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2. Use of statins after liver transplantation is associated with improved survival: results of a nationwide study

Author

Chiara, Becchetti, Melisa, Dirchwolf, Jonas, Schropp, Giulia, Magini, Beat, Müllhaupt, Franz, Immer, Jean-François, Dufour, Vanessa, Banz, Annalisa, Berzigotti, Jaume, Bosch, Patrick, Yerly, University of Zurich, and Bosch, Jaume

Subjects
Adult, Male, 610 Medicine & health, 360 Social problems & social services, Risk Factors, Humans, 2736 Pharmacology (medical), 2715 Gastroenterology, Pharmacology (medical), Aged, Retrospective Studies, Hepatology, Graft Survival, 360 Soziale Probleme, Sozialdienste, Gastroenterology, Middle Aged, Liver Transplantation, Treatment Outcome, 10219 Clinic for Gastroenterology and Hepatology, 10036 Medical Clinic, 10032 Clinic for Oncology and Hematology, 10209 Clinic for Cardiology, 2721 Hepatology, Hydroxymethylglutaryl-CoA Reductase Inhibitors, 10178 Clinic for Pneumology, 610 Medizin und Gesundheit
Abstract

BACKGROUND There is limited information on the effects of statins on the outcomes of liver transplantation (LT), regarding either their use by LT recipients or donors. AIM To analyse the association between statin exposure and recipient and graft survival. METHODS We included adult LT recipients with deceased donors in a nationwide prospective database study. Using a multistate modelling approach, we examined the effect of statins on the transition hazard between LT, biliary and vascular complications and death, allowing for recurring events. The observation time was 3 years. RESULTS We included 998 (696 male, 70%, mean age 54.46 ± 11.14 years) LT recipients. 14% of donors and 19% of recipients were exposed to statins during the study period. During follow-up, 141 patients died; there were 40 re-LT and 363 complications, with 66 patients having two or more complications. Treatment with statins in the recipient was modelled as a concurrent covariate and associated with lower mortality after LT (HR = 0.35; 95% CI 0.12-0.98; p = 0.047), as well as a significant reduction of re-LT (p = 0.004). However, it was not associated with lower incidence of complications (HR = 1.25; 95% CI = 0.85-1.83; p = 0.266). Moreover, in patients developing complications, statin use was significantly associated with decreased mortality (HR = 0.10; 95% CI = 0.01-0.81; p = 0.030), and reduced recurrence of complications (HR = 0.43; 95% CI = 0.20-0.93; p = 0.032). CONCLUSIONS Statin use by LT recipients may confer a survival advantage. Statin administration should be encouraged in LT recipients when clinically indicated.

Published
2022

6. Supplementary Figure Legends from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Author

Jean-François Dufour, Valentin Djonov, Luigi Terracciano, Maresa Afthinos, Vesna Radojevic, Paul M.J. McSheehy, Marie V. St-Pierre, Ruslan Hlushchuk, Bettina Saar, and Anne-Christine Piguet

Abstract

Supplementary Figure Legends from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Published
2023

7. Data from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Author

Jean-François Dufour, Valentin Djonov, Luigi Terracciano, Maresa Afthinos, Vesna Radojevic, Paul M.J. McSheehy, Marie V. St-Pierre, Ruslan Hlushchuk, Bettina Saar, and Anne-Christine Piguet

Abstract

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib. Mol Cancer Ther; 10(6); 1007–17. ©2011 AACR.

Published
2023

10. Validation of the Blood Test MACK-3 for the Noninvasive Diagnosis of Fibrotic Nonalcoholic Steatohepatitis: An International Study With 1924 Patients

Author

Clémence M. Canivet, Ming-Hua Zheng, Sami Qadri, Luisa Vonghia, Kee-Huat Chuah, Charlotte Costentin, Jacob George, Angelo Armandi, Leon A. Adams, Naomi F. Lange, Odile Blanchet, Valérie Moal, Ramy Younes, Marine Roux, Wah-Kheong Chan, Nathalie Sturm, Mohammed Eslam, Elisabetta Bugianesi, Zhengyi Wang, Jean-François Dufour, Sven Francque, Hannele Yki-Järvinen, Kenneth I. Zheng, and Jérôme Boursier

Subjects
Hepatology, Gastroenterology
Published
2023

11. Review article: vascular effects of <scp>PPARs</scp> in the context of <scp>NASH</scp>

Author

Sergi Guixé‐Muntet, Louise Biquard, Gyongyi Szabo, Jean‐François Dufour, Frank Tacke, Sven Francque, Pierre‐Emmanuel Rautou, and Jordi Gracia‐Sancho

Subjects
Hepatology, Pharmacology. Therapy, Peroxisome Proliferator-Activated Receptors, Gastroenterology, nutritional and metabolic diseases, digestive system, digestive system diseases, Diabetes Mellitus, Type 2, Liver, Cardiovascular Diseases, Non-alcoholic Fatty Liver Disease, Humans, Pharmacology (medical), Human medicine
Abstract

Background Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors known to regulate glucose and fatty acid metabolism, inflammation, endothelial function and fibrosis. PPAR isoforms have been extensively studied in metabolic diseases, including type 2 diabetes and cardiovascular diseases. Recent data extend the key role of PPARs to liver diseases coursing with vascular dysfunction, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Aim This review summarises and discusses the pathobiological role of PPARs in cardiovascular diseases with a special focus on their impact and therapeutic potential in NAFLD and NASH. Results and Conclusions PPARs may be attractive for the treatment of NASH due to their liver-specific effects but also because of their efficacy in improving cardiovascular outcomes, which may later impact liver disease. Assessment of cardiovascular disease in the context of NASH trials is, therefore, of the utmost importance, both from a safety and efficacy perspective.

Published
2022

12. Data from Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Plasma Metabolomics and Lipid Profiling

Author

Jeffrey R. Idle, Jean-François Dufour, Frank J. Gonzalez, Thomas Pabst, Kristopher W. Krausz, Christian Lanz, Diren Beyoğlu, Olivier Maurhofer, and Andrew D. Patterson

Abstract

There has been limited analysis of the effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating endogenous metabolites. Here, we report the findings of a plasma metabolomic investigation of HCC patients by ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), random forests machine learning algorithm, and multivariate data analysis. Control subjects included healthy individuals as well as patients with liver cirrhosis or acute myeloid leukemia. We found that HCC was associated with increased plasma levels of glycodeoxycholate, deoxycholate 3-sulfate, and bilirubin. Accurate mass measurement also indicated upregulation of biliverdin and the fetal bile acids 7α-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochol-4,6-dien-24-oic acid in HCC patients. A quantitative lipid profiling of patient plasma was also conducted by ultraperformance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UPLC-ESI-TQMS). By this method, we found that HCC was also associated with reduced levels of lysophosphocholines and in 4 of 20 patients with increased levels of lysophosphatidic acid [LPA(16:0)], where it correlated with plasma α-fetoprotein levels. Interestingly, when fatty acids were quantitatively profiled by gas chromatography-mass spectrometry (GC-MS), we found that lignoceric acid (24:0) and nervonic acid (24:1) were virtually absent from HCC plasma. Overall, this investigation illustrates the power of the new discovery technologies represented in the UPLC-ESI-QTOFMS platform combined with the targeted, quantitative platforms of UPLC-ESI-TQMS and GC-MS for conducting metabolomic investigations that can engender new insights into cancer pathobiology. Cancer Res; 71(21); 6590–600. ©2011 AACR.

Published
2023

15. 2D shear wave elastography of the rectus femoris muscle in patients with cirrhosis: feasibility and clinical findings. A pilot study

Author

Chiara Becchetti, Naomi F. Lange, Maria Gabriela Delgado, Michael P. Brönnimann, Martin H. Maurer, Jean-François Dufour, and Annalisa Berzigotti

Subjects
Hepatology, Gastroenterology, 610 Medicine & health
Abstract

BACKGROUND AND AIMS Frailty is frequent in cirrhosis and associated with skeletal muscle abnormalities and worse prognosis. 2D shear-wave elastography (2D-SWE) could mirror biomechanical properties of skeletal muscle reflecting muscle quality. However, there is no data on 2D-SWE on skeletal muscle stiffness assessment in cirrhosis and on frailty. METHODS Outpatients with cirrhosis were prospectively included in a single center. Skeletal muscle stiffness was studied at the rectus femoris by 2D-SWE. Ileo-psoas area and index (area/height2), and antero-posterior diameter of rectus femoris (RF) was measured on ultrasound. RESULTS We included 44 patients (24 male, age 59 [IQR 49-66]) with a median liver frailty index (LFI) of 3.7 (IQR 3.2-4.0). Measurement of RF muscle stiffness (RFMS) was feasible in all with high inter-measurement reproducibility. RFMS did not correlate with LFI, liver function and skeletal muscle diameters. Ileo-psoas index was lower in frail patients (1.7 vs 1.0 cm2/m2, p=0.024). RF antero-posterior diameter inversely correlated with LFI (r -0.578: p

Published
2023
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16. Prevention of NAFLD-associated HCC: Role of lifestyle and chemoprevention

Author

Pompilia Radu, Naomi Lange, and Jean-François Dufour

Subjects
Oncology, medicine.medical_specialty, Carcinoma, Hepatocellular, 610 Medicine & health, Disease, Chemoprevention, digestive system, Diabetes Complications, Non-alcoholic Fatty Liver Disease, Risk Factors, Weight loss, Internal medicine, Diabetes Mellitus, medicine, Humans, Obesity, Life Style, Aspirin, Hepatology, business.industry, Liver Neoplasms, Fatty liver, nutritional and metabolic diseases, medicine.disease, digestive system diseases, Metformin, Hepatocellular carcinoma, medicine.symptom, Steatohepatitis, 610 Medizin und Gesundheit, business, Tertiary Prevention, medicine.drug
Abstract

In many countries worldwide, the burden of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. Preventive strategies are needed to counteract this trend. In this review, we provide an overview of the evidence on preventive strategies in NAFLD-associated HCC. We consider the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, antidiabetic treatments and statins is summarised. The role of adjuvant therapies for tertiary prevention of HCC is briefly reviewed.

Published
2021

17. Vasculitis and familial Mediterranean fever: Description of 22 French adults from the juvenile inflammatory rheumatism cohort

Author

Salam Abbara, Jean-Benoit Monfort, Léa Savey, Philippe Moguelet, David Saadoun, Claude Bachmeyer, Olivier Fain, Benjamin Terrier, Zahir Amoura, Alexis Mathian, Laurent Gilardin, David Buob, Chantal Job-Deslandre, Jean-François Dufour, Rebecca Sberro-Soussan, Gilles Grateau, and Sophie Georgin-Lavialle

Subjects
General Medicine
Abstract

ObjectiveThe frequency of vasculitis may be increased in patients with Familial Mediterranean Fever (FMF), according to several studies. Our aim was to assess the characteristics of French adult patients with both diseases.MethodsPatients with vasculitis were selected from patients followed for FMF in the French JIR-cohort.ResultsTwenty-two patients were included [polyarteritis nodosa (PAN) n = 10, IgA vasculitis n = 8, unclassified vasculitis n = 2, granulomatosis with polyangiitis n = 1, and microscopic polyangiitis n = 1]. Pathogenic mutations in exon 10 were found in all 21 patients (96%) for which MEFV testing results were available, and 18 (82%) had two pathogenic mutations. Histology showed vasculitis in 59% of patients. Most patients with FMF-associated PAN were HBV-negative and had an inactive FMF before PAN onset, and 40% had a peri-renal or central nervous system bleeding. Most patients with FMF-associated IgA vasculitis had an active FMF before vasculitis onset, and 25% had digestive bleeding. Both patients with unclassified vasculitis had ischemic and/or hemorrhagic complications.ConclusionThis study confirms the predominance of PAN and IgA vasculitis in patients with FMF and the high frequency of bleeding in FMF-associated PAN. FMF should be considered in case of persistent symptoms and/or inflammatory syndrome despite vasculitis treatment in Mediterranean patients.

