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Multiple cells of origin in cholangiocarcinoma underlie biological,epidemiological and clinical heterogeneity

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World Journal of Gastrointestinal Oncology 2012年第5期4卷 94-102页

作者： Vincenzo Cardinale Guido Carpino Lola Reid Eugenio Gaudio domenico alvaro Department of MedicoSurgical Sciences and Biotechnologies Polo PontinoSapienza University of Rome00137 RomeItaly Department of Health Sciences University of Rome "Foro Italico"000135 RomeItaly Department of Anatomical HistologicalForensic Medicine and Orthopedics SciencesSapienza University of Rome000137 RomeItaly Department of Cell and Molecular Physiology Biomedical EngineeringProgram in Molecular Biology and BiotechnologyUNC School of MedicineChapel HillNC 27599United States Eleonora Lorillard Spencer-Cenci Foundation 00156 RomeItaly

Recent histological and molecular characterization of cholangiocarcinoma(CCA) highlights the heterogeneity of this cancer that may emerge at different sites of the biliary tree and with different macroscopic or morphological ***,different stem cell niches have been recently described in the liver and biliarytree,suggesting this as the basis of the heterogeneity of intrahepatic(IH)-and extrahepatic(EH)-CCAs,which are two largely different tumors from both biological and epidemiological points of *** complexity of the organization of the liver stem cell compartments could underlie the CCA clinical-pathological heterogeneity and the criticisms in classifying primitive liver *** recent advances highlight a possible new classification of CCAs based on cells of origin and this responds to the need of generating homogenous diagnostic,prognostic and,hopefully,therapeutic categories of IH-and EH-CCAs.

关键词： Intrahepatic cholangiocarcinoma Extrahepatic cholangiocarcinoma Cholangiocarcinoma classification Cholangiolocarcinoma Cells of origin Cancer stem cells Peribiliary glands Biliary tree stem/progenitor cells Human hepatic stem cells Risk factors Targeted therapies

Intra-hepatic and extra-hepatic cholangiocarcinoma:New insight into epidemiology and risk factors

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World Journal of Gastrointestinal Oncology 2010年第11期2卷 407-416页

作者： Vincenzo Cardinale Rossella Semeraro Alessia Torrice Manuela Gatto Cristina Napoli Maria Consiglia Bragazzi Raffaele Gentile domenico alvaro Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche Sapienza University of Rome00185 RomeItaly

Cholangiocarcinoma(CCA) is a malignant tumour that arises from biliary epithelium at any portion of the biliary *** is currently classified as intra-hepatic or extra-hepatic CCA(EH-CCA).Recent evidences suggest that intra-hepatic CCA(IH-CCA) and EH-CCA are biologically different cancers,giving further support to a number of recent epidemiological studies showing large differences in terms of incidence,mortality and risk *** purpose of this manuscript is to review recent literature dealing with the descriptive epidemiology and risk factors of CCA with a special effort to compare IH-with EH-CCA.

关键词： Liver flukes Viral hepatitis Liver stem cells Peribiliary glands Epidemiology Extra-hepatic cholangiocarcinoma Risk factors Primary sclerosing cholangitis Intra-hepatic cholangiocarcinoma Liver cirrhosis

Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas

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World Journal of Gastroenterology 2019年第31期25卷 4343-4359页

作者： Piera Zaccari Vincenzo Cardinale Carola Severi Federica Pedica Guido Carpino Eugenio Gaudio Claudio Doglioni Maria Chiara Petrone domenico alvaro Paolo Giorgio Arcidiacono Gabriele Capurso Department of Internal Medicine and Medical Specialties Gastroenterology UnitSapienza University of RomeRome 00161Italy Department of Medico-Surgical Sciences and Biotechnologies Sapienza University of Rome00161 RomeItaly Pathology Department Pancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilan 20132Italy Department of Movement Human and Health SciencesDivision of Health SciencesUniversity of Rome"Foro Italico"Rome 00161Italy Department of Anatomical HistologicalForensic Medicine and Orthopedics SciencesDivision of Human AnatomySapienza University of RomeRome 00161Italy PancreatoBiliary Endoscopy and EUS Division Pancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilan 20132Italy Department of Translational and Precision Medicine Sapienza University of RomeRome 00161Italy

the bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological ***,preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular,histological and pathophysiological *** neoplasms are reported in biliary tract,as biliary intraepithelial neoplasm(BilIN),and in pancreas,as pancreatic intraepithelial neoplasm(PanIN).Both can evolve to invasive carcinomas,respectively cholangiocarcinoma(CCA)and pancreatic ductal adenocarcinoma(PDAC).Intraductal papillary neoplasms arise in biliary tract and *** papillary neoplasm of the biliary tract(IPNB)share common histologic and phenotypic features such as pancreatobiliary,gastric,intestinal and oncocytic types,and biological behavior with the pancreatic counterpart,the intraductal papillary mucinous neoplasm of the pancreas(IPMN).All these neoplastic lesions exhibit similar immunohistochemical phenotypes,suggesting a common carcinogenic ***,CCA and PDAC display similar clinic-pathological features as growth pattern,poor response to conventional chemotherapy and radiotherapy and,as a consequence,an unfavorable *** objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells.

关键词： Biliary Pancreatic Progenitors Preneoplastic Common Tumor

An isolate alpha-fetoprotein producing gastric cancer liver metastasis emerged in a patient previously affected by radiation induced liver disease

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World Journal of Hepatology 2013年第7期5卷 398-403页

作者： Vincenzo Cardinale Gianmaria De Filippis Alessandro Corsi Augusto La Penna Michele Rossi Carlo Catalano Paolo Bianco Adriano De Santis domenico alvaro Department of Medico-Surgical Sciences and Biotechnologies Sapienza University of Rome Department of Radiology Sapienza University of Rome Department of Molecular Science Sapienza University of Rome Department of Clinical Medicine Sapienza University of Rome Department of Radiology Sant'Andrea Hospital Sapienza University of Rome

We report a case of an isolated hepatic neoplasia which originated in a site of the liver previously affected by radiation induced liver disease (RILD) in a patient resected for gastric cancer and referred to us for high serum alpha-fetoprotein (AFP) levels. This case challenged us in distiguishing, even histologically, between primary liver cancer and AFP producing gastric cancer metastasis. Only a panel of immunohis-tochemical markers allowed the definitive diagnosis of liver metastasis of endodermal stem cell-derived and AFP producing gastric cancer. We discuss the criteria for a differential diagnosis, as well as the possible link between RILD and emergence of liver neoplasia.

关键词： Alpha-fetoprotein producing gastric cancer Hepatoid adenocarcinoma Liver metastasization Radiation induced liver disease

Estrogens and the pathophysiology of the biliary tree

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World Journal of Gastroenterology 2006年第22期12卷 3537-3545页

作者： domenico alvaro Maria Grazia Mancino Paolo Onori Antonio Franchitto Gianfranco Alpini Heather Francis Shannon Glaset Eugenio Gaudio Division of Gastroenterology University of Rome "La Sapienza"RomeItaly University of Rome "La Sapienza"Polo PontinoLatinaItaly Division of Gastroenterology University of Rome "La Sapienza"RomeItaly Department of Experimental Medicine Section of Human and Clinical Anatomy State University of L'AquilaL'AquilaItaly Department of Anatomy University of Rome "La Sapienza" RomeItaly Department of Medicine The Texas A&M University System Health Science Center College of Medicine Scott & White HospitalTempleTX 76504United States ResearchCentral Texas Veterans Health Care SystemScott & White HospitalTempleTX 76504United States Systems Biology and Translational MedicineThe Texas A&M University System Health Science Center College of MedicineTX 76504United States Division of R&E Scott & White Hospital TempleTX 76504United States Eugenio Gaudio Department of Anatomy University of Rome "La Sapienza"RomeItaly

The scientific framework concerning estrogen effects on different tissues has expanded enormously during the last decades, when estrogen receptor （ER） subtypes were identified. Estrogens are not only essential for the female reproductive system, but they also control fundamental functions in other tissues including the cardiovascular system, bone, brain and liver. Recently, estrogens have been shown to target the biliary tree, where they modulate the proliferative and secretory activities of cholangiocytes, the epithelial cells lining bile ducts. By acting on both estrogen receptors （ER-α） and （ER-β） subtypes, and by activating either genomic or non-genomic pathways, estrogens play a key role in the complex loop of growth factors and cytokines, which modulates the proliferative response of cholangiocytes to damage. Specifically, estrogens activate intracellular signalling cascades JERK1/2 （extracellular regulated　kinases 1/2, PI3-kinase/AKT （phosphatidylinositol-3＇ kinase/AKT）] typical of growth factors such as insulin like growth factor （IGF1）, nerve growth factor （NGF） and vascular endothelial growth factor （VEGF）, thus potentiating their action. In addition, estrogens stimulate the secretion of different growth factors in proliferating cholangiocytes. This review specifically deals with the recent advances related to the role and mechanisms by which estrogens modulate cholangiocyte functions in normal and pathological conditions.

