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Intrahepatic cholangiocarcinoma (iCCA) arises from bile ducts within the liver. Thailand has the highest incidence of CCA worldwide, with a high mortality rate. Early diagnosis and accurate prognostic stratification can improve overall survival. We aim to modify the AJCC/UICC 8th edition staging system for iCCA by creating the Khon Kaen University (KKU) staging system for more precise patient stratification and prognostic prediction.A total of 298 iCCA patients who underwent hepatectomy were included in this retrospective study at the Srinagarind Hospital, Khon Kaen University, Thailand. Univariate and multivariate analysis were performed to examine survival rate, hazard ratio, and prognostic factors.Univariate and multivariate analysis of the cohort showed that growth patterns, histological type, histological grade, lymph node metastasis and distant metastasis were independent prognostic factors when compared to the respective reference groups. The 8th AJCC staging system incorporated growth patterns into the KKU staging system. This model modified AJCC stages I, II, and III for better prediction of patient survival.Growth patterns were incorporated to improve the 8th AJCC staging system for prognostication of iCCA patients in Northeast Thailand. We propose the KKU staging system as an alternative model for iCCA staging to augment the accuracy of survival prognostication.

Background: Cholangiocarcinoma (CCA) is a potentially lethal disease that requires surgical treatment. There are many benign conditions, those that do not require surgical treatment, displaying imaging characteristics that resemble CCA, leading to therapeutic misadventures. This study aimed to evaluate the proportion of benign conditions that underwent hepatic resection for presumed CCA, and explore the differences between the characteristics of these two entities stratified by primary imaging features of the lesions. Methods: This retrospective study ran between January 2004 and December 2011. We reviewed the pathological records of all 1,402 patients who underwent curative-intent hepatic resection for preoperatively diagnosed CCA. All clinical and pathological parameters were analyzed. Results: The proportion of benign conditions that underwent hepatic resection was 3.78% (53/1,402). For mass-forming lesions, CCA was associated with higher age, alkaline phosphatase, tumor markers, neutrophil to lymphocyte ratio, and mass size. The patients with mass-forming benign conditions were more associated with diabetes mellitus. For lesions with bile duct dilatation, intraductal tumor, including CCA, had higher CA19-9 level and NLR with statistical significance. For cystic lesions, biliary cystic neoplasm had statistical significance in the rate of abdominal pain. Conclusions: The proportion of hepatic resection for benign conditions was quite low. There were many characteristic differences used to differentiate benign mass-forming conditions from CCA, whereas only few markers in the setting of cystic lesions and biliary dilatation. We recommend performing standard hepatic resection in every case, regardless of the type of imaging features, if the lesion has a chance of being CCA.

Gastrointestinal stromal tumor (GIST) is a common mesenchymal neoplasm of the gastrointestinal (GI) tract. Paraneoplastic syndromes of GISTs are rare; in particular, GIST-induced hyperglycemia has not been reported. A 67-year-old woman presented with recurrent alteration of consciousness and uncontrolled hyperglycemia. Computed tomography scans showed a huge hypervascular mass, located medial to the superior mesenteric vessels. Endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) showed spindle cell tumors, diagnosed as borderline resectable duodenal GIST. There was partial response after 6 months of Imatinib treatment. En-bloc resection was performed via the laparotomy. The histology confirmed a high-risk GIST at the third part of the duodenum. The abnormal symptoms then dramatically disappeared. She has remained recurrence free for 22 months. Uncontrolled hyperglycemia and abnormal neurological conditions are rare in GIST; however, a large hypervascular GIST could cause paraneoplastic syndromes or consume the products from an adjacent structure, requiring complete tumor resection. This case adds the knowledge of an extremely rare presentation of GIST and, moreover, extremely rare cause of uncontrolled hyperglycemia.

