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challenges of advanced hepatocellular carcinoma

World Journal of Gastroenterology 2016年第34期22卷 7645-7659页

作者： Stefano Colagrande Andrea L Inghilesi Sami Aburas Gian G Taliani Cosimo Nardi Fabio Marra Dipartimento di Scienze Biomediche Sperimentali e Cliniche University of Florence Dipartimento di Medicina Sperimentale e Clinica Centro di Ricerca DenotheUniversity of Florence

Hepatocellular carcinoma(HCC) is an aggressive malignancy,resulting as the third cause of death by cancer each year. The management of patients with HCC is complex,as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging,clinical and biochemical parameters is routinely performed,a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer. Since the introduction of sorafenib in clinical practice,several phase Ⅲ clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting. Locoregional therapies have also been tested as first line treatment,but their role in advanced HCC is still matter of debate. No single agent or combination therapies have been shown to impact outcomes after sorafenib failure. Therefore this review will focus on the range of experimental therapeutics for patients with advanced HCC and highlights the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally,robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomized trials.

关键词： Barcelona Clinic Liver Cancer Portal vein thrombosis Modified Response Evaluation Criteria in Solid Tumors Advanced hepatocellular carcinoma management Advanced hepatocellular carcinoma second line therapies Sorafenib

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Quick and easy assessment of sarcopenia in cirrhosis: Can ultrasound be the solution?

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World Journal of Gastroenterology 2024年第17期30卷 2287-2293页

作者： Francesca Campani Tancredi Vincenzo Li Cavoli Umberto Arena Fabio Marra Erica Nicola Lynch Claudia Campani Department of Health Science University Hospital CareggiUniversity of FlorenceFlorence 50134Italy Internal Medicine and Liver Unit University Hospital CareggiUniversity of FlorenceFlorence 50134Italy Department of Experimental and Clinical Medicine University of FlorenceFlorence 50134Italy Gastroenterology Research Unit Department of Experimental and Clinical Biomedical Sciences“Mario Serio”University of FlorenceFlorence 50134Italy Department of Medical Biotechnologies University of SienaSiena 53100Italy

Cirrhosis is frequently associated with sarcopenia,with reported rates of over 80%in patients with decompensated alcohol-related liver disease.Sarcopenia nega-tively impacts the prognosis of cirrhotic patients and affects the response to treatment of patients with hepatocellular carcinoma(HCC).For these reasons,identifying an easy-to-perform method to assess sarcopenia in is a key element in the optimization of care in this patient population.Assessment of muscle mass by computed tomography is considered the standard of care for the diagnosis of sarcopenia,but exposure to radiation and high costs limit its application in this setting,especially for repeated assessments.We believe that ultrasound,a cheap and harmless technique also used for HCC screening in cirrhotic patients,could have an expanding role in the diagnosis and follow-up of sarcopenia in these patients.

关键词： Sarcopenia Ultrasound Cirrhosis Hepatocellular carcinoma Computed tomography

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Delayed-release oral mesalamine tablet mimicking a small jejunal gastrointestinal stromal tumor:A case report

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World Journal of Clinical Cases 2022年第19期10卷 6710-6715页

作者： fabio Frosio Emanuele Rausa Paolo marra Marie-Christine Boutron-Ruault Alessandro Lucianetti Department of General Surgery ASST Papa Giovanni XXIII HospitalBergamo 24127Italy Department of Radiology ASST Papa Giovanni XXIII HospitalBergamo 24127Italy Paris-Saclay University UVSQInsermGustave RoussyExposome and Heredity TeamCentre for Epidemiology and Population Health(CESP U1018)Villejuif 94800France

