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Molecular mechanisms of liver carcinogenesis related to metabolic syndrome

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Hepatoma Research 2022年第1期8卷 22-34页

作者： claudia campani Jean-Charles Nault Team of Functional Genomics of Solid Tumors Centre de Recherche des CordeliersSorbonne UniversitéInsermUniversitéde ParisParis F-75006France Equipe labellisée Ligue Nationale Contre le Cancer Labex OncoImmunologyParis F-75006France Department of Experimental and Clinical Medicine University of FlorenceFlorence 50139Italy Service d’hépatologie Hôpital AvicenneHôpitaux Universitaires Paris-Seine-Saint-DenisAssistance-Publique Hôpitaux de ParisBobigny 93000France Unitéde Formation et de Recherche SantéMédecine et Biologie Humaine UniversitéParis 13Communautéd’Universités et Etablissements Sorbonne Paris CitéBobigny 93000France

Global prevalence of non-alcoholic fatty liver disease(NAFLD)and of NAFLD-hepatocellular carcinoma(HCC)is estimated to grow in the next years.The burden of NAFLD and the evidence that NAFLD-HCC arises also in noncirrhotic patients,explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression.Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines,an increase in oxidative stress,DNA damage,and the activation of multiple signaling pathways involved in cell proliferation.Moreover,a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system,dysbiosis,and alterations in bile acids metabolism.Several dietary,genetic,or combined mouse models have been used to study nonalcoholic steatohepatitis(NASH)development and its progression to HCC,but models that fully recapitulate the biological and prognostic features of human NASH are still lacking.In humans,four single nucleotide polymorphisms(PNPLA3,TM6SF2,GCKR,and MBOAT7)have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients,whereas HSD17B13 polymorphism has a protective effect.In addition,higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients.The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC.

关键词： Hepatocellular carcinoma mouse model genetic predisposition cirrhosis non-alcoholic fatty liver disease immune system

Practical insights into chronic management of hepatic Wilson’s disease

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World Journal of Clinical Cases 2022年第14期10卷 4334-4347页

作者： Erica Nicola Lynch claudia campani Tommaso Innocenti Gabriele Dragoni Paolo Forte Andrea Galli Gastroenterology Research Unit Department of Experimental and Clinical Biomedical Sciences“Mario Serio”University of FlorenceFlorence 50134Italy Department of Experimental and Clinical Medicine University of FlorenceFlorence 50134Italy Department of Medical Biotechnologies University of SienaSiena 53100Italy Division of Gastroenterology University Hospital“Careggi”Florence 50134Italy

Wilson’s disease(WD)is a rare inherited disorder of human copper metabolism,with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations.In healthy individuals,the bile is the main route of elimination of copper.In WD patients,copper accumulates in the liver,it is released into the bloodstream,and is excreted in urine.Copper can also be accumulated in the brain,kidneys,heart,and osseous matter and causes damage due to direct toxicity or oxidative stress.Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood.Adherent,non-cirrhotic WD patients seem to have a normal life expectancy.Nevertheless,chronic management of patients with Wilson’s disease is challenging,as available biochemical tests have many limitations and do not allow a clear identification of non-compliance,overtreatment,or treatment goals.To provide optimal care,clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment.The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD.In particular,it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment.It also analyses available evidence on pregnancy and the role of low-copper diet in WD.Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.

关键词： Wilson’s disease Urinary copper excretion Non-ceruloplasmin-bound copper D-penicillamine Trientine Zinc salts

Understanding fatigue in primary biliary cholangitis:From pathophysiology to treatment perspectives

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World Journal of Hepatology 2022年第6期14卷 1111-1119页

作者： Erica Nicola Lynch claudia campani Tommaso Innocenti Gabriele Dragoni Maria Rosa Biagini Paolo Forte Andrea Galli Gastroenterology Research Unit Department of Experimental and Clinical Biomedical Sciences“Mario Serio”University of FlorenceFlorence 50134Italy Department of Experimental and Clinical Medicine University of FlorenceFlorence 50134Italy Department of Medical Biotechnologies University of SienaSiena 53100Italy Division of Gastroenterology University Hospital“Careggi”Florence 50134Italy

Fatigue is considered one of the most frequent and debilitating symptoms in primary biliary cholangitis(PBC),affecting over 50%of PBC patients.One in five patients with PBC suffer from severe fatigue,which significantly impairs quality of life.Fatigue is made up of a central and a peripheral component,whose pathophysiology is still greatly unresolved.Central fatigue is characterised by a lack of self-motivation and can manifest both in physical and mental activities(lack of intention).Peripheral fatigue includes neuromuscular dysfunction and muscle weakness(lack of ability).Peripheral fatigue could be explained by an excessive deviation from aerobic to anaerobic metabolism leading to excessive lactic acid accumulation and therefore accelerated decline in muscle function and prolonged recovery time.As opposed to itching,and with the exception of endstage liver disease,fatigue is not related to disease progression.The objective of this review is to outline current understanding regarding the pathophysiology of fatigue,the role of comorbidities and contributing factors,the main tools for fatigue assessment,the failed therapeutic options,and future treatment perspectives for this disabling symptom.Since fatigue is an extremely common and debilitating symptom and there is still no licensed therapy for fatigue in PBC patients,further research is warranted to understand its causative mechanisms and to find an effective treatment.

