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Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver

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World Journal of Gastroenterology 2005年第40期11卷 6262-6268页

作者： A Quaglia MA Jutand A Dhillon A Godfrey R Togni p bioulac-sage C Balabaud M Winnock Ap Dhillon Department of Histopathology INSERM U593 Lab pathology

AIM： To design a classification tool for the histological assessment of hepatocellular carcinoma （HCC）, dysplastic nodules （DN）, and macroregenerative nodules （MRN） in cirrhotic liver. METHODS： Two hundred and twelve hepatocellular nodules （106 HCC; 74 IRN, 32 DN） were assessed systematically, quantitatively, and semiquantitatively as appropriate for 10 histological features that have been described as helpful in distinguishing small HCC, DN, and MRN in cirrhotic livers. The data were analyzed by multiple correspondence analysis （MCA）. RESULTS： HCA distributed HCC, DN, and HRN as defined by traditional histological evaluation as well as the individual histological variables, in a ＂malignancy scale＂. Based on the MCA data representation, we created a classification tool, which categorizes an individual nodular lesion as MRN, DN, or HCC based on the balance of all histological features （i.e., vascular invasion, capsular invasion, tumor necrosis, tumor heterogeneity, reticulin loss, capillarization of sinusoids, trabecular thickness, nuclear atypia, and mitotic activity）. The classification tool classified most （83%） of a validation set of 47 nodules in the same way as the routine histological assessment. No discrepandes were present for DN and MRN between the routine histological assignment and the dassification tool. Of 25 HCC assigned by routine assessment in the validation set, 8 were assigned to the DN category by the classification tool. CONCLUSION： We have designed a classification tool for the histological assessment of HCC and its putative precursors in cirrhotic liver. Application of this toolsystematically records histological features of diagnostic importance in the evaluation of small HCC.

关键词： Hepatocellular carcinoma Cirrhosis Multiplecorrespondence analysis Large regenerative nodule Dysplastic nodule

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Unexpected discovery of 2 cases of hepatocyte nuclear factor 1α-mutated infracentimetic adenomatosis

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World Journal of Gastroenterology 2008年第30期14卷 4830-4833页

作者： Hervé Laumonier Anne Rullier Jean Saric Charles Balabaud paulette bioulac-sage Department of Radiology Hpital Saint André CHU Bordeaux Department of pathology Hpital Pellegrin CHU Bordeaux Department of Surgery Hpital Saint André CHU Bordeaux Department of Hepatology Hpital Saint André CHU Bordeaux

We present 2 cases of hepatocyte nuclear factor 1α (HNF1α)-mutated adenomatosis, discovered for reasons unrelated to this disease, and identified using immunohistochemical methods. These new tools may further our understanding of the link between adenomas/adenomatosis subtypes and their complications, and their association with other abnormalities.

关键词： Hepatocellular adenoma Adenomatosis Hepatocyte nuclear factor 1 Hepatocyte nuclear factor 1α mutation β-catenin mutation Focal nodular hyperplasia

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Tp53基因突变参与成人肝脏未分化(胚胎)肉瘤的生成,不同于Wnt和端粒酶途径:3例病例的免疫组化研究及2例病例的基因相关研究

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世界核心医学期刊文摘（胃肠病学分册） 2005年第7期1卷 54-54页

作者： Lepreux S. Rebouissou S. Le Bail B. p. bioulac- sage 王铮 Service d'Anatomie pathologique Hpital Pellegrin CHU Bordeaux 33076 Bordeaux France

Background/Aims: Hepatic undifferentiated (embryonal) sarcoma (HUS) is an exc eptional hepatic malignant tumor in adults. Genetic studies were never reported in adult cases. Methods: In this study concerning three cases of HUS occurring i n adult, we studied the three classical ways of carcinogenesis i.e. the Tp53 (p5 3), Wnt (CTNNB1/β - catenin and AXIN1) and telomerase (hTERT) pathways. We stu died the expression of p53, β - catenin and telomerase catalytic subunit hTERT by immunohistochemistry in the three cases; we determined Tp53 gene mutation in two cases and the genome- wide allelotype, AXIN1, and CTNNB1/β - catenin gen e mutation in one case. Results: Immunohistochemistry showed an overexpression o f p53 in more than 80% of tumoral cells; furthermore, mutations of Tp53 were o bserved in two cases, involving the sequence- specific DNA binding domain. In c ontrast, no mutation was found in CTNNB1/β - catenin and AXIN1 genes. Tumoral cells did not show hTERT staining nor nuclear expression of β - catenin. In ad dition, allelotype analysis in one case showed loss of heterozygosity of chromos ome 7p, 11p, 17p, 22q, and allelic imbalance of 1p, 8p, 20q. Conclusions: In thi s report of HUS in three adult patients, we emphasize the role of Tp53 pathway i n carcinogenesis of this rare tumor. This point could be of interest for therape utic strategies.

