1   852 176 CHOLANGIOCARCINOMA IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC): A COMPREHENSIVE REVIEW. CHOLANGIOCARCINOMA (CCA) IS THE MOST COMMON MALIGNANCY IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) AND CARRIES A HIGH RATE OF MORTALITY. ALTHOUGH THE PATHOGENESIS OF CCA IN PSC IS LARGELY UNKNOWN, INFLAMMATION-DRIVEN CARCINOGENESIS CONCOMITANT WITH VARIOUS GENETIC AND EPIGENETIC ABNORMALITIES ARE UNDERLYING FACTORS. THE MAJORITY OF CCA CASES DEVELOP FROM A DOMINANT STRICTURE (DS), WHICH IS DEFINED AS A STRICTURE WITH A DIAMETER < 1.5 MM IN THE COMMON BILE DUCT OR < 1.0 MM IN THE HEPATIC DUCT. IN PSC PATIENTS PRESENTING WITH AN ABRUPT AGGRAVATION OF JAUNDICE, PAIN, FATIGUE, PRURITUS, WEIGHT LOSS, OR WORSENING LIVER BIOCHEMISTRIES, CCA SHOULD BE SUSPECTED AND EVALUATED UTILIZING A VARIETY OF DIAGNOSTIC MODALITIES. HOWEVER, EARLY RECOGNITION OF CCA IN PSC REMAINS A MAJOR CHALLENGE. IMPORTANTLY, 30-50% OF CCA IN PSC PATIENTS ARE OBSERVED WITHIN THE FIRST YEAR FOLLOWING THE DIAGNOSIS OF PSC FOLLOWED BY AN ANNUAL INCIDENCE RANGING FROM 0.5 TO 1.5 PER 100 PERSONS, WHICH IS NEARLY 10 TO 1000 TIMES HIGHER THAN THAT IN THE GENERAL POPULATION. CUMULATIVE 5-YEAR, 10-YEAR, AND LIFETIME INCIDENCES ARE 7%, 8-11%, AND 9-20%, RESPECTIVELY. WHEN PSC-ASSOCIATED CCA IS DIAGNOSED, MOST TUMORS ARE UNRESECTABLE, AND NO EFFECTIVE MEDICATIONS ARE AVAILABLE. GIVEN THE POOR THERAPEUTIC OUTCOME, THE SURVEILLANCE AND MANAGEMENT OF PSC PATIENTS WHO ARE AT AN INCREASED RISK OF DEVELOPING CCA ARE OF IMPORTANCE. SUCH PATIENTS INCLUDE OLDER MALES WITH LARGE-DUCT PSC AND POSSIBLY CONCURRENT ULCERATIVE COLITIS. THUS, MORE ATTENTION SHOULD BE PAID TO PATIENTS WITH THESE CLINICAL FEATURES, IN PARTICULAR WITHIN THE FIRST YEAR AFTER PSC DIAGNOSIS. IN CONTRAST, CCA IS LESS FREQUENTLY OBSERVED IN PEDIATRIC OR FEMALE PSC PATIENTS OR IN THOSE WITH SMALL-DUCT PSC OR CONCURRENT CROHN'S DISEASE. RECENTLY, NEW BIOMARKERS SUCH AS ANTIBODIES TO GLYCOPROTEIN 2 HAVE BEEN FOUND TO BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CCA IN PSC. HEREIN, WE REVIEW THE LITERATURE ON THE PATHOGENESIS, INCIDENCE, CLINICAL FEATURES, AND RISK FACTORS, WITH A FOCUS ON VARIOUS DIAGNOSTIC MODALITIES OF PSC-ASSOCIATED CCA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  2936  52 GENETIC AND EPIGENETIC ABNORMALITIES IN PRIMARY SCLEROSING CHOLANGITIS-ASSOCIATED CHOLANGIOCARCINOMA. PRIMARY SCLEROSING CHOLANGITIS (PSC) IS A CHOLESTATIC LIVER DISEASE OF UNKNOWN ETIOLOGY, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE BILIARY TREE WITH SUBSEQUENT FIBROSIS AND CIRRHOSIS OF THE LIVER. PATIENTS WITH PSC ARE AT INCREASED RISK FOR THE DEVELOPMENT OF CHOLANGIOCARCINOMA (CCA), A HIGHLY MALIGNANT EPITHELIAL TUMOR ARISING FROM THE INTRAHEPATIC AND EXTRAHEPATIC BILE DUCTS. CURRENTLY, ORTHOTOPIC LIVER TRANSPLANTATION IS THE ONLY CURATIVE TREATMENT. THE LACK OF EFFICIENT DIAGNOSTIC METHODS FOR EARLY DETECTION AND THE LIMITED THERAPEUTIC OPTIONS FOR CCA ARE MAJOR PROBLEMS AND ARE ASSOCIATED WITH POOR SURVIVAL. THE PATHOGENESIS OF PSC-ASSOCIATED CCA IS COMPLEX AND POORLY UNDERSTOOD. IT SEEMS THAT PRO-INFLAMMATORY CYTOKINES PLAY AN IMPORTANT ROLE IN GENETIC AND EPIGENETIC CHANGES THAT CONTRIBUTE TO THE CARCINOGENIC PROCESS. THE MAPPING OF GENETIC ALTERATIONS MAY ELUCIDATE MOLECULAR TARGETS THAT MAY BE APPLIED AS BIOMARKERS TO FACILITATE EARLY DIAGNOSIS OF MALIGNANT DEGENERATION TO IMPROVE PATIENT OUTCOME. IN THE LAST DECADE, THE INTRODUCTION OF SEVERAL NOVEL MOLECULAR TECHNIQUES AVAILABLE FOR GENOME-WIDE SCREENING HAS ADVANCED OUR KNOWLEDGE ON MANY OF THE GENETIC ABNORMALITIES THAT ARE PREVALENT IN CCA AND PSC-ASSOCIATED CCA. THIS REVIEW SUMMARIZES GENETIC AND EPIGENETIC ABNORMALITIES, WHICH HAVE IMPORTANT POTENTIAL FOR CLINICAL APPLICATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  2422  36 EPIGENETIC SIGNATURES DISCRIMINATE PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE COLITIS FROM PATIENTS WITH ULCERATIVE COLITIS. BACKGROUND: PRIMARY SCLEROSING CHOLANGITIS (PSC) IS A CHRONIC INFLAMMATORY LIVER DISEASE AFFECTING THE INTRA- AND EXTRAHEPATIC BILE DUCTS, AND IS STRONGLY ASSOCIATED WITH ULCERATIVE COLITIS (UC). IN THIS STUDY, WE EXPLORED THE PERIPHERAL BLOOD DNA METHYLOME AND ITS IMMUNE CELL COMPOSITION IN PATIENTS WITH PSC-UC, UC, AND HEALTHY CONTROLS (HC) WITH THE AIM TO DEVELOP A PREDICTIVE ASSAY IN DISTINGUISHING PATIENTS WITH PSC-UC FROM THOSE WITH UC ALONE. METHODS: THE PERIPHERAL BLOOD DNA METHYLOME OF MALE PATIENTS WITH PSC AND CONCOMITANT UC, UC AND HCS WAS PROFILED USING THE ILLUMINA HUMANMETHYLATION INFINIUM EPIC BEADCHIP (850K) ARRAY. DIFFERENTIALLY METHYLATED CPG POSITION (DMP) AND REGION (DMR) ANALYSES WERE PERFORMED ALONGSIDE GRADIENT BOOSTING CLASSIFICATION ANALYSES TO DISCERN PSC-UC FROM UC PATIENTS. AS OBSERVED DIFFERENCES IN THE DNA METHYLOME COULD BE THE RESULT OF DIFFERENCES IN CELLULAR POPULATIONS, WE ADDITIONALLY EMPLOYED MASS CYTOMETRY (CYTOF) TO CHARACTERIZE THE IMMUNE CELL COMPOSITIONS. RESULTS: GENOME WIDE METHYLATION ANALYSIS DID NOT REVEAL LARGE DIFFERENCES BETWEEN PSC-UC AND UC PATIENTS NOR HCS. NONETHELESS, USING GRADIENT BOOSTING WE WERE CAPABLE OF DISCERNING PSC-UC FROM UC WITH AN AREA UNDER THE RECEIVER OPERATOR CURVE (AUROC) OF 0.80. FOUR CPG SITES ANNOTATED TO THE NINJ2 GENE WERE FOUND TO STRONGLY CONTRIBUTE TO THE PREDICTIVE PERFORMANCE. WHILE CYTOF ANALYSES CORROBORATED THE LARGELY SIMILAR BLOOD CELL COMPOSITION AMONG PATIENTS WITH PSC-UC, UC AND HC, A HIGHER ABUNDANCE OF MYELOID CELLS WAS OBSERVED IN UC COMPARED TO PSC-UC PATIENTS. CONCLUSION: DNA METHYLATION ENABLES DISCERNING PSC-UC FROM UC PATIENTS, WITH A POTENTIAL FOR BIOMARKER DEVELOPMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  3720  26 INHIBITION OF CLASS I HISTONE DEACETYLASES ABROGATES TUMOR GROWTH FACTOR BETA EXPRESSION AND DEVELOPMENT OF FIBROSIS DURING CHRONIC PANCREATITIS. PANCREATIC FIBROSIS IS THE HALLMARK OF CHRONIC PANCREATITIS, A HIGHLY DEBILITATING DISEASE FOR WHICH THERE IS CURRENTLY NO CURE. THE KEY EVENT AT THE BASIS OF PANCREATIC FIBROSIS IS THE DEPOSITION OF EXTRACELLULAR MATRIX PROTEINS BY ACTIVATED PANCREATIC STELLATE CELLS (PSCS). TRANSFORMING GROWTH FACTOR BETA (TGFBETA) IS A POTENT PROFIBROTIC FACTOR IN THE PANCREAS AS IT PROMOTES THE ACTIVATION OF PSC; THUS, PHARMACOLOGIC INTERVENTIONS THAT EFFECTIVELY REDUCE TGFBETA EXPRESSION HARBOR CONSIDERABLE THERAPEUTIC POTENTIAL IN THE TREATMENT OF CHRONIC PANCREATITIS. IN THIS STUDY, WE INVESTIGATED WHETHER TGFBETA EXPRESSION IS REDUCED BY PHARMACOLOGIC INHIBITION OF THE EPIGENETIC MODIFIERS HISTONE DEACETYLASES (HDACS). TO ADDRESS THIS AIM, CHRONIC PANCREATITIS WAS INDUCED IN C57BL/6 MICE WITH SERIAL INJECTIONS OF CERULEIN, AND THE SELECTIVE CLASS 1 HDAC INHIBITOR MS-275 WAS ADMINISTERED IN VIVO IN A PREVENTIVE AND THERAPEUTIC MANNER. BOTH MS-275 REGIMENS POTENTLY REDUCED DEPOSITION OF EXTRACELLULAR MATRIX AND DEVELOPMENT OF FIBROSIS IN THE PANCREAS AFTER 4 WEEKS OF CHRONIC PANCREATITIS. REDUCED PANCREATIC FIBROSIS WAS CONCOMITANT WITH LOWER EXPRESSION OF PANCREATIC TGFBETA AND CONSEQUENT REDUCED PSC ACTIVATION. IN SEARCH OF THE CELL TYPES TARGETED BY THE INHIBITOR, WE FOUND THAT MS-275 TREATMENT ABROGATED THE EXPRESSION OF TGFBETA IN ACINAR CELLS STIMULATED BY CERULEIN TREATMENT. OUR STUDY DEMONSTRATES THAT MS-275 IS AN EFFECTIVE ANTIFIBROTIC AGENT IN THE CONTEXT OF EXPERIMENTAL CHRONIC PANCREATITIS AND THUS MAY CONSTITUTE A VALID THERAPEUTIC INTERVENTION FOR THIS SEVERE DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  5220  31 PRIMARY BILIARY CHOLANGITIS: A TALE OF EPIGENETICALLY-INDUCED SECRETORY FAILURE? PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE ASSOCIATED WITH AUTOIMMUNE-RELATED DESTRUCTION OF SMALL TO MEDIUM SIZE INTRAHEPATIC BILE DUCTS. THE AETIOLOGY OF PBC IS UNKNOWN AND ITS PATHOGENESIS REMAINS OBSCURE. BOTH GENETIC VARIANTS AND ENVIRONMENTAL FACTORS HAVE BEEN LINKED TO INCREASED PBC SUSCEPTIBILITY, WITH