关键词： Fatigue Primary biliary cholangitis Treatment Pathophysiology Central fatigue Peripheral fatigue

Main factors influencing long-term outcomes of liver transplantation in 2022

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World Journal of Hepatology 2023年第3期15卷 321-352页

作者： Elisa Fuochi Lorenzo Anastasio Erica Nicola Lynch claudia campani Gabriele Dragoni Stefano Milani Andrea Galli Tommaso Innocenti Gastroenterology Research Unit Department of Experimental and Clinical Biomedical Sciences“Mario Serio”University of FlorenceFlorence 50134Italy Department of Experimental and Clinical Medicine University of FlorenceFlorence 50134Italy Department of Medical Biotechnologies University of SienaSiena 53100Italy

Liver transplant(LT)outcomes have markedly improved in the recent decades,even if long-term morbidity and mortality are still considerable.Most of late deaths are independent from graft function and different comorbidities,including complications of metabolic syndrome and de novo neoplasms,seem to play a key role in determining long-term outcomes in LT recipients.This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation.In particular,the reduction of drug toxicity,the use of tools to identify high-risk patients,and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.

关键词： Alcohol Liver transplantation Long term survival Metabolic syndrome Renal dysfunction Therapy adherence

Evaluating the best treatment for multifocal hepatocellular carcinoma:A propensity score-matched analysis

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World Journal of Gastroenterology 2022年第29期28卷 3981-3993页

作者： Matteo Risaliti Ilenia Bartolini claudia campani Umberto Arena Carlotta Xodo Valentina Adotti Martina Rosi Antonio Taddei Paolo Muiesan Amedeo Amedei Giacomo Batignani Fabio Marra Department of Experimental and Clinical Medicine AOU CareggiFlorence 50134Italy

BACKGROUND Hepatocellular carcinoma(HCC)is a common tumour often diagnosed with a multifocal presentation.Patients with multifocal HCC represent a heterogeneous group.Although Trans-Arterial ChemoEmbolization(TACE)is the most frequently employed treatment for these patients,previous data suggested that liver resection(LR)could be a safe and effective procedure.AIM To compare LR and TACE in patients with multifocal HCC in terms of procedurerelated morbidity and oncologic outcomes.METHODS All patients with multifocal HCC who underwent LR or TACE as the first procedure between May 2011 and March 2021 were enrolled.The decision to perform surgery or TACE was made after a multidisciplinary team evaluation.Only patients in Child-Pugh class A or B7 and stage B(according to the Barcelona Clinic Liver Cancer staging system,without severe portal hypertension,vascular invasion,or extrahepatic spread)were included in the final analysis.Propensity score matching was used to adjust the baseline differences between patients undergoing LR and the TACE group[number and diameter of lesions,presence of cirrhosis,alpha-fetoprotein(AFP)levels,and Model for End-Stage Liver Disease score].The Kaplan-Meier method was used to estimate overall survival(OS)and disease-free survival(DFS).The outcomes of LR and TACE were compared using the log-rank test.RESULTS After matching,30 patients were eligible for the final analysis,15 in each group.Morbidity rates were 42.9% and 40% for LR and TACE,respectively(P=0.876).Median OS was not different in the LR and TACE groups(53 mo vs 18 mo,P=0.312),while DFS was significantly longer with LR(19 mo vs 0 mo,P=0.0001).Subgroup analysis showed that patients in the Italian Liver Cancer(ITA.LI.CA)B2 stage,with AFP levels lower than 400 ng/mL,less than 3 lesions,and lesions bigger than 41 mm,benefited more from LR in terms of DFS.Patients classified as ITA.LI.CA B3,with AFP levels higher than 400 ng/mL and with more than 3 lesions,appeared to receive more benefit from TACE in terms of OS.CONCLUSION In a small

关键词： Hepatocellular carcinoma Multifocal hepatocellular carcinoma Liver resection Trans-arterial chemoembolization Guidelines Liver tumour management

Systemic treatment of hepatocellular carcinoma:the times they are a-changin’

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Hepatobiliary Surgery and Nutrition 2021年第6期10卷 893-895页

作者： claudia campani Jean-Charles Nault Centre de Recherche des Cordeliers Sorbonne UniversitéInsermUniversitéde ParisTeam“Functional Genomics of Solid Tumors”ParisFrance Equipe labellisée Ligue Nationale Contre le Cancer Labex OncoImmunologyParisFrance Department of Experimental and Clinical Medicine University of FlorenceFlorenceItaly Service d’Hépatologie Hôpital AvicenneHôpitaux Universitaires Paris-Seine-Saint-DenisAssistance-Publique Hôpitaux de ParisBobignyFrance Unitéde Formation et de Recherche SantéMédecine et Biologie Humaine UniversitéParis 13Communautéd’Universités et Etablissements Sorbonne Paris CitéParisFrance

For a decade,sorafenib remained the only drug approved for the treatment of advanced hepatocellular carcinoma(HCC)due to the failure of several phase III trials in which alternative angiogenesis inhibitors were tested(1).In recent years,the field of systemic treatments of HCC has evolved quickly and a recent position paper of the European Association for the Study of the Liver has well described the current advances in the systemic treatment of advanced HCC as well as the unmet needs in the field(1).First,lenvatinib was approved as an alternative to sorafenib in the first-line setting,and,thus,regorafenib,cabozantinib and ramucirumab as second-line treatments for patients who progressed on sorafenib(1).

关键词： hepatocellular treatment Liver