Published
2022

18. Effects of Home Care on patients with hepatocellular carcinoma treated with sorafenib

Author

Iuliana-Pompilia Radu, Jean-François Dufour, and Monika Moser

Subjects
Sorafenib, medicine.medical_specialty, Psychological intervention, 610 Medicine & health, RC799-869, liver cancer, Quality of life, Internal medicine, medicine, treatment, Hepatology, business.industry, Gastroenterology, Original Articles, Diseases of the digestive system. Gastroenterology, medicine.disease, quality of life, Hepatocellular carcinoma, oncology, Cohort, Original Article, sorafenib, business, Liver cancer, Psychosocial, Cohort study, medicine.drug
Abstract

Background and Aim Treatment with sorafenib causes diverse side effects, which limits adherence. This work assesses whether Home Care, a psychosocial nursing intervention, prolongs the duration of treatment in patients with advanced hepatocellular carcinoma (HCC) and if it influences health‐related quality of life (HRQL). Methods and Results This is a cohort study using data from patients receiving sorafenib in the prospective Bern HCC Cohort at the University Hospital. Duration of treatment, overall survival, and HRQL using the Functional Assessment of Cancer Therapy‐Hepatobiliary questionnaire were compared in the two groups. A total of 173 patients were eligible for the analysis. Among them, 141 were in the Home Care program, and 32 were not. Patients with Home Care had a significantly longer duration of treatment (265 days vs 152 days, P = 0.003) and a better functional well‐being (17.7 vs 12.5, P = 0.015). Conclusion Psychosocial interventions such as Home Care are a valid method in improving adherence to sorafenib and can therefore be recommended., Home Care is a psychosocial intervention in patients with hepatocellular carcinoma treated with sorafenib. This article shows the effectiveness of prolonging treatment duration and enhancing functional wellbeing.

Published
2021

19. IDDF2022-ABS-0120 Hepatocyte apoptosis fragment product cytokeratin-18 M30 and non-alcoholic steatohepatitis risk prediction: an international registry study

Author

Huai Zhang, Rafael S Rios, Jerome Boursier, Rodolphe Anty, Wah-Kheong Chan, Jacob George, Yusuf Yilmaz, Vincent Wai-Sun Wong, Silvia Sookoian, Jian-Gao Fan, Jean-François Dufour, George Papatheodoridis, Li Chen, Jörn M Schattenberg, Jun-Ping Shi, Liang Xu, Grace Lai-Hung Wong, Carlos J Pirola, Naomi F Lange, Margarita Papatheodoridi, Yu-Qiang Mi, Yu-Jie Zhou, Christopher D Byrne, Giovanni Targher, Gong Feng, and Ming-Hua Zheng

Published
2022

20. Endoplasmic Reticulum and Mitochondria Contacts Correlate with the Presence and Severity of NASH in Humans

Author

Chaonan, Jin, Eric, Felli, Naomi Franziska, Lange, Annalisa, Berzigotti, Jordi, Gracia-Sancho, and Jean-François, Dufour

Subjects
Metabolic Syndrome, Diabetes Mellitus, Type 2, Liver, Non-alcoholic Fatty Liver Disease, Liver Neoplasms, Humans, Endoplasmic Reticulum, Mitochondria
Abstract

The interaction between the mitochondria and the endoplasmic reticulum (ER) is essential for hepatocyte function. An increase in ER-mitochondria contacts (ERMCs) is associated with various metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and its progressive form non-alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. However, the role of ERMCs in the progression of NAFL to NASH is still unclear. We assessed whether ERMCs could correlate with NAFLD severity. We used a proximity ligation assay to measure the abundance of ERMCs in liver biopsies from patients with biopsy-proven NAFLD (

Published
2022

21. Dietary Interventions in Liver Diseases: Focus on MAFLD and Cirrhosis

Author

Naomi Lange, Carlotta Riebensahm, Jean-François Dufour, Élise Vuille-Lessard, and Annalisa Berzigotti

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, Mediterranean diet, business.industry, Fatty liver, 610 Medicine & health, Overweight, medicine.disease, Chronic liver disease, 03 medical and health sciences, Liver disease, Malnutrition, 0302 clinical medicine, Virology, Internal medicine, medicine, Red meat, 030211 gastroenterology & hepatology, 030212 general & internal medicine, medicine.symptom, business
Abstract

Purpose of Review Dietary interventions (DI) aimed at improving overweight and metabolic abnormalities in metabolic dysfunction-associated fatty liver disease (MAFLD) and at reducing malnutrition and sarcopenia in cirrhosis should become part of routine care in hepatology. This review focuses on recent advances in this field. Recent Findings In patients with MAFLD, a gradual reduction, respectively, of 7–10% of body weight if overweight or of 3–5% if lean, obtained by moderately reducing caloric intake, is effective to improve liver disease. Intermittent energy restriction might be an alternative to continuous energy restriction with higher adherence. Qualitative dietary adjustments should include increased intake of unprocessed foods including fruits and vegetables, whole grains, fiber, and unsaturated fatty acids (FAs), for example, through a Mediterranean diet. Refined carbohydrates (CHOs), saturated FA (SFAs), red meat, and processed meat should be limited. DI studies in HIV-infected subjects with MAFLD are very limited, and this is a field for future research. In patients with cirrhosis, DI should aim at correcting malnutrition and improving skeletal muscle mass. Daily diet contents should aim at achieving 30–35 kcal/kg of body weight, including 1.2–1.5 g/kg proteins, and oral or enteral supplementation might be used in patients unable to achieve these targets. In some studies, branched-chain amino acids (BCAAs) proved to be effective in improving muscle mass and were associated with a lower risk of hepatic encephalopathy. Obesity requires adjustment of the above-mentioned targets, and its management is challenging. Studies looking at the efficacy of DI recommended by the existing guidelines on clinical endpoints are a field for future research. Summary Dietary interventions are able to improve MAFLD and show potential to reduce complications in liver disease. Despite its key importance, there are many barriers limiting the implementation of DI in patients with chronic liver disease. Patients’ empowerment is crucial and should be the focus of specific educational programs. In addition, liver clinics would benefit from multidisciplinary teams involving experts in nutrition, physical exercise, primary care physicians, and psychologists when needed.

Published
2021

22. Hepatic manifestations of drug reaction with eosinophilia and systemic symptoms syndrome

Author

Matteo Montani, Felix Brunner, Annalisa Berzigotti, Stefania Casu, Jean-François Dufour, Nasser Semmo, and Maria Gabriela Delgado

Subjects
medicine.medical_specialty, treatment, business.industry, diagnosis, liver manifestations, 610 Medicine & health, medicine.disease, Gastroenterology, Drug reaction with eosinophilia and systemic symptoms, 030207 dermatology & venereal diseases, 03 medical and health sciences, Other systems of medicine, 0302 clinical medicine, 030228 respiratory system, 360 Social problems & social services, Internal medicine, medicine, drug reaction with eosinophilia and systemic symptoms, 570 Life sciences, biology, business, RZ201-999
Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening drug reaction, which can affect multiple organs. Patients with DRESS syndrome and hepatic manifestations may present alterations ranging from mild hepatitis to acute liver failure. The diagnosis might be difficult, and the management of these patients is challenging. This report analyzes a series of five cases reporting the clinical presentation, which ranged from acute hepatitis to liver failure, and discussed their treatment.

Published
2021

23. Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns

Author

Sheida Moghadamrad, Mohsin Hassan, Cornelius Engelmann, Irene Keller, Frank Tacke, Oriol Juanola, Jean-François Dufour, Bahtiyar Yilmaz, Andrea De Gottardi, Cedric Simillion, and Pavitra Kumar

Subjects
0301 basic medicine, Male, Intestinal microbiota, Gene Expression, RC799-869, Gut flora, Pathogenesis, chemistry.chemical_compound, Liver disease, Mice, 0302 clinical medicine, Gene expression, 610 Medicine & health, Liver injury, Cholestasis, biology, Gastroenterology, Diseases of the digestive system. Gastroenterology, 3. Good health, Infectious Diseases, Liver, 030211 gastroenterology & hepatology, medicine.symptom, Research Article, Research Paper, Microbiology (medical), medicine.medical_specialty, Inflammation, Microbiology, digestive system, Bile Acids and Salts, 03 medical and health sciences, germ-free mice, Internal medicine, medicine, Animals, Germ-Free Life, Ligation, bile acids, Fatty acid metabolism, Host Microbial Interactions, medicine.disease, biology.organism_classification, acute cholestasis, Lipid Metabolism, Gastrointestinal Microbiome, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Bile Ducts, metabolism
Abstract

Intestinal microbiota regulates multiple host metabolic and immunological processes. Consequently, any difference in its qualitative and quantitative composition is susceptible to exert significant effects, in particular along the gut-liver axis. Indeed, recent findings suggest that such changes modulate the severity and the evolution of a wide spectrum of hepatobiliary disorders. However, the mechanisms linking intestinal microbiota and the pathogenesis of liver disease remain largely unknown. In this work, we investigated how a distinct composition of the intestinal microbiota, in comparison with germ-free conditions, may lead to different outcomes in an experimental model of acute cholestasis. Acute cholestasis was induced in germ-free (GF) and altered Schaedler’s flora (ASF) colonized mice by common bile duct ligation (BDL). Studies were performed 5 days after BDL and hepatic histology, gene expression, inflammation, lipids metabolism, and mitochondrial functioning were evaluated in normal and cholestatic mice. Differences in plasma concentration of bile acids (BA) were evaluated by UHPLC-HRMS. The absence of intestinal microbiota was associated with significant aggravation of hepatic bile infarcts after BDL. At baseline, we found the absence of gut microbiota induced altered expression of genes involved in the metabolism of fatty and amino acids. In contrast, acute cholestasis induced altered expression of genes associated with extracellular matrix, cell cycle, autophagy, activation of MAPK, inflammation, metabolism of lipids, and mitochondrial functioning pathways. Ductular reactions, cell proliferation, deposition of collagen 1 and autophagy were increased in the presence of microbiota after BDL whereas GF mice were more susceptible to hepatic inflammation as evidenced by increased gene expression levels of osteopontin, interleukin (IL)-1β and activation of the ERK/MAPK pathway as compared to ASF colonized mice. Additonally, we found that the presence of microbiota provided partial protection to the mitochondrial functioning and impairment in the fatty acid metabolism after BDL. The concentration of the majority of BA markedly increased after BDL in both groups without remarkable differences according to the hygiene status of the mice. In conclusion, acute cholestasis induced more severe liver injury in GF mice compared to mice with limited intestinal bacterial colonization. This protective effect was associated with different hepatic gene expression profiles mostly related to tissue repair, metabolic and immune functions. Our findings suggest that microbial-induced differences may impact the course of cholestasis and modulate liver injury, offering a background for novel therapies based on the modulation of the intestinal microbiota.

