofluorescence measurements were performed in both nodules and adjacent parenchyma. The spectra derivatives of the 635 and 670 nm autofluorescence peaks observed in nodules and in adjacent liver parenchyma were compared (Kruskal-Wallis and Mann-Whitney when appropriate).

Results: A total of 42 potentially evolutive primary liver nodules-34 hepatocellular carcinomas, 4 intrahepatic cholangiocarcinomas, 4 hepatocellular adenomas-and 11 benign nodules-5 focal nodular hyperplasias, 6 regenerative nodules-were included. Both 635 and 670 nm Δderivatives were significantly higher in benign as compared to potentially evolutive (PEV) nodules (respectively 32.9 ± 4.5 vs 15.3 ± 1.4; p < 0.0001 and 5.7 ± 0.6 vs 2.5 ± 0.1; p < 0.0001) with respective sensitivity and specificity of 78% and 91% for distinguishing PEV from benign nodules.

Conclusion: 405 nm-induced autofluorescence enables the discrimination of benign from PEV primary liver nodules, suggesting that autofluorescence imaging could be used to optimize US targeted liver biopsies.

Key Points: • 405 nm-induced autofluorescence can distinguish liver tumors from the adjacent liver parenchyma. • The analysis of autofluorescence imaging observed within primary liver tumors can discriminate benign tumors from those requiring follow-up or targeted liver biopsy. • In current practice, autofluorescence imaging could be embedded within biopsy needle, to enable, in addition to ultrasound guidance, optimal targeting of liver nodules which could optimize tissue sampling.
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http://dx.doi.org/10.1007/s00330-021-08307-9DOI Listing
April 2022

Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.

J Hepatol 2022 02 6;76(2):343-352. Epub 2021 Oct 6.

Université de Paris, Paris, France; APHP, Department of Pathology, Hôpital Beaujon, 100 boulevard du Général Leclerc, Clichy, 92110, France; INSERM UMR 1149, Centre de Recherche sur l'Inflammation, 16 rue Henri Huchard, Paris, 75018, France. Electronic address:

Background & Aims: Microvascular invasion (MVI), a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma (HCC), is only detectable by microscopic examination of the surgical specimen. We aimed to define a transcriptomic signature associated with MVI in HCC than can be applied to formalin-fixed paraffin-embedded (FFPE) biopsies for use in clinical practice.

Methods: To identify a gene expression signature related to MVI by using NanoString technology, we selected a set of 200 genes according to the literature and RNA-sequencing data obtained from a cohort of 150 frozen HCC samples previously published. We used 178 FFPE-archived HCC samples, including 109 surgical samples for the training set and 69 paired pre-operative biopsies for the validation set. In 14 cases of the training set, a paired biopsy was available and was also analyzed.

Results: We identified a 6-gene signature (ROS1, UGT2B7, FAS, ANGPTL7, GMNN, MKI67) strongly associated with MVI in the training set of FFPE surgical HCC samples, with 82% accuracy (sensitivity 82%, specificity 81%, AUC 0.82). The NanoString gene expression was highly correlated in 14 paired surgical/biopsy HCC samples (mean R: 0.97). In the validation set of 69 FFPE HCC biopsies, the 6-gene NanoString signature predicted MVI with 74% accuracy (sensitivity 73%, specificity 76%, AUC 0.74). Moreover, on multivariate analysis, the MVI signature was associated with overall survival in both sets (hazard ratio 2.29; 95% CI 1.03-5.07; p = 0.041).

Conclusion: We defined a 6-gene signature that can accurately predict MVI in FFPE HCC biopsy samples, which is also associated with overall survival, although its survival impact must be confirmed by extensive study with further clinical data.

Lay Summary: Microvascular invasion, a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma, is only detectable by microscopic examination of a surgical specimen. In this study, we defined a relevant surrogate signature of microvascular invasion in hepatocellular carcinoma that may be applied in clinical practice with routine tumor biopsy and integrated into the therapeutic strategy.
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http://dx.doi.org/10.1016/j.jhep.2021.09.034DOI Listing
February 2022

Pathologic, Molecular, and Prognostic Radiologic Features of Hepatocellular Carcinoma.

Radiographics 2021 Oct;41(6):1611-1631

From the Departments of Radiology (K.J.F., C.B.S.), Medicine (A.B.), and Pathology (M.H.), University of California San Diego, 200 W Arbor Dr, #8756, San Diego, CA 92103; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (T.J.F.); Department of Radiology, University of Yamanashi, Chuo, Yamanashi, Japan (S.I.); Departments of Radiology (S.K.) and Pathology (N.D.T.), New York University Grossman School of Medicine, New York, NY; Department of Radiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan (A.K.); Department of Radiology, Seoul National University Hospital, Seoul, Korea (J.M.L.); Service d'Anatomie Pathologique, Université de Paris, Hôpital Beaujon APHP, Clichy, France (V.P.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (B.T.); Université de Paris, INSERM U1149 "Centre de Recherche sur l'Inflammation," Paris, France (V.V.); Department of Radiology, AP-HP, Hôpital Beaujon APHP Nord, Clichy, France (V.V.); Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (J.W.); and Department of Radiology, Montefiore Medical Center, Bronx, NY (V.C.).