Attapol Titapun,1,2 Vor Luvira,1,2 Tharatip Srisuk,1,2 Apiwat Jareanrat,1,2 Vasin Thanasukarn,1,2 Malinee Thanee,2,3 Prakasit Sa-Ngiamwibool,2,3 Sureerat Padthaisong,2,4 Kassaporn Duangkumpha,2,4 Manida Suksawat,2,4 Watcharin Loilome,2,4 Paiboon Sithithaworn,2,5 Anchalee Techasen,2,6 Bandit Thinkhamrop,2,7 Alexa Dzienny,8 Ayse Caglayan,9 David Park,9 Simran Mahmud,9 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; 3Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; 4Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; 5Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; 6Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand; 7Department of Epidemiology and Biostatistics, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand; 8School of Medicine and Health Sciences, George Washington University, Washington, DC, USA; 9Faculty of Medicine, Imperial College London, London, UKCorrespondence: Attapol TitapunDepartment of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, ThailandTel +66-43-363252Email attati@kku.ac.thBackground: Opisthorchis viverrini (OV)-associated cholangiocarcinoma (CCA) has a high immune response with chronic inflammation and oxidative stress. CD44 and Nestin, two cancer stem cell (CSC) markers, play major roles in cancer cell survival. Effects of immune response and expression CSC markers on survival of patients with CCA remain unclear.Objective: To investigate the effects of level of OV IgG together with CSC marker expression and also the combination of these markers on survival of CCA patients after curative resection.Methods: All serum specimens from CCA patients who underwent curative surgery from 2005 to 2015 were examined for IgG for OV antigen by ELISA. Tissue specimens were studied for CD44 and Nestin expression. Survival analysis by Cox proportional hazard model was used for estimating hazard ratio (HR) with a 95% confidence interval (CI).Results: In this study, 122 (69.3%) of 176 were positive for OV IgG, and 35 (19.9%) were considered to have high-positive OV IgG. CD44s positive expression was found in 54 (40%), CD44v6 high expression in 96 (69.6%), CD44v8-10 high expression in 87 (63.5%) and Nestin high expression in 21 (16.1%). Multivariate survival analysis found that high-positive OV IgG and late stage tumor were independent prognostic factors with the adjusted HR of 2.24 (95% CI 1.27– 3.93) and 2.78 (95% CI 1.46– 5.29), respectively. Subgroup analysis in early and late stage CCA showed that a combined positive OV IgG and CD44s expression with the high expression of CD44v8-10 had the significantly poorest prognosis with HR of 3.75 (95% CI 1.61– 8.72) and HR of 1.76 (95% CI 1.02– 3.03), respectively.Conclusion: A high level of OV IgG as well as a high level of CSC markers resulted in an aggressive CCA. OV IgG level together with CSC markers can be used as the prognostic markers for CCA patients’ survival. The study of the CD44 pathway is promising for adjuvant treatment.Keywords: CCA, OV‐associated CCA, survival, OV IgG antibody, CD44s, CD44v8-10

The Pringle maneuver using a urinary catheter has been described and proven to be one of the best methods for laparoscopic intracorporeal vascular control. Selective vascular control provides many advantages over total inflow occlusion by the Pringle maneuver. However, laparoscopic selective vascular control by urinary catheter has not been described. We, herein, describe laparoscopic selective vascular control using a combined small urinary catheter with an endo mini-retractor, which inserted in a new way, named ‘The J-shaped Loop’. This method makes the instrument more compact so we can selectively control the vascular pedicle. When selective vascular occlusion is desired, the loop is tightened and the tension is held just by the catheter itself. This novel technique is simple, safe, effective and reproducible, and, therefore, can be used as a good alternative to other intracorporeal techniques for laparoscopic liver resection.

Background 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.

Distal cholangiocarcinoma (dCCA) is a rare type of CCA in Asia, even in

Highlight Luvira and colleagues present images of the intraoperative findings of Opisthorchis viverrini coexistent with intraductal papillary neoplasm of the bile duct. Along with evidence from previous reports, these findings suggest that Opisthorchis viverrini may play some role in the tumorigenesis of intraductal papillary neoplasm of the bile duct.

Background: Opisthorchiasis is caused by an infection with fish-borne liver flukes of the genus Opisthorchis. Opisthorchiasis frequently leads to chronic inflammation in the biliary tract and is classified as a group 1 biological carcinogen by the International Agency for Research on Cancer: a definitive risk for cholangiocarcinoma (CCA). Methods: We used the rapid immunochromatographic test (ICT) to detect anti-Opisthorchis viverrini IgG and IgG4 subclass antibodies in sera of patients with CCA. The ICT kits were developed based on soluble antigens excreted and secreted by O. viverrini adult worms. Results: ICT indicated sera was positive for IgG and IgG4 antibodies, respectively, in 22 (61.1%) and 15 (41.6%) participants of the 36 study participants diagnosed with CCA (P > 0.05). Our study also included groups with other cancers and with liver cirrhosis, where the IgG ICT and IgG4 ICT kits were 27.7% (13/47) and 25.5% (12/47) positive, respectively (P > 0.05). Neither total the IgG ICT nor the IgG4 ICT yielded positive results in a control group of 20 healthy participants. Moreover, the percentage positivity rate using the ICT for total IgG between the CCA group and the other cancers and liver cirrhosis group was significantly different (P < 0.05). By contrast, no significant difference between these groups was apparent in the ICT for IgG4 antibody. The CCA group was 6.53 times more likely to have positive anti–O. viverrini IgG antibody (odds ratio 6.53, P < 0.001) and 3.27 times more likely to have positive anti–O. viverrini IgG4 antibody (odds ratio 3.27, P = 0.010) than the non-CCA group. Conclusion: This information is of potential value for the development of a diagnostic biomarker to predict risk for O. viverrini infection-associated CCA.