Published
2021

24. The NAFLD-MAFLD debate:Is there a Consensus-on-Consensus methodology?

Author

Yasser Fouad, Jean‐François Dufour, Ming‐Hua Zheng, Steven Bollipo, Hailemichael Desalegn, Henning Grønbaek, and Robert G. Gish

Subjects
Consensus, Hepatology, Non-alcoholic Fatty Liver Disease, Gastroenterology, Humans, consensus, Delphi, MAFLD
Abstract

Polarizing opinions have recently arisen in hepatology on the name and redefinition of fatty liver disease associated with metabolic dysfunction. In spite of growing and robust evidence of the superior utility of the term metabolic (dysfunction) associated fatty liver disease (MAFLD) definition for clinical and academic practice, controversy abounds. It should therefore come, as no surprise that the most common arguments used in contrarian op-eds is that there are no consensus on any name change. In this context, we suggest that discourse on an accurate understanding of what scientific consensus means, the various methods of achieving consensus, as well as other alternative models for reaching agreement is pivotal for the field. In this opinion piece, we provide an overview of these aspects as it applies to the case of fatty liver disease. We provide evidence that consensus on a change from non-alcoholic fatty liver disease (NAFLD) to MAFLD has already been achieved. We believe that the time has come for redirecting stakeholder focus and energy on capitalizing on the momentum generated by the debate to improve the lives of people at its centre, our patients.

Published
2022

25. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Author

Pamela Filpe, Melanie Laschinger, Cristina García-Cáceres, Silke Hegenbarth, Dominik Pfister, Adrien Guillot, Valentina Leone, Simon Reider, Dietmar Zehn, Pierluigi Ramadori, Robert Thimme, Roland Rad, Gabriel Seifert, Mathias Heikenwalder, Martina Anton, Danijela Heide, Marcial Sebode, Tim Gruber, Daniel Hartmann, Jennifer Wigger, Susanne Roth, Rafael Käser, Donato Inverso, Friedrich Koch-Nolte, Michael Dudek, Jan P. Böttcher, Annika Schneider, Philippa Meiser, Sainitin Donakonda, Frank Tacke, Dirk Haller, Adrian T. Billeter, Jean-François Dufour, Edward J. Pearce, Felix Bayerl, Ron M. A. Heeren, Beat P. Müller-Stich, Florian Müller, Maria Effenberger, Peter J. Murray, Andrew P. Bowman, Agnieszka M. Kabat, Jan-Philipp Mallm, Herbert Tilg, Rupert Öllinger, Norbert Hüser, Percy A. Knolle, Tobias Boettler, Imaging Mass Spectrometry (IMS), and RS: M4I - Imaging Mass Spectrometry (IMS)

Subjects
0301 basic medicine, Mouse, MODELS, BIOLOGY, EFFECTOR FUNCTION, FOXO1, Inflammation, METABOLISM, digestive system, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Immune system, Downregulation and upregulation, medicine, Cytotoxic T cell, 610 Medicine & health, RELEASE, Il-15, Multidisciplinary, biology, NONALCOHOLIC STEATOHEPATITIS, Purinergic receptor, nutritional and metabolic diseases, medicine.disease, digestive system diseases, TRANSCRIPTION FACTORS, 030104 developmental biology, Granzyme, 030220 oncology & carcinogenesis, Cancer research, biology.protein, medicine.symptom
Abstract

Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps . Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer(1,2). The accumulation of metabolites leads to cell stress and inflammation in the liver(3), but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6(+) CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6(+) CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6(+) CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Published
2021

26. Should we undertake surveillance for HCC in patients with MAFLD?

Author

Blanca Norero and Jean-François Dufour

Subjects
Endocrinology, Diabetes and Metabolism
Abstract

Over the last decade, metabolic-associated fatty liver disease (MAFLD) has become an important public health issue worldwide. In many countries, MAFLD has become the most common cause of chronic liver disease. On the contrary, hepatocellular carcinoma (HCC) mortality is rising. Liver tumors have become the third cause of cancer mortality worldwide. HCC is the most frequent liver tumor. While the burden of HCC related to viral hepatitis is declining, the prevalence of MAFLD-related HCC is rising rapidly. Classical screening criteria for HCC consider cirrhotic, advanced fibrosis, and viral hepatitis patients. Metabolic syndrome with liver involvement or MAFLD is associated with a higher risk of HCC development, even in the absence of cirrhosis. The question about the cost effectiveness of surveillance for HCC in MAFLD is yet not fully answered. There are no guidelines that address the question of when to start or how to define the population who can benefit of surveillance for HCC in MAFLD patients. This review aims to revise the evidence of HCC development in MAFLD. It hopes to be a step closer to defining screening criteria for HCC in MAFLD.

Published
2023

28. Elective percutaneous liver biopsy and use of aspirin

Author

Maxence Emmanuel Reynard and Jean‐François Dufour

Subjects
Oncology, Aspirin, Liver, Biopsy, Gastroenterology, Humans, Hemorrhage, Platelet Aggregation Inhibitors
Abstract

OBJECTIVES Percutaneous liver biopsy is an essential diagnostic investigation in hepatology. Among complications, which are rare, bleeding is the most feared. Many patients scheduled for a liver biopsy are taking aspirin. Surprisingly no information is available in the literature on this frequent clinical situation. The American Association for the Study of Liver Diseases (AASLD) position paper on percutaneous liver biopsy does not specifically recommend stopping low dose aspirin prior to an elective percutaneous liver biopsy. The European Association for the Study of the Liver also remains unspecific without giving clear recommendation on stopping or not low dose aspirin before the procedure. The aim of this study is to document current practice concerning the management of patients scheduled for an elective percutaneous biopsy and taking low dose aspirin. DESIGN An online questionnaire was designed to gather data on current practice on the perioperative management of percutaneous liver biopsy and use of aspirin. SETTINGS The questionnaire was emailed to AASLD members in September 2018. PARTICIPANTS Four hundred sixty six responses were collected. RESULTS Seventy eight percent postpone elective percutaneous liver biopsy if International Normalised Ratio is ≥1.5 or Quick ≤50%. Ninety five percent postpone biopsy if platelet count is ≤50,000 × 106 /L. Seventy five percent stop low dose aspirin, on average, 6 days prior to the percutaneous liver biopsy. This choice of management does not seem to be related to previous complications since 86% report not having experienced any bleeding in patients taking low dose aspirin. Nevertheless, this practice has logistic consequences since 61% of the respondents postponed a liver biopsy due to intake of low dose aspirin. CONCLUSIONS Despite the lack of clear statement in guidelines and evidence supporting this practice, three quarters of physicians practicing in hepatology stop low dose aspirin before elective percutaneous liver biopsy.

Published
2022

29. Genetic variation in

Author

Stephan, Buch, Hamish, Innes, Philipp Ludwig, Lutz, Hans Dieter, Nischalke, Jens U, Marquardt, Janett, Fischer, Karl Heinz, Weiss, Jonas, Rosendahl, Astrid, Marot, Marcin, Krawczyk, Markus, Casper, Frank, Lammert, Florian, Eyer, Arndt, Vogel, Silke, Marhenke, Johann, von Felden, Rohini, Sharma, Stephen Rahul, Atkinson, Andrew, McQuillin, Jacob, Nattermann, Clemens, Schafmayer, Andre, Franke, Christian, Strassburg, Marcella, Rietschel, Heidi, Altmann, Stefan, Sulk, Veera Raghavan, Thangapandi, Mario, Brosch, Carolin, Lackner, Rudolf E, Stauber, Ali, Canbay, Alexander, Link, Thomas, Reiberger, Mattias, Mandorfer, Georg, Semmler, Bernhard, Scheiner, Christian, Datz, Stefano, Romeo, Stefano, Ginanni Corradini, William Lucien, Irving, Joanne R, Morling, Indra Neil, Guha, Eleanor, Barnes, M Azim, Ansari, Jocelyn, Quistrebert, Luca, Valenti, Sascha A, Müller, Marsha Yvonne, Morgan, Jean-François, Dufour, Jonel, Trebicka, Thomas, Berg, Pierre, Deltenre, Sebastian, Mueller, Jochen, Hampe, and Felix, Stickel

Abstract

Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis.Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina).Associations with variants rs738409 inThis study identifies rs2242652 in

Published
2022

30. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Raluca Pais, Rachel Ostroff, Stephen Harrison, Lars Friis Mikkelsen, Elisabeth Erhardtsen, Sudha Shankar, Kimmo Porthan, Jérôme Boursier, Antonia Sinisi, Michael Kalutkiewicz, Sven Francque, Miljen Martic, Vanessa Pellegrinelli, Phil N. Newsome, Guido Hanauer, Hannele Yki-Järvinen, Rebecca Darlay, Joel Myers, Carla Yunis, Salvatore Petta, Mette Skalshøi Kjær, Pablo Ortiz, Ann K. Daly, James H. Clark, Dina Tiniakos, Yasaman Vali, Hadi Zafarmand, Matej Orešič, Maurizio Parola, Estelle Sandt, Lori L. Jennings, Matt Kelly, Tuulia Hyötyläinen, Detlef Schuppan, Céline Fournier, Chiara Rosso, Diane E. Shevell, Maria Manuela Tonini, Paul Hockings, Aidan McGlinchey, Salma Akhtar, Mette Juul Fisker, Morten A. Karsdal, Diane Whalley, Melissa R. Miller, Aldo Trylesinski, Mattias Ekstedt, Stefan Neubauer, Jeremy M. Palmer, Partho Sen, Michael Pavlides, Per Qvist, Isabel Fernández, Luca Miele, Fabio Marra, Stergios Kechagias, Richard Torstenson, Katherine Johnson, Jean-François Dufour, Elisabetta Bugianesi, M. Julia Brosnan, George V. Papatheodoridis, Kay M. Pepin, Daniel Guldager Kring Rasmussen, Henrik Landgren, Rachel Queen, Simon Cockell, Michael Allison, Patrick M.M. Bossuyt, Rocío Gallego-Durán, Christian Rosenquist, Leigh Alexander, Elizabeth Shumbayawonda, Michele Vacca, Antonio Vidal-Puig, David Wenn, Rémy Hanf, Oscar Millet, Michalina Zatorska, R. Myers, José M. Mato, Jenny Lee, Theresa Tuthill, James Twiss, Ramy Younes, Peter Leary, Lynda Doward, Kristy Wonders, Guruprasad P. Aithal, Sarah Charlton, Vlad Ratziu, Cecília M. P. Rodrigues, Christian Trautwein, Helena Cortez-Pinto, Gideon Ho, Matt J. Barter, Judith Ertle, Jörn M. Schattenberg, Maria-Magdalena Balp, Yang-Lin Liu, Clifford A. Brass, Olivier Govaere, Amalia Gastaldelli, Sergio Rodriguez Cuenca, Pierre Chaumat, Fiona Oakley, Luca Valenti, Simon J. Cockell, Saskia W.C. van Mil, Ferenc E. Mózes, Andreas Geier, Timothy Hardy, Pierre Bedossa, Andrea Dennis, Richard L. Ehman, Charlotte Erpicum, Karine Clément, Jeremy F. L. Cobbold, Christopher P. Day, Rajarshi Banerjee, Manuel Romero-Gómez, Quentin M. Anstee, Adriaan G. Holleboom, Heather J. Cordell, Kevin L. Duffin, Diana Julie Leeming, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Graduate School, Investigators, LITMUS Consortium, Johnson K., Leary P.J., Govaere O., Barter M.J., Charlton S.H., Cockell S.J., Tiniakos D., Zatorska M., Bedossa P., Brosnan M.J., Cobbold J.F., Ekstedt M., Aithal G.P., Clement K., Schattenberg J.M., Boursier J., Ratziu V., Bugianesi E., Anstee Q.M., Daly A.K., Clark J., Cordell H.J., Darlay R., Day C.P., Hardy T., Liu Y.-L., Oakley F., Palmer J., Queen R., Wonders K., Bossuyt P.M., Holleboom A.G., Zafarmand H., Vali Y., Lee J., Pais R., Schuppan D., Allison M., Cuenca S.R., Pellegrinelli V., Vacca M., Vidal-Puig A., Hyotylainen T., McGlinchey A., Oresic M., Sen P., Mato J., Millet O., Dufour J.-F., Harrison S., Neubauer S., Pavlides M., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Romero-Gomez M., Gallego-Duran R., Fernandez I., Karsdal M., Leeming D., Fisker M.J., Erhardtsen E., Rasmussen D., Qvist P., Sinisi A., Sandt E., Tonini M.M., Parola M., Rosso C., Marra F., Gastaldelli A., Francque S., Kechagias S., Yki-Jarvinen H., Porthan K., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Petta S., Miele L., Geier A., Trautwein C., Hockings P., Newsome P., Wenn D., Pereira Rodrigues C.M., Hanf R., Chaumat P., Rosenquist C., Trylesinski A., Ortiz P., Duffin K., Yunis C., Miller M., Tuthill T., Ertle J., Younes R., Alexander L., Ostroff R., Kjaer M.S., Mikkelsen L.F., Brass C., Jennings L., Balp M.-M., Martic M., Hanauer G., Shankar S., Torstenson R., Fournier C., Ehman R., Kalutkiewicz M., Pepin K., Myers J., Shevell D., Ho G., Landgren H., Myers R., Doward L., Whalley D., Twiss J., Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Kjær, Mette Skalshøi, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Fournier, Céline, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, Twiss, James, Clark, James, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, Hyötyläinen, Tuulia, McGlinchey, Aidan, Orešič, Matej, Sen, Partho, Mato, Jose, Millet, Óscar, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Gallego-Durán, Rocío, Fernández, Isabel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Pereira Rodrigues, Cecília Maria, Hanf, Rémy, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, and Yunis, Carla