关键词： Estrogens Cholangiocytes IGF1 Proliferation APDKD PBC Cholangiocarcinoma SERMs

Cholangiocytes and blood supply

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World Journal of Gastroenterology 2006年第22期12卷 3546-3552页

作者： Eugenio Gaudio Antonio Franchitto Luigi Pannarale Guido Carpino Gianfranco Alpini Heather Francis Shannon Glaser domenico alvaro Paolo Onori Department of Human Anatomy University of Rome "La Sapienza" RomeItaly Central Texas Veterans Health Care System and Department of Medicine and Systems Biology and Translational Medicine College of MedicineTempleTXUnited States Division of Research and Education Scott & White Hospital and The Texas A&M University System Health Science Center College of MedicineTempleTXUnited States Department of Medicine and Division of Research and Education Scott & White Hospital and The Texas A&M University System Health Science Center College of MedicineTempleTXUnited States Division of Gastroenterology University of Rome "La Sapienza" RomeItaly University of Rome "La Sapienza" Polo PontinoLatinaItaly Department of Experimental Medicine Section of Human and Clinical Anatomy State University of L'AquilaL'AquilaItaly

The microvascular supply of the biliary tree, the peribiliary plexus （PBP）, stems from the hepatic artery branches and flows into the hepatic sinusoids. A detailed three-dimensional study of the PBP has been performed by using the Scanning Electron Microscopy vascular corrosion casts （SEMvcc） technique. Considering that the PBP plays a fundamental role in supporting the secretory and absorptive functions of the biliary epithelium, their organization in either normalcy and pathology is explored. The normal liver shows the PBP arranged around extra-and intrahepatic biliary tree. In the small portal tract PBP was characterized by a single layer of capillaries which progressively continued with the extrahepatic PBP where it showed a morecomplex vascular network. After common duct ligation （BDL）, progressive modifications of bile duct and PBP proliferation are observed. The PBP presents a three-dimensional network arranged around many bile ducts and appears as bundles of vessels, composed by capillaries of homogeneous diameter with a typical round mesh structure. The PBP network is easily distinguishable from the sinusoidal network which appears normal. Considering the enormous extension of the PBP during BDL, the possible role played by the Vascular Endothelial Growth Factor （VEGF） is evaluated. VEGF-A,VEGF-C and their related receptors appeared highly immunopositive in proliferating cholangiocytes of BDL rats. The administration of anti-VEGF-A or anti-VEGF-C antibodies to BDL rats as well as hepatic artery ligation induced a reduced bile duct mass. The administration of rVEGF-A to BDL hepatic artery ligated rats prevented the decrease of cholangiocyte proliferation and VEGF-A expression as compared to BDL control rats. These data suggest the role of arterial blood supply of the biliary tree in conditions of cholangiocyte proliferation, such as it occurs during chronic cholestasis. On the other hand,the role played by VEGF as a tool of cross-talk between cholangiocytes

关键词： Peribiliary plexus Periportal plexus Cholangiocytes

Intrahepatic cholangiocarcinoma: review and update

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Hepatoma Research 2018年第6期4卷 25-40页

作者： Vincenzo Cardinale Maria Consiglia Bragazzi Guido Carpino Sabina Di Matteo Diletta Overi Lorenzo Nevi Eugenio Gaudio domenico alvaro Department of Medico-Surgical Sciences and Biotechnologies Polo PontinoSapienza University of RomeRome 00198Italy Department of Movement Human and Health SciencesDivision of Health SciencesUniversity of Rome“Foro Italico”Rome 00100Italy Department of Medicine and Medical Specialties Sapienza University of RomeRome 00198Italy Division of Human Anatomy Department of AnatomicalHistologicalForensic Medicine and Orthopedics SciencesSapienza University of RomeRome 00198Italy

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that could develop at any level from the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar and distal on the basis of its anatomical location. Of note, these three CCA subtypes have common features but also important inter-tumor and intra-tumor differences that can affect the pathogenesis and outcome. A unique feature of iCCA is that it recognizes as origin tissues, the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, which are furnished by two distinct stem cell niches, the canals of Hering and the peribiliary glands, respectively. The complexity of iCCA pathogenesis highlights the need of a multidisciplinary, translational and systemic approach to this malignancy. This review will focus on the advances of iCCA epidemiology, histo-morphology, risk factors, molecular pathogenesis, revealing the existence of multiple subsets of iCCA.