Aim of the study Intraductal papillary neoplasm of the bile duct (IPNB) can present at various stages of the disease. Each stage needs different treatment. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have been described as predictive markers for several tumors. There has been no investigation on the role of NLR and PLR in IPNB. Material and methods We retrospectively reviewed the medical records of 112 patients who underwent curative-intent hepatic resection for IPNB between January 2007 and December 2011. All clinical parameters and survival were analyzed for their association with NLR and PLR. Results For prediction of malignancy, the best respective cut-off for NLR and PLR was 2.74 and 130, with area under the ROC curve being 0.662 and 0.763. For micro-papillary IPNB, both markers well predict malignancy and lymph node involvement. The respective area under the ROC curve of NLR and PLR for prediction of malignancy was 0.78 and 0.88. Both markers had an area under the ROC curve for prediction of lymph node involvement of 1.0. The median overall survival of those with PLR < 130 was 86.4 months compared with 45.0 months for those with PLR > 130 (p = 0.02). Conclusions NLR and PLR seem likely candidates for predicting malignancy, lymph node involvement, and survival of the patients. PLR performed better than NLR for all predictions. The markers worked very well for micro-papillary IPNB; however, we recommend using these markers in conjunction with the radiologic appearance of tumors.

Background: Frailty, a risk of unfavorable outcomes from disability to adapt to stressors, is common in the elderly but could occur in younger patients with cancer. This study focused on the prevalence of frailty in biliary tract cancer (BTC) and associated factors. Methods: A total of 75 BTC patients receiving chemotherapy from January 2016 to September 2017 were enrolled. Frailty was diagnosed by the FRAIL (Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight) scale. Univariate and multivariate regression analyses were used to analyze factors associated with frailty. Results: The prevalence rates of frailty and pre-frailty were 12% (9 cases) and 60% (45 cases). According to multivariate logistic analysis, three factors were associated with frailty, including old age, high body mass index (BMI), and history of liver surgery. The adjusted odds ratios of the factors were 1.12 (95% CI: 1.01, 1.24), 1.28 (95% CI: 1.01, 1.64), and 6.16 (95% CI: 1.11, 34.16), respectively. Conclusion: Frailty is not uncommon in BTC patients. Old age, high BMI, and history of liver surgery are important risk factors for frailty.

Background Cholangiocarcinoma (CCA) is a common malignancy in northeastern Thailand. Over the last 4 decades, several policies have been implemented for its prevention, but there has been no update on the trends and relative survival (RS). Our aim was (a) to perform a statistical assessment of the incidence trends of CCA and project future trends, and (b) to estimate relative survival. Methods All cases of CCA diagnosed from 1989 through 2013 were abstracted from the Khon Kaen Cancer Registry (KKCR). A jointpoint regression model was used to estimate the annual percentage change (APC) and to project future trends. We also calculated RS. Results There were 11,711 cases of CCA. The incidence rate increased with an APC of 1.79% (95% confidence interval [CI], -0.2 to 3.8) from 1989 through 2002, and decreased with an APC of -6.09% (95% CI, -8.2 to -3.9) from 2002 through 2013. The projected incidence of CCA should stable over the next 10 years, albeit higher than the world rate. The respective 5-year RS for both sexes for age groups of 30-40, 41-45, 51-60, and 61-98 years was 22.3% (95% CI, 16.8-29.5), 14.3% (95% CI, 12.0-17.0), 8.6% (95% CI, 7.8-10.0), and 7.2% (95% CI, 6.4-8.0). Conclusion The incidence rate of CCA has decreased since 2002, representing a real decline in the risk of CCA. The incidence of CCA is projected to stabilize by 2025. The survival of patients with CCA remains poor.