Subjects
SCORING SYSTEM, CPM, counts per million, AUROC, area under the receiver operating characteristic, RC799-869, AST, aspartate aminotransferase, MicroRNA, Non-alcoholic fatty liver disease, Biomarker, Sequencing, TGF-β, transforming growth factor-beta, Gastroenterology, STEATOHEPATITIS, Liver disease, 0302 clinical medicine, Fibrosis, miRNA, microRNA, logFC, log2 fold change, FIBROSIS, Immunology and Allergy, 0303 health sciences, education.field_of_study, NAS, NAFLD activity score, medicine.diagnostic_test, Fatty liver, GTEx, Genotype-Tissue Expression, Diseases of the digestive system. Gastroenterology, 3. Good health, Real-time polymerase chain reaction, Biomarker, MicroRNA, Non-alcoholic fatty liver disease, Sequencing, Liver biopsy, ACID, Biomarker (medicine), 030211 gastroenterology & hepatology, Life Sciences & Biomedicine, Research Article, EXPRESSION, medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, Population, Gastroenterology and Hepatology, SAF, steatosis–activity–fibrosis, VALIDATION, ER, endoplasmic reticulum, 03 medical and health sciences, cDNA, complementary DNA, Internal medicine, ALT, alanine aminotransferase, Gastroenterologi, Internal Medicine, medicine, NAFL, non-alcoholic fatty liver, ALGORITHM, FIB-4, fibrosis-4, education, 030304 developmental biology, PCA, principal component analysis, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, FC, fold change, medicine.disease, digestive system diseases, FLIP, fatty liver inhibition of progression, Ct, cycle threshold, Steatosis, qPCR, quantitative PCR, business
Abstract

Background & Aims Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy., Graphical abstract, Highlights • Serum miRNA was sequenced in 183 NAFLD cases of varying severity and 10 population controls. • Plasma levels of miR-193a-5p were significantly increased in patients with advanced fibrosis, high NAS scores, or high SAF scores. • Other miRNAs including miR378d and miR378e were also significantly increased in certain comparisons. • The findings for miR-193a-5p were replicated in a cohort of 372 additional NAFLD cases.

Published
2022

31. HCV disease burden and population segments in Switzerland

Author

Beat Müllhaupt, Nasser Semmo, Homie Razavi, Francesco Negro, Claude Scheidegger, Philip Bruggmann, Florian Bihl, Erika Castro Batänjer, David Semela, Daniel Lavanchy, Sarah Blach, Jean-François Dufour, University of Zurich, and Bihl, Florian

Subjects
Adult, Burden of disease, Hepatitis C virus, Population, Stigma (botany), 610 Medicine & health, Hepacivirus, medicine.disease_cause, Antiviral Agents, Cost of Illness, medicine, Humans, education, Disease burden, Hepatitis, education.field_of_study, Hepatology, business.industry, medicine.disease, Hepatitis C, Hcv elimination, 10219 Clinic for Gastroenterology and Hepatology, 2721 Hepatology, Viral hepatitis, business, Switzerland, Demography
Abstract

BACKGROUND Switzerland has made strides towards hepatitis C virus elimination, but as of 2019, elimination was not guaranteed. However, political interest in viral hepatitis has been increasing. We sought to develop a better understanding of Switzerland's progress towards HCV elimination and the profile of remaining HCV-RNA-positive patients. METHODS A previously described Markov model was updated with recent diagnosis and treatment data and run to generate new forecasts for HCV disease burden. Two scenarios were developed to evaluate HCV morbidity and mortality under the status quo and a scenario that achieves the Swiss Hepatitis Strategy Elimination targets. Next, an analysis was conducted to identify population segments bearing a high burden of disease, where future elimination efforts could be directed. RESULTS At the beginning of 2020, an estimated 32��100 viremic infections remained in Switzerland (0.37% viremic prevalence). Adult (���18��years of age) permanent residents born abroad represented the largest subpopulation, accounting for 56% of HCV infections. Thirteen countries accounted for ���60% of viremic infections amongst permanent residents born abroad, with most people currently residing in Zurich, Vaud, Geneva, Bern, Aargau and Ticino. Amongst Swiss-born HCV-RNA-positive persons, two-thirds had a history of IDU, corresponding to 33% of total infections. CONCLUSIONS In Switzerland, extra efforts for diagnosis and linkage to care are warranted in foreign-born populations and people with a history of drug use. Population-level measures (eg increasing the number of providers, increase screening) can identify patients who may have otherwise fallen through the gaps or avoided care because of stigma.

Published
2022

32. Humoral response to SARS-CoV-2 infection among liver transplant recipients

Author

Chiara Becchetti, Annelotte G C Broekhoven, Géraldine Dahlqvist, Montserrat Fraga, Marco Fabrizio Zambelli, Olga Ciccarelli, Anne-Catherine Saouli, Arianna Trizzino, Vanessa Banz, Jean-François Dufour, Anna H E Roukens, Shessy P Torres Morales, Sebenzile K Myeni, Marjolein Kikkert, Mariet C W Feltkamp, Minneke J Coenraad, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service de chirurgie et transplantation abdominale, and UCL - (SLuc) Service de gastro-entérologie

Subjects
Immunosuppression Therapy, Male, Hepatology, liver transplantation, SARS-CoV-2, Gastroenterology, COVID-19, Middle Aged, Transplant Recipients, immune response, Immunity, Humoral, Case-Control Studies, Antibody Formation, Humans, Female, Prospective Studies, 610 Medicine & health, Immunosuppressive Agents
Abstract

ObjectiveImmunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody response to SARS-CoV-2 in liver transplant (LT) recipients after COVID-19.DesignProspective multicentre case–control study, analysing antibodies against the nucleocapsid protein, spike (S) protein of SARS-CoV-2 and their neutralising activity in LT recipients with confirmed SARS-CoV-2 infection (COVID-19-LT) compared with immunocompetent patients (COVID-19-immunocompetent) and LT recipients without COVID-19 symptoms (non-COVID-19-LT).ResultsOverall, 35 LT recipients were included in the COVID-19-LT cohort. 35 and 70 subjects fulfilling the matching criteria were assigned to the COVID-19-immunocompetent and non-COVID-19-LT cohorts, respectively. We showed that LT recipients, despite immunosuppression and less symptoms, mounted a detectable antinucleocapsid antibody titre in 80% of the cases, although significantly lower compared with the COVID-19-immunocompetent cohort (3.73 vs 7.36 index level, pConclusionsOur findings suggest that the humoral response of LT recipients is only slightly lower than expected, compared with COVID-19 immunocompetent controls. Testing for anti-S antibodies alone can lead to an overestimation of the neutralising ability in LT recipients. Altogether, routine antibody testing against separate SARS-CoV-2 antigens and functional testing show that the far majority of LT patients are capable of mounting an adequate antibody response with neutralising ability.