BACKGROUND Enteric-coated medications are supposed to pass intact through the gastric environment and to release the drug content into the small intestine or the colon.Before dissolution of the enteric coating,they may appear hyperdense on computed tomography(CT).Unfortunately,few reports have been published on this topic so far.In this case report,the hyperdense appearance on contrastenhanced CT of an enteric-coated mesalamine tablet was initially misinterpreted as a jejunal gastrointestinal stromal tumor(GIST).CASE SUMMARY An asymptomatic 81-year-old male patient,who had undergone laparoscopic right nephrectomy four years earlier for stage 1 renal carcinoma,was diagnosed with a jejunal GIST at the 4-year follow-up thoraco-abdominal CT scan.He was referred to our hub hospital for gastroenterological evaluation,and subsequently underwent 18-fluorodeoxyglucose positron emission tomography,abdominal magnetic resonance imaging,and video capsule endoscopy.None of these examinations detected any lesion of the small intestine.After reviewing all the CT images in a multidisciplinary setting,the panel estimated that the hyperdense jejunal image was consistent with a tablet rather than a GIST.The tablet was an 800 mg delayed-release enteric-coated oral mesalamine tablet(Asacol®),which had been prescribed for non-specific colitis,while not informing the hospital physicians.CONCLUSION Delayed-release oral mesalamine(Asacol®),like other enteric-coated medications,can appear as a hyperdense image on a CT scan,mimicking a small intestinal GIST.Therefore,adetailed knowledge of the patients’medications and a multidisciplinary review of the images areessential.

关键词： Mesalamine Enteric-coating Asacol Tablet Gastrointestinal stromal tumor Case report

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Stemness features in liver cancer

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Hepatoma Research 2018年第11期4卷 1-15页

作者： Margherita Correnti Richell Booijink Giovanni Di Maira Chiara Raggi Fabio Marra Center for Autoimmune Liver Diseases Humanitas Clinical and Research CenterRozzano20089Italy Department of Biomaterial Science and Technology University of TwenteEnschede7500AEThe Netherlands Department of Clinical and Experimental Medicine University of FlorenceFlorence50141Italy

Heterogeneity is a cardinal hallmark of cancer, including primary liver cancer (PLC), and occurs at different layers including putative cell-of-origin. Current evidence suggests that within cellular subpopulations in PLC there are stem-like cells, the cancer stem cells (CSCs). The CSC concept has been recently proposed as an explanation of such intra-tumor heterogeneity. According to this model, CSCs are responsible for tumor initiation, recurrence, metastasis as well as drug-resistance. However, although the CSC hypothesis is intriguing and supported by a large number of experimental studies, there are still open questions regarding the origin of putative CSCs. Since chemo-resistance and recurrence represent major issues in PLC treatment, the development of new therapeutic strategies is needed, for which a good understanding of tumor behavior and in particular of CSCs biology is an imperative prerequisite. In this review we summarize the regulatory pathways that support CSC features in PLC. Moreover, we highlight the key features of hepatic CSC, in terms of enhanced drug-resistance, increased metastatic potential and metabolic rearrangement. Knowledge of the molecular mechanisms underlying CSC biology may provide novel options for PLC combination therapies.

关键词： Hepatocellular carcinoma cholangiocarcinoma cancer stem cells tumor heterogeneity drug-resistance

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Therapeutic application of stem cells in gastroenterology:An up-date

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World Journal of Gastroenterology 2011年第34期17卷 3870-3880页

作者： Patrizia Burra Debora Bizzaro Rachele Ciccocioppo Fabio Marra Anna Chiara Piscaglia Laura Porretti Antonio Gasbarrini Francesco Paolo Russo Department of Surgical and Gastroenterological Sciences Gastroenterology Section University of Padua First Department of Internal Medicine IRCCS Policlinico San Matteo Foundation University of Pavia Department of Internal Medicine University of Florence Department of Internal Medicine Gemelli Hospital "Gastrointestinal and Liver Stem Cell Research Group" (GILSteR) Catholic University of Rome Center of Transfusion Medicine Cell Therapand Cryobiology IRCCS Fondazione Ospedale Maggiore Poli-clinico Mangiagalli e Regina Elena