Hepatocellular carcinoma (HCC) is a malignancy with variable biologic aggressiveness based on the tumor grade, presence or absence of vascular invasion, and pathologic and molecular classification. Knowledge and understanding of the prognostic implications of different pathologic and molecular phenotypes of HCC are emerging, with therapeutics that promise to provide improved outcomes in what otherwise remains a lethal cancer. Imaging has a central role in diagnosis of HCC. However, to date, the imaging algorithms do not incorporate prognostic features or subclassification of HCC according to its biologic aggressiveness. Emerging data suggest that some imaging features and further radiologic, pathologic, or radiologic-molecular phenotypes may allow prediction of the prognosis of patients with HCC. RSNA, 2021.
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http://dx.doi.org/10.1148/rg.2021210009DOI Listing
October 2021

Liver surface nodularity on non-contrast MRI identifies advanced fibrosis in patients with NAFLD.

Eur Radiol 2022 Mar 17;32(3):1781-1791. Epub 2021 Sep 17.

INSERM U1149 "Centre de Recherche Sur L'inflammation", CRI, Université de Paris, 75018, Paris, France.

Objectives: To evaluate the diagnostic performance of liver surface nodularity (LSN) for the assessment of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

Methods: We retrospectively analysed patients with pathologically proven NAFLD who underwent liver MRI. Demographic, clinical, and laboratory data (including FIB-4 scores) were gathered. The SAF score was used to assess NAFLD. MRI-proton density fat fraction (PDFF) and LSN were determined on pre-contrast MR sequences. ROC curve analysis was performed to evaluate the diagnostic performance of MRI-LSN for the diagnosis of advanced (F3-F4) liver fibrosis.

Results: The final population included 142 patients. Sixty-seven (47%) patients had non-alcoholic steatohepatitis (NASH), and 52 (37%) had advanced fibrosis. The median MRI-PDFF increased with the grades of steatosis: 8.1%, 18.1%, and 31% in S1, S2, and S3 patients, respectively (p < 0.001). The area under the ROC curve (AUC) of MRI-LSN ≥ 2.50 was 0.838 (95%CI 0.767-0.894, sensitivity 67.3%, specificity 88.9%, positive and negative predictive values 77.8% and 82.5%, respectively) for the diagnosis of advanced fibrosis. Combining FIB-4 and MRI-LSN correctly classified 103/142 (73%) patients. This was validated in an external cohort of 75 patients.

Conclusions: MRI-LSN has good diagnostic performance in diagnosis of advanced fibrosis in NAFLD patients. A combination of FIB-4 and MRI-LSN derived from pre-contrast MRI could be helpful to detect advanced fibrosis.

Key Points: • MRI-LSN ≥ 2.5 was accurate for the diagnosis of advanced hepatic fibrosis in NAFLD patients. • The combination of FIB-4 and MRI-LSN improved the detection of advanced fibrosis. • MRI-LSN can be easily derived by unenhanced MRI sequences that are routinely acquired.
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http://dx.doi.org/10.1007/s00330-021-08261-6DOI Listing
March 2022

Cholangitis in three critically ill patients after a severe CoVID-19 infection.

IDCases 2021 31;26:e01267. Epub 2021 Aug 31.

Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.

Coronavirus disease 2019 (CoVID-19) is a viral disease. Although the predominant presentation is respiratory disease, other manifestations such as gastrointestinal manifestations are commonly reported. Nevertheless, it has not been associated with chronic cholangitis or hepatic injury. In this study, we report three cases of severe CoVID-19 infection that required ICU admission, intubation, and sedation with ketamine. All three patients had abnormal liver function despite recovery and were diagnosed with cholangitis in the context of CoVID-19.
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http://dx.doi.org/10.1016/j.idcr.2021.e01267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406543PMC
August 2021

Prospective external validation of a new non-invasive test for the diagnosis of non-alcoholic steatohepatitis in patients with type 2 diabetes.

Aliment Pharmacol Ther 2021 10 16;54(7):952-966. Epub 2021 Aug 16.

Paris, France.

Background: One of the unmet needs in patients with type 2 diabetes mellitus (T2DM) is the prediction of non-alcoholic liver disease by non-invasive blood tests, for each of the three main histological features, fibrosis, non-alcoholic steatohepatitis (NASH) and steatosis.