Published
2022

34. Global multi-stakeholder endorsement of the MAFLD definition

Author

Nahum Méndez-Sánchez, Elisabetta Bugianesi, Robert G Gish, Frank Lammert, Herbert Tilg, Mindie H Nguyen, Shiv K Sarin, Núria Fabrellas, Shira Zelber-Sagi, Jian-Gao Fan, Gamal Shiha, Giovanni Targher, Ming-Hua Zheng, Wah-Kheong Chan, Shlomo Vinker, Takumi Kawaguchi, Laurent Castera, Yusuf Yilmaz, Marko Korenjak, C Wendy Spearman, Mehmet Ungan, Melissa Palmer, Mortada El-Shabrawi, Hans-Juergen Gruss, Jean-François Dufour, Anil Dhawan, Heiner Wedemeyer, Jacob George, Luca Valenti, Yasser Fouad, Manuel Romero‐Gomez, Mohammed Eslam, Maria Lorena Abate, Bahaa Abbas, Ahmed Amr Abbassy, Waleed Abd El Ghany, Amira Abd Elkhalek, Emad Abd ElMajeed, Mohammad Abdalgaber, Mohamed AbdAllah, Marwa Abdallah, Nourhan Abdallah, Shereen Abdelaleem, Yasser Abdelghani, Wael Abdelghany, Safaa Mohamed Abdelhalim, Wafaa Abdelhamid, Nehal Abdelhamid, Nadia A. Abdelkader, Elsayed Abdelkreem, Aly Mohamed Abdelmohsen, Awny Ali Abdelrahman, Sherief M Abd-elsalam, Doaa Abdeltawab, Abdulbaset Abduh, Nada Abdulhakam, Maheeba Abdulla, Navid Abedpoor, Ludovico Abenavoli, Fredrik Åberg, Omala Ablack, Mostafa Abo elftouh, Yousry Esam-Eldin Abo-Amer, Ashraf Aboubkr, Alaa Aboud, Amr M. Abouelnaga, Galal A. Aboufarrag, Ashraf Aboutaleb, Leticia Abundis, Gupse Adalı, Enrique Adames, Leon Adams, Danjuma Adda, Noor Adel, Nada Adel, Muhammad Adel Sayed, Taiba Jibril Afaa, Nawal Afredj, Gulnara Aghayeva, Alessio Aghemo, Carlos A. Aguilar-Salinas, Golo Ahlenstiel, Walid Ahmady, Wafaa Ahmed, Amira Ahmed, Samah Nasser Ahmed, Heba Mostafa Ahmed, Rasha Ahmed, Elmar Aigner, Mesut Akarsu, Maisam Akroush, Umit Akyuz, Mamun Al Mahtab, Tahani Al Qadiri, Yusriya Al Rawahi, Razzaq AL rubaee, Muna Al Saffar, Shahinul Alam, Zaid Al-Ani, Agustín Albillos, Mohamed Alboraie, Said Al-Busafi, Mohamed Al-Emam, Jawaher Alharthi, Kareem Ali, Basma Abdelmoez Ali, Mohammad Ali, Raja Affendi Raja Ali, Anna Alisi, Ali Raad AL-Khafaji, Maryam Alkhatry, Rocio Aller, Yahya Almansoury, Khalid Al-Naamani, Alaa Alnakeeb, Anna Alonso, Saleh A. Alqahtani, Leina Alrabadi, Khalid Alswat, Mahir Altaher, Turki Altamimi, Jose Altamirano, Mario R. Alvares-da-Silva, Elsragy Adel M. Aly, Amgad Alzahaby, Ahmed Alzamzamy, Keisuke Amano, Maysa A. Amer, Mona A. Amin, Sayed A. Amin, Ashraf A. Amir, Javier Ampuero, Noha Anas, Pietro Andreone, Soa Fy Andriamandimby, Mahmoud Anees, Peltec Angela, Manal Antonios, Wael Arafat, Jose Moreno Araya, Juan Armendariz-Borunda, Matthew J. Armstrong, Hassan Ashktorab, Patricia Aspichueta, Fathia Assal, Mira Atef, Dina Attia, Hoda Atwa, Reham Awad, Mohyeldeen Abd Elaziz Awad, Sally Awny, Obafemi Awolowo, Yaw Asante Awuku, Ibrahim Ayada, Than Than Aye, Sherif Ayman, Hedy Ayman, Hesham Ayoub, Hosny M. Azmy, Romiro P. Babaran, Omneya Badreldin, Ahmed Badry, İbrahim Halil Bahçecioğlu, Amira Bahour, Jiajia Bai, Yasemin Balaban, Muthuswamy Balasubramanyam, Khaled Bamakhrama, Jesus M Banales, Babu Bangaru, Jianfeng Bao, Jorge Suazo Barahona, Salma Barakat, Sandra Maria Barbalho, Bikwa Barbra, Beatriz Barranco, Francisco Barrera, Ulrich Baumann, Shamardan Bazeed, Eva Bech, Aourarh Benayad, Andreas Benesic, David Bernstein, Fernando Bessone, Susie Birney, Cyrille Bisseye, Martin Blake, Bilal Bobat, Leonilde Bonfrate, Dmitry S Bordin, Francisco Bosques-Padilla, Jerome Boursier, Boushab Mohamed Boushab, David Bowen, Patricia Medina Bravo, Paul N Brennan, Bisi Bright, Ilse Broekaert, Xabier Buque, Diego Burgos-Santamaría, Julio Burman, Luca Busetto, Chris D. Byrne, Patricia Anne I. Cabral-Prodigalidad, Guillermo Cabrera-Alvarez, Wei Cai, Francesca Cainelli, Ali Riza Caliskan, Ali Canbay, Ana Cano-Contreras, Hai-Xia Cao, Zhujun Cao, Andres Carrion, Francesca Carubbi, Teresa Casanovas, Marlen Ivón Castellanos Fernández, Jin Chai, Siew Pheng Chan, Phunchai Charatcharoenwitthaya, Norberto Chavez-Tapia, Kazuaki Chayama, Jinjun Chen, Lin Chen, Zhong-Wei Chen, Huiting Chen, Sui-Dan Chen, Qiang Chen, Yaxi Chen, Gang Chen, En-Quang Chen, Fei Chen, Pei-Jer Chen, Robert Cheng, Wendy Cheng, Jack Tan Wei Chieh, Imad Chokr, Evangelos Cholongitas, Ashok Choudhury, Abhijit Chowdhury, Evaristus Sunday Chukwudike, Stefano Ciardullo, Michelle Clayton, Karine Clement, Marie Michelle Cloa, Cecilia Coccia, Cristina Collazos, Massimo Colombo, Arif Mansur Cosar, Helma Pinchemel Cotrim, Joris Couillerot, Alioune Coulibaly, Gonzalo Crespo, Javier Crespo, Maria Cruells, Ian Homer Y. Cua, Hesham K. Dabbous, George N Dalekos, Patricia D'Alia, Li Dan, Viet Hang Dao, Mostafa Darwish, Christian Datz, Milagros B Davalos-Moscol, Heba Dawoud, Blanca Olaechea de Careaga, Robert de Knegt, Victor de Ledinghen, Janaka de Silva, Nabil Debzi, Marie Decraecker, Elvira Del Pozo, Teresa C Delgado, Manuel Delgado-Blanco, Łukasz Dembiński, Adilson Depina, Moutaz Derbala, Hailemichael Desalegn, Christèle Desbois-Mouthon, Mahmoud Desoky, Anouk Dev, Agostino Di Ciaula, Moisés Diago, Ibrahima Diallo, Luis Antonio Díaz, Melisa Dirchwolf, Paola Dongiovanni, Andrriy Dorofeyev, Xiaoguang Dou, Mark W. Douglas, Michael Doulberis, Cecil K. Dovia, Adam Doyle, Ivana Dragojević, Joost PH Drenth, Xuefei Duan, Audrius Dulskas, Dan L Dumitrascu, Oliver Duncan, Vincent Dusabejambo, Rev. Shem N.A. Dwawhi, Sho Eiketsu, Doaa El Amrousy, Ahmed El Deeb, Ghada El Deriny, Hesham Salah El Din, Salwa El Kamshishy, Mohamed El Kassas, Maissa El Raziky, Osama A Elagamy, Wafaa Elakel, Dina Elalfy, Hanaa Elaraby, Heba ElAwady, Reda Elbadawy, Hanaa Hassan Eldash, Manal S. Eldefrawy, Carol Lezama Elecharri, Amel Elfaramawy, Mohammed Elfatih, Mahmoud Elfiky, Mohamed Elgamsy, Mohamed Elgendy, Mohamed A. El-Guindi, Nagi Elhussieny, Ahmed Maher Eliwa, Zeineb Elkabbany, Hesham El-Khayat, Nehal M. El-Koofy, Alaa Elmetwalli, Amr Elrabat, Fathiya El-Raey, Fatma Elrashdy, Medhat Elsahhar, Esraa M. Elsaid, Shimaa Elsayed, Hany Elsayed, Aly Elsayed, Amr M. Elsayed, Hamdy Elsayed, Magdy El-Serafy, Ahmed M. Elsharkawy, Reem Yehia Elsheemy, Eman Elsayed Elshemy, Sara Elsherbini, Naglaa Eltoukhy, Reda Elwakil, Ola Emad, Shaimaa Emad, Mohamed Embabi, Ilkay Ergenç, Tatiana Ermolova, Gamal Esmat, Doaa M. 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L, Kaya, E, Kayasseh, M, Keenan, B, Keklikkiran, C, Keml, W, Khalaf, D, Khalefa, R, Khamis, S, Khater, D, Khattab, H, Khavkin, A, Khlynova, O, Khmis, N, Kobyliak, N, Koffas, A, Koike, K, Kok, K, Koller, T, Komas, N, Korochanskaya, N, Koulla, Y, Koya, S, Kraft, C, Kraja, B, Krawczyk, M, Kuchay, M, Kulkarni, A, Kumar, A, Kumar, M, Lakoh, S, Lam, P, Lan, L, Lange, N, Lankarani, K, Lanthier, N, Lapshyna, K, Lashen, S, Laure, K, Lazebnik, L, Lebrec, D, Lee, S, Lee, W, Lee, Y, Leeming, D, Leite, N, Leon, R, Lesmana, C, Li, J, Li, Q, Li, Y, Li, L, Li, M, Liang, H, Lijuan, T, Lim, S, Lim, L, Lin, S, Lin, H, Lin, R, Lithy, R, Liu, Y, Liu, X, Liu, W, Liu, S, Liu, K, Liu, T, Lonardo, A, Lopez, M, Lopez-Benages, E, Lopez-Jaramillo, P, Lu, H, Lu, L, Lu, Y, Lubel, J, Lui, R, Lupasco, I, Luzina, E, Lv, X, Lynch, K, Ma, H, Machado, M, Maduka, N, Madzharova, K, Magdaong, R, Mahadeva, S, Mahfouz, A, Mahmood, N, Mahmoud, E, Mahrous, M, Maiwall, R, Majeed, A, Majumdar, A, Mak, L, Maklouf, M, Malekzadeh, R, Mandato, C, Mangia, A, Mann, J, Mansour, H, Mansouri, A, Mantovani, A, Mao, J, Maramag, F, Marchesini, G, Marcus, C, Marinho, R, Martinez-Chantar, M, Martins, A, Marwan, R, Mason, K, Masoud, G, Massoud, M, Matamoros, M, Mateos, R, Mawed, A, Mbanya, J, Mbendi, C, Mccolaugh, L, Mcleod, D, Medina, J, Megahed, A, Mehrez, M, Memon, I, Merat, S, Mercado, R, Mesbah, A, Meskini, T, Metwally, M, Metwaly, R, Miao, L, Micah, E, Miele, L, Milivojevic, V, Milovanovic, T, Mina, Y, Mishkovik, M, Mishriki, A, Mitchell, T, Mohamed, A, Mohamed, M, Mohamed, S, Mohammed, S, Mohammed, A, Mohan, V, Mohie, S, Mokhtar, A, Moniem, R, Montilla, M, Morales, J, Morata, M, Moreno-Planas, J, Morise, S, Mosaad, S, Moselhy, M, Mostafa, A, Mostafa, E, Mouane, N, Mousa, N, Moustafa, H, Msherif, A, Muller, K, Munoz, C, Munoz-Urribarri, A, Murillo, O, Mustapha, F, Muzurovic, E, Nabil, Y, Nafady, S, Nagamatsu, A, Nakajima, A, Nakano, D, Nan, Y, Nascimbeni, F, Naseef, M, Nashat, N, Natalia, T, Negro, F, Nersesov, A, Neuman, M, Ng'Wanasayi, M, Ni, Y, Nicoll, A, Niizeki, T, Nikolova, D, Ningning, W, Niriella, M, Nogoibaeva, K, Nordien, R, O Sullivan, C, O'Beirne, J, Obekpa, S, Ocama, P, Ochwoto, M, Ogolodom, M, Ojo, O, Okrostsvaridze, N, Oliveira, C, Omana, R, Omar, O, Omar, H, Omar, M, Omran, S, Omran, R, Osman, M, Owise, N, Owusu-Ansah, T, Padilla- Machaca, P, Palle, S, Pan, Z, Pan, X, Pan, Q, Papaefthymiou, A, Paquissi, F, Par, G, Parkash, A, Payawal, D, Peltekian, K, Peng, X, Peng, L, Peng, Y, Pengoria, R, Perez, M, Perez, J, Perez, N, Persico, M, Pessoa, M, Petta, S, Philip, M, Plaz Torres, M, Polavarapu, N, Poniachik, J, Portincasa, P, Pu, C, Purnak, T, Purwanto, E, Qi, X, Qian, Z, Qiang, Z, Qiao, Z, Qiao, L, Queiroz, A, Rabiee, A, Radwan, M, Rahetilahy, A, Ramadan, Y, Ramadan, D, Ramli, A, Ramm, G, Ran, A, Rankovic, I, Rao, H, Raouf, S, Ray, S, Reau, N, Refaat, A, Reiberger, T, Remes-Troche, J, Reyes, E, Richardson, B, Ridruejo, E, Riestra Jimenez, S, Rizk, I, Roberts, S, Roblero, J, Robles, J, Rockey, D, Rodriguez, M, Rodriguez Hernandez, H, Roman, E, Romeiro, F, Romeo, S, Rosales-Zabal, J, Roshdi, G, Rosso, N, Ruf, A, Ruiz, P, Runes, N, Ruzzenente, A, Ryan, M, Saad, A, Sabbagh, E, Sabbah, M, Saber, S, Sabrey, R, Sabry, R, Saeed, M, Said, D, Said, E, Sakr, M, Salah, Y, Salama, R, Salama, A, Saleh, H, Saleh, A, Salem, A, Salifou, A, Salih, A, Salman, A, Samouda, H, Sanai, F, Sanchez-Avila, J, Sanker, L, Sano, T, Sanz, M, Saparbu, T, Sawhney, R, Sayed, F, Sayed, S, Sayed, A, Sayed, M, Sebastiani, G, Secadas, L, Sediqi, K, Seif, S, Semida, N, Senates, E, Serban, E, Serfaty, L, Seto, W, Sghaier, I, Sha, M, Shabaan, H, Shalaby, L, Shaltout, I, Sharara, A, Sharma, V, Shawa, I, Shawkat, A, Shawky, N, Shehata, O, Sheils, S, Shewaye, A, Shi, G, Shi, J, Shimose, S, Shirono, T, Shou, L, Shrestha, A, Shui, G, Sievert, W, Sigurdardottir, S, Sira, M, Siradj, R, Sison, C, Smyth, L, Soliman, R, Sollano, J, Sombie, R, Sonderup, M, Sood, S, Soriano, G, Stedman, C, Stefanyuk, O, Stimac, D, Strasser, S, Strnad, P, Stuart, K, Su, W, Su, M, Sumida, Y, Sumie, S, Sun, D, Sun, J, Suzuki, H, Svegliati-Baroni, G, Swar, M, Taharboucht, S, Taher, Z, Takamura, S, Tan, L, Tan, S, Tanwandee, T, Tarek, S, Tatiana, G, Tavaglione, F, Tecson, G, Tee, H, Teschke, R, Tharwat, M, Thong, V, Thursz, M, Tine, T, Tiribelli, C, Tolmane, I, Tong, J, Tongo, M, Torkie, M, Torre, A, Torres, E, Trajkovska, M, Treeprasertsuk, S, Tsutsumi, T, Tu, T, Tur, J, Turan, D, Turcan, S, Turkina, S, Tutar, E, Tzeuton, C, Ugiagbe, R, Uygun, A, Vacca, M, Vajro, P, Van der Poorten, D, Van Kleef, L, Vashakidze, E, Velazquez, C, Velazquez, M, Vento, S, Verhoeven, V, Vespasiani-Gentilucci, U, Vethakkan, S, Vilaseca, J, Vitek, L, Volkanovska, A, Wallace, M, Wan, W, Wang, Y, Wang, X, Wang, C, Wang, M, Wangchuk, P, Weltman, M, White, M, Wiegand, J, Wifi, M, Wigg, A, Wilhelmi, M, William, R, Wittenburg, H, Wu, S, Wubeneh, A, Xia, H, Xiao, J, Xiao, X, Xiaofeng, W, Xiong, W, Xu, L, Xu, J, Xu, W, Xu, K, Xu, Y, Xu, S, Xu, M, Xu, A, Xu, C, Yan, H, Yang, J, Yang, R, Yang, Y, Yang, Q, Yang, N, Yao, J, Yara, J, Yaras, S, Yilmaz, N, Younes, R, Younes, H, Young, S, Youssef, F, Yu, Y, Yu, M, Yuan, J, Yue, Z, Yuen, M, Yun, W, Yurukova, N, Zakaria, S, Zaky, S, Zaldastanishvili, M, Zapata, R, Zare, N, Zerem, E, Zeriban, N, Zeshuai, X, Zhang, H, Zhang, X, Zhang, Y, Zhang, W, Zhang, Z, Zhao, J, Zhao, R, Zhao, H, Zheng, C, Zheng, Y, Zheng, R, Zheng, T, Zheng, K, Zhou, X, Zhou, Y, Zhou, H, Zhou, L, Zhu, L, Zhu, Y, Zhu, P, Ziada, E, Ziring, D, Ziyi, L, Zou, S, Zou, Z, Zou, H, Zuart Ruiz, R, and Global Multi-Stakeholder Consensus on the Redefinition of Fatty Liver Disease