OTHER ALTERATIONS KNOWN TO COOPERATE IN DISEASE PATHOBIOLOGY. INCREASING EVIDENCE INDICATES THE PRESENCE OF EPIGENETIC ABNORMALITIES IN PBC, PARTICULARLY ALTERATIONS OF CHOLANGIOCELLULAR MICRORNAS (MIRNAS OR MIRS). THIS REVIEW HIGHLIGHTS AND DISCUSSES THE MOST RELEVANT EPIGENETIC ALTERATIONS FOUND IN PATIENTS WITH PBC, FOCUSING ON THE ROLE OF MIR-506 IN THE PROMOTION OF CHOLESTASIS AND IMMUNE ACTIVATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  4724  32 NONINVASIVE MULTIMODAL METHODS TO DIFFERENTIATE INFLAMED VS FIBROTIC STRICTURES IN PATIENTS WITH CROHN'S DISEASE. FIBROTIC STRICTURES OCCUR IN 30% OF PATIENTS WITH CROHN'S DISEASE (CD). HOWEVER, THERE ARE NO THERAPEUTIC AGENTS THAT PREVENT OR REVERSE FIBROTIC STRICTURES. STRICTURES ARE TREATED BY ENDOSCOPIC DILATATION PROCEDURES AND SURGICAL PROCEDURES, BUT THERE ARE HIGH RATES OF RECURRENCE. TWO ANTIFIBROTIC AGENTS (NINTEDANIB AND PIRFENIDONE) RECENTLY WERE APPROVED FOR THE TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS AND INHIBITORS OF RHO-ASSOCIATED PROTEIN KINASES 1 AND 2 REVERSED FIBROSIS IN MICE WITH CHRONIC INTESTINAL INFLAMMATION. CROSS-SECTIONAL IMAGING TECHNIQUES, SUCH AS MAGNETIC RESONANCE (MR) ENTEROGRAPHY, COMPUTED TOMOGRAPHY ENTEROGRAPHY, AND BOWEL ULTRASOUND, ARE USED TO ASSESS SMALL-BOWEL AND CD-RELATED COMPLICATIONS, INCLUDING STRICTURES. IT IS IMPORTANT TO BE ABLE TO DETERMINE THE DEGREE OF INFLAMMATION AND FIBROSIS IN STRICTURES TO SELECT THE BEST THERAPY; THIS CAN BE A CHALLENGE BECAUSE INFLAMMATION AND FIBROSIS CO-EXIST TO VARYING DEGREES IN A DAMAGED BOWEL SEGMENT. DELAYED GADOLINIUM ENHANCEMENT, MAGNETIZATION TRANSFER MR IMAGING, AND ULTRASOUND ELASTOGRAPHY SEEM TO BE PROMISING TOOLS FOR ASSESSING FIBROSIS IN PATIENTS WITH CD. WE REVIEW NONINVASIVE TECHNIQUES FOR FIBROSIS ASSESSMENT, INCLUDING ANALYSES OF GENETIC, EPIGENETIC, AND PROTEIN MARKERS. WE DISCUSS THE POTENTIAL OF IMAGING TECHNIQUES SUCH AS DIFFUSION-WEIGHTED AND MAGNETIZATION TRANSFER MR IMAGING, STRAIN ELASTOGRAPHY, SHEAR-WAVE IMAGING, AND POSITRON EMISSION TOMOGRAPHY TO GUIDE THERAPEUTIC DECISIONS FOR PATIENTS WITH STRICTURING CD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  3012  34 GENETICS AND EPIGENETICS IN THE PATHOGENESIS OF PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC, SLOWLY PROGRESSIVE CHOLESTATIC AUTOIMMUNE LIVER DISEASE PREDOMINANTLY AFFLICTING WOMEN. PBC IS CHARACTERIZED BY THE PRESENCE OF DISEASE-SPECIFIC ANTIMITOCHONDRIAL ANTIBODIES AND THE HISTOLOGICAL DESTRUCTION OF INTRAHEPATIC BILE DUCTS, WHICH EVENTUALLY LEAD TO CIRRHOSIS AND HEPATIC FAILURE. FORTUNATELY, URSODEOXYCHOLIC ACID THERAPY HAS IMPROVED THE OUTCOME OF THE VAST MAJORITY OF PBC CASES. ALTHOUGH THE ETIOLOGY OF PBC HAS NOT YET BEEN ELUCIDATED, HUMAN LEUKOCYTE ANTIGEN (HLA) CLASS II ALLELES HAVE BEEN CONSISTENTLY ASSOCIATED WITH DISEASE ONSET FOR DECADES. PBC PATIENTS MAY ALSO HAVE GENETICALLY DETERMINED RISK FACTORS IN NON-HLA REGIONS. MEANWHILE, EXPOSURE TO ENVIRONMENTAL FACTORS, SUCH AS INFECTIOUS DISEASES AND HARMFUL CHEMICALS, CAN PRODUCE EPIGENETIC ALTERATIONS IN SOME INDIVIDUALS AND SUBSEQUENT PBC ONSET. IN THIS REVIEW, WE DESCRIBE THE INFLUENCE OF HLA ALLELES AND OTHER GENE POLYMORPHISMS ON PBC ALONG WITH THE RESULTS OF GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE AND ITS FUTURE PROSPECTS IN TERMS OF EPIGENETICS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  1978  39 EPIGENETIC ALTERATIONS IN CHOLANGIOCARCINOMA-SUSTAINED IL-6/STAT3 SIGNALING IN CHOLANGIO- CARCINOMA DUE TO SOCS3 EPIGENETIC SILENCING. CHOLANGIOCARCINOMA (CCA) IS A HIGHLY LETHAL MALIGNANT TUMOR ARISING FROM THE BILIARY TRACT EPITHELIUM, CHARACTERIZED BY ITS TYPICALLY LATE CLINICAL PRESENTATION AND LACK OF EFFECTIVE THERAPEUTIC MODALITIES. CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PRIMARY SCLEROSING CHOLANGITIS, LIVER FLUKE INFESTATION AND HEPATOLITHIASIS, ARE LISTED IN THE RISK FACTORS, BUT FOR MOST CASES OF CCA THE CAUSE IS UNKNOWN. RECENT ADVANCES IN MOLECULAR PATHOGENESIS HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC ALTERATIONS INCLUDING PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION IN ADDITION TO GENETIC CHANGES IN THE PROCESS OF CHOLANGIOCARCINOGENESIS. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE GENES HYPERMETHYLATED IN CCA TO DATE AND THEIR PUTATIVE ROLES IN CHOLANGIOCARCINOGENESIS. AMONG GENES HYPERMETHYLATED, WE FOUND THE CPG ISLAND HYPERMETHYLATION IN SUPPRESSOR OF CYTOKINE SIGNALING 3 (SOCS3) GENE PROMOTER IN CCA. INTERLEUKIN-6 (IL-6)-MEDIATED SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3 (STAT3) ACTIVATION ARE ABERRANTLY SUSTAINED IN CCA CELLS, RESULTING IN RESISTANCE TO APOPTOSIS. SOCS3 CONTROLS THE IL-6/STAT3 SIGNALING PATHWAY BY A CLASSIC FEEDBACK LOOP. INDEED, SOCS3 EPIGENETIC SILENCING IS RESPONSIBLE FOR SUSTAINED IL-6/STAT3 SIGNALING IN CCA. THESE FINDINGS PROVIDE NEW PERSPECTIVES FOR EPIGENETIC THERAPY TO RESTORE SOCS3 IN THIS CANCER.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  4951  32 PATHOGENESIS OF CHOLANGIOCARCINOMA: FROM GENETICS TO SIGNALLING PATHWAYS. CHOLANGIOCARCINOMA (CCA) IS A MALIGNANT TUMOUR OF BILE DUCT EPITHELIAL CELLS WITH DISMAL PROGNOSIS AND RISING INCIDENCE. CHRONIC INFLAMMATION RESULTING FROM LIVER FLUKE INFECTION, HEPATITIS AND OTHER INFLAMMATORY BOWEL DISEASES IS A MAJOR CONTRIBUTING FACTOR TO CHOLANGIOCARCINOGENESIS, LIKELY THROUGH ACCUMULATION OF SERIAL GENETIC AND EPIGENETIC ALTERATIONS RESULTING IN ABERRATION OF ONCOGENES AND TUMOUR SUPPRESSORS. RECENT STUDIES MAKING USE OF ADVANCES IN HIGH-THROUGHPUT GENOMICS HAVE REVEALED THE GENETIC LANDSCAPE OF CCA, GREATLY INCREASING OUR UNDERSTANDING OF ITS UNDERLYING BIOLOGY. A SERIES OF HIGHLY RECURRENT MUTATIONS IN GENES SUCH AS TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 AND BAP1, WHICH ARE KNOWN TO BE INVOLVED IN CELL CYCLE CONTROL, CELL SIGNALLING PATHWAYS AND CHROMATIN DYNAMICS, HAVE LED TO INVESTIGATIONS OF THEIR ROLES, THROUGH MOLECULAR TO MOUSE MODELLING STUDIES, IN CHOLANGIOCARCINOGENESIS. THIS REVIEW FOCUSES ON THE LANDSCAPE GENETIC ALTERATIONS IN CCA AND ITS FUNCTIONAL RELEVANCE TO THE FORMATION AND PROGRESSION OF CCA.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  6650  33 UPDATE ON ETIOLOGY AND PATHOGENESIS OF BILIARY ATRESIA. BILIARY ATRESIA IS A RARE INFLAMMATORY SCLEROSING OBSTRUCTIVE CHOLANGIOPATHY THAT INITIATES IN INFANCY AS COMPLETE CHOLEDOCHAL BLOCKAGE AND PROGRESSES TO THE INVOLVEMENT OF INTRAHEPATIC BILIARY EPITHELIUM. GROWING EVIDENCE SHOWS THAT BILIARY ATRESIA IS NOT A SINGLE ENTITY WITH A SINGLE ETIOLOGY BUT A PHENOTYPE RESULTING FROM MULTIFACTORIAL EVENTS WHOSE COMMON PATH IS OBLITERATIVE CHOLANGIOPATHY. THE ETIOLOGY OF BILIARY ATRESIA HAS BEEN EXPLAINED AS RESULTING FROM GENETIC VARIANTS, TOXINS, VIRAL INFECTION, CHRONIC INFLAMMATION OR BILE DUCT LESIONS MEDIATED BY AUTOIMMUNITY, ABNORMALITIES IN THE DEVELOPMENT OF THE BILE DUCTS, AND DEFECTS IN EMBRYOGENESIS, ABNORMAL FETAL OR PRENATAL CIRCULATION AND SUSCEPTIBILITY FACTORS. IT IS INCREASINGLY EVIDENT THAT THE GENETIC AND EPIGENETIC PREDISPOSITION COMBINED WITH THE ENVIRONMENTAL FACTORS TO WHICH THE MOTHER IS EXPOSED ARE POTENTIAL TRIGGERS FOR BILIARY ATRESIA. THERE IS ALSO AN INDICATION THAT A PROGRESSIVE THICKENING OF THE ARTERIAL MIDDLE LAYER OCCURS IN THIS DISEASE, SUGGESTIVE OF VASCULAR REMODELING AND DISAPPEARANCE OF THE INTERLOBULAR BILE DUCTS. IT IS SUGGESTED THAT THE HYPOXIA/ISCHEMIA PROCESS CAN AFFECT PORTAL STRUCTURES IN BILIARY ATRESIA AND IS ASSOCIATED WITH BOTH THE EXTENT OF BILIARY PROLIFERATION AND THE THICKENING OF THE MEDIAL LAYER.