关键词：端粒酶途径 Tp53基因 Wnt 成人肝脏基因突变免疫组化研究肝脏恶性肿瘤 β-连环蛋白等位基因失衡序列特异性

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Genotype phenotype classification of hepatocellular adenoma

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World Journal of Gastroenterology 2007年第19期13卷 2649-2654页

作者： paulette bioulac-sage Jean Frédéric Blanc Sandra Rebouissou Charles Balabaud Jessica Zucman-Rossi CHU Bordeaux Hpital Pellegrin Department of Pathology Bordeaux F-33076 France Charles Balabaud Inserm U889 Bordeaux F-33076 GREF Univ Victor Segalen Bordeaux 2 Bordeaux F-33076 France Charles Balabaud CHU Bordeaux Hpital Saint André Department of Hepatology Bordeaux F-33075 France Inserm U674 CEPH Univ Paris 7 Paris F-75010 France CHU Bordeaux Hpital Saint André Department of Hepatology Bordeaux F-33075 France

Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria （presence of a TCFI/HNF1α or β-catenin mutation）, and an additional histological criterion （presence or absence of an inflammatory infiltrate）, subgroups of hepatocellular adenoma can be defined and distinguished from focal nodular hyperplasia. Analysis of 96 hepatocellular adenomas performed by a French collaborative network showed that they can be divided into four broad subgroups： the first one is defined by the presence of mutations in TCF1 gene inactivating the hepatocyte nuclear factor 1 （HNF1α）, the second by the presence of β-catenin activating mutations; the category without mutations of HNF1α or β-catenin is further divided into 2 subgroups depending on the presence or absence of inflammation. Therefore, the approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era directed by new molecular information. It is hoped that immunohistological tools will improve significantly diagnosis of liver biopsy in our ability to distinguish hepatocellular adenoma from focal nodular hyperplasia （FNH）, and to delineate clinically meaningful entities within each group to define the best clinical management. The optimal care of patients with a liver nodule will benefit from the recent knowledge coming from molecular biology and the combined expertise of hepatologists, pathologists, radiologists, and surgeons.

关键词： Hepatocellular adenoma HNF1α mutation β-catenin mutation Inflammatory adenoma Telangiectatic adenoma Maturity-onset diabetes of theyoung Hepatocyte nuclear factor 1 CTNNB1 Focal nodular hyperplasia

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Smoothelin,a new marker to determine the origin of liver fibrogenic cells

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World Journal of Gastroenterology 2013年第48期19卷 9343-9350页

作者： Sébastien Lepreux Christelle Guyot Fabrice Billet Chantal Combe Charles Balabaud paulette bioulac-sage Alexis Desmoulière CHU Bordeaux Hopital Pellegrin Service d’Anatomie Pathologique F-33076 Bordeaux France U889 and Université Victor Segalen Bordeaux 2 F-33076 Bordeaux France Division of Clinical pharmacology and Toxicology Department of Medicine University Hospital Zurich 8006 Zurich Switzerland Facultés de Médecine et de pharmacie Université de Limoges EA 6309 F-87025 LimogesFrance

AIM: To explore this hypothesis that smooth muscle cells may be capable of acquiring a myofibroblastic phenotype, we have studied the expression of smoothelin in fibrotic conditions.

关键词： Smooth muscle cells, Myofibroblasts, α -smooth muscle actin, Smoothelin, Fibrosis/cirrhosis, Hepatocellular carcinoma

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Transient and etiology-related transcription regulation in cirrhosis prior to hepatocellular carcinoma occurrence

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World Journal of Gastroenterology 2009年第3期15卷 300-309页

