The landscape of etiological patterns of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in Thailand.

Thailand is among countries with the highest global incidence and mortality rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). While viral hepatitis and liver fluke infections have been associated with HCC and iCCA, respectively, other environmental risk factors, overall risk factor commonality and combinatorial roles, and effects on survival have not been systematically examined. We conducted a TIGER-LC consortium-based population study covering all high-incidence areas of both malignancies across Thailand: 837 HCC, 1474 iCCA, and 1112 controls (2011-2019) were comprehensively queried on lifelong environmental exposures, lifestyle, and medical history. Multivariate logistic regression and Cox proportional hazards analyses were used to evaluate risk factors and associated survival patterns. Our models identified shared risk factors between HCC and iCCA, such as viral hepatitis infection, liver fluke infection, and diabetes, including novel and shared associations of agricultural pesticide exposure (OR range of 1.50; 95% CI: 1.06-2.11 to 2.91; 95% CI: 1.82-4.63) along with vulnerable sources of drinking water. Most patients had multiple risk factors, magnifying their risk considerably. Patients with lower risk levels had better survival in both HCC (HR 0.78; 95% CI: 0.64-0.96) and iCCA (HR 0.84; 95% CI: 0.70-0.99). Risk factor co-exposures and their common associations with HCC and iCCA in Thailand emphasize the importance for future prevention and control measures, especially in its large agricultural sector. The observed mortality patterns suggest ways to stratify patients for anticipated survivorship and develop plans to support medical care of longer-term survivors, including behavioral changes to reduce exposures.

Pesticide exposure and risk of cholangiocarcinoma: A hospital-based matched case-control study.

BACKGROUND: Cholangiocarcinoma (CCA) caused by Opisthorchis viverrini is a well-known and significant public health issue in northeastern Thailand; however, a link between pesticide exposure (PE) and CCA risk has not yet been established. Therefore, our research objective was to investigate the relationship between PE and CCA risk. METHODS: A hospital-based matched case-control study was carried out. All cases (in-patients) and controls (out-patients) were volunteers at a tertiary hospital in northeast Thailand. Between 2015 and 2019, 178 incident cases of pathologically-confirmed CCA and 356 controls were selected from the check-up clinic from the Srinagarind Hospital outpatient database (two controls per case). The recruited controls were individually-matched to the CCA cases based on sex, age (±5 years) and admission date (±3 months). During face-to-face interviews, a standardised pre-tested questionnaire was used to collect data. Multivariable conditional logistic regression was used to analyse the data. RESULTS: The respective frequency of PE between the 178 CCA cases and 356 controls was 77.0% versus 87.6% for never used, 14.6% versus 5.3% for have used but stopped and 8.4% versus 7.0% for currently using. After adjusting for the highest educational attainment, smoking behaviour, alcohol use and family history of cancer, PE was not significantly associated with CCA (p-value = 0.086). Using volunteers who have never used PE as the reference group, the respective odds of developing CCA for those who have ever used but have since stopped and are currently using was 2.04 (adjusted OR = 2.04; 95% CI: 1.03-4.04) versus 0.83 (adjusted OR = 0.83; 95% CI: 0.39-1.76) times more likely to develop CCA than those who had never used PE. CONCLUSION: There is no association between PE and the risk of CCA. Notwithstanding the finding, future research should focus on enhancing PE assessment methods that consider complex chemical mixtures, chemicals of interest, historical exposure and exposure pathways. Moreover, there is need for more extensive and longer population-based cohort studies that include younger, non-occupationally exposed individuals during periods of developmental susceptibility.

En bloc groin node resection reconstructed with external oblique flap for solitary metastatic cholangiocarcinoma: a case report.

Cholangiocarcinoma requires complete surgical resection for cure. Even so, the recurrence and metastasis rates are high, and further treatment is typically through palliative systemic chemotherapy. Curative-intent resection of metastatic site may provide survival benefit in selected cases. However, there were no previous reports of groin node dissection in cholangiocarcinoma. We have reported the first case of intrahepatic mass-forming cholangiocarcinoma with isolated synchronous groin node metastasis, successfully treated with   resection of the liver mass followed by groin node resection, reconstructed with musculofascial flap. A 73-year-old man presented with right upper quadrant abdominal pain radiating to the right groin for two months. Magnetic resonance cholangiopancreatography revealed a 3.1 × 1.2 cm enhancing mass between hepatic segment 4 and the anterior peritoneum, invading the abdominal wall. Computed tomography of the abdomen revealed a 2.4 × 2.2 cm focal enhancing mass at the anterior aspect of the right lower abdominal wall, just anterior to the right inguinal ligament and iliac vessel. He underwent en bloc resection of hepatic segment 4, gallbladder, and anterior abdominal wall, and the histology result is cholangiocarcinoma. After systemic chemotherapy, he underwent en bloc resection of the right groin mass, reconstructed with external oblique musculofascial flap. The patient was able to achieve a 20-month recurrence free survival after the final operation. This case has demonstrated that in a carefully selected case, resection of distant metastasis cholangiocarcinoma can provide survival benefits, even in the rare site of metastasis.