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  1972  38 EPIGENETIC ALTERATIONS ASSOCIATED WITH CHOLANGIOCARCINOMA (REVIEW). CHOLANGIOCARCINOMA (CCA) IS A HIGHLY LETHAL MALIGNANT TUMOR ARISING FROM THE BILIARY TRACT EPITHELIUM. CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PRIMARY SCLEROSING CHOLANGITIS, LIVER FLUKE INFESTATION, AND HEPATOLITHIASIS, ARE CONSIDERED RISK FACTORS, BUT THE CAUSE IS STILL UNKNOWN IN MOST CASES. RECENT ADVANCES IN MOLECULAR PATHOGENESIS HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC ALTERATIONS, INCLUDING PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION, IN THE PROCESS OF CHOLANGIOCARCINOGENESIS. MORE RECENTLY, RESEARCH INTEREST HAS BEEN FOCUSING ON MICRORNA (MIR), A MAJOR SUBTYPE OF NON-CODING RNA. MIR IS HIGHLY CONSERVED AMONG SPECIES AND REGULATES THE EXPRESSION OF SPECIFIC TARGET GENES BY BINDING TO THE 3'-UNTRANSLATED REGIONS OF MESSENGER RNA. THE NUMBER OF STUDIES ON A POSSIBLE LINK BETWEEN MIR AND VARIOUS CANCERS IS GROWING. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE GENES CURRENTLY KNOWN TO BE HYPERMETHYLATED IN CCA AND THEIR PUTATIVE ROLES IN CHOLANGIOCARCINOGENESIS. THE EPIGENETIC ROLE OF MIR IN THE PATHOGENESIS OF CCA IS ALSO DISCUSSED.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  3251  28 HEPATITIS B VIRUS INFECTION: AN INSIGHT INTO THE CLINICAL CONNECTION AND MOLECULAR INTERACTION BETWEEN HEPATITIS B VIRUS AND HOST EXTRAHEPATIC CANCER RISK. THE EVIDENCE FOR CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND HEPATOCELLULAR CARCINOMA (HCC) OCCURRENCE IS WELL ESTABLISHED. THE HEPATOCYTE EPITHELIUM CARCINOGENESIS CAUSED BY HBV HAS BEEN INVESTIGATED AND REVIEWED IN DEPTH. NEVERTHELESS, RECENT FINDINGS FROM PRECLINICAL AND OBSERVATIONAL STUDIES SUGGESTED THAT CHRONIC HBV INFECTION IS EQUALLY IMPORTANT IN EXTRAHEPATIC CANCER OCCURRENCE AND SURVIVAL, SPECIFICALLY GASTROINTESTINAL SYSTEM-DERIVED CANCERS. IMMUNE MICROENVIRONMENT CHANGES (IMMUNE-SUPPRESSIVE CYTOKINE INFILTRATION), EPIGENETIC MODIFICATION (N6-METHYLADENOSINE), MOLECULAR SIGNALING PATHWAYS (PI3K-AKT AND WNT), AND SERUM BIOMARKERS SUCH AS HEPATITIS B VIRUS X (HBX) PROTEIN ARE POTENTIAL UNDERLYING MECHANISMS IN CHRONIC HBV INFECTION-INDUCED EXTRAHEPATIC CANCERS. THIS NARRATIVE REVIEW AIMED TO COMPREHENSIVELY SUMMARIZE THE MOST RECENT ADVANCES IN EVALUATING THE ASSOCIATION BETWEEN CHRONIC HBV INFECTION AND EXTRAHEPATIC CANCER RISK AND EXPLORE THE POTENTIAL UNDERLYING MOLECULAR MECHANISMS IN THE CARCINOGENESIS INDUCTION OF EXTRAHEPATIC CANCERS IN CHRONIC HBV CONDITIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  5221  40 PRIMARY BILIARY CHOLANGITIS: PATHOGENESIS AND THERAPEUTIC OPPORTUNITIES. PRIMARY BILIARY CHOLANGITIS IS A CHRONIC, SEROPOSITIVE AND FEMALE-PREDOMINANT INFLAMMATORY AND CHOLESTATIC LIVER DISEASE, WHICH HAS A VARIABLE RATE OF PROGRESSION TOWARDS BILIARY CIRRHOSIS. SUBSTANTIAL PROGRESS HAS BEEN MADE IN PATIENT RISK STRATIFICATION WITH THE GOAL OF PERSONALIZED CARE, INCLUDING EARLY ADOPTION OF NEXT-GENERATION THERAPY WITH LICENSED USE OF OBETICHOLIC ACID OR OFF-LABEL FIBRATE DERIVATIVES FOR THOSE WITH INSUFFICIENT BENEFIT FROM URSODEOXYCHOLIC ACID, THE CURRENT FIRST-LINE DRUG. THE DISEASE BIOLOGY SPANS GENETIC RISK, EPIGENETIC CHANGES, DYSREGULATED MUCOSAL IMMUNITY AND ALTERED BILIARY EPITHELIAL CELL FUNCTION, ALL OF WHICH INTERACT AND ARISE IN THE CONTEXT OF ILL-DEFINED ENVIRONMENTAL TRIGGERS. A CURRENT FOCUS OF RESEARCH ON NUCLEAR RECEPTOR PATHWAY MODULATION THAT SPECIFICALLY AND POTENTLY IMPROVES BILIARY EXCRETION, REDUCES INFLAMMATION AND ATTENUATES FIBROSIS IS REDEFINING THERAPY. PATIENTS ARE BENEFITING FROM PHARMACOLOGICAL AGONISTS OF FARNESOID X RECEPTOR AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS. IMMUNOTHERAPY REMAINS A CHALLENGE, WITH A LACK OF TARGET DEFINITION, PLEIOTROPIC IMMUNE PATHWAYS AND AN INTERPLAY BETWEEN HEPATIC IMMUNE RESPONSES AND CHOLESTASIS, WHEREIN BILE ACID-INDUCED INFLAMMATION AND FIBROSIS ARE DOMINANT CLINICALLY. THE MANAGEMENT OF PATIENT SYMPTOMS, PARTICULARLY PRURITUS, IS A NOTABLE GOAL REFLECTED IN THE DEVELOPMENT OF RATIONAL THERAPY WITH APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  4472  46 MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA. BACKGROUND: CHOLANGIOCARCINOMAS ARE A HETEROGENEOUS GROUP OF MALIGNANCIES ARISING FROM A NUMBER OF CELLS OF ORIGIN ALONG THE BILIARY TREE. ALTHOUGH MOST CASES IN WESTERN COUNTRIES ARE SPORADIC, LARGE POPULATION-BASED STUDIES HAVE IDENTIFIED A NUMBER OF RISK FACTORS. THIS REVIEW SUMMARISES THE EVIDENCE BEHIND REPORTED RISK FACTORS AND CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA, WITH A FOCUS ON INFLAMMATION AND CHOLESTASIS AS THE DRIVING FORCES IN CHOLANGIOCARCINOMA DEVELOPMENT. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS: CHOLESTATIC LIVER DISEASES (E.G. PRIMARY SCLEROSING CHOLANGITIS AND FIBROPOLYCYSTIC LIVER DISEASES), LIVER CIRRHOSIS, AND BILIARY STONE DISEASE ALL INCREASE THE RISK OF CHOLANGIOCARCINOMA. CERTAIN BACTERIAL, VIRAL OR PARASITIC INFECTIONS SUCH AS HEPATITIS B AND C AND LIVER FLUKES ALSO INCREASE CHOLANGIOCARCINOMA RISK. OTHER RISK FACTORS INCLUDE INFLAMMATORY DISORDERS (SUCH AS INFLAMMATORY BOWEL DISEASE AND CHRONIC PANCREATITIS), TOXINS (E.G. ALCOHOL AND TOBACCO), METABOLIC CONDITIONS (DIABETES, OBESITY AND NON-ALCOHOLIC FATTY LIVER DISEASE) AND A NUMBER OF GENETIC DISORDERS. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS CAUSE CHRONIC INFLAMMATION OR CHOLESTASIS. CHRONIC INFLAMMATION LEADS TO INCREASED EXPOSURE OF CHOLANGIOCYTES TO THE INFLAMMATORY MEDIATORS INTERLEUKIN-6, TUMOUR NECROSIS FACTOR-A, CYCLO-OXYGENASE-2 AND WNT, RESULTING IN PROGRESSIVE MUTATIONS IN TUMOUR SUPPRESSOR GENES, PROTO-ONCOGENES AND DNA MISMATCH-REPAIR GENES. ACCUMULATING BILE ACIDS FROM CHOLESTASIS LEAD TO REDUCED PH, INCREASED APOPTOSIS AND ACTIVATION OF ERK1/2, AKT AND NF-KAPPAB PATHWAYS THAT ENCOURAGE CELL PROLIFERATION, MIGRATION AND SURVIVAL. OTHER MEDIATORS UPREGULATED IN CHOLANGIOCARCINOMA INCLUDE TRANSFORMING GROWTH FACTOR-BETA, VASCULAR ENDOTHELIAL GROWTH FACTOR, HEPATOCYTE GROWTH FACTOR AND SEVERAL MICRORNAS. INCREASED EXPRESSION OF THE CELL SURFACE RECEPTOR C-MET, THE GLUCOSE TRANSPORTER GLUT-1 AND THE SODIUM IODIDE SYMPORTER LEAD TO TUMOUR GROWTH, ANGIOGENESIS AND CELL MIGRATION. STROMAL CHANGES ARE ALSO OBSERVED, RESULTING IN ALTERATIONS TO THE EXTRACELLULAR MATRIX COMPOSITION AND RECRUITMENT OF FIBROBLASTS AND MACROPHAGES THAT CREATE A MICROENVIRONMENT PROMOTING CELL SURVIVAL, INVASION AND METASTASIS. CONCLUSION: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS FOR CHOLANGIOCARCINOMA CAUSE CHRONIC INFLAMMATION AND/OR CHOLESTASIS, LEADING TO THE ACTIVATION OF COMMON INTRACELLULAR PATHWAYS THAT RESULT IN REACTIVE CELL PROLIFERATION, GENETIC/EPIGENETIC MUTATIONS AND CHOLANGIOCARCINOGENESIS. AN UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA IS VITAL WHEN DEVELOPING NEW DIAGNOSTIC BIOMARKERS AND TARGETED THERAPIES FOR THIS DISEASE.	2019	

15  6778  40 [BILIARY TRACT CANCERS : MOLECULAR CHARACTERIZATION AND IDENTIFICATION OF NOVEL PROGNOSTIC MARKERS]. BACKGROUND: BILE DUCT CANCERS (BTCS) ARE HIGHLY AGGRESSIVE TUMORS WITH A DISMAL PROGNOSIS AND AN INCREASING INCIDENCE. BTC IS A TUMORBIOLOGICALLY AND CLINICALLY HETEROGENEOUS TUMOR GROUP AND CAN BE SUBDIVIDED ACCORDING TO ANATOMICAL ASPECTS INTO INTRAHEPATIC CHOLANGIOCARCINOMAS (ICCA), EXTRAHEPATIC CHOLANGIOCARCINOMAS (ECCA) AND GALLBLADDER CARCINOMAS (GBC). NEW THERAPY OPTIONS: CHRONIC INFLAMMATORY PROCESSES OF THE BILIARY SYSTEM SEEM TO PLAY A ROLE IN THE DEVELOPMENT OF THESE TUMORS. INSIGHTS INTO MOLECULAR CHOLANGIOCARCINOGENESIS COULD MAKE AN IMPORTANT CONTRIBUTION TO NOVEL AND MORE PRECISE CLASSIFICATION ATTEMPTS AND TO THE DEVELOPMENT OF NEW, TARGETED THERAPIES FOR BTC. EPIGENETIC AND GENETIC ALTERATIONS IN CHOLANGIOCARCINOMAS: THE FIRST DESCRIPTION OF GENOME-WIDE DNA METHYLATION PATTERNS IN CCA SHOWED DRASTIC GLOBAL METHYLATION DIFFERENCES BETWEEN CCA AND CORRESPONDING NON-NEOPLASTIC TISSUE (MATCHED-PAIR ANALYSES). MOREOVER, SIGNIFICANT METHYLATION DIFFERENCES BETWEEN THE CCA SUBTYPES (ECCA AND ICCA) COULD BE FOUND. USING IMMUNOHISTOCHEMISTRY AND SANGER SEQUENCING, IT WAS SHOWN THAT THE ACTUAL BRAF V600E MUTATION RATE SEEMS TO BE SIGNIFICANTLY LOWER (1.3%) THAN PREVIOUSLY DESCRIBED IN THE LITERATURE. IMMUNEPHENOTYPING IN BILIARY TRACT CANCERS: A COMPREHENSIVE, SUBTYPE-SPECIFIC CHARACTERIZATION OF TUMOR-INFILTRATING IMMUNE CELLS AS WELL AS AN EXPRESSION ANALYSIS OF MAJOR HISTOCOMPATIBILITY COMPLEX I WAS PERFORMED IN A LARGE AND WELL-CHARACTERIZED BTC COHORT. FOR FURTHER STUDIES ON THE EFFICACY OF IMMUNOMODULATORY THERAPY APPROACHES FOR BTC, THE PRESENTED RESULTS PROVIDE A SOLID BASIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  5506  36 RHEUMATOID ARTHRITIS AND PRIMARY BILIARY CIRRHOSIS: CAUSE, CONSEQUENCE, OR COINCIDENCE? PRIMARY BILIARY CIRRHOSIS (PBC) IS A PROGRESSIVE CHOLESTATIC LIVER DISEASE CHARACTERIZED SEROLOGICALLY BY CHOLESTASIS AND THE PRESENCE OF HIGH-TITRE ANTIMITOCHONDRIAL ANTIBODIES AND HISTOLOGICALLY BY CHRONIC NONSUPPURATIVE CHOLANGITIS AND GRANULOMATA. PBC PATIENTS OFTEN HAVE CONCOMITANT AUTOIMMUNE DISEASES, INCLUDING ARTHROPATHIES. THIS RAISES THE QUESTION AS TO WHETHER THERE ARE SHARED FEATURES IN THE PATHOGENESIS OF THOSE DISEASES WITH THE PATHOGENESIS OF PBC. EPIDEMIOLOGICAL AND LARGE CASE STUDIES HAVE INDICATED THAT ALTHOUGH THE INCIDENCE OF RHEUMATOID ARTHRITIS (RA) IS NOT SIGNIFICANTLY RAISED IN PBC PATIENTS, THERE APPEARS TO BE A HIGHER RATE OF RA IN PBC PATIENTS AND THEIR RELATIVES. GENETIC STUDIES HAVE DEMONSTRATED THAT SEVERAL GENES IMPLICATED IN PBC HAVE ALSO BEEN IMPLICATED IN RA. EPIGENETIC STUDIES PROVIDED A WEALTH OF DATA REGARDING RA, BUT THE FINDINGS ON EPIGENETIC CHANGES IN PBC ARE VERY LIMITED. AS WELL, CERTAIN INFECTIOUS AGENTS IDENTIFIED IN THE PATHOGENESIS OF PBC MAY ALSO PLAY A ROLE IN THE PATHOGENESIS OF RA. THESE DATA SUGGEST THAT ALTHOUGH RA IS NOT SIGNIFICANTLY PRESENT IN PBC, SOME INDIVIDUALS WITH CERTAIN GENETIC TRAITS AND ENVIRONMENTAL EXPOSURES MAY DEVELOP BOTH CONDITIONS. THIS CONCEPT MAY ALSO APPLY TO OTHER CONCOMITANT DISEASES FOUND IN PBC PATIENTS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17   778  37 CELL-FREE DNA METHYLATION: THE NEW FRONTIERS OF PANCREATIC CANCER BIOMARKERS' DISCOVERY. PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS AMONG THE MOST LETHAL CANCER TYPES WORLD-WIDE. ITS HIGH MORTALITY IS RELATED TO THE DIFFICULTY IN THE DIAGNOSIS, WHICH OFTEN OCCURS WHEN THE DISEASE IS ALREADY ADVANCED. AS OF TODAY, NO EARLY DIAGNOSTIC TESTS ARE AVAILABLE, WHILE ONLY A LIMITED NUMBER OF PROGNOSTIC TESTS HAVE REACHED CLINICAL PRACTICE. THE MAIN REASON IS THE LACK OF RELIABLE BIOMARKERS THAT ARE ABLE TO CAPTURE THE EARLY DEVELOPMENT OR THE PROGRESSION OF THE DISEASE. HENCE, THE DISCOVERY OF BIOMARKERS FOR EARLY DIAGNOSIS OR PROGNOSIS OF PDAC REMAINS, DE FACTO, AN UNMET NEED. AN INCREASING NUMBER OF STUDIES HAS SHOWN THAT CELL-FREE DNA (CFDNA) METHYLATION ANALYSIS REPRESENTS A PROMISING NON-INVASIVE APPROACH FOR THE DISCOVERY OF BIOMARKERS WITH DIAGNOSTIC OR PROGNOSTIC POTENTIAL. IN PARTICULAR, CFDNA METHYLATION COULD BE UTILIZED FOR THE IDENTIFICATION OF DISEASE-SPECIFIC SIGNATURES IN PRE-NEOPLASTIC LESIONS OR CHRONIC PANCREATITIS (CP), REPRESENTING A SENSITIVE AND NON-INVASIVE METHOD OF EARLY DIAGNOSIS OF PDAC. IN THIS REVIEW, WE WILL DISCUSS THE ADVANTAGES AND PITFALLS OF CFDNA METHYLATION STUDIES. FURTHER, WE WILL PRESENT THE CURRENT ADVANCES IN THE DISCOVERY OF PANCREATIC CANCER BIOMARKERS WITH EARLY DIAGNOSTIC OR PROGNOSTIC POTENTIAL, FOCUSING ON PANCREAS-SPECIFIC (E.G., CUX2 OR REG1A) OR ABNORMAL (E.G., ADAMTS1 OR BNC1) CFDNA METHYLATION SIGNATURES IN HIGH RISK PRE-NEOPLASTIC CONDITIONS AND PDAC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
