• Clonorchis sinensis
• Complications
• Hepatobiliary
• Opisthorchis felineus
• Opisthorchis viverrini
• Risk

• Animals
• Humans
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/parasitology
• Bile Duct Neoplasms/pathology
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/parasitology
• Cholangiocarcinoma/pathology
• Clonorchiasis/complications
• Clonorchiasis/epidemiology
• Clonorchiasis/parasitology
• Clonorchiasis/pathology
• Clonorchis sinensis/pathogenicity
• Opisthorchiasis/complications
• Opisthorchiasis/epidemiology
• Opisthorchiasis/parasitology
• Opisthorchiasis/pathology
• Opisthorchis/pathogenicity
• Risk Factors

• Clonorchis sinensis
• Fish-borne trematodes
• Liver flukes
• Opisthorchis felineus
• Opisthorchis viverrini

• Animals
• Humans
• Opisthorchis/pathogenicity
• Opisthorchiasis/epidemiology
• Opisthorchiasis/parasitology
• Clonorchiasis/epidemiology
• Clonorchiasis/parasitology
• Clonorchiasis/prevention & control
• Clonorchiasis/drug therapy
• Clonorchis sinensis/pathogenicity
• Clonorchis sinensis/genetics
• Clonorchis sinensis/physiology
• Bile Duct Neoplasms/parasitology
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/pathology
• Cholangiocarcinoma/parasitology
• Cholangiocarcinoma/epidemiology

• Cancer
• Clonorchis
• Inflammation
• Opisthorchis
• Schistosoma

• Animals
• Humans
• Carcinogens
• Helminths
• Carcinogenesis
• Helminthiasis/parasitology
• Neoplasms/parasitology

• foodborne trematodiasis
• modelling
• morbidity
• neglected tropical diseases
• schistosomiasis
• trachoma

• Humans
• Morbidity
• Carcinogenesis
• London
• Neglected Diseases/epidemiology
• Policy

• 215919/Z/19/Z Wellcome Trust
• Royal Society
• Bill and Melinda Gates Foundation
• Engineering and Physical Sciences Research Council

Cholangiocarcinoma (CCA) is an intractable cancer, and its incidence in northeastern Thailand is the highest worldwide. Infection with the liver fluke Opisthorchis viverrini (OV) has been associated with CCA risk. However, animal experiments have suggested that OV alone does not induce CCA, but its combination with a chemical carcinogen like nitrosamine can cause experimentally induced CCA in hamsters. Therefore, in humans, other environmental and genetic factors may also be involved.

To examine relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing and inflammation-related genes.

This hospital-based case-control study enrolled 95 case-control pairs matched by age (± 5 years) and sex. We examined relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing and inflammation-related genes, serum anti-OV, alcohol consumption, and smoking. Polymorphisms of CYP2E1, IL-6 (-174 and -634), IL-10 (-819), and NF-κB (-94) and their co-occurrence with polymorphisms in the drug-metabolizing enzyme gene GSTT1 or GSTM1 were also analyzed.

Although CCA risk was not significantly associated with any single polymorphism, persons with the GSTT1 wild-type and CYP2E1 c1/c2 + c2/c2 genotype had an increased risk (OR = 3.33, 95%CI: 1.23-9.00) as compared with persons having the GSTT1 wild-type and CYP2E1 c1/c1 wild genotype. The presence of anti-OV in serum was associated with a 7- to 11-fold increased risk, and smoking level was related to an OR of 1.5-1.8 in multivariable analyses adjusted for each of the seven genetic polymorphisms.

In addition to infection with OV, gene-gene interactions may be considered as one of the risk factors for CCA development.

• Opisthorchis
• Glutathione transferase
• Cytochrome P-450 CYP2E1
• Case-control study

• Humans
• Cholangiocarcinoma/genetics
• Bile Duct Neoplasms/genetics
• Bile Ducts, Intrahepatic

• Humans
• Opisthorchiasis/complications
• Opisthorchiasis/epidemiology
• Opisthorchiasis/prevention & control
• Carcinogenesis
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/prevention & control
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/prevention & control
• Bile Ducts, Intrahepatic

Humans continue to be constantly exposed to mycotoxins, mainly through oral exposure (dietary), inhalation, or dermal contact. Recently, it has been of increasing interest to investigate mycotoxin-linked carcinogenicity. This systematic review was conducted to synthesize evidence of the association between mycotoxin-linked mutations and the risk of cancer, to provide an overview of the data linking exposure to different mycotoxins with human cancer risk, and to provide an update on current research on the risk of cancer associated with human exposure to mycotoxins. PRISMA guidelines were used when conducting the systematic review. PubMed, MEDLINE, and CINAHL electronic databases were comprehensively searched to extract the relevant studies published from inception to May 2022. A total of sixteen relevant studies (4907 participants) were identified and included in this review. Of these, twelve studies were from Asia, while four of the studies were conducted in Africa. The overall meta-analysis result found no significant association, although some of the studies confirmed an association between mycotoxin-linked mutations and primary liver cancer risk. Mainly, the experimental studies have shown associations between mycotoxin-linked mutations and cancer risk, and there is a need for researchers to confirm these links in epidemiological studies in order to guide public health policies and interventions.

• aflatoxin
• cancer
• exposure
• food
• fumonisin
• fungal metabolites
• mycotoxins

• Animals
• Environmental Exposure/adverse effects
• Food Contamination
• Humans
• Mycotoxins/adverse effects
• Neoplasms/chemically induced
• Neoplasms/epidemiology

• 001 World Health Organization

• cancer registry
• cholangiocarcinoma
• epidemiology
• trends

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms/epidemiology
• Cholangiocarcinoma/epidemiology
• Female
• Humans
• Incidence
• Male
• Middle Aged
• Time Factors

• 001 World Health Organization
• Z01 CP010158 Intramural NIH HHS

• Biliary tract cancers
• Cholangiocarcinoma
• Genome sequencing
• Immunotherapy
• Targeted therapy

• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biliary Tract Neoplasms/genetics
• Biliary Tract Neoplasms/immunology
• Biliary Tract Neoplasms/mortality
• Biliary Tract Neoplasms/therapy
• Biomarkers, Tumor/genetics
• Clinical Decision-Making
• Humans
• Immunotherapy/adverse effects
• Immunotherapy/mortality
• Molecular Targeted Therapy/adverse effects
• Molecular Targeted Therapy/mortality
• Precision Medicine
• Treatment Outcome
• Tumor Microenvironment

• ATP-binding cassette A1
• ATP-binding cassette G1
• cholangiocarcinoma
• cholesterol
• statin

• MR/N01247X/1 Medical Research Council

Cholangiocarcinoma (CCA) is a malignant neoplasm of the biliary tract. Thailand reports the highest incidence of CCA in the world. The aim of this study was to map the distribution of CCA and identify spatial disease clusters in Northeast Thailand. Individual-level data of patients with histopathologically confirmed CCA, aggregated at the sub-district level, were obtained from the Cholangiocarcinoma Screening and Care Program (CASCAP) between February 2013 and December 2017. For analysis a multivariate Zero-inflated, Poisson (ZIP) regression model was developed. This model incorporated a conditional autoregressive (CAR) prior structure, with posterior parameters estimated using Bayesian Markov chain Monte Carlo (MCMC) simulation with Gibbs sampling. Covariates included in the models were age, sex, normalized vegetation index (NDVI), and distance to water body. There was a total of 1,299 cases out of 358,981 participants. CCA incidence increased 2.94 fold (95% credible interval [CrI] 2.62–3.31) in patients >60 years as compared to ≤60 years. Males were 2.53 fold (95% CrI: 2.24–2.85) more likely to have CCA when compared to females. CCA decreased with a 1 unit increase of NDVI (Relative Risk =0.06; 95% CrI: 0.01–0.63). When posterior means were mapped spatial clustering was evident after accounting for the model covariates. Age, sex and environmental variables were associated with an increase in the incidence of CCA. When these covariates were included in models the maps of the posterior means of the spatially structured random effects demonstrated evidence of spatial clustering.

• biliary tract cancer
• extrahepatic cholangiocarci-noma
• gallbladder cancer
• genome sequencing
• immunotherapy
• intrahepatic cholangiocarcinoma
• molecular targets

• Clonorchis sinensis
• Fish-borne trematodes
• Liver flukes
• Opisthorchis felineus
• Opisthorchis viverrini

Chronic inflammation and repeated infection with Opisthorchis viverrini (O. viverrini) induces intrahepatic cholangiocarcinoma (ICC). Inflammatory cytokines such as interleukin (IL) and tumor necrosis factor (TNF) are substances in the immune system that promote inflammation and causes disease to progress. Genes that help express proinflammatory cytokines can affect an individual’s susceptibility to disease, especially in cancer-related chronic inflammation. This study aimed to investigate risk factors for ICC with a focus on opisthorchiasis and polymorphisms of proinflammatory cytokines (IL-1β and TNF-α).

This study was a nested case-control study within a cohort study. 219 subjects who developed a primary ICC were identified and matched with two non-cancer controls from the same cohort based on sex and age at recruitment (±3 years). An O. viverrini-IgG antibody was assessed using enzyme linked immunosorbent assay. IL-1β and TNF-α polymorphisms were analyzed using a polymerase chain reaction with high resolution melting analysis. Associations between variables and ICC were assessed using conditional logistic regression.

Subjects with a high infection intensity had higher risk of ICC than those who had a low level (OR = 2.1; 95% CI: 1.2–3.9). Subjects with all genotypes of TNF-α (GG, GA, AA) and high infection intensity were significantly related to an increased risk of ICC (p < 0.05).

Polymorphisms of IL-1β and TNF-α are not a risk of ICC, but an individual with O. viverrini infection has an effect on all genotypes of the TNF-α gene that might promote ICC. Primary prevention of ICC in high-risk areas is based on efforts to reduce O. viverrini infection.

• Cholangiocarcinoma
• IL-1β
• Opisthorchiasis
• Polymorphism
• TNF-α

Cholangiocarcinoma (CCA) is a fatal bile duct cancer associated with infection by the liver fluke, Opisthorchis viverrini, in the lower Mekong region. Numerous public health interventions have focused on reducing exposure to O. viverrini, but incidence of CCA in the region remains high. While this may indicate the inefficacy of public health interventions due to complex social and cultural factors, it may further indicate other risk factors or interactions with the parasite are important in pathogenesis of CCA. This systematic review aims to provide a comprehensive analysis of described risk factors for CCA in addition to O. viverrini to guide future integrative interventions.

We searched five international and seven Thai research databases to identify studies relevant to risk factors for CCA in the lower Mekong region. Selected studies were assessed for risk of bias and quality in terms of study design, population, CCA diagnostic methods, and statistical methods. The final 18 included studies reported numerous risk factors which were grouped into behaviors, socioeconomics, diet, genetics, gender, immune response, other infections, and treatment for O. viverrini. Seventeen risk factors were reported by two or more studies and were assessed with random effects models during meta-analysis. This meta-analysis indicates that the combination of alcohol and smoking (OR = 11.1, 95% CI: 5.63–21.92, P <  0.0001) is most significantly associated with increased risk for CCA and is an even greater risk factor than O. viverrini exposure. This analysis also suggests that family history of cancer, consumption of raw cyprinoid fish, consumption of high nitrate foods, and praziquantel treatment are associated with significantly increased risk. These risk factors may have complex relationships with the host, parasite, or pathogenesis of CCA, and many of these risk factors were found to interact with each other in one or more studies.

Our findings suggest that a complex variety of risk factors in addition to O. viverrini infection should be addressed in future public health interventions to reduce CCA in affected regions. In particular, smoking and alcohol use, dietary patterns, and socioeconomic factors should be considered when developing intervention programs to reduce CCA.

The online version of this article (10.1186/s40249-018-0434-3) contains supplementary material, which is available to authorized users.

• Cholangiocarcinoma
• Mekong
• Opisthorchis viverrini
• Public health
• Risk factors
• Southeast Asia
• Thailand

Similar to bile duct cancer or cholangiocarcinoma (CCA) in the western world, opisthorchiasis-associated CCA in Southeast Asia is an aggressive cancer with high mortality rates. It is known to cause a significant health burden in the opisthorchiasis region in Thailand and possibly throughout mainland Southeast. To reduce this health burden, a comprehensive prevention and control program for opisthorchiasis, as well as CCA, is required. In this review, our aim is to provide a brief update of the current situation regarding the natural history of opisthorchiasis and health burden of CCA in Southeast Asia. A comprehensive approach to tackling these issues being implemented in Thailand under the “Cholangiocarcinoma Screening and Care Program” is described. This comprehensive program consists of a three stage prevention and patient care program. The primary prevention component involves opisthorchiasis screening using a new and sensitive urine assay. The secondary prevention component involves screening for CCA and periductal fibrosis, with suspected CCA patients following the protocol for confirmation and appropriate treatment. Due to the eco-epidemiology of opisthorchiasis-induced CCA, the anticipated impacts and outcomes of the program include short-, medium-, and the long-term goals for the reduction of CCA incidence. To achieve long-term sustainable impacts, concerted efforts to raise social awareness and participating action by general public, non-government organizations, and government agencies are necessary. The strategic plans developed for this program can be expanded for use in other endemic areas as well as being a model for use in other chronic diseases.

• Opisthorchis viverrini
• cholangiocarcinoma
• primary prevention
• screening
• secondary prevention
• tertiary care program

• Antineoplastic Combined Chemotherapy Protocols/standards
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/etiology
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/therapy
• Bile Ducts/pathology
• Bile Ducts/surgery
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/genetics
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/etiology
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/therapy
• Hepatectomy/methods
• Hepatectomy/standards
• Humans
• Incidence
• Liver Transplantation
• Lymph Node Excision/methods
• Lymph Node Excision/standards
• Lymphatic Metastasis
• Patient Selection
• Practice Guidelines as Topic
• Risk Factors
• Treatment Outcome

Cholangiocarcinoma remains a serious public health concern in Thailand. While many of the risk factors for cholangiocarcinoma in western countries are well-recognized, it remains unclear whether they are the same in Thailand. We set out to investigate the risk factors for cholangiocarcinoma in Thailand.

Starting March 4, 2016, we reviewed studies found using pre-specified keywords on SCOPUS, Pro Quest Science Direct, PubMed, and online public access catalog of Khon Kaen University. Two review authors independently screened studies for inclusion criteria, extracted data, and assessed the studied Risk of Bias. The Newcastle-Ottawa Scale and the Joanna Briggs Institute Critical Appraisal Tools were used to assess the quality of included studies. The risk effects of factors were estimated as a pooled adjusted odds ratio with a 95% confidence interval. The heterogeneity of results was considered using the I-square, Tau-square and Chi-square statistics.

A strong association was found between cholangiocarcinoma and age, Opisthorchis viverrini infection, eating raw cyprinoid fish, family history of cancer, liquor consumption, and taking praziquantel. There was only a mild association found between eating nitrite-containing foods, fresh vegetables, education, smoking behavior, and sex. No association was found between cholangiocarcinoma and eating fermented fish (Pla-ra), northeastern Thai or Chinese sausage, sticky rice, meat, chewing betel nut, or eating fruit. There were two protective factors including fresh vegetables consumption and education attainment.

There are unique risk factors of cholangiocarcinoma in Thailand, including age, Opisthorchis viverrini infection, eating raw cyprinoid fish, family history of cancer, liquor consumption, and taking praziquantel.

• Cholangiocarcinoma
• risk factors
• systematic review
• Thailand

• Cholangiocarcinoma
• Family
• Financial burden
• Northeast Thailand
• Socioeconomic burden

Sorafenib is a multiple kinase inhibitor which targets Raf kinases, VEGFR, and PDGFR and is approved for the treatment of hepatocellular carcinoma (HCC). Previously, we found that p-STAT3 is a major target of SC-43, a sorafenib derivative. In this study, we report that SC-43-induced apoptosis in cholangiocarcinoma (CCA) via a novel mechanism. Three CCA cell lines (HuCCT-1, KKU-100 and CGCCA) were treated with SC-43 to determine their sensitivity to SC-43-induced cell death and apoptosis. We found that SC-43 activated SH2 domain-containing phosphatase 1 (SHP-1) activity, leading to p-STAT3 and downstream cyclin B1 and Cdc2 downregulation, which induced G2-M arrest and apoptotic cell death. Importantly, SC-43 augmented SHP-1 activity by direct binding to N-SH2 and relief of its autoinhibition. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 counteracted the effect of SC-43-induced SHP-1 phosphatase activation and antiproliferation ability in CCA cells. In vivo assay revealed that SC-43 exhibited xenograft tumor growth inhibition, p-STAT3 reduction and SHP-1 activity elevation. In conclusion, SC-43 induced apoptosis in CCA cells through the SHP-1/STAT3 signaling pathway.

• SC-43
• SHP-1
• STAT3
• cholangiocarcinoma
• inflammatory cancer

• Anti-inflammatory agents
• Cholangiocarcinoma
• Inflammation
• Pancreatic adenocarcinoma

• Cholangiocarcinoma
• Epidemiology
• Risk factors
• Screening
• Surveillance

• Brain
• Cathepsins B and L
• Corticosterone
• IL-6
• Liver
• Opisthorchis felineus
• Plus-maze test
• Social defeat stress
• Spleen

Infection by the liver fluke, Opisthorchis viverrini, remains an important public health problem in Thailand and has resulted in the highest prevalence of infection and incidence of subsequent cholangiocarcinoma (CCA) in the world. Praziquantel (PZQ) is the antihelminthic drug of choice for treatment. Previous studies in hamsters showed that repeated infection and PZQ treatment could increase the risk of CCA. However, the few available epidemiology studies in humans have shown unclear evidence of an increased risk of CCA with frequency of PZQ intake. The present study investigated the relationship between the number of repeated PZQ treatments and CCA.

A hospital-based matched case–control study was conducted. All cases and controls were inpatients of a tertiary hospital in Northeast Thailand. During 2012–2014 a total of 210 incident cases of pathologically diagnosed CCA and 840 control subjects were selected from a hospital inpatient database (four controls per case). The four recruited controls were individually matched with CCA cases by gender, age and date of admission. Data were collected in face-to-face interviews using a standardised pre-tested questionnaire. Multivariable conditional logistic regression was used in the analysis of the data.

The frequencies of PZQ usage among the 210 cases and 840 controls were 48.6 vs. 66.0 for never, 32.9 vs. 24.4 for once, 8.6 vs. 4.9 for twice, and 10.0 % vs. 4.8 % for more than twice, respectively. There was a statistically significant dose–response relationship (p < 0.001). Compared with subjects who never used PZQ, those who used the medication once, twice, and more than twice were 1.49, 1.82, and 2.30 times more likely to develop CCA (95 % confidence intervals: 1.02 - 2.20, 0.92 - 3.60, and 1.20 - 4.40). These odds ratios (adjusted ORs) had already been adjusted for the effects of eating raw fish, a family history of cancer, and highest educational attainment. Additional PZQ usage increased the odds of developing CCA by 23.0 % (adjusted OR = 1.23; 95 % CI: 1.07 - 1.43).

The findings show that repeated PZQ treatments are associated with an increased risk of CCA. Paradoxically, this contradicts the common belief that repeated PZQ treatments decrease the risk of CCA. The study also showed a strong association between the number of repeated PZQ treatments and the consumption of raw freshwater fish. This suggests that repeated PZQ treatments may be a surrogate marker of habit of eating raw fish.

The online version of this article (doi:10.1186/s12885-015-1788-6) contains supplementary material, which is available to authorized users.

• Hepatocellular carcinoma
• Heterogeneity
• Intrahepatic cholangiocarcinoma
• Personalized therapy

• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Humans
• Liver Neoplasms/epidemiology
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Molecular Diagnostic Techniques
• Molecular Targeted Therapy
• Phenotype
• Precision Medicine/methods
• Risk Factors
• Signal Transduction/drug effects
• Tumor Microenvironment

• Animals
• Bile Ducts/parasitology
• Bile Ducts/pathology
• Case-Control Studies
• Cholangiocarcinoma/parasitology
• Cholangiocarcinoma/pathology
• Cohort Studies
• Fasciola hepatica/physiology
• Fascioliasis/parasitology
• Fascioliasis/pathology
• Humans
• Liver/parasitology
• Liver/pathology
• Publication Bias
• Regression Analysis
• Risk Factors

• Cholangiocarcinoma
• Risks
• Staging systems
• Symptoms

• Asia/epidemiology
• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/etiology
• Bile Ducts, Intrahepatic/pathology
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/etiology
• Humans
• Incidence
• Risk Factors

• Adenocarcinoma/epidemiology
• Adult
• Biliary Tract Neoplasms/epidemiology
• Case-Control Studies
• Female
• Humans
• Male
• Middle Aged
• Odds Ratio
• Registries
• Reproductive History
• Risk Factors
• Sweden/epidemiology
• Young Adult

• cholangiocarcinoma
• polymeric micelles
• docetaxel
• apoptosis
• cancer chemotherapy

• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/chemistry
• Apoptosis/drug effects
• Bile Duct Neoplasms/drug therapy
• Bile Duct Neoplasms/pathology
• Cell Line, Tumor/drug effects
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/pathology
• Chondroitin Sulfates/chemistry
• Delayed-Action Preparations/chemistry
• Docetaxel
• Drug Carriers/administration & dosage
• Drug Carriers/chemistry
• Drug Delivery Systems/methods
• Histamine/chemistry
• Humans
• Hydrogen-Ion Concentration
• Mice, Nude
• Micelles
• Nanocomposites/administration & dosage
• Nanocomposites/chemistry
• Taxoids/administration & dosage
• Taxoids/chemistry
• Xenograft Model Antitumor Assays

Cholangiocarcinoma (CCA) is a difficult cancer to diagnose in the early stage and to treat by curative resection. The incidence of CCA in the northeast of Thailand is the highest in the world. To make progress in detecting a high risk group and in the prevention and detection of CCA, we have been analyzing the risk factors for CCA. Although liver fluke infection is known to be a risk factor, there are patients who are not infected with the liver fluke and not all people infected with the liver fluke will suffer from the disease. Therefore, it is of the utmost importance to analyze the risk factors and the mechanism to prevent the disease and also to detect the disease in its early stage to save patients’ lives. Through collaboration among Thai and Japanese researchers, we analyzed the genetic and environmental determinants of risks for CCA. Also, we have been trying to develop methods to detect the disease in a non-invasive way. Without repeating findings reported in various reviews on CCA, we will first discuss the environmental and genetic determinants of the risks for CCA. Second, we will discuss the properties of CCA, including the etiological agents and the mechanism of cholangiocarcinogenesis, and finally, we will discuss future approaches to prevent and cure CCA from the standpoint of evidence-based medicine. We will discuss these points by including the data from our laboratories. We would like to emphasize the importance of the genetic data, especially whole genome approaches, to understand the properties of CCA, to find a high risk population for CCA and to develop effective preventative methods to stop the carcinogenic steps toward CCA in the near future. In addition, it is of the upmost importance to develop a non-invasive, specific and sensitive method to detect CCA in its early stage for the application of modern medical approaches to help patients with CCA.

• Alcohol drinking
• Cholangiocarcinoma
• DNA polymorphism
• Glutathione S transferase
• 8-oxoguanine glycosylase 1
• Liver fluke
• Opisthorchis viverrini
• Thailand

• EPIDEMIOLOGY
• PUBLIC HEALTH

• Adult
• Aged
• Alcohol Drinking/epidemiology
• Asian People/genetics
• Asian People/statistics & numerical data
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/genetics
• Bile Ducts, Intrahepatic
• Case-Control Studies
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/genetics
• DNA Glycosylases/genetics
• DNA-Binding Proteins/genetics
• Female
• Gene-Environment Interaction
• Genetic Predisposition to Disease
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Real-Time Polymerase Chain Reaction
• Smoking/epidemiology
• Thailand/epidemiology
• X-ray Repair Cross Complementing Protein 1

• Bile duct stent
• Cholangiocarcinoma
• Membrane-covered self-expanding metal stent (SEMS)
• Pheophorbide A
• Photodynamic therapy

• Animals
• Bile Ducts/drug effects
• Chlorophyll/analogs & derivatives
• Chlorophyll/chemistry
• Chlorophyll/pharmacology
• Chlorophyll/therapeutic use
• Cholangiocarcinoma/drug therapy
• Endoscopy
• Fluorescence
• HeLa Cells
• Humans
• Metals/chemistry
• Mice
• NIH 3T3 Cells
• Photochemotherapy
• Photosensitizing Agents/pharmacology
• Photosensitizing Agents/therapeutic use
• Polymers/chemical synthesis
• Polymers/chemistry
• Stents
• Subcutaneous Tissue/pathology
• Swine
• Swine, Miniature
• Time Factors
• Xenograft Model Antitumor Assays

• Biliary tract cancer · Cholangiocarcinoma · Opisthorchis viverrini · Tumor marker

The influence of Glucagon-like peptide-1 (GLP-1) and Exendin-4 on development of intrahepatic cholangiocarcinoma (ICC) is evaluated in the study. In vitro tests, including acute toxicity test, cell colony formation assays, cells proliferation and apoptosis, transwell assay, were performed. An ICC in situ tumor animal model was established. Then, animals were randomly divided into four groups (n = 6): control, Exendin-4 treatment, oxaliplatin treatment and Exendin-4-oxaliplatin treatment. Animals in the Exendin-4 treatment and Exendin-4-oxaliplatin treatment groups received a subcutaneous injection of Exendin-4 (100 μg/kg/day) for 1 week, and then received oxaliplatin (10 mg/kg/week) by tail vein injection. Animals in the control group received PBS. Immunohistochemistry tests were used for PCNA, Ki67, Caspase 3 expression in tumor tissue. Results show that that, after incubation of human cholangiocarcinoma cell lines, HuCCTI and GLP-1, or HuCCTI and Exendin-4, colony formation number was sharply decreased. However, GLP-1, HuCCTI or Exendin-4 did not affect the colony of normal cells. Combination treatment with oxaliplatin and Exendin-4 can significantly inhibit tumor cells’ proliferation and promote apoptosis. The combined effect is stronger than that of oxaliplatin or Exendin-4. Combination treatment with oxaliplatin and Exendin4 can significantly decrease Ki67 and PCNA proteins’ expression in subcutaneous tumors of nude mice. The inhibitory effect of Combination treatment with oxaliplatin and Exendin4 is clearly stronger than that of oxaliplatin. In addition, Combination treatment with oxaliplatin and Exendin4 can significantly increase Caspase3 protein positive expression. In short, these results show that combination treatment with oxaliplatin and Exendin4 can inhibit tumor cells’ proliferation, and promote apoptosis.