Aims: To validate externally the performances of a recent panel, Nash-FibroTest, for the assessment of the severity of fibrosis stages, NASH grades and steatosis grades.

Methods: We prospectively analysed 272 patients with T2DM. Standard definitions of stages and grades were used, and analyses were centralised and blinded. The performances of the FibroTest, NashTest-2 and SteatoTest-2 were assessed using the Obuchowski measure (OM), the main outcome recommended as a summary measure of accuracy includeing all pairwise stages and grades comparisons, which is not provided par the extensively used binary area under the ROC curve.

Results: The diagnostic performance of each component of the panel was significant. OM (SE; significance) of the FibroTest, the NashTest-2 and the SteatoTest-2 was 0.862 (0.012; P < 0.001), 0.827 (0.015; P < 0.001) and 0.794 (0.020; P < 0.01), respectively. For ballooning and lobular inflammation, OM was 0.794 (0.021; P < 0.001) and 0.821 (0.017; P < 0.001), respectively. In a post hoc analysis the FibroTest outperformed VCTE by 4.1% (2.5-6.5; P < 0.001) for reliability, with a non-significant difference for OM for fibrosis staging, 0.859 (0.012) for FibroTest vs 0.870 (0.009) for VCTE.

Conclusions: From a single blood sample, the panel provides non-invasive diagnosis of the stages of fibrosis, and the grades of NASH and steatosis in patients with T2DM.

Trial Registration Number: NCT03634098.
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http://dx.doi.org/10.1111/apt.16543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518776PMC
October 2021

Long-term outcomes following resection of hepatocellular adenomas with small foci of malignant transformation or malignant adenomas.

JHEP Rep 2021 Aug 29;3(4):100326. Epub 2021 Jun 29.

Department of HPB and Liver Transplantation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France.

Background & Aims: Malignant transformation of hepatocellular adenoma (MT-HCA) may occur in up to 5% of tumours. However, the prognostic value of this event remains poorly described. In this study, we aimed to analyse the long-term outcomes of patients undergoing liver resection (LR) for MT-HCA compared to those of patients resected for hepatocellular carcinoma (HCC) occurring on normal liver parenchyma (NP-HCC).

Methods: This single-centre retrospective study included all patients who underwent LR for MT-HCA at Beaujon Hospital between 2001 and 2019. MT-HCAs were classified as small foci of malignant transformation HCA (SF-HCA) and as malignant HCA (M-HCA) in cases of predominant HCC foci. Recurrence-free survival (RFS) of MT-HCA was compared with that of NP-HCC after propensity score matching.

Results: Forty patients (24 men, 16 women) underwent LR for MT-HCA, including 23 with SF-HCA and 17 with M-HCA. Of these cases, 16/40 (40%) had β-catenin mutations, 19/40 (47.5%) were inflammatory, 1 was HNF1α-mutated HCA and 4 (10%) were unclassified HCA. Microvascular invasion (12% 0%, 0.091) and satellite nodules (25% 4%, 0.028) were more frequently observed in M-HCA than in SF-HCA. After a median follow-up of 67 months, 10 (25%) patients with MT-HCA had tumour recurrence, including 9 with M-HCA and 1 with SF-HCA ( 0.007). M-HCA was linked to significantly poorer 1-, 3-, 5- and 10-year RFS rates than SF-HCA (76%, 63%, 39%, 37% 100%, 100%, 100%, 91%, 0.003). Multivariate analysis showed that SF-HCA was independently associated with improved RFS (hazard ratio 0.064; 95% CI 0.008-0.519; 0.01). After propensity score matching, NP-HCC was associated with significantly poorer 1-, 3-, 5- and 10-year RFS rates than MT-HCA ( 0.01).

Conclusions: HCA with malignant transformation yields a better long-term prognosis than NP-HCC. Among MT-HCA, SF-HCA is associated with a better prognosis than M-HCA.

Lay Summary: The prognostic relevance of malignant transformation of hepatocellular adenoma (HCA) remains unknown. Thus, the aim of our study was to compare the outcomes of patients undergoing liver resection for malignant transformation to those of patients undergoing liver resection for hepatocellular carcinoma (HCC). The main long-term risk after resection for carcinoma is recurrence. In this study, 10/40 patients with malignant transformation of HCA relapsed after resection and we identified age >55 years, presence of satellite nodes, and microvascular invasion as risk factors for long-term recurrence. Compared to patients with HCC, patients who underwent liver resection for HCA with malignant transformation had better long-term survival.
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http://dx.doi.org/10.1016/j.jhepr.2021.100326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326806PMC
August 2021
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