作者： Frédérique Caillot Céline Derambure paulette bioulac-sage Arnaud Franois Michel Scotte Odile Goria Martine Hiron Maryvonne Daveau Jean-philippe Salier Inserm Unité 905 and Institut Fédératif de Recherches Multidisciplinaires sur les peptides Faculté de Médecine-Pharmacie76183 RouenFrance Service d'Anatomie pathologique Centre Hospitalier Universitaireand Inserm U88933000 BordeauxFrance Département pathologie Centre Hospitalier Universitaire76183 RouenFrance Service de Chirurgie Générale et Digestive Centre Hospitalier Universitaire76183 RouenFrance Service d'Hépato-gastro-entérologie Centre Hospitalier Universitaire76183 RouenFrance

AIM： To search for transcription dysregulation that could （1） differentiate hepatocellular carcinoma （HCC）-free from HCC-related cirrhosis （2） differentiate HCC-free cirrhosis related to HCV from that related to alcohol intake. METHODS： Using microarray analysis, we compared transcript levels in HCC-free cirrhosis （alcoholism： 7; hepatitis C： 7）, HCC-associated cirrhosis （alcoholism： 10; hepatitis C： 10） and eight control livers. The identified transcripts were validated by qRT-pCR in an independent cohort of 45 samples （20 HCC-free cirrhosis; 15 HCC-associated cirrhosis and 10 control livers）. We also confirmed our results by ***： In HCC-free livers, we identified 70transcripts which differentiated between alcoholicrelated-cirrhosis, HCV-related cirrhosis and control livers. They mainly corresponded to down-regulation. Dysregulation of Signal Transduction and Activator of Transcription-3 （STAT-3） was found along with related changes in STAT-3 targets which occurred in an etiology-dependent fashion in HCC-free cirrhosis. In contrast, in HCC, such transcription dysregulations were not observed. CONCLUSION： We report that transcriptional dysregulations exist in HCC-free cirrhosis, are transiently observed prior to detectable HCC onset and may be appear like markers from cirrhosis to HCC transition.

关键词： Liver pathology Alcoholism Hepatitis Cvirus Gene expression Carcinogenesis

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pictures of focal nodular hyperplasia and hepatocellular adenomas

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World Journal of Hepatology 2014年第8期6卷 580-595页

作者： Christine Sempoux Charles Balabaud paulette bioulac-sage Service d’Anatomie pathologique Cliniques universitaires Saint Luc Université catholique de Louvain 1200 Brussels Belgium Inserm U 1053 Université Bordeaux Segalen33076 Bordeaux cedex France Inserm U 1053 Université Bordeaux Segalen 33076 Bordeaux cedex France

This practical atlas aims to help liver and non liver pa-thologists to recognize benign hepatocellular nodules on resected specimen. Macroscopic and microscopic views together with immunohistochemical stains illustrate typical and atypical aspects of focal nodular hyperplasia and of hepatocellular adenoma, including hepatocel-lular adenomas subtypes with references to clinical and imaging data. Each step is important to make a correct diagnosis. The specimen including the nodule and the non-tumoral liver should be sliced, photographed and all different looking areas adequately sampled for par-affin inclusion. Routine histology includes HE, trichrome and cytokeratin 7. Immunohistochemistry includes glu-tamine synthase and according to the above results ad-ditional markers such as liver fatty acid binding protein, C reactive protein and beta catenin may be realized to differentiate focal nodular hyperplasia from hepatocel-lular adenoma subtypes. Clues for differential diagnosis and pitfalls are explained and illustrated.

关键词： Focal nodular hyperplasia Hepatocellular adenoma Inflammatory hepatocellular adenoma Beta catenin Hepatocyte nuclear factor 1 alpha

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SYSTEMS ENGINEERING RESEARCH

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Journal of Systems Science and Systems Engineering 2008年第3期17卷 319-333页

作者： Abd-El-Kader SAHRAOUI Dennis M.BUEDE Andrew p.sage LAAS-CNRS and Universitéde Toulouse 7 Avenue du Colonel Roche Toulouse31077France Innovative Decisions Inc.2139 Golf Course Dr.RestonVA 20191 USA Dept.of Systems Engineering and Operations Research George Mason UniversityFairfaxVA 22030 USA

In this paper, we propose selected research topics that are believed central to progress and growth in the application of systems engineering （SE）. As a professional activity, and as an intellectual activity, systems engineering has strong links to such associated disciplines as decision analysis, operation research, project management, quality management, and systems design. When focussing on systems engineering research, we should distinguish between subjects that are of systems engineering essence and others that more closely correspond to those that are more relevant for related disciplines.

