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Thiopurine-methyltransferase variants in inflammatory bowel disease:Prevalence and toxicity in Brazilian patients

World Journal of Gastroenterology 2014年第12期20卷 3327-3334页

作者： Ana Teresa P Carvalho Barbara C Esberard Renata S B Fróes Davy C M Rapozo Ana B Grinman Tatiana A Simo Juliana C V C Santos Antonio José V Carneiro Luis Felipe Ribeiro-Pinto Heitor S P de Souza Disciplina de gastroenterologia e Endoscopia Digestiva Universidade do Estado do Rio de Janeiro Programa de Carcinogênese Molecular Instituto Nacional de Cancer Laboratório de Toxicologia e Biologia Molecular Universidade do Estado do Rio de Janeiro Servi?o de gastroenterologia Departamento de Clínica MédicaUniversidade Federal do Rio de Janeiro

AIM:To analyze the prevalence of thiopurine-methyltransferase(TPMT)genotypes and their associationwith drug toxicity in inflammatory bowel disease(IBD)patients from southeastern Brazil.METHODS:A total of 219 consecutive patients with IBD,of which 146 had Crohn’s disease and 73 had ulcerative colitis,regularly seen at the outpatient unit of the Division of Gastroenterology at the University Hospital Pedro Ernesto of the State University of Rio de Janeiro,a tertiary referral center,were enrolled in this study from February 2009 to January 2011.We analyzed the presence of major TPMT genetic variants(TPMT*2,*3A,*3C)in IBD patients by means of a specific allele and RFLP-PCR.Genomic DNA was isolated from peripheral blood leukocytes by proteinase-K/Sodium Dodecyl Sulfate digestion and phenol-chloroform extraction.TPMT*2(C238G),TPMT*3A(G460A/A719G),and TPMT*3C(A719G)genotypes were detected by real-time polymerase chain reaction followed by direct sequencing with specific primers.Clinical data were systematically recorded,and correlated with the genotype results.RESULTS:The distribution of the selected TPMT gene polymorphism TPMT*2(C238G),TPMT*3A(G460A/A719G),and TPMT*3C(A719G)genotypes was 3.6%,5.4%,and 7.7%of the patients,respectively.Among the side effects recorded from patients taking azathioprine,14 patients presented with pancreatitis and/or an elevation of pancreatic enzymes,while 6 patients had liver toxicity,and 2 patients exhibited myelosuppression/neutropenia.TPMT polymorphisms were detected in 37/219 patients(8 heterozygous for*2,11 heterozygous for*3A,and 18 heterozygous for*3C).No homozygotic polymorphisms were found.Despite the prevalence of the TPMT*3C genotype,no differences among the genotype frequencies were significant.Although no association was detected regarding myelotoxicity or hepatotoxicity,a trend towards the elevation of pancreatic enzymes was observed for TPMT*2 and TPMT*3C genotypes.CONCLUSION:The prevalence of TPMT genotypes was high among Brazilian patients.Variants genes*2and*3C may be ass

关键词： Inflammatory bowel disease Thiopurinemethyl-transf

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Budd-Chiari syndrome management:Lights and shadows

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World Journal of Hepatology 2011年第10期3卷 262-264页

作者： Andrea Mancuso Epatologia e gastroenterologia Ospedale Niguarda Ca'Granda

Budd-Chiari syndrome (BCS) is a rare disease whose management should follow a step by step strategy.Anticoagulation and medical therapy should be the first line treatment.Revascularization or TIPS are indicated in case of no response to medical therapy.OLT should be indicated as a rescue therapy and anticoagulation be started soon after OLT.However,no clear indica-tion can actually be given about the timing of different treatments.Moreover,there is some concern about treatment of some subgroup of patients,especially regarding the risk of recurrence after liver transplanta-tion.The topic of this paper is to critically review the actual knowledge of BCS management.

关键词： Budd-Chiari syndrome Management Liver transplantation

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Identification of IL11RA and MELK amplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines

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World Journal of Gastroenterology 2016年第43期22卷 9506-9514页

作者： Danielle Queiroz Calcagno Sylvia Santomi Takeno Carolina Oliveira Gigek Mariana Ferreira Leal Fernanda Wisnieski Elizabeth Suchi Chen Taíssa Maíra Thomaz Araújo Eleonidas Moura Lima Maria Isabel Melaragno Samia Demachki Paulo Pimentel Assumpcao Rommel Rodriguez Burbano Marília Cardoso Smith Disciplina de Genética Departamento de Morfologia e GenéticaUniversidade Federal de Sao Paulo Núcleo de Pesquisas em Oncologia Hospital Universitário Joao de Barros Barreto Departamento de Biologia Molecular Universidade Federal da Paraíba Disciplina de gastroenterologia Cirúrgica Universidade Federal de Sao Paulo Departamento de Ortopedia e Traumatologia Universidade Federal de Sao Paulo