Subjects
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Hepatology, Non-alcoholic Fatty Liver Disease, NAFLD, consensu, Gastroenterology, MAFLD, definition, Humans, MAFLD, NAFLD, Human medicine
Abstract

Contains fulltext : 252162.pdf (Publisher’s version ) (Closed access)

Published
2022

35. Le carcinome hépatocellulaire

Author

Jean-François Dufour

Subjects
Gynecology, medicine.medical_specialty, business.industry, medicine, General Medicine, business
Abstract

Le carcinome hepatocellulaire est la tumeur maligne la plus frequente du foie. Il se developpe le plus souvent dans le contexte d’une maladie chronique du foie. Les patients a risque d’avoir un carcinome hepatocellulaire doivent etre enroles dans un programme de surveillance pour que le diagnostic soit fait a un stade precoce. En consequence les patients avec une cirrhose du foie doivent avoir tous les 6 mois un examen ultrasonographique du foie. Si une lesion apparait il faut faire des examens diagnostics essentiellement radiologiques. Le traitement du carcinome hepatocellulaire est complexe et doit etre conduit par des specialistes de facon multidisciplinaire. Les patients diagnostiques a un stade precoce peuvent etre gueri. Pour les autres de nouvelles options therapeutiques existent. L’introduction de traitements immuno-oncologiques offre des chances de survie prolongee.

Published
2020

36. First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma

Author

Vincenzo Mazzaferro, Jung Hwan Yoon, Chia Jui Yen, Sunil Sharma, Max Sung, Josep M. Llovet, Tim Meyer, Meera Tugnait, Sandrine Faivre, Stephen L. Chan, Antoine Hollebecque, Daniel H. Palmer, Christoph Lengauer, Teresa Macarulla, Margit Hagel, Ho Yeong Lim, Joong-Won Park, Su Pin Choo, Andrew X. Zhu, Lynn G. Feun, Cori Ann Sherwin, Debashis Sarker, Thomas Yau, Melissa Manoogian, Yoon-Koo Kang, Hongliang Shi, Oleg Schmidt-Kittler, Nicolas Stransky, Zhong Zhe Lin, Beni B. Wolf, Nancy E. Kohl, Richard D. Kim, Jean-François Dufour, Joerg Trojan, and Klaus P. Hoeflich

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, Nausea, FGF19, medicine.disease, Clinical trial, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Internal medicine, medicine, Carcinoma, Vomiting, Biomarker (medicine), medicine.symptom, business, Adverse effect
Abstract

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7–not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. Significance: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection. See related commentary by Subbiah and Pal, p. 1646. This article is highlighted in the In This Issue feature, p. 1631

Published
2019

37. Current therapies and new developments in NASH

Author

Jean-François Dufour, Quentin M Anstee, Elisabetta Bugianesi, Stephen Harrison, Rohit Loomba, Valerie Paradis, Herbert Tilg, Vincent Wai-Sun Wong, and Shira Zelber-sagi

Subjects
screening and diagnosis, Gastroenterology & Hepatology, Liver Disease, Chronic Liver Disease and Cirrhosis, Clinical Sciences, Gastroenterology, Hepatitis, 4.1 Discovery and preclinical testing of markers and technologies, Paediatrics and Reproductive Medicine, Substance Misuse, Detection, Good Health and Well Being, Clinical Research, Digestive Diseases
Abstract

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.

Published
2021

38. Immune thrombocytopenia with clinical significance in systemic lupus erythematosus: a retrospective cohort study of 90 patients

Author

Mickaël Roussotte, Mathieu Gerfaud-Valentin, Arnaud Hot, Sylvain Audia, Bernard Bonnotte, Thomas Thibault, Hervé Lobbes, Guillaume Le Guenno, Radjiv Goulabchand, Pascal Cathebras, Loig Varron, Jean François Dufour, Alban Deroux, Caroline Compain, Antoine Baudet, Ludovic Karkowski, Laurent Pérard, Mikael Ebbo, Jean-Christophe Lega, Pascal Sève, Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Médecine Interne [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Métropole Savoie [Chambéry], Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Hôpital d'Instruction des Armées Desgenettes, Service de Santé des Armées, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Research on Healthcare Performance (RESHAPE - Inserm U1290 - UCBL1), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Purpura, Thrombocytopenic, Idiopathic, Lupus, Thrombosis, Antiphospholipid, Thrombocytopenia, Immune thrombocytopenia, Thrombopoietin receptor agonists, Rheumatology, Haemorrhage, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, immune system diseases, Splenectomy, Humans, Lupus Erythematosus, Systemic, Pharmacology (medical), Rituximab, Receptors, Thrombopoietin, Retrospective Studies
Abstract

Objectives To describe the characteristics, treatment and outcome of patients with immune thrombocytopenia with clinical significance (ITPCS) associated with SLE. Methods This retrospective multicentre study included SLE patients who experienced ≥1 ITPCS (defined as ITP with attributable bleeding disorders and/or a platelet count 8 and/or WHO score >2. Results A total of 90 patients were included, the median (range) follow-up duration was 80 (6–446) months. ITP was diagnosed before SLE in 25 patients. They presented a high rate of autoimmune haemolytic anaemia (15%), antiphospholipid antibody (62%) and antiphospholipid syndrome (19%). The 25 (28%) patients who experienced MBG had significantly more bleedings at ITP diagnosis and higher bleeding scores, and serositis and thrombosis during follow-up. They required significantly more treatment lines, transfusions and hospitalizations. The 11 (12%) patients who experienced no bleeding event presented a significantly more restricted SLE phenotype (cutaneous and/or articular). Patients received a mean (range) of 4.2 (1–11) treatment lines. Corticosteroids and HCQ allowed ITPCS overall response in one-third of patients. The median relapse-free survival of rituximab (n = 34), AZA (n = 19), MMF (n = 8), thrombopoietin-receptor agonists (n = 16) and splenectomy (n = 19) were 53, 31.5, 61, 24.5 and 78 months, respectively. Four patients experienced thrombotic events after splenectomy and one occurred under thrombopoietin-receptor agonist treatment. Conclusion SLE-ITCS patients displayed a high rate of haematological abnormalities and MBG patients exhibited higher morbidity. Management of thrombocytopenia was highly heterogeneous and many options seem viable.

Published
2021

39. The global NAFLD policy review and preparedness index: Are countries ready to address this silent public health challenge?

