• biliary tract cancer
• cholangiocarcinoma
• ctDNA
• liquid biopsy
• minimal residual disease
• molecular profiling

• Cancer
• Cell biology
• Molecular biology

• Primary Sclerosing Cholangitis
• RNA-binding proteins
• bioinformatics
• biomarkers
• cholangiocarcinoma
• data mining
• extracellular vesicles

• Acute liver failure
• acute decompensation
• acute-on-chronic liver failure
• biomarker
• chronic liver disease
• hepatocellular carcinoma microRNA
• prognostication
• regeneration

• Humans
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/genetics
• MicroRNAs/genetics
• Liver Neoplasms/diagnosis
• Liver Neoplasms/genetics
• Biomarkers, Tumor/genetics
• Liver Cirrhosis
• Liver Failure/complications

• biomarkers
• cholangiocarcinoma
• diagnosis
• pathogenesis
• primary sclerosing cholangitis
• surveillance

• Biomarker
• High-dose
• PSC
• Serum
• UDCA
• miRNA

• Artificial intelligence
• Cholangiocarcinoma
• Deep learning
• Hepatocellular carcinoma
• Liver cancer
• Machine learning
• Metastasis
• Nanomedicine

• Bile duct strictures
• Cholangiocarcinoma
• Indeterminate stricture
• Molecular diagnosis

• Biomarker
• Cholangiocarcinoma
• Diagnostics

The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4⁺ and CD19⁺ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.

• Epigenesis, Genetic
• Fibrosis
• Hepatitis, Autoimmune
• Humans
• Liver Cirrhosis/metabolism
• MicroRNAs/genetics
• MicroRNAs/therapeutic use

• Biomarker
• Cholangiocarcinoma
• Circulating nucleic acids
• Extracellular vesicles
• Metabolomics
• Proteomics

• Adenocarcinoma/pathology
• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/therapy
• Bile Ducts, Intrahepatic/pathology
• Biomarkers
• Biomarkers, Tumor/metabolism
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/therapy
• Humans
• Liver Neoplasms/pathology
• Pancreatic Neoplasms

MicroRNAs (miRNAs) are implicated in the pathogenesis of autoimmune diseases and could be biomarkers of disease activity. This study aimed to identify highly expressed circulating miRNAs in patients with autoimmune hepatitis (AIH) and to evaluate their association with clinical characteristics.

Microarray analyses were performed, and miRNA expression profiling for AIH, primary biliary cholangitis (PBC) and overlap syndrome (OS) using the serum of patients and healthy individuals was done. Samples were divided into discovery and test sets to identify candidate miRNAs that could discriminate AIH from PBC; the former included 21 AIH and 23 PBC samples, while the latter included five AIH and eight PBC samples.

Among 11 candidate miRNAs extracted in the discovery set, 4 (miR-3196, miR-6125, miR-4725–3 p and miR-4634) were specifically and highly expressed in patients with AIH in the test set. These four miRNAs discriminated AIH from PBC with high sensitivity (0.80–1.00) and specificity (0.88–1.00). In situ hybridisation analysis revealed that these miRNAs were expressed in the cytoplasm of hepatocytes in patients with AIH. Their expression levels were highest in untreated patients with AIH, followed by those in untreated patients with OS. They drastically or moderately decreased after prednisolone treatment. Histological analysis demonstrated that the expression levels of miR-3196, miR-6125 and miR-4634 in patients with AIH and OS were correlated with severe hepatic necroinflammatory activity.

These circulating miRNAs are suggested to reflect hepatic necroinflammatory activity and serve as AIH-related and treatment-responsive biomarkers. These miRNAs could be beneficial in developing new therapeutic strategies for AIH.

• AUTOIMMUNE LIVER DISEASE
• PRIMARY BILIARY CIRRHOSIS
• autoimmune hepatitis
• biomarker
• circulating microRNA

• bile duct cysts
• cholangiocarcinoma
• cirrhosis
• liver fluke
• primary sclerosing cholangitis
• risk factor

• DK119421 NIH HHS
• AA025157 NIH HHS
• IK6 BX005226 BLRD VA
• DK115184 NIH HHS
• DK110035 NIH HHS
• DK076898 NIH HHS
• IK2 BX005306 BLRD VA
• DK054811 NIH HHS
• I01 BX000574 BLRD VA
• I01 BX003031 BLRD VA
• DK108959 NIH HHS
• DK062975 NIH HHS
• AA025997 NIH HHS
• DK107310 NIH HHS
• IK6 BX004601 BLRD VA

• Cholangiocarcinoma
• epigenetics
• genetic mutations
• immunotherapy
• inhibitors

• biliary tract cancer
• biomarker
• cholangiocarcinoma
• circulating DNA
• immunotherapy
• methylation
• mutation
• targeted therapy

• Cell-free DNA
• Circulating epithelial cells
• Liquid biopsy
• Liver diseases
• MicroRNAs

Cholangiocarcinoma is an uncommon and highly aggressive biliary tract malignancy with few manifestations until late disease stages. Diagnosis is currently achieved through a combination of clinical, biochemical, radiological and histological techniques. A number of reported cancer biomarkers have the potential to be incorporated into diagnostic pathways, but all lack sufficient sensitivity and specificity limiting their possible use in screening and early diagnosis. The limitations of standard serum markers such as CA19-9, CA125 and CEA have driven researchers to identify multiple novel biomarkers, yet their clinical translation has been slow with a general requirement for further validation in larger patient cohorts. We review recent advances in the diagnostic pathway for suspected CCA as well as emerging diagnostic biomarkers for early detection, with a particular focus on non-invasive approaches.

• ERCP (Endoscopic Retrograde Cholangiopancreatography)
• biliary strictures
• biomarkers
• cholangiocarcinoma
• early detection
• primary sclerosing cholangitis (PSC)

• exosomal miRNA
• liver cirrhosis
• liver fibrosis
• microRNA

• Animals
• Biomarkers/blood
• Cholangitis, Sclerosing/blood
• Cholangitis, Sclerosing/complications
• Circulating MicroRNA/blood
• Circulating MicroRNA/genetics
• Epigenesis, Genetic
• Exosomes/metabolism
• Fatty Liver, Alcoholic/blood
• Fatty Liver, Alcoholic/complications
• Gene Expression Regulation
• Hepatitis, Autoimmune/blood
• Hepatitis, Autoimmune/complications
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/etiology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Liver Cirrhosis, Biliary/blood
• Liver Cirrhosis, Biliary/complications
• Non-alcoholic Fatty Liver Disease/blood
• Non-alcoholic Fatty Liver Disease/complications

Early and non-invasive diagnosis of cholangiocarcinoma (CCA) is still challenging, thus largely contributing to the increased mortality rates observed worldwide. Consequently, several efforts have been made in order to report novel biomarkers for CCA, that would aid on diagnosis and also to predict prognosis and therapy response. We herein aim to provide an in-depth and critical revision on the next-generation biomarkers for CCA that have been recently proposed.

The increasing mortality rates of cholangiocarcinoma (CCA) registered during the last decades are, at least in part, a result of the lack of accurate non-invasive biomarkers for early disease diagnosis, making the identification of patients who might benefit from potentially curative approaches (i.e., surgery) extremely challenging. The obscure CCA pathogenesis and associated etiological factors, as well as the lack of symptoms in patients with early tumor stages, highly compromises CCA identification and to predict tumor development in at-risk populations. Currently, CCA diagnosis is accomplished by the combination of clinical/biochemical features, radiological imaging and non-specific serum tumor biomarkers, although a tumor biopsy is still needed to confirm disease diagnosis. Furthermore, prognostic and predictive biomarkers are still lacking and urgently needed. During the recent years, high-throughput omics-based approaches have identified novel circulating biomarkers (diagnostic and prognostic) that might be included in large, international validation studies in the near future. In this review, we summarize and discuss the most recent advances in the field of biomarker discovery in CCA, providing new insights and future research directions.

• biomarkers
• cholangiocarcinoma
• diagnosis
• omics
• prognosis

• chromosomal imbalance
• epigenetics
• immunohistochemistry
• mutation
• next-generation sequencing

Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant cancer. More than 70% of patients are diagnosed at an advanced stage. The aim of this study was to evaluate the diagnostic value of plasma miR-21, miR-122, and CA19-9, hoping to establish a novel model to improve the accuracy for diagnosing iCCA. Materials and methods: Plasma miR-21 and miR-122 were detected in 359 iCCA patients and 642 controls (healthy, benign liver lesions, other malignant liver tumors). All 1001 samples were allocated to training cohort (n = 668) and validation cohort (n = 333) in a chronological order. A logistic regression model was applied to combine these markers. Area under the receiver operating characteristic curve (AUC) was used as an accuracy index to evaluate the diagnostic performance. Results: Plasma miR-21 and miR-122 were significantly higher in iCCA patients than those in controls. Higher plasma miR-21 level was significantly correlated with larger tumor size (p = 0.030). A three-marker model was constructed by using miR-21, miR-122 and CA19-9, which showed an AUC of 0.853 (95% CI: 0.824–0.879; sensitivity: 73.0%, specificity: 87.4%) to differentiate iCCA from controls. These results were subsequently confirmed in the validation cohort with an AUC of 0.866 (0.825–0.901). The results were similar for diagnosing early (stages 0–I) iCCA patients (AUC: 0.848) and CA19-9^negative iCCA patients (AUC: 0.795). Conclusions: We established a novel three-marker model with a high accuracy based on a large number of participants to differentiate iCCA from controls. This model showed a great clinical value especially for the diagnosis of early iCCA and CA19-9^negative iCCA.

• CA19-9
• circulating biomarker
• diagnosis
• intrahepatic cholangiocarcinoma
• microRNA

• Chronic disease
• Circulating biomarkers
• Liver diseases
• Non-coding RNAs
• Viral hepatitis
• microRNAs

• LncRNA
• biliary tract cancer
• biomarker
• miRNA
• non-coding RNA
• therapy

• liver disease
• microRNA
• regulatory networks

• Cholangiocarcinoma
• Diagnosis
• Dominant stricture
• Epidemiology
• Incidence
• Inflammatory bowel disease
• Primary sclerosing cholangitis
• Risk factor
• Surveillance
• Ulcerative colitis

• biliary tract cancer
• cancer

• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/etiology
• Bile Duct Neoplasms/therapy
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/etiology
• Cholangiocarcinoma/therapy
• Humans

• K08 CA236874 NCI NIH HHS
• P30 DK034989 NIDDK NIH HHS
• P50 CA210964 NCI NIH HHS
• UL1 TR001863 NCATS NIH HHS

• Apoptosis
• Autoimmune liver diseases
• Biomarkers
• Inflammation
• MicroRNAs

Cholangiocarcinoma (CCA) is a highly fatal malignancy of the bile ducts that arises in up to 20% of patients with primary sclerosing cholangitis (PSC). Current detection methods for CCA display suboptimal sensitivity and/or specificity, and there is no evidence-based screening strategy for CCA in patients with PSC. Consequently, CCA is often detected too late for surgical resection, contributing to the high mortality associated with this malignancy. Recently, biomarkers have emerged with potential to complement current detection methods, and/or be used for cancer surveillance in high-risk patient groups, including patients with PSC. Aberrant DNA methylation patterns represent promising biomarkers with great potential for CCA detection. Such aberrations are frequent in CCA, often occur early, and can be detected in liquid biopsies, including blood, bile and urine. This review summarises and highlights the most promising DNA methylation biomarkers identified for CCA detection so far, focusing on patients with PSC. Other promising molecular biomarkers for detection of PSC-associated CCA in liquid biopsies will also be briefly covered.

• BilIN, biliary intraepithelial neoplasia
• Bile
• Bile duct cancer
• Biomarker
• Blood
• CA19-9, carbohydrate antigen 19-9
• CCA, cholangiocarcinoma
• Cholangiocarcinoma
• DNA methylation
• ERCP, endoscopic retrograde cholangiopancreatography
• Early detection
• FISH, fluorescent in situ hybridization
• IPNL/B, intraductal papillary neoplasm of the liver/bile ducts
• Liquid biopsy
• PSC, primary sclerosing cholangitis
• Primary sclerosing cholangitis
• Urine

• biomarker
• cholangiocyte-derived microRNA
• hepatocyte-derived microRNA
• miR-122
• miR-222
• transplantation

• Circulating MicroRNA
• Humans
• Liver
• Liver Transplantation/adverse effects
• Living Donors
• Organ Preservation
• Perfusion

• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/therapy
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/therapy
• Cholangitis, Sclerosing/diagnosis
• Cholangitis, Sclerosing/epidemiology
• Cholangitis, Sclerosing/therapy
• Humans
• Risk Assessment

• body fluids
• liquid biopsy
• long noncoding RNAs
• microRNAs
• noncoding RNAs
• piRNAs

• . Estate of C. G. Johnson, Jr
• year 2018 Fulbright Research Scholarships (year 2018)
• . UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project
• #CA096297 U54
• n° D15D18000410001 Ministero dell'Istruzione, dell'Università e della Ricerca - MIUR project "Dipartimenti di Eccellenza 2018 - 2022"
• 2017 grant Sister Institution Network Fund (SINF)
• CA160445P1 Team DOD
• UH3TR00943-01 NIH HHS
• 1R01 CA182905-01 NCI NIH HHS
• CA17118 COST action STSM fellowship
• #CA096300 U54
• U54 CA096297 NCI NIH HHS
• . Chronic Lymphocytic Leukemia Moonshot Flagship project
• rif 2018.0648 Fondazione CRT
• U54 CA096300 NCI NIH HHS
• 1R01CA222007-01A1 NCI NIH HHS
• 1R01GM122775-01 NIGMS NIH HHS

• Biomarkers
• CA19-9
• Cholangiocarcinoma
• Primary sclerosing cholangitis
• Screening

• CCA prognosis
• biliary cancer
• biomarker
• early diagnosis
• omics

Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy. Despite tremendous research activities, the prognosis for the majority of patients is still poor. Only in case of early diagnosis, liver resection might potentially lead to long-term survival. However, it is still unclear which patients benefit most from extensive liver surgery, highlighting the need for new diagnostic and prognostic stratification strategies.

Serum concentrations of a 4 miRNA panel (miR-122, miR-192, miR-29b and miR-155) were analyzed using semi-quantitative reverse-transcriptase PCR in serum samples from 94 patients with cholangiocarcinoma undergoing tumour resection and 40 healthy controls. Results were correlated with clinical data.

Serum concentrations of miR-122, miR-192, miR-29b and miR-155 were significantly elevated in patients with CCA compared to healthy controls or patients with primary sclerosing cholangitis without malignant transformation. Although preoperative levels of these miRNAs were unsuitable as a prognostic marker of survival, a strong postoperative decline of miR-122 serum levels was significantly associated with a favorable patients’ prognosis.

Analysis of circulating miRNAs represents a promising tool for the diagnosis of even early stage CCA. A postoperative decline in miRNA serum concentrations might be indicative for a favorable patients’ outcome and helpful to identify patients with a good prognosis after extended liver surgery.

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms/blood
• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/surgery
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Case-Control Studies
• Cholangiocarcinoma/blood
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/surgery
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• MicroRNAs/blood
• MicroRNAs/genetics
• Middle Aged
• Prognosis
• Young Adult

• Deutsche Krebshilfe
• Deutsche Forschungsgemeinschaft
• Medizinische Fakultät, RWTH Aachen University

Several dysregulated microRNAs (miRNAs) have been implicated in the pathogenesis of cholangiocarcinoma (CCA); however, small sample sizes and invariable research designs are limitations, hindering a thorough analysis of miRNAs as diagnostic and prognostic tools for CCA. This study aimed to systematically summarize the clinical value of miRNAs in human CCA both for all available miRNAs and single miRNA with multiple researches.

Pooled parameters included the area under the curve (AUC), sensitivity, specificity, and hazard ratios (HRs) to separately determine overall diagnostic and prognostic performance. Subgroup and sensitivity analyses were performed only in the event of heterogeneity. Thirty-four studies including 12 diagnostic studies and 22 prognostic studies were eligible for inclusion in this meta-analysis.

We observed that miR-21, miR-26, miR-483, miR-106a, miR-150, miR-192, and miR-194 were employed for distinguishing patients with CCA from healthy controls. Pooled sensitivity, specificity, and AUC were 0.82 (95% confidence interval [CI] 0.77–0.86), 0.83 (95% CI 0.75–0.89), and 0.88 (95% CI 0.85–0.91), respectively. Abnormal expression of miR-21, miR-26a, miR-192, miR-200c, miR-221, miR-29a, miR-191, miR-181c, miR-34a, miR-106a, miR-203, and miR-373 in patients was confirmed to associate with poor survival rate. Pooled HRs and 95% CIs were calculated using STATA, resulting in the pooled HR of 1.47 (95% CI 0.91–2.37) for overall survival (OS), 0.67 (95% CI 0.16–2.81) for disease-free survival (DFS), 2.31 (95% CI 1.59–3.36) for progression-free survival (PFS), and 2.68 (95% CI 0.88–8.15) for relapse-free survival (RFS). Thus, CCA patients with dysregulated miRNA expression were confirmed to have shorter OS, DFS, PFS, and RFS. Data regarding the diagnostic and prognostic roles of miR-21 suggested pooled diagnostic results of miR-21 for sensitivity, specificity, and AUC were 0.85 (95% CI 0.76–0.91), 0.92 (95% CI 0.81–0.97), and 0.93 (95% CI 0.91–0.95), respectively, suggesting better diagnostic performance of miR-21 compared with other miRNAs. Meanwhile, pooled prognostic result of miR-21 for HR was 1.88 (95% CI 1.41–2.51), indicating miR-21 could more appropriately predict shorter OS in patients with CCA.

miRNAs may provide a new approach for clinical application, and miR-21 may be a promising biomarker for diagnosis and prognosis of CCA.

• cholangiocarcinoma
• diagnosis
• meta-analysis
• miR-21
• microRNAs
• prognosis

• Primary sclerosing cholangitis
• cholangiocarcinoma

• Adult
• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/pathology
• Cell Transformation, Neoplastic/pathology
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/pathology
• Cholangitis, Sclerosing/diagnosis
• Cholangitis, Sclerosing/epidemiology
• Cholangitis, Sclerosing/pathology
• Disease Progression
• Humans
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/epidemiology
• Middle Aged
• Predictive Value of Tests
• Prognosis
• Risk Factors

• Biomarker
• Carbohydrate antigen 19–9
• Carcinoembryonic antigen
• Cholangiocarcinoma
• MicroRNA

• autoimmune hepatitis
• epigenetics
• gene function
• interventions
• pathogenesis

• Cholangiopathies
• Diagnosis
• Extracellular vesicles
• Pathogenesis
• Therapy
• microRNAs

• Animals
• Bile Duct Diseases/diagnosis
• Bile Duct Diseases/etiology
• Bile Duct Diseases/pathology
• Bile Ducts/cytology
• Bile Ducts/metabolism
• Bile Ducts/pathology
• Biomarkers/analysis
• Biomarkers/metabolism
• Disease Models, Animal
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Extracellular Vesicles/metabolism
• Gene Expression Profiling
• Humans
• MicroRNAs/analysis
• MicroRNAs/metabolism

• Biliary cancer
• Biomarker
• Differential diagnosis
• Liver cancer
• Omics

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/therapy
• Bile Ducts/pathology
• Bile Ducts/surgery
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Biopsy/methods
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/mortality
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/therapy
• Epigenomics/methods
• Gene Expression Profiling/methods
• Humans
• Immunotherapy/methods
• Metabolomics/methods
• Neoplasm Recurrence, Local/diagnosis
• Neoplasm Recurrence, Local/mortality
• Neoplasm Recurrence, Local/pathology
• Neoplasm Recurrence, Local/therapy
• Prognosis
• Proteomics/methods
• Survival Rate
• Treatment Outcome

There is high need of novel diagnostic and prognostic tools for tumors of the digestive system, such as gastric cancer and cholangiocarcinoma. We recently found that miR-204 was deeply downregulated in gastric cancer tissues. Here we investigated whether this was common to other tumors of the digestive system and whether this elicited a miR-204-dependent gene target signature, diagnostically and therapeutically relevant. Finally, we assessed the contribution of the identified target genes to the cell cycle progression and clonogenicity of gastric cancer and cholangiocarcinoma cell lines.

We employed quantitative PCR and Affymetrix profiling for gene expression studies. In silico analysis aided us to identifying a miR-204 target signature in publicly available databases (TGCA). We employed transient transfection experiments, clonogenic assays and cell cycle profiling to evaluate the biological consequences of miR-204 perturbation.

We identified a novel miR-204 gene target signature perturbed in gastric cancer and in cholangiocarcinoma specimens. We validated its prognostic relevance and mechanistically addressed its biological relevance in GC and CC cell lines.

We suggest that restoring the physiological levels of miR-204 in some gastrointestinal cancers might be exploited therapeutically.

• cholangiocarcinoma
• gastric cancer
• micro-RNA, miR-204, prognostic

• MicroRNA
• clinical value
• digestive tract cancers
• miR-483
• regulatory mechanism