Fluorouracil (5-FU) is the first-line chemotherapeutic drug for cholangiocarcinoma (CCA), but its efficacy has been compromised by the development of resistance. Development of 5-FU resistance is associated with elevated expression of its cellular target, thymidylate synthase (TYMS). E2F1 transcription factor has previously been shown to modulate the expression of FOXM1 and TYMS. Immunohistochemical (IHC) analysis revealed a strong correlated upregulation of FOXM1 (78%) and TYMS (48%) expression at the protein levels in CCA tissues. In agreement, RT-qPCR and western blot analyses of four human CCA cell lines at the baseline level and in response to high doses of 5-FU revealed good correlations between FOXM1 and TYMS expression in the CCA cell lines tested, except for the highly 5-FU-resistant HuCCA cells. Consistently, siRNA-mediated knockdown of FOXM1 reduced the clonogenicity and TYMS expression in the relatively sensitive KKU-D131 but not in the highly resistant HuCCA cells. Interestingly, silencing of TYMS sensitized both KKU-D131 and HuCCA to 5-FU treatment, suggesting that resistance to very high levels of 5-FU is due to the inability of the genotoxic sensor FOXM1 to modulate TYMS expression. Consistently, ChIP analysis revealed that FOXM1 binds efficiently to the TYMS promoter and modulates TYMS expression at the promoter level upon 5-FU treatment in KKU-D131 but not in HuCCA cells. In addition, E2F1 expression did not correlate with either FOXM1 or TYMS expression and E2F1 depletion has no effects on the clonogenicity and TYMS expression in the CCA cells. In conclusion, our data show that FOXM1 regulates TYMS expression to modulate 5-FU resistance in CCA and that severe 5-FU resistance can be caused by the uncoupling of the regulation of TYMS by FOXM1. Our findings suggest that the FOXM1–TYMS axis can be a novel diagnostic, predictive and prognostic marker as well as a therapeutic target for CCA.

Background Cholangiocarcinoma (CCA) is a leading cause of cancer death in northeastern Thailand. We reported on the incidence of CCA using only one method. In the current study, we used three different statistical methods to forecast future trends and estimate relative survival. Methods We reviewed the CCA cases diagnosed between 1989 and 2018 recorded in the population-based Khon Kaen Cancer Registry (KKCR). Annual percent change (APC) was calculated to quantify the incidence rate trends using Joinpoint regression. Age-period-cohort models (APC model) were used to examine the temporal trends of CCA by age, calendar year, and birth cohort. We projected the incidence of CCA up to 2028 using three independent approaches: the Joinpoint, Age-period-cohort, and Nordpred models. Survival assessments were based on relative survival (RS). Results The respective APC in males and females decreased significantly (-3.1%; 95%CI: -4.0 to -2.1 and -2.4%; 95%CI: -3.6 to -1.2). The APC model—AC-P for male CCA—decreased according to a birth-cohort. The CCA incidence for males born in 1998 was 0.09 times higher than for those born in 1966 (Incidence rate ratios, IRR = 0.09; 95%CI: 0.07 to 0.12). The relative incidence for female CCA similarly decreased according to a birth-cohort (IRR = 0.11; 95%CI: 0.07 to 0.17). The respective projection for the age-standardized rate for males and females for 2028 will be 7.6 per 100,000 (102 patients) and 3.6 per 100,000 (140 patients). The five-year RS for CCA was 10.9% (95%CI: 10.3 to 11.6). Conclusion The incidence rate of CCA has decreased. The projection for 2028 is that the incidence will continue to decline. Nevertheless, the survival of patients with CCA remains poor.

Background. Major hepatectomy is the mainstay of the treatment for cholangiocarcinoma. Infrahepatic inferior vena cava (IVC) clamping is an effective maneuver for reducing blood loss during liver transection. The impact of this procedure on major hepatectomy for cholangiocarcinoma is unknown. This study evaluated the effect of infrahepatic IVC clamping on blood loss during liver transection. Methods. Clinical and pathological data were collected retrospectively for 116 cholangiocarcinoma patients who underwent major hepatectomy between January 2015 and December 2016, to investigate the benefit of infrahepatic IVC clamping. Two of five surgeons adapted the policy performing infrahepatic IVC clamping during liver transection in all cases. Patients, therefore, were divided into those ( n = 39 ; 33.6%) who received infrahepatic IVC clamping during liver transection (C1) and those ( n = 77 ; 66.4%) who did not (C0). Results. The patients’ backgrounds, operative parameters, and extent of hepatectomy did not differ significantly between the 2 groups, except for gender. A significantly lower blood loss ( p = 0.028 ), blood transfusion ( p = 0.011 ), and rate of vascular inflow occlusion requirement ( p < 0.001 ) were observed in the C1 group. The respective blood losses in the C1 group and the C0 group were 498.9 (95% CI: 375.8-622.1) and 685.6 (95% CI: 571-800.2) millilitres. Conclusions. The current study found infrahepatic IVC clamping during liver transection for cholangiocarcinoma reduces blood loss, blood transfusion, and rate of vascular inflow occlusion requirement.