Author

Jeffrey V. Lazarus, Henry E. Mark, Marcela Villota-Rivas, Adam Palayew, Patrizia Carrieri, Massimo Colombo, Mattias Ekstedt, Gamal Esmat, Jacob George, Giulio Marchesini, Katja Novak, Ponsiano Ocama, Vlad Ratziu, Homie Razavi, Manuel Romero-Gómez, Marcelo Silva, C. Wendy Spearman, Frank Tacke, Emmanuel A. Tsochatzis, Yusuf Yilmaz, Zobair M. Younossi, Vincent W.-S. Wong, Shira Zelber-Sagi, Helena Cortez-Pinto, Quentin M. Anstee, Samir Rouabhia, Hasmik Ghazinyan, Natacha Jreige Iskandar, Michael Trauner, Gulnara Aghayeva, Flloyd Carter, Kannan Sridharan, Mamun Al Mahtab, Sven Francque, Nicolas Kodjoh, Ruben Muñoz Camacho, Motswedi Anderson, Claudia Pinto Marques Souza de Oliveira, Lyudmila Mateva, Abdel Karim Serme, Antonieta A. Soares Martins, Mark G. Swain, Narcisse Patrice Komas, Ming-Hua Zheng, Patricio Lopez Jaramillo, Omar Alfaro Murillo, Ivana Mikolasevic, Emmelia Vounou, Radan Brůha, Charles Mbendi Nlombi, Maja Thiele, Marlene Perez, Juan José Suárez M, Imam Waked, Riina Salupere, Hailemichael Desalegn, Hannele Yki-Järvinen, Tengiz Tsertsvadze, Lali Sharvadze, Maia Butsashvili, Yaw Asante Awuku, Georgios Papatheodoridis, Bela Hunyady, Einar Stefan Bjornsson, Ajay Duseja, Cosmas Rinaldi A. Lesmana, Reza Malekzadeh, Suzanne Norris, Kazuhiko Koike, Alexander V. Nersesov, Missiani Ochwoto, Mohammad Jamal, Tobokalova Saparbu, Ieva Tolmane, Raymond Sayegh, Dhastagir Sultan Sheriff, Jonas Valantinas, Joseph Weber, Isaac Thom Shawa, Soek-Siam Tan, Sophia E. Martínez Vázquez, Oidov Baatarkhuu, Undram Lkhagvaa, Tsolmon Jadamba, Tahiri Mohammed, K.C Sudhamshu, Kirsten Coppell, Charles Onyekwere, Dafina Nikolova, Mette Vesterhus, Khalid Al-Naamani, Saeed Hamid, Juan Paredes Méndez, María Cecilia Cabrera Cabrejos, Robert Flisiak, Esther A. Torres, Shahrad Taheri, Ki-Chul Sung, Turcanu Adela, Liana Gheorghe, Faisal M. Sanai, Tamara Milovanovic, George Boon Bee Goh, Marek Rac, Anuradha Dassanayake, Shahinaz Bedri Osama, M. Elsanousi, Jean-François Dufour, Jia-Horng Kao, Dilshod Saidi, Sombat Treeprasertsuk, Ger Koek, Asma Labidi, Igor Skrypnyk, Maryam Salem AlKhatry, Shakhlo Sadirova, Shokhista Bakieva, Edford Sinkala, Repositório da Universidade de Lisboa, Lazarus, Jeffrey V., Mark, Henry E., Villota-Rivas, Marcela, Palayew, Adam, Carrieri, Patrizia, Colombo, Massimo, Ekstedt, Mattias, Esmat, Gamal, George, Jacob, Marchesini, Giulio, Novak, Katja, Ocama, Ponsiano, Ratziu, Vlad, Razavi, Homie, Romero-Gómez, Manuel, Silva, Marcelo, Spearman, C. Wendy, Tacke, Frank, Tsochatzis, Emmanuel A., Yilmaz, Yusuf, Younossi, Zobair M., Wong, Vincent W.-S., Zelber-Sagi, Shira, Cortez-Pinto, Helena, Anstee, Quentin M., NAFLD policy review collaborators, University of Barcelona, EASL International Liver Foundation [Geneva, Switzerland] (ILF), University of Washington [Seattle], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), IRCCS San Raffaele Hospital, Linköping University (LIU), Cairo University, The University of Sydney, University of Bologna/Università di Bologna, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Makerere University [Kampala, Ouganda] (MAK), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Center for Disease Analysis Foundation [Lafayette, CO, États-Unis], Biomedicine Institute of Sevilla [Seville, Spain], Hospital Universitario Austral, University of Cape Town, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institute for Liver & Digestive Health [London, UK], Marmara University [Kadıköy - İstanbul], Inova Medicine [Falls Church, Virginia, USA] (IM), The Chinese University of Hong Kong [Hong Kong], University of Haifa [Haifa], Tel Aviv Sourasky Medical Center [Te Aviv], Universidade de Lisboa = University of Lisbon (ULISBOA), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, EASL International Liver Foundation, Bristol-Myers Squibb, Genfit, MSD, Gilead Sciences, Allergan Foundation, Pfizer, Resoundant, Wong, Vincent Wai-Sun, and Malbec, Odile

Subjects
policy preparedness, Adult, [SDV]Life Sciences [q-bio], non-alcoholic steatohepatitis (NASH), multiple correspondence analysis, Global Health, digestive system, Policy preparednesss, Non-alcoholic fatty liver disease (NAFLD), liver health, Non-alcoholic Fatty Liver Disease, Humans, Obesity, Non-alcoholic steatohepatitis (NASH), BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Internal Medicine, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Interna medicina, global public health, Hepatology, Liver health, nutritional and metabolic diseases, health policy, digestive system diseases, Health policy, Multiple correspondence analysis, [SDV] Life Sciences [q-bio], Policy, Policy preparedness, Public Health, Global public health
Abstract

[Background & Aims]: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent, yet largely underappreciated liver condition which is closely associated with obesity and metabolic disease. Despite affecting an estimated 1 in 4 adults globally, NAFLD is largely absent on national and global health agendas., [Methods]: We collected data from 102 countries, accounting for 86% of the world population, on NAFLD policies, guidelines, civil society engagement, clinical management, and epidemiologic data. A preparedness index was developed by coding questions into 6 domains (policies, guidelines, civil awareness, epidemiology and data, NAFLD detection, and NAFLD care management) and categorising the responses as high, medium, and low; a multiple correspondence analysis was then applied., [Results]: The highest scoring countries were India (42.7) and the United Kingdom (40.0), with 32 countries (31%) scoring zero out of 100. For 5 of the domains a minority of countries were categorised as high-level while the majority were categorised as low-level. No country had a national or sub-national strategy for NAFLD and, [Conclusions]: Although NAFLD is a pressing public health problem, no country was found to be well prepared to address it. There is a pressing need for strategies to address NAFLD at national and global levels., The data collection and analysis were funded by the EASL International Liver Foundation with support from, Intercept, Bristol-Myers-Squibb Company, Genfit, and MSD. Data collection for the original European data was funded by the EASL International Liver Foundation supported by Gilead Sciences Europe Ltd., Allergan Pharmaceutical International Ltd., Bristol-Myers-Squibb Company, Pfizer Inc., and Resoundant Inc.

Published
2021

40. Coincidence of NOD2-Associated Autoinflammatory Disease (Yao Syndrome) and HCV Infection With Fatal Consequences: Interaction Between Genes and Environment

Author

Beat Trueb, Stefan Kuchen, Lei Zhuang, Jean-François Dufour, Peter M. Villiger, Irene Keller, and Leona Isabella von Köckritz

Subjects
030203 arthritis & rheumatology, 0301 basic medicine, YAO SYNDROME, business.industry, Hereditary Autoinflammatory Diseases, MEDLINE, Nod2 Signaling Adaptor Protein, 610 Medicine & health, Hepatitis C, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Fatal Outcome, Rheumatology, NOD2, Immunology, Mutation, Medicine, Humans, Autoinflammatory disease, business, Gene
Published
2021

41. Breakthroughs in hepatology

Author

Norah A. Terrault, Jean-François Dufour, Robert F. Schwabe, and Vincent Wai-Sun Wong

Subjects
Hepatology, Gastroenterology
Published
2022

42. The MELD upgrade exception: a successful strategy to optimize access to liver transplantation for patients with high waiting list mortality

Author

Melisa Dirchwolf, Chiara Becchetti, Sarah G. Gschwend, Christian Toso, Philipp Dutkowski, Franz Immer, Franziska Beyeler, Simona Rossi, Jonas Schropp, Jean-François Dufour, Vanessa Banz, Patrizia Amico, Andres Axel, John-David Aubert, Beckmann Sonja, Guido Beldi, Christian Benden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud, Sanda Branca, Heiner Bucher, Thierry Carrel, Emmanuelle Catana, Yves Chalandon, Sabina de Geest, Olivier de Rougemont, Michael Dickenmann, Joëlle L. Dreifuss, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Christian Garzoni, Paola G. Soccal, Christophe Gaudet, Emiliano Giostra, Déla Golshayan, Karine Hadaya, Jörg Halter, Dimitri Hauri, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Günther Hofbauer, Uyen Huynh-Do, Michael Koller, Bettina Laesser, Brian Lang, Roger Lehmann, Alexander Leichtle, Christian Lovis, Oriol Manuel, Hans-Peter Marti, Pierre Y. Martin, Michele Martinelli, Katell Mellac, Aurélia Merçay, Karin Mettler, Pascal Meylan, Nicolas Mueller, Antonia Müller, Thomas Müller, Ulrike Müller-Arndt, Beat Müllhaupt, Mirjam Nägeli, Manuel Pascual, Klara Posfay-Barbe, Juliane Rick, Anne Rosselet, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Aurelia Schnyder, Macé Schuurmans, Federico Simonetta, Katharina Staufer, Susanne Stampf, Jürg Steiger, Guido Stirniman, Ueli Stürzinger, Christian Van Delden, Jean-Pierre Venetz, Jean Villard, Julien Vionnet, Madeleine Wick, Markus Wilhlem, and Patrick Yerly

Subjects
Adult, Cohort Studies, Hepatology, Waiting Lists, Gastroenterology, Humans, Severity of Illness Index, Switzerland, Liver Transplantation
Abstract

MELD exceptions are designed to equipoise liver transplant waiting list survival. We aimed to analyze the impact of the MELD Upgrade rule and all other MELD exceptions on the liver transplant waiting list outcomes during 2012-2017 in Switzerland.We conducted a nationwide cohort study including all adult patients registered on the Swiss liver transplant waiting list between 2012 and 2017. Waiting list mortality and access to transplantation were analyzed, considering MELD exceptions as time-dependent covariates.730 patients were included. Patients with MELD Upgrade exceptions had a higher risk of dying while on the waiting list (OR 2.13; CI 95% 1.30-3.47) and also an increased likelihood of receiving a liver transplantation, when compared to patients without MELD exceptions. Patients with any type of MELD exceptions were more likely to be transplanted when compared to patients without MELD exceptions. The proportion of patients with MELD exceptions increased from 2012 to 2017 (44% vs 88%). Allocation MELD at the time of transplantation showed an annual increase (23 ± 8 points vs 32 ± 5 points, p 0.001).Only patients with MELD Upgrade exceptions had the expected combination of higher waiting list mortality and quicker access to liver transplantation.