关键词： Systems engineering systems of systems requirements engineering systems families

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Relationship between the severity of hepatitis C virus-related liver disease and the presence of Helicobacter species in the liver: A prospective study

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World Journal of Gastroenterology 2006年第45期12卷 7278-7284页

作者： Laurent Castéra Anne pedeboscq Marcia Rocha Brigitte Le Bail Corinne Asencio Victor de Lédinghen pierre-Henri Bernard Christophe Laurent Marie-Edith Lafon Maylis Capdepont patrice Couzigou paulette bioulac-sage Charles Balabaud FrancisMégraud Armelle Ménard Service d'Hépato-Gastroentérologie H?pital St-André Bordeaux France Service d'Hépato-Gastroentérologie H?pital Haut Lévêque Pessac France INSERM ERI 10 Laboratoire deBactériologie Université Victor Segalen Bordeaux 2 BordeauxFrance INSERM E0362Groupe de Recherche pour l'étude du Foie Université VictorSegalen Bordeaux 2 Bordeaux France Service d'Anatomie pathologique H?pital Pellegrin Bordeaux France Service de ChirurgieDigestive H?pital St-André Bordeaux France Laboratoire de Virologie Université VictorSegalen Bordeaux 2 Bordeaux France

AIM: To determine the presence of Helicobacter species DNA in the liver of chronic hepatitis C (CHC) patients with and without cirrhosis as compared to controls, and to identify the bacterial species involved. METHODS: Seventy-nine consecutive patients (HBV and HIV negative) with a liver sample obtained after liver biopsy or hepatic resection were studied: 41 with CHC without cirrhosis, 12 with CHC and cirrhosis, and 26 controls (HCV negative). polymerase chain reactions (pCRs) targeting Helicobacter 16S rDNA and species- specific were performed on DNA extracted from the liver. A gastric infection with H pylori was determined by serology and confirmed by 13C-urea breath test. RESULTS: Overall, Helicobacter 16S rDNA was found in 16 patients (20.2%). Although positive cases tended to be higher in CHC patients with cirrhosis (41.6%) than in those without cirrhosis (17.0%) or in controls (15.4%), the difference was not statistically significant (p =0.08). H pylori-like DNA was identified in 12 cases and H. pullorum DNA in 2, while 2 cases remained unidenti- fied. Gastric infection with H pylori was found in only 2 of these patients. CONCLUSION: Our results do not confirm the associ- ation of Helicobacter species DNA in the liver of CHC patients with advanced liver disease. The lack of correlation between positive H pylori serology and the presence of H pylori-like DNA in the liver may indicate the presence of a variant of this species.

关键词： Hepatitis C virus Hepatitis Cirrhosis Helicobacter

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RNA polymerases in plasma cells trav-ELL2 the beat of a different drum

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World Journal of Immunology 2015年第3期5卷 99-112页

作者： sage M Smith Nolan T Carew Christine Milcarek Department of Immunology School of MedicineUniversity of Pittsburgh

There is a major transformation in gene expression between mature B cells （including follicular, marginal zone, and germinal center cells） and antibody secreting cells （ASCs）, i.e. , ASCs, （including plasma blasts, splenic plasma cells, and long-lived bone marrow plasma cells）. This signifcant change-over occurs to accommodate the massive amount of secretory-specific immunoglobulin that ASCs make and the export processes itself. It is well known that there is an up-regulation of a small number of ASC-specific transcription factors prdm1 （B-lymphocyte-induced maturation protein 1）, interferon regulatory factor 4, and Xbp1, and the reciprocal down-regulation of pax5, Bcl6 and Bach2, which maintain the B cell program. Less well appreciated are the major alterations in transcription elongation and RNA proce-ssing occurring between B cells and ASCs. The three ELL family members ELL1, 2 and 3 have different protein sequences and potentially distinct cellular roles in transcription elongation. ELL1 is involved in DNA repair and small RNAs while ELL3 was previously described as either testis or stem-cell specifc. After B cell stimulation to ASCs, ELL3 levels fall precipitously while ELL1 falls off slightly. ELL2 is induced at least 10-fold in ASCs relative to B cells. All of these changes cause the RNA polymerase Ⅱ in ASCs to acquire different properties, leading to differences in RNA processing and histone modifcations.

关键词： Interferon regulatory factor 4 Antibody secreting cells B cell differentiation ELL2 Secretory-specific antibody B-lymphocyte-induced maturation protein 1 OCA-B Super elongation complex Xbp-1 Mammalian target of rapamycin

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