Adult stem cells represent the self-renewing progenitors of numerous body tissues, and they are currently classified according to their origin and differentiation ability. In recent years, the research on stem cells has expanded enormously and holds therapeutic promises for many patients suffering from currently disabling diseases. This paper focuses on the possible use of stem cells in the two main clinical settings in gastro-enterology, i.e., hepatic and intestinal diseases, which have a strong impact on public health worldwide. Despite encouraging results obtained in both regenerative medicine and immunemediated conditions,further studies are needed to fully understand the biology of stem cellsand carefully assess their put ativeonco- genicproperties.Moreover,there searchonstemcellsarousesferventethical,socialandpoliticaldebate.TheItalianSocietyofGastroenterologysponsoredaworkshoponstemcellsheldinVeronaduringtheⅩⅥCongressoftheFederationofItalianSocietiesofDigestiveDiseases(March 6-9,2010).Here,we report on the issues discussed,including liver and intestinal diseases that may benefit from stemcell therapy,the biology of hepatic and intestinal tissue repair,and stem cell usage inclinical trials.

关键词：干细胞治疗胃肠病应用肠道疾病自我更新分化能力公众健康世界范围

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Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy:A prospective pilot study

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World Journal of Gastroenterology 2015年第10期21卷 3013-3019页

作者： Cristina Stasi Alessia Piluso Umberto Arena Elena Salomoni Paolo Montalto Monica Monti Barbara Boldrini Giampaolo Corti Fabio Marra Giacomo Laffi Stefano Milani Anna Linda Zignego Department of Experimental and Clinical Medicine University of Florence Health Agency of Tuscany Gastrointestinal Endoscopy Unit Ospedale SS Cosma e Damiano Department of Biomedical Experimental and Clinical sciencesUniversity of Florence

AIM:To evaluate the association between liver stiffness(LS) prior to the initiation of dual/triple therapy and viral response.METHODS:LS was measured in all patients before treatment was administered.The therapeutic approach was based on hepatic,virological,and immunological evaluations and considered the fact that patients with severe fibrosis(F3)or compensated cirrhosis(F4)in Child-Pugh class A are the primary candidates for triple therapy.In total,65 hepatitis C virus(HCV)patients were treated with Peg-interferon/ribavirin(Peg-IFN/RBV);24patients were classified as genotypes 1/4(36.92%),and41 patients were classified as genotypes 2/3(63.08%)(dual therapy).In addition,20 HCV treatment-experienced genotype 1 patients were treated with Peg IFN-RBV and boceprevir(triple therapy).Wilcoxon rank-sum tests were used to compare the groups.RESULTS:LS significantly differed between dual therapy and triple therapy(P=0.002).The mean LS value before dual therapy treatment was 8.61±5.79k Pa and was significantly different between patients achieving a sustained virologic response(SVR)24weeks after therapy and those who did not(7.23±5.18 k Pa vs 11.72±5.99 k Pa,respectively,P=0.0003).The relative risk of non-response to therapy was 4.45(95%CI:2.32-8.55).The attributable risk of non-response to therapy was 49%.The mean LSvalue before triple therapy treatment was 13.29±8.57k Pa and was significantly different between patients achieving and not achieving SVR24(9.41±5.05 vs19.11±9.74,respectively;P=0.008).The relative risk of non-response to therapy was 5.57%(95%CI:1.50-20.65).The attributable risk of non-response to therapy(70%)was increased compared with dual therapy patients.Pre-treatment stiffness>12 k Pa was significantly associated with non-SVR(P<0.025)in both groups.CONCLUSION:Pre-treatment liver stiffness may be useful for predicting the response to treatment in patients treated with either dual or triple anti-HCV therapy.

关键词： Antiviral therapy Chronic hepatitis C Fibrosis Liv

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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

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Predictors of survival in patients with established cirrhosis and hepatocellular carcinoma treated with sorafenib

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World Journal of Gastroenterology 2014年第3期20卷 786-794页

作者： Andrea L Inghilesi Donatella Gallori Lorenzo Antonuzzo Paolo Forte Daniela Tomcikova Umberto Arena Stefano Colagrande Silvia Pradella Bernardo Fani Elena Gianni Luca Boni Giacomo Laffi Francesco Di Costanzo Fabio Marra Dipartimento di Medicina Sperimentale e Clinica Università degli Studi di Firenze Oncologia Medica Azienda Ospedaliero-Universitaria Careggi Gastroenterologia 2 Azienda Ospedaliero-Universitaria Careggi Centro per il Coordinamento delle Sperimentazioni Cliniche Istituto Toscano Tumoriand Azienda Ospedaliero-Universitaria Careggi Dipartimento di Scienze Biomediche Sperimentali e ClinicheUniversità degli Studi di Firenze

AIM:To investigate in greater detail the efficacy and safety of sorafenib for the treatment of hepatocellular carcinoma(HCC)in patients with established cirrhosis.METHODS:From October 2009 to July 2012 patients with an established diagnosis of cirrhosis and HCC treated with sorafenib were consecutively enrolled.According to the Barcelona Clinic Liver Cancer(BCLC)classification,patients were in the advanced stage(BCLC-C)or in the intermediate stage(BCLC-B)but unfit or unresponsive to other therapeutic strategies.Treatment was evaluated performing a 4-phase computed tomography or magnetic resonance imaging scan every 2-3 mo,and analyzed according to the modified Response Evaluation Criteria in Solid Tumors.Sorafenib was administered at 800 mg/d,until radiological progression or occurrence of unacceptable adverse events(AEs).Univariate and multivariate analyses identified predictors of 16-wk clinical benefit and overall survival.RESULTS:Forty-four patients were enrolled,15 had intermediate HCC and 14 a Child-Pugh score of B7.AEs caused treatment interruption in 19 patients(43%),and median treatment duration was shorter in this subset(5 wk vs 19 wk,P<0.001)and in the BCLC-C subgroup(13 wk vs 40 wk,P=0.015).No significant differences in the reason for treatment interruption or in treatment duration were found comparing patients in Child-Pugh class A vs B or in patients older or younger than 70 years.After 16 wk of treatment,18 patients(41%)had stable disease or partial response.Patients with viral infection or BCLC-C were at higher risk of disease progression.ECOG,extrahepatic spread,macrovascular invasion,alpha-fetoprotein or alkaline phosphatase levels at admission were independent predictors of overall survival.CONCLUSION:In patients with cirrhosis and HCC treated with sorafenib,AEs are a common cause of early treatment withdrawal.Vascular invasion and extrahepatic spread condition early response to treatment and survival.Baseline biochemical parameters may be helpful to identify patients at higher risk of shorter

关键词： Hepatocellular carcinoma Sorafenib Cirrhosis Adver

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Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis

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World Journal of Gastroenterology 2005年第32期11卷 4931-4938页

作者： Fabio Marra Raffaella DeFranco Gaia Robino Erica Novo Eva Efsen Sabrina Pastacaldi Elena Zamara Alessandro Vercelli Benedetta Lottini Carlo Spirli Mario Strazzabosco Massimo Pinzani Maurizio Parola Dipartimento di Medicina Interna and Center for ResearchTransfer and High Education ‘DENOTHE'University of FlorenceItaly Dipartimento di Medicina e Oncologia SperimentaleUniversity of Turin Italy Benedetta LottiniMassimo Pinzani Dipartimento di Medicina Interna and Center for ResearchTransferand High Education ‘DENOTHE'University of FlorenceItaly Dipartimento di AnatomiaFarmacologia e Medicina Legale University of TurinItaly Istituto Veneto di Medicina MolecolarePadua Italy

AIM: To investigate the effects of troglitazone (TGZ), an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-γ (PPAR-γ), for liver tissue repair, and the development of ductular reaction, following common bile duct ligation (BDL) in rats.METHODS: Rats were supplemented with TGZ (0.2% w/w in the pelleted food) for 1 wk before BDL or sham operation.Animals were killed at 1, 2, or 4 wk after surgery.RESULTS: The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type Ⅰ gene expression and liver hydroxyproline levels. Accumulation of α-smooth-muscle actin (SMA)-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells (HSC) and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase (GGT).CONCLUSION: Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.

关键词：胆管增生胆管纤维化小鼠动物实验慢性胆汁郁积治疗方法

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