AIM To identify common copy number alterations on gastric cancer cell lines.METHODS Four gastric cancer cell lines(ACP02, ACP03, AGP01 and PG100) underwent chromosomal comparative genome hybridization and array comparative genome hybridization. We also confirmed the results by fluorescence in situ hybridization analysis using the bacterial artificial chromosome clone and quantitative real time PCR analysis.RESULTS The amplification of 9p13.3 was detected in all cell lines by both methodologies. An increase in the copy number of 9p13.3 was also confirmed by fluorescence in situ hybridization analysis. Moreover, the interleukin 11 receptor alpha(IL11RA) and maternal embryonic leucine zipper kinase(MELK) genes, which are present in the 9p13.3 amplicon, revealed gains of the MELK gene in all the cell lines studied. Additionally, a gain in the copy number of IL11 RA and MELK was observed in 19.1%(13/68) and 55.9%(38/68) of primary gastric adenocarcinoma samples, respectively. CONCLUSION The characterization of a small gain region at 9p13.3 in gastric cancer cell lines and primary gastric adenocarcinoma samples has revealed MELK as a candidate target gene that is possibly related to the development of gastric cancer.

关键词： IL11RA Gastric cancer Genomic profiling MELK 9p13.3

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Hepatocellular Carcinoma and Liver Transplantation:State of the Art

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Journal of Clinical and Translational Hepatology 2014年第3期2卷 176-181页

作者： Andrea Mancuso Giovanni Perricone Epatologia e gastroenterologia Ospedale Niguarda Ca'GrandaMilanoItaly Medicina Interna 1 Azienda di Rilievo Nazionale ad Alta Specializzazione Civico-Di Cristina-BenfratelliPalermoItaly

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in chronic liver disease and cirrhosis.The incidence of HCC is growing worldwide.With respect to any other available treatment for liver cancer,liver transplantation (LT) has the highest potential to cure.LTallows for removal at once of both the tumor ("seed")and the damaged-hepatic tissue ("soil") where cancerogenesis and chronic liver disorders have progressed together.The Milan criteria (MC) have been applied worldwide to select patients with HCC for LT,yielding a 4-year survival rate of 75%.These criteria represent the benchmark for patient selection and are the basis for comparison with any other suggested criteria.However,MC are often considered to be too restrictive,and recent data show that between 25% and 50% of patients with HCC are currently transplanted beyond conventional indications.Consequently,any unrestricted expansion of selection criteria will increase the need for donor organs,lengthen waiting periods,increase drop-out rates,and impair outcomes on intention-to-treat analysis.Management of HCC recurrence after LT is challenging.There are a few reports available regarding the safety and efficacy of sorafenib for HCC recurrence after LT,but the data are heterogeneous.A multi-center prospective randomized controlled trial comparing placebo with sorafenib is advised.Alternatively,a metaanalysis of patient survival with sorafenib for HCC recurrence after LT could be helpful to characterize the therapeutic benefit and safety of sorafenib.Here,we review the use of LT for HCC,with particular emphasis on the selection criteria for transplantation in patients with HCC and management of HCC recurrence after LT.

关键词： Hepatocellular carcinoma Liver transplantation Selection criteria Milan criteria Recurrence Sorafenib

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Protective benefit of minimally invasive liver surgery for hepatocellular carcinoma prior to transplant

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Hepatoma Research 2022年第1期8卷 179-187页

作者： Simone Khouzam Duilio Pagano Marco Barbara Vito Di Marco Giada Pietrosi Marco Maringhini Marco Canzonieri Sergio Calamia Salvatore Gruttadauria Sidney Kimmel Medical College Thomas Jefferson UniversityPhiladelphiaPA 19107USA Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation IRCCS-ISMETT(Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per I Trapianti e Terapie ad Alta Specializzazione)UPMC(University of Pittsburgh Medical Center)via E.Tricomi 5Palermo 90127Italy Sezione di gastroenterologia e Epatologia Dipartimento Biomedico di Medicina Interna e SpecialisticaUniversity of PalermoPalermo 90128Italy Medicina Interna Universitàdi Palermo/ISMETTVia del Vespro 129Palermo 90127Italy Department of Surgery and Medical and Surgical Specialties University of CataniaCatania 95124Italy