Pan-viral serology uncovers distinct virome patterns as risk predictors of hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

This study evaluates the pan-serological profiles of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) compared to several diseased and non-diseased control populations to identify risk factors and biomarkers of liver cancer. We used phage immunoprecipitation sequencing, an anti-viral antibody screening method using a synthetic-phage-displayed human virome epitope library, to screen patient serum samples for exposure to over 1,280 strains of pathogenic and non-pathogenic viruses. Using machine learning methods to develop an HCC or iCCA viral score, we discovered that both viral scores were positively associated with several liver function markers in two separate at-risk populations independent of viral hepatitis status. The HCC score predicted all-cause mortality over 8 years in patients with chronic liver disease at risk of HCC, while the viral hepatitis status was not predictive of survival. These results suggest that non-hepatitis viral infections may contribute to HCC and iCCA development and could be biomarkers in at-risk populations.

Surgery.

This chapter provides a comprehensive background from basic to applied knowledge of surgical anatomy which is necessary for the surgical treatment of cholangiocarcinoma (CCA) patients. Significant advances that have been made in the surgical treatment of CCA were examined. For instance, in-depth details are provided for appropriate preoperative assessment and treatment to optimize patient status and to improve the outcome of surgical treatment(s). Comprehensive details are provided for the surgical techniques and outcomes of treatments for each type of CCA with clear illustrations and images. This chapter also describes the role of minimally invasive surgery and liver transplantation in CCA treatment.

Compliance with enhanced recovery after surgery predicts long-term outcome after hepatectomy for cholangiocarcinoma.

BACKGROUND: Enhanced recovery after surgery (ERAS) program has been proved to improve postoperative outcome for many surgical procedures, including liver resection. There was limited evidence regarding the feasibility and benefit of ERAS in patients who underwent liver resection for cholangiocarcinoma. AIM: To evaluate the feasibility of ERAS in patients who underwent liver resection for cholangiocarcinoma and its association with patient outcomes. METHODS: We retrospectively analyzed 116 cholangiocarcinoma patients who underwent hepatectomy at Srinagarind Hospital, Khon Kaen University between January 2015 and December 2016. The primary outcome was the compliance with ERAS. To determine the association between ERAS compliance and patient outcomes. the patients were categorized into those adhering more than and equal to 50% (ERAS ≥ 50), and below 50% (ERAS < 50) of all components. Details on type of surgical procedure, preoperative and postoperative care, tumor location, postoperative laboratory results, and survival time were evaluated. The compliance with ERAS was measured by the percentage of ERAS items achieved. The Kaplan-Meier curve was used for survival analysis. RESULTS: The median percentage of ERAS goals achieved was 40% (± 12%). Fourteen patients (12.1%) were categorized into the ERAS ≥ 50 group, and 102 patients were in the ERAS < 50 group. Postoperative hospital stay was significantly shorter in the ERAS ≥ 50 group [8.9 d, 95% confidence interval (CI): 7.3-10.4 d] than in the ERAS < 50 group (13.7 d, 95%CI: 12.2-15.2 d) (P = 0.0217). No hepatobiliary-related complications or in-hospital mortality occurred in the ERAS ≥ 50 group. Overall survival was significantly higher in the ERAS ≥ 50 group. The median survival of the patients in the ERAS < 50 group was 1257 d (95%CI: 853.2-1660.8 d), whereas that of the patients in the ERAS ≥ 50 group was not reached. CONCLUSION: Overall ERAS compliance for patients who underwent liver resection for cholangiocarcinoma is poor. Greater ERAS compliance could predict in-hospital, short-term, and long-term outcomes of the patients.

Co-existence of intraductal papillary neoplasm of the bile duct and Opisthorchis viverrini.

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.

Infrahepatic Inferior Vena Cava Clamping Reduces Blood Loss during Liver Transection for Cholangiocarcinoma.

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.

Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (cancer in the bile duct) is an aggressive tumour for which surgical resection is a mainstay of treatment. Despite complete resection, recurrences of the cancer are common and lead to poor prognosis in patients. Postoperative adjuvant chemotherapy given after surgical resection may reduