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Additional file 1: Table S1. Snail species composition (%) in the surrounding water bodies of BN and BT villages. Table S2. Potential influences of perceptual and behavioral factors on consumption habits of BN and BT villagers. Consumption frequency was based on all three raw fish dishes consumed. Odds ratio for the analysis of willingness to avoid consumption and O. viverrini (O.v.) infection status was included for the relation that was statistically significant. Table S3. Potential influences of reasons of consumption (comparing five individual reasons vs. two reasons of ecosystem services), and perceptual and behavioral factors on consumption frequencies of BN and BT villagers. Consumption frequency was based on higher risk raw fish dishes, koi pla and pla som. Table S4. Potential influences of perceptual and behavioral factors, and network indices of degree centrality and betweenness centrality on consumption habits of BN and BT villagers. Consumption frequency wasbased on all three raw fish dishes consumed. Table S5. Potential influences of ecosystem services, perceptual and behavioral factors, and network indices of degree centrality and betweenness centrality on consumption habits of BN and BT villagers. Consumption frequency was based on all three raw fish dishes consumed.

Background Human infection with Opisthorchis viverrini, a carcinogenic liver fluke inhabiting the biliary tree, is endemic in Southeast Asia. Chronic infection is associated with a fatal complication, cholangiocarcinoma (CCA), a late-presenting and aggressive malignancy. Currently, annual mortality rates from CCA mirror trends in incidence, due in part to limited availability of efficient prognostic and early diagnostic biomarkers. With ability to detect thousands of urinary metabolites using metabonomics, the urine metabolome holds great potential in providing an insight into system-level alterations in carcinogenesis and in identifying metabolic markers altered in response to disturbed homoeostasis. Methods Global molecular profiling using reversed-phase ultraperformance liquid chromatography mass spectrometry was utilised to acquire the urinary spectral profile of 137 Thai subjects (48 at high risk of infection, 41 with O. viverrini infection, 34 periportal fibrosis and 14 CCA) from Khon Kaen, Thailand. Results Multivariate statistical analysis identified perturbation in several molecular classes related to purine metabolism and lipid metabolism in the CCA urine metabolome. These markers mainly reflect changes in energy metabolism to support proliferation (increased fatty acid oxidation and purine recycling), DNA methylation and hepatic injury. Conclusions Several metabolites of biological interest were discovered from this proof-of-principle dataset. Augmenting these findings is essential to accelerate the development of urinary metabolic markers in CCA.

Attapol Titapun,1,2 Anchalee Techasen,2,3 Prakasit Sa-Ngiamwibool,2,4 Paiboon Sithithaworn,2,5 Vor Luvira,1,2 Tharatip Srisuk,1,2 Apiwat Jareanrat,1,2 Hasaya Dokduang,2,6 Watcharin Loilome,2,6 Bandit Thinkhamrop,2,7 Narong Khuntikeo1,2 1Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; 2Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand; 3Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand; 4Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; 5Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; 6Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; 7Department of Epidemiology and Biostatistics, Faculty of Public Health, Khon Kaen University, Khon Kaen, ThailandCorrespondence: Attapol TitapunDepartment of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, ThailandTel +66-43-363252Email attati@kku.ac.thBackground: Serum antibody for Opisthorchis viverrini (OV) is strong evidence for a history of OV infection in people. Currently, no studies have examined whether varying cholangiocarcinoma (CCA) prevalence levels are linked to previous OV infection nor have they provided comprehensive assessment and characterization of OV-associated CCA.Objective: Our study examined the prevalence of serum IgG antibodies for OV-positive CCA cases and determined whether there were correlations of IgG antibodies with histopathologic features, HER2, PD-L1, and FGFR2 expression, as well as their roles on the patients’ survival.Methods: The study involved 221 CCA surgical patients at Khon Kaen University Hospital, Thailand, from 2005 to 2017. Serum specimens were tested for OV IgG by ELISA. CCA tissue microarrays were used to examined for HER2, PD-L1, and FGFR2 expression. Logistic regression was used to investigate an association between factors and IgG. Cox regression was used to determine factors that affected CCA patient survival.Results: IgG for OV were positive in 162 cases, and the prevalence was 73.3% (95% CI=68.0– 78.7). About three quarters (78.3%) had large duct type tumors and concomitant intraductal papillary neoplasm of bile ducts (IPNB) occurred in 92 (50%) cases. HER2 expression was positive in 94 (61.4%) cases. Positive PD-L1 and FGFR2 expression occurred in 125 (83.9%) and 100 (67.1%) cases. IgG for OV had no significant correlation to any histological feature but had significant correlation with HER2 overexpression with adjusted OR=2.32 (95% CI=1.09– 4.96, P=0.03). Cases of CCA with OV IgG positive had a significantly poor prognosis with adjusted HR=1.66 (95% CI=1.13– 2.43, P=0.01).Conclusion: We found a high prevalence of serum IgG for OV-positive CCA patients and a correlation with overexpression of HER2. Moreover, IgG for OV and HER2 expression indicated poor survival of CCA. Therefore, future clinical studies for anti-HER2 treatments should focus on OV-associated CCA.Keywords: survival, intraductal type, FGFR2, PD-L1, immunoglobulin G, fluke-associated CCA

The prevalence of cholangiocarcinoma (CCA) in Southeast Asia is much higher than other areas of the world. Eating raw, fermented, or undercooked cyprinid fish, infected with the liver fluke, Opisthorchis viverrini sensu lato (sl), results in chronic biliary inflammation, periductal fibrosis, and increased cancer risk. There may be associated glomerulonephritis. The process of infection is difficult to disrupt because eating practices have proven extremely difficult to change, and the life cycle of the fluke cannot be broken due to high prevalence in canine and feline reservoir hosts. Fecal analysis and enzyme-linked immunosorbent assay tests can be used to diagnose opisthorchiasis. Diagnosis of CCA is complex, partly due to the lack of definitive imaging characteristics but also due to the difficulty of obtaining samples for cytology or histology. This cancer has proven to be resistant to common chemotherapy treatments and so the two avenues of treatment available are surgical resection and liver transplantation, both requiring early detection of the tumor for the best chances of success. Late presentation of symptoms reduces the chances of successful surgical intervention. While liver fluke infections can be treated with praziquantel, individuals will often become reinfected, and multiple reinfections can be more harmful than a singular, long-term infection. A key research on the detection and characterization of novel biomarkers in all parts of the carcinogenic pathway for early diagnosis is needed.

Munirah Alsaleh,1 Zoe Leftley,1 Thomas A Barbera,1 Paiboon Sithithaworn,2 Narong Khuntikeo,2 Watcharin Loilome,2 Puangrat Yongvanit,2 I Jane Cox,3 Nittaya Chamodol,2 Richard RA Syms,4 Ross H Andrews,1,2 Simon D Taylor-Robinson1 1Division of Surgery and Cancer, Imperial College London, London W2 INY, UK; 2Cholangiocarcinoma Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; 3Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NT, UK; 4Department of Electrical and Electronic Engineering, Imperial College London, London SW7 2AZ, UK Abstract: Cholangiocarcinoma (CCA) is a tumor with increasing prevalence around the world. The prevalence of CCA is highest in East Asia and most significantly in the countries through which the Mekong River flows, owing to the presence of liver flukes, which are consumed in raw fish dishes. Outside Asia, the causes of bile duct cancers for the most part are unknown. In this review, we assess the current state of knowledge in both fluke-associated and sporadic CCA, from etiological, diagnostic, and treatment perspectives. Keywords: cholangiocarcinoma, etiology, diagnosis, treatment, bile ducts