Published
2021

43. NTCP: a pharmacological target for multiple liver conditions

Author

Jordi Gracia-Sancho and Jean-François Dufour

Subjects
Hepatitis B virus, medicine.medical_specialty, Symporters, business.industry, Liver Diseases, Gastroenterology, Organic Anion Transporters, Sodium-Dependent, Hepatology, Chronic liver disease, medicine.disease, medicine.disease_cause, Liver, Fibrosis, Hepatocellular carcinoma, Internal medicine, medicine, Cancer research, Hepatic stellate cell, Humans, Hepatic fibrosis, business, Myofibroblast
Abstract

Despite major therapeutic advances to treat patients with chronic liver diseases, one target remains elusive in hepatology and this is the most important one: liver fibrosis. We can cure patients from chronic hepatitis C; we can vaccinate against hepatitis B virus and control chronic hepatitis B; we have new drugs to treat cholestatic liver diseases and several lines of treatment to treat patients with hepatocellular carcinoma. But the process driving the prognosis of patients with chronic liver disease and the scarring process of the hepatic parenchyma are beyond our armamentarium. Hepatic fibrosing is a highly complex process which has been extensively studied in patients and in great details in animal models. Activation of quiescent hepatic stellate cells into α-smooth muscle actin (α-SMA)-positive myofibroblasts is a key mechanism since once activated, these cells secrete collagens and other matrix components participating actively in the scarring process. Numerous potential druggable mechanisms have been investigated and pharmacologically tested with success in animal models. However, despite great interest from the academic community and from the pharma only a few drugs have been tested in clinical trials with disappointing results. Salhab et al conducted an elegant series of experiments studying an unlikely target to treat hepatic fibrosis namely the Na+/taurocholate cotransporting polypeptide (NTCP).1 NTCP was the first bile acid transporter to be cloned. This feat was achieved in 1989 by Hagenbruch et al when he worked in the laboratory of the late P. Meier-Abt in Zurich using an expression cloning strategy.2 NTCP is expressed on the basolateral membrane of hepatocytes allowing the hepatocellular uptake …

Published
2021

44. Prognostic Factors and Treatment Efficacy in Spinal Cord Sarcoidosis: An Observational Cohort With Long-term Follow-up

Author

Antoine Gavoille, Anne-Claire Desbois, Bastien Joubert, Cécile-Audrey Durel, Clément Auvens, Emilie Berthoux, Thierry Delboy, Jean François Dufour, Alin Turcu, Bernard Bonnotte, Thibault Moreau, Guillaume Le Guenno, Marc André, Marc Ruivard, Jean-Philippe Camdessanche, Jean-Christophe G. Antoine, Romain Marignier, Catherine Chapelon-Abric, David Saadoun, and Pascal Sève

Subjects
Treatment Outcome, Sarcoidosis, Spinal Cord, Contrast Media, Humans, Gadolinium, Neurology (clinical), Prognosis, Immunosuppressive Agents, Follow-Up Studies, Retrospective Studies
Abstract

Background and ObjectivesSpinal cord sarcoidosis is a rare manifestation of sarcoidosis with a consequent risk of neurologic sequelae for the patient. We investigated prognostic factors and efficacy of immunosuppressive treatments in a longitudinal cohort.MethodsWe retrospectively studied patients with spinal cord sarcoidosis followed between 1995 and 2021 in 7 centers in France. Patients with definite, probable, or possible spinal cord sarcoidosis according to the Neurosarcoidosis Consortium Consensus Group criteria and with spinal cord involvement confirmed by MRI were included. We analyzed relapse or progression rate with a Poisson model, initial Rankin score with a linear model, and change in the Rankin score during follow-up with a logistic model.ResultsA total of 97 patients were followed for a median of 7.8 years. Overall mean relapse or progression rate was 0.17 per person-year and decreased over time. At last visit, 46 (47.4%) patients had a loss of autonomy (Rankin score ≥2). The main prognostic factors significantly associated with relapse or progression rate were gadolinium enhancement (relative rate [95% CI] 0.61 [0.4, 0.95]) or meningeal involvement (relative rate [95% CI] 2.05 [1.31, 3.19]) on spinal cord MRI and cell count (relative rate [95% CI] per 1 log increase 1.16 [1.01, 1.33]) on CSF analysis. Relapse or progression rate was not significantly associated with initial Rankin score or Expanded Disability Status Scale. Tumor necrosis factor–α (TNF-α) antagonists significantly decreased relapse or progression rate compared with corticosteroids alone (relative rate [95% CI] 0.33 [0.11, 0.98]). Azathioprine was significantly less effective than methotrexate on relapse or progression rate (relative rate [95% CI] 2.83 [1.04, 7.75]) and change in Rankin score (mean difference [95% CI] 0.65 [0.23, 1.08]).DiscussionRegarding the relapse or progression rate, meningeal localization of sarcoidosis was associated with a worse prognosis, TNF-α antagonists resulted in a significant decrease compared to corticosteroids alone, and methotrexate was more effective than azathioprine.Classification of EvidenceThis study provides Class IV evidence that in individuals with spinal cord neurosarcoidosis, TNF-α antagonists were associated with decreased relapse or progression rate compared to corticosteroids alone, but other therapies showed no significant benefit.

Published
2021

45. Immunotherapy as a Downstaging Therapy for Liver Transplantation

Author

Birgit Schwacha-Eipper, Iulia Minciuna, Jean-François Dufour, and Vanessa Banz

Subjects
Male, 0301 basic medicine, Sorafenib, Oncology, medicine.medical_specialty, Carcinoma, Hepatocellular, medicine.medical_treatment, Liver transplantation, Milan criteria, Systemic therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Carcinoma, Humans, Medicine, 610 Medicine & health, Immune Checkpoint Inhibitors, neoplasms, Response rate (survey), Hepatology, business.industry, Liver Neoplasms, Immunotherapy, Middle Aged, medicine.disease, digestive system diseases, Liver Transplantation, Nivolumab, 030104 developmental biology, Hepatocellular carcinoma, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

Locoregional therapies are downstaging methods for patients with hepatocellular carcinoma (HCC) outside Milan criteria. Sorafenib was the first systemic therapy tested in a neoadjuvant setting of liver transplantation, but with unsatisfactory results due to minimal response rate(1). Recently, immune checkpoint inhibitors have been shown to control HCC in a significant fraction of patients and to even induce complete response (2).

Published
2020

46. The global epidemiology of nonalcoholic steatohepatitis (NASH) and associated risk factors–A targeted literature review

Author

Jean-François Dufour, Maria-Magdalena Balp, Marcos Pedrosa, Nico Janssens, Patricia Lopez, Roger Scherer, and S.J. Mckenna

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, MEDLINE, digestive system, Diseases of the endocrine glands. Clinical endocrinology, Endocrinology, Internal medicine, NAFLD, Epidemiology, Nonalcoholic fatty liver disease, medicine, Prevalence, education, education.field_of_study, Disease progression, business.industry, NASH, Type 2 Diabetes Mellitus, nutritional and metabolic diseases, medicine.disease, RC648-665, Obesity, digestive system diseases, Risk factors, Observational study, business, Cohort study
Abstract

Background: There is a wide variation across studies in the reported prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). A targeted literature review was conducted to understand the prevalence of NALFD and NASH in the general population and specific sub-populations as well as identify risk factors associated with NASH. Methods: Embase and Medline databases (2003–July 2018, English language) and relevant conferences were searched to identify observational studies and meta-analysis reporting outcomes of interest. Small cohort studies (

Published
2021

47. Comparison of long-term survivals following hepatectomy for hepatocellular carcinoma according to the time-point of recurrence and treatment modalities for recurrent disease

Author

C Di Pietro Martinelli, Corina Kim-Fuchs, Jean-François Dufour, Banz, Andreas Andreou, Guido Beldi, Daniel Candinas, Severin Gloor, and Anja Lachenmayer

Subjects
medicine.medical_specialty, Palliative care, business.industry, medicine.medical_treatment, Liver transplantation, medicine.disease, Chemotherapy regimen, Surgery, Term (time), Hepatocellular carcinoma, medicine, Liver function, Hepatectomy, Time point, business
Abstract

Objective Disease recurrence following curatively intended hepatectomy for hepatocellular carcinoma (HCC) limits oncologic outcome. Based on the extent, location and time-point of tumor recurrence, different therapeutic modalities are available to treat recurrent HCC. Therefore, our aim was to investigate the role of these treatments and the time-point of recurrence on long-term survival. Methods Clinicopathological data of patients, who underwent hepatectomy for HCC at a major hepatobiliary center in Switzerland between 2012 and 2019, were assessed. Patients suffering tumor recurrence were stratified according to the treatment modalities for recurrent HCC including surgical treatment (repeat hepatectomy or liver transplantation), interventional treatment, and conservative treatment (chemotherapy or best supportive care). Groups were compared regarding to overall survival (OS). Additionally, long-term outcomes were compared between patients with early (≤ 12 months) and late (> 12 months) tumor recurrence. Results During the study period, 159 patients underwent hepatectomy for HCC. Median follow-up time was 53 months. After a median time of seven (1-64) months, 74 patients were diagnosed with tumor recurrence (47 %). The majority of patients developed early recurrence (n = 49) and 58 patients had intrahepatic recurrence only. Treatment options were re-resection, liver transplantation, interventional methods, and palliative therapy in 5, 15, 23, and 31 patients, respectively. Surgical treatment was significantly associated with improved OS compared to interventional and conservative treatment (5-year OS: 84% vs. 39% vs. 30%, p Conclusion Repeat hepatectomy or liver transplantation for recurrent HCC following hepatectomy is associated with better long-term survival compared to interventional or conservative therapies, especially for patients with late tumor recurrence. Patients with intrahepatic HCC recurrence should be evaluated according to the extent of tumor burden, liver function, and functional status to identify the best candidates for a surgical treatment.

Published
2021

48. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667]

Subjects
Male, Carcinogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 13/2, 13/1, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, LIVER-CANCER, R PACKAGE, RNA-SEQ, 14/19, Cancer, 0303 health sciences, Multidisciplinary, NONALCOHOLIC STEATOHEPATITIS, Liver Neoplasms, article, ddc, 3. Good health, 13/31, Multidisciplinary Sciences, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Science & Technology - Other Topics, [SDV.IMM]Life Sciences [q-bio]/Immunology, 64/60, Tumor necrosis factor alpha, Immunotherapy, Adjuvant, 631/67, Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, 14/32, 03 medical and health sciences, 14/34, 13/21, [SDV.CAN] Life Sciences [q-bio]/Cancer, ADVANCED HEPATOCELLULAR-CARCINOMA, NAFLD, medicine, Animals, Humans, 14/35, 030304 developmental biology, Science & Technology, Tumor Necrosis Factor-alpha, business.industry, 631/250/251, medicine.disease, PHASE-III, digestive system diseases, 13/51, 14/63, 59/57, T-CELLS, Cancer research, Steatohepatitis, business, CD8
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Published
2021

49. Laparoscopic Liver Findings—An Instructional Collection for Endoscopic Surgeons

Author

Jean-François Dufour, Franziska Siegenthaler, Sara Imboden, Annette Kuhn, Michael D. Mueller, and Stefan Mohr

Subjects
medicine.medical_specialty, medicine.diagnostic_test, Adenoma, business.industry, General surgery, Endometriosis, Focal nodular hyperplasia, Gynecologic Diseases, Hepatology, medicine.disease, body regions, Internal medicine, medicine, Hamartoma, Laparoscopy, business, Ovarian cancer
Abstract

Introduction: During laparoscopy all viscera should be viewed. This is particularly true for the upper abdomen regarding gynecologic diseases such as ovarian cancer and endometriosis. Freq...

Published
2021

50. Systemic therapy of advanced hepatocellular carcinoma

Author

Markus Peck-Radosavljevic, Jean-François Dufour, Arndt Vogel, Jörg Trojan, and Peter R. Galle

Subjects
Oncology, Sorafenib, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, medicine.drug_class, Immune checkpoint inhibitors, medicine.medical_treatment, Clinical Decision-Making, 610 Medicine & health, Systemic therapy, Tyrosine-kinase inhibitor, Internal medicine, medicine, Humans, Neoplasm Metastasis, Neoplasm Staging, business.industry, Liver Neoplasms, Cancer, Disease Management, General Medicine, Immunotherapy, medicine.disease, Sequential treatment, Combined Modality Therapy, Treatment Outcome, Hepatocellular carcinoma, Disease Susceptibility, business, medicine.drug
Abstract

For a decade, sorafenib remained the only approved first-line treatment and standard of care for advanced hepatocellular carcinoma. The treatment landscape has been evolving rapidly over the past 2 years with the approval of additional first-and second-line systemic treatments, most of which are targeted therapies. The expected approval of immunotherapies constitutes a paradigm shift: for the first time in years, a checkpoint inhibitor in combination with a VEGF antibody recently outperformed sorafenib with regards to efficacy. The wider availability of systemic therapies increases the chance for longer overall survival but raises new questions concerning the role of local options, treatment choice and sequential treatment. Following an expert discussion at the German Cancer Congress 2020 in Berlin, this article aims to summarize the current evidence on and experience of treatment choice and sequence in first- and second-line therapy.

Published
2021

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