18  5222  33 PRIMARY BILIARY CIRRHOSIS: FAMILY STORIES. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC IMMUNE-MEDIATED CHOLESTATIC LIVER DISEASE OF UNKNOWN AETIOLOGY WHICH AFFECTS MOSTLY WOMEN IN MIDDLE AGE. FAMILIAL PBC IS WHEN PBC AFFECTS MORE THAN ONE MEMBER OF THE SAME FAMILY, AND DATA SUGGEST THAT FIRST-DEGREE RELATIVES OF PBC PATIENTS HAVE AN INCREASED RISK OF DEVELOPING THE DISEASE. MOST OFTEN, THESE FAMILIAL CLUSTERS INVOLVE MOTHER-DAUGHTER PAIRS, WHICH IS CONSISTENT WITH THE FEMALE PREPONDERANCE OF THE DISEASE. THESE CLUSTERS PROVIDE EVIDENCE TOWARDS A GENETIC BASIS UNDERLYING PBC. HOWEVER, CLUSTERS OF NONRELATED INDIVIDUALS HAVE ALSO BEEN REPORTED, GIVING STRENGTH TO AN ENVIRONMENTAL COMPONENT. TWIN STUDIES HAVE DEMONSTRATED A HIGH CONCORDANCE FOR PBC IN MONOZYGOTIC TWINS AND A LOW CONCORDANCE AMONG DIZYGOTIC TWINS. IN CONCLUSION, STUDIES OF PBC IN FAMILIES CLEARLY DEMONSTRATE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF THE DISEASE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  3271  35 HEPATOCELLULAR CARCINOMA RISK AFTER VIRAL RESPONSE IN HEPATITIS C VIRUS-ADVANCED FIBROSIS: WHO TO SCREEN AND FOR HOW LONG? HEPATITIS C VIRUS (HCV) CHRONIC INFECTION IS ASSOCIATED WITH FIBROSIS PROGRESSION, END-STAGE LIVER COMPLICATIONS AND HCC. NOT SURPRISINGLY, HCV INFECTION IS A LEADING CAUSE OF LIVER-RELATED MORBIDITY AND MORTALITY WORLDWIDE. AFTER SUSTAINED VIROLOGICAL RESPONSE (SVR), THE RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA IS NOT COMPLETELY ELIMINATED IN PATIENTS WITH ESTABLISHED CIRRHOSIS OR WITH ADVANCED FIBROSIS. THEREFORE, LIFELONG SURVEILLANCE IS CURRENTLY RECOMMENDED. THIS STRATEGY IS LIKELY NOT UNIVERSALLY COST-EFFECTIVE AND HARMLESS, CONSIDERING THAT NOT ALL PATIENTS WITH ADVANCED FIBROSIS HAVE THE SAME RISK OF DEVELOPING HCC. FACTORS RELATED TO THE SEVERITY OF LIVER DISEASE AND ITS POTENTIAL TO IMPROVE AFTER SVR, THE MOLECULAR AND EPIGENETIC CHANGES THAT OCCUR DURING INFECTION AND OTHER ASSOCIATED COMORBIDITIES MIGHT ACCOUNT FOR DIFFERENT RISK LEVELS AND ARE LIKELY ESSENTIAL FOR IDENTIFYING PATIENTS WHO WOULD BENEFIT FROM SCREENING PROGRAMS AFTER SVR. EFFORTS TO DEVELOP PREDICTIVE MODELS AND RISK CALCULATORS, BIOMARKERS AND GENETIC PANELS AND EVEN DEEP LEARNING MODELS TO ESTIMATE THE INDIVIDUAL RISK OF HCC HAVE BEEN MADE IN THE DIRECT-ACTING ANTIVIRAL AGENTS ERA, WHEN THOUSANDS OF PATIENTS WITH ADVANCED FIBROSIS AND CIRRHOSIS HAVE REACHED SVR. THESE TOOLS COULD HELP TO IDENTIFY PATIENTS WITH VERY LOW HCC RISK IN WHOM SURVEILLANCE MIGHT NOT BE JUSTIFIED. IN THIS REVIEW, FACTORS AFFECTING THE PROBABILITY OF HCC DEVELOPMENT AFTER SVR, THE BENEFITS AND RISKS OF SURVEILLANCE, SUGGESTED STRATEGIES TO ESTIMATE INDIVIDUALIZED HCC RISK AND THE CURRENT EVIDENCE TO RECOMMEND LIFELONG SURVEILLANCE ARE DISCUSSED.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20  3257  41 HEPATITIS B X ANTIGEN (HBX) IS AN IMPORTANT THERAPEUTIC TARGET IN THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS (HBV) IS A HUMAN PATHOGEN THAT HAS INFECTED AN ESTIMATED TWO BILLION PEOPLE WORLDWIDE. DESPITE THE AVAILABILITY OF HIGHLY EFFICACIOUS VACCINES, UNIVERSAL SCREENING OF THE BLOOD SUPPLY FOR VIRUS, AND POTENT DIRECT ACTING ANTI-VIRAL DRUGS, THERE ARE MORE THAN 250 MILLION CARRIERS OF HBV WHO ARE AT RISK FOR THE SEQUENTIAL DEVELOPMENT OF HEPATITIS, FIBROSIS, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). MORE THAN 800,000 DEATHS PER YEAR ARE ATTRIBUTED TO CHRONIC HEPATITIS B. MANY DIFFERENT THERAPEUTIC APPROACHES HAVE BEEN DEVELOPED TO BLOCK VIRUS REPLICATION, AND ALTHOUGH EFFECTIVE, NONE ARE CURATIVE. THESE TREATMENTS HAVE LITTLE OR NO IMPACT UPON THE PORTIONS OF INTEGRATED HBV DNA, WHICH OFTEN ENCODE THE VIRUS REGULATORY PROTEIN, HBX. ALTHOUGH GIVEN LITTLE ATTENTION, HBX IS AN IMPORTANT THERAPEUTIC TARGET BECAUSE IT CONTRIBUTES IMPORTANTLY TO (A) HBV REPLICATION, (B) IN PROTECTING INFECTED CELLS FROM IMMUNE MEDIATED DESTRUCTION DURING CHRONIC INFECTION, AND (C) IN THE DEVELOPMENT OF HCC. THUS, THE DEVELOPMENT OF THERAPIES TARGETING HBX, COMBINED WITH OTHER ESTABLISHED THERAPIES, WILL PROVIDE A FUNCTIONAL CURE THAT WILL TARGET VIRUS REPLICATION AND FURTHER REDUCE OR ELIMINATE BOTH THE MORBIDITY AND MORTALITY ASSOCIATED WITH CHRONIC LIVER DISEASE AND HCC. SIMULTANEOUS TARGETING OF ALL THESE CHARACTERISTICS UNDERSCORES THE IMPORTANCE OF DEVELOPING THERAPIES AGAINST HBX.	2021