Aim:The purpose of this study is to assess the benefit of laparoscopic liver resection(LLR)for hepatocellular carcinoma(HCC)given recurrence and future need for liver transplantation(LT).Methods:Data on liver resections were gathered from the Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione(IRCCS-ISMETT)from 2003-2021.A retrospective analysis of 1408 consecutive adult patients who had a liver resection was performed with categorization based on the underlying disease process.A sub-analysis studied the 291 patients who had an LLR with an intention to transplant approach after LLR.Results:From 2012 to 2020,ISMETT’s mean annual LLR rate was 45%.Data suggests that a laparoscopic approach to iterative surgical treatment for HCC has demonstrated protective benefits.Compared to open surgery or LT,LLR is protective against the risk of de-listing,post-transplant patient death,tumor recurrence,adhesions,and bleeding in a cirrhotic patient.Kaplan Meier’s analysis showed no difference between post-LT survival curves for those with prior open abdominal surgery or LLR(P=0.658).Conclusion:Laparoscopic surgery has important protective advantages over laparotomy surgery for the surgical treatment of HCC,particularly since treatment is not always curative.LLR can be considered a bridge therapy for transplantation,ensuring less crowding of waiting lists,a desirable condition in areas of donor storage.

关键词： Laparoscopic liver resection hepatocellular carcinoma minimally invasive liver surgery

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Gut microbiota role in irritable bowel syndrome:Newtherapeutic strategies

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World Journal of Gastroenterology 2016年第7期22卷 2219-2241页

作者： Eleonora Distrutti Lorenzo Monaldi Patrizia Ricci Stefano Fiorucci S.C.di gastroenterologia ed Epatologia Azienda Ospedaliera di Perugia06100 PerugiaItaly Dipartimento di Scienze Chirurgiche e Biomediche Universitàdegli Studi di Perugia06100 PerugiaItaly

In the last decade the impressive expansion of our knowledge of the vast microbial community that resides in the human intestine, the gut microbiota, has provided support to the concept that a disturbed intestinal ecology might promote development and maintenance of symptoms in irritable bowel syndrome(IBS). As a correlate, manipulation of gut microbiota represents a new strategy for the treatment of this multifactorial disease. A number of attempts have been made to modulate the gut bacterial composition, following the idea that expansion of bacterial species considered as beneficial(Lactobacilli and Bifidobacteria) associated with the reduction of those considered harmful(Clostridium, Escherichia coli, Salmonella, Shigella and Pseudomonas) should attenuate IBS symptoms. In this conceptual framework, probiotics appear an attractive option in terms of both efficacy and safety, while prebiotics, synbiotics and antibiotics still need confirmation. Fecal transplant is an old treatment translated from the cure of intestinal infective pathologies that has recently gained a new life as therapeutic option for those patients with a disturbed gut ecosystem, but data on IBS are scanty and randomized, placebo-controlled studies are required.

关键词： Irritable bowel syndrome Gut microbiota Probiotics Prebiotics Synbiotics Antibiotics Fecaltransplantation

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Production of reactive oxygen species and expression of inducible nitric oxide synthase in rat isolated Kupffer cells stimulated by Leptospira interrogans and Borrelia burgdorfen

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World Journal of Gastroenterology 2006年第19期12卷 3077-3081页

作者： Antonella Marangoni Silvia Accardo Rita Aldini Massimo Guardigli Francesca Cavrini Vittorio Sambri Marco Montagnani Aldo Roda Roberto Cevenini Sezione di Microbiologia DMCSS University of Bologna BolognaItaly Istituto di Scienze Chimiche University of Bologna BolognaItaly Dipartimento di Scienze Farmaceutiche University of Bologna BolognaItaly Dipartimento di Medicina Interna e gastroenterologia University of Bologna BolognaItaly

瞄准：为了评估反应的氧种类(ROS ) 和可诱导的氮的氧化物的表示的生产，在老鼠的 synthase (i NOS ) 孤立肾脏钩端螺旋体和包柔氏螺旋体属 burgdorferi 刺激的 Kupffer 房间(KC ) 。方法：老鼠 Kupffer 房间被肝的灌注用 0.05% 胶原酶... 详细信息

瞄准：为了评估反应的氧种类(ROS ) 和可诱导的氮的氧化物的表示的生产，在老鼠的 synthase (i NOS ) 孤立肾脏钩端螺旋体和包柔氏螺旋体属 burgdorferi 刺激的 Kupffer 房间(KC ) 。方法：老鼠 Kupffer 房间被肝的灌注用 0.05% 胶原酶分开，并且由 Percoll 坡度净化了。净化的 Kupffer 房间是有活着的 L 的测试在试管内。interogans 和 B。burgdorferi 准备。ROS 的生产被化合光决定，而 i NOS 蛋白质表达式被西方的污点试金用 anti-iNOS 抗体计算。结果：B。burgdorferi 并且到一更少的程度 L。interrogans 与一座山峰导致了 ROS 生产在感染以后的 35 min。化合光信号日益增多地减少了并且由孵化的 180 min 是无法发现的。Leptospirae 和 borreliae 在在 6 个小时达到顶点并且仍然是明显的 Kupffer 房间导致了增加的 i NOS 表情在感染以后的 22 h。结论：螺旋菌的两个类在老鼠 Kupffer 细胞导致了 ROS 和 i NOS 生产。自从在 leptospiral 以及在 borrelial 感染的肝损坏的原因，仍然是未知的，我们建议那螺旋体和肝的包柔氏螺旋体属损坏能被氧激进分子开始调停，并且然后被氮的氧化物部分地至少维持。

关键词：一氧化氮合酶钩端螺旋体包柔氏螺旋体菌细菌感染

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Management of hepatocellular carcinoma: Enlightening the gray zones

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World Journal of Hepatology 2013年第6期5卷 302-310页

作者： Andrea Mancuso Epatologia e gastroenterologia Ospedale Niguarda Cà Granda20162 Milano Italy Medicina Interna 1 Azienda di Rilievo Nazionale ad Alta Specializzazione Ospedale Civico90127 Palermo Italy

Management of hepatocellular carcinoma (HCC) has been continuously evolving during recent years. HCC is a worldwide clinical and social issue and typically a complicates cirrhosis. The incidence of HCC is increasing, not only in the general population of patients with cirrhosis, but particularly in some subgroups of patients, like those with human immunodeficiency virus infection or thalassemia. Since a 3% annual HCC incidence has been estimated in cirrhosis, a biannual screening is generally suggested. The diagnostic criteria of HCC has recently had a dramatic evolution during recent years. HCC diagnosis is now made only on radiological criteria in the majority of the cases. In the context of cirrhosis, the universally accepted criteria for HCC diagnosis is contrast enhancement in arterial phase and washout in venous/late phase at imaging, the so called "typical pattern". However, recently up- dated guidelines slightly differ in diagnostic criteria. Apart from liver transplantation, the only cure of both HCC and underlying liver cirrhosis, all the other treatments have to match with higher rate of HCC recurrence. The latter can be classified into curative (resection and percutaneous ablation) and palliative treatments. The aim of this paper was to review the currentknowledge on management of HCC and to enlighten the areas of uncertainty.

关键词： Hepatocellular carcinoma Management Trans-arterial chemoembolization Orthotopic liver transplantation Surgery

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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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Liver carcinogenesis: diagnostic and clinical aspects of preneoplastic nodules

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Hepatoma Research 2019年第5期5卷 10-25页

作者： Mauro Borzio Fabio Paladino Giampiero Francica U.O.gastroenterologia ed Endoscopia Digestiva ASST Melegnano-MartesanaMelegnanoVizzolo Predabissi 20070MIItaly U.O.Chirurgia ASST Melegnano-MartesanaMelegnanoVizzolo Predabissi 20070MIItaly U.O.Ecografia ed Econterventistica Pineta Grande HospitalCastel Volturno 81030CEItaly

In multistep hepatocarcinogenesis,sizable lesions can precede the development of hepatocellular carcinoma(HCC).These lesions are currently classified as low grade(LG)-and high grade(HG)-dysplastic nodules.Following international guidelines recommending the surveillance of cirrhotic patients,a growing number of 1-2 cm hepatocellular nodules are recognized including early hepatocellular carcinoma(eHCC)and DN the latter accounting for as many as 70%of nodules<1 cm.HG-DN are currently considered the most advanced HCC precursors.The histological diagnosis of low-grade dysplastic nodule(LG-DN),high-grade dysplastic nodule(HG-DN)and eHCC in small liver biopsies requires a comprehensive stepwise morphological and immunocytochemical approach.By imaging the differential diagnosis among these lesions is a challenge.According to vascular enhancement at dynamic computed tomography(CT)or magnetic resonance imaging(MRI)these precursors are classified as hypo-vascular/indeterminate nodules even though distinction between LG-DN and HG-DN is almost impossible.The introduction of gadoexetic acid-enhanced MRI has represented an extremely important advance in this field allowing a better differentiation of dysplastic lesions from eHCC and progressed HCC.Additional MRI features as diffusion-weighted imaging further improved diagnostic accuracy of imaging.According to Liver Imaging Reporting and Data System(LI-RADS),either CT/MRI or Contrast-Enhanced Ultrasound LI-RADS,the dysplastic lesions should be categorized as LR-3 or LR-4.Natural history of these lesions confirmed that HCC can develop from HG-DN but which nodule and when it will undergo malignant transformation is not predictable.The search and validation of radiological and tissue markers able to select lesions more prone to HCC development,is currently underway.Whether and how HG-DN should be ablated or closely followed up is currently debated.

关键词： Low-grade dysplastic nodule high-grade dysplastic nodule early hepatocellular carcinoma progressed hepatocellular carcinoma dynamic imaging gadoexetic acid-enhanced resonance imaging hepatobiliary phase

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