关键词： Cholangiocarcinoma classifications inflammation cells of origin stem cells molecular profiling

Diagnostic Yield of Non-Invasive Testing in Patients with Anomalous Aortic Origin of Coronary Arteries:A Multicentric Experience

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Congenital Heart Disease 2022年第4期17卷 375-385页

作者： Alberto Cipriani Pietro Bernardo Dall’Aglio Laura Mazzotta domenico Sirico George Sarris Mark Hazekamp Thierry Carrel Alessandro Frigiola Vladimir Sojak Mauro Lo Rito Jurgen Horer Regine Roussin Julie Cleuziou Bart Meyns Jose Fragata Helena Telles Anastasios C.Polimenakos Katrien Francois Altin Veshti Jukka Salminen alvaro Gonzalez Rocafort Matej Nosal Eleftherios Protopapas Roberto Tumbarello Patrizio Sarto Cinzia Pegoraro Raffaella Motta Giovanni Di Salvo domenico Corrado Vladimiro LVida Massimo A.Padalino Department of Cardio-Thoracic Vascular Sciences and Public HealthUniversity of PadovaPadovaItaly Department of Woman and Child’s Health Pediatric CardiologyUniversity of PadovaPadovaItaly Athens Heart Surgery Institute and Iaso Children’s Hospital AthensGreece Department for Cardiovascular Surgery University Medical CenterLeidenThe Netherlands Department for Cardiovascular Surgery University Hospital BernBernSwitzerland Department of Congenital Cardiac Surgery IRCCS Policlinico San DonatoSan Donato MilaneseItaly Department of Pediatric Cardiology and Congenital Heart Disease Hôpital Marie LannelongueUniversitéParis-SudLe Plessis-RobinsonFrance Deutsch Herz Zentrum MunichGermany Katholieke Universiteit Leuven LeuvenBelgium Cardiothoracic Surgery Hospital de Santa Marta Rua LisbonPortugal Department of Pediatric Cardiothoracic Surgery Children’s Hospital of GeorgiaGeorgiaUSA Department of Cardiac Surgery University Hospital GhentGhentBelgium Division of Cardiac Surgery University Hospital Center of TiranaTiranaAlbania Department of Pediatric Cardiac Surgery Hospital for Children and AdolescentsUniversity of HelsinkiHelsinkiFinland Congenital Cardiac Surgery Department Hospital Universitario La PazMadridSpain Department of Pediatric Cardiac Surgery National Institute of Cardio-Vascular Diseases-Children’s Heart CenterBratislavaSlovakia Division of Pediatric Cardiology Ospedale BrotzuCagliariItaly Division of Sport Medicine Ospedale Ca’FoncelloTrevisoItaly Department of Medicine Radiology ClinicUniversity of Padua Medical SchoolPadovaItaly

Background:Anomalous aortic origin of a coronary artery(AAOCA)is a congenital heart disease with a 0.3%−0.5%*** is challenging due to nonspecific clinical *** stratification and treatment are currently based on expert consensus and single-center case ***:Demographical and clinical data of AAOCA patients from 17 tertiary-care centers were *** imaging studies(Bidimensional echocardiography,coronary computed tomography angiography[CCTA]were *** correlations with anomalous coronary course and origin were ***:Data from 239 patients(42%males,mean age 15 y)affected by AAOCA were collected;154 had AAOCA involving the right coronary artery(AAORCA),62 the left(AAOLCA),23 other anomalies.211(88%)presented with an inter-arterial *** electrocardiogram(ECG)was abnormal in 37(16%).AAOCA was detected by transthoracic echocardiography and CCTA in 53%and 92%of patients,*** of the patients reported cardiac symptoms(119/239;50%),mostly during exercise in 121/178(68%).An ischemic response was demonstrated in 37/106(35%)and 16/31(52%)of patients undergoing ECG stress test and stress-rest single positron emission cardiac *** with AAORCA,patients with AAOLCA presented more frequently with syncope(18%vs.5%,P=0.002),in particular when associated with inter-arterial course(22%vs.5%,P<0.001).Conclusion:Diagnosis of AAOCA is a clinical challenge due to nonspecific clinical presentations and low sensitivity of first-line cardiac screening *** seems to be strictly correlated to AAOLCA with inter-arterial course.

关键词： Anomalous coronary arteries congenital echocardiography coronary computed tomography angiography