Wound healing assay is a simple and cost-effective in vitro assay for assessing therapeutic impacts on cell migration. Its key limitation is the possible confoundment by other cellular phenotypes, causing misinterpretation of the experimental outcome. In this study, we attempted to address this problem by developing a simple analytical approach for scoring therapeutic influences on both cell migration and cell death, while normalizing the influence of cell growth using Mitomycin C pre-treatment. By carefully mapping the relationship between cell death and wound closure rate, contribution of cell death and cell migration on the observed wound closure delay can be quantitatively separated at all drug dosing. We showed that both intrinsic cell motility difference and extrinsic factors such as cell seeding density can significantly affect final interpretation of therapeutic impacts on cellular phenotypes. Such discrepancy can be rectified by using the actual wound closure time of each treatment condition for the calculation of phenotypic scores. Finally, we demonstrated a screen for strong pharmaceutical inhibitors of cell migration in cholangiocarcinoma cell lines. Our approach enables accurate scoring of both migrastatic and cytotoxic effects, and can be easily implemented for high-throughput drug screening.

Background & Aims Intraductal papillary neoplasm of the bile duct (IPNB) is a specific type of bile duct tumor. Studies about the surgical outcomes for IPNB are few; therefore, we investigated the survival of patients who underwent curative surgical resection of IPNB. Methods We retrospectively reviewed the medical and pathological records of 148 IPNB patients who underwent curative-intent hepatic resection between January 2005 and December 2011, to examine the prognosis of IPNB. All demographic and operative parameters were analyzed the effect on survival of patients. Results: The median survival of IPNB patients was 1,326 days with a respective 1, 3, and 5 year overall survival of 83.6% (95%CI:76.5-88.7), 64.4% (95%CI:56.0-71.6), and 47% (95%CI:38.4-55.7). The level of invasiveness of IPNB predicted survival very well. For malignant IPNB, univariate analysis showed that serum CA19-9 level, lymph node metastasis, and completeness of resection were significant prognostic factors. Lymph node metastasis and completeness of resection were found in multivariate analysis to be significantly related to survival of the patients. Conclusions The level of invasiveness and lymph node status were found to be associated with patient survival, as was adequacy of surgery. We recommend R0 resection be attempted for patients with IPNB.

Three cholangiocarcinoma (CCA) cell line—formerly named, M156, M213 and M214 have been intensively used with discrepancy of their tumor origins. They were assumed to be originated from three different donors without authentication. To verify the origins of these cell lines, the short tandem repeat (STR) analysis of the currently used cell lines, the cell stocks from the establisher and the primary tumor of a CCA patient were performed. Their phenotypic and genotypic originality were compared. The currently used 3 CCA cell lines exhibited similar STR as CCA patient ID-M213 indicating the same origin of these cells. The cell stocks from the establisher, however, revealed the same STR of M213 and M214 cells, but not M156. The misidentification of M214 and M156 is probably due to the mislabeling and cross-contamination of M213 cells during culture. These currently used cell lines were renamed as KKU-213A, -213B and -213C, for the formerly M213, M214 and M156 cells, respectively. These cell lines were established from a male with an intrahepatic mass-forming CCA stage-4B. The tumor was an adenosquamous carcinoma with the liver fluke ova granuloma in evidence. All cell lines had positive CK19 with differential CA19-9 expression. They exhibited aneuploidy karyotypes, distinct cell morphology, cell growth, cytogenetic characteristic and progressive phenotypes. KKU-213C formed a adenosquamous carcinoma, whereas KKU-213A and KKU-213B formed poorly- and well-differentiated squamous cell carcinomas in xenografted mice. mRNA microarray revealed different expression profiles among these three cell lines. The three cell lines have unique characteristics and may resemble the heterogeneity of tumor origin.

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Background and objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Intraductal papillary neoplasm of the bile duct is now considered to be a specific type of bile duct tumor. The progenitor cells of intraductal papillary neoplasms of the bile duct are located in the peribiliary gland, which are distributed along the intrahepatic bile duct, extrahepatic bile duct, and gallbladder; therefore, these neoplasms could arise in any area. The mainstay of treatment for patients with intraductal papillary neoplasm of the bile duct is complete surgical resection. Neoplasms involving both lobes of the liver can only be treated with liver transplant. There have been 11 reported cases of patients with biliary papillomatosis treated with liver transplant. In all of these cases, involvement was limited to the bile duct. Herein, we present the first case of papillomatosis with extensive involvement in the intrahepatic bile duct, the extrahepatic bile duct, and the gallbladder, which was successfully treated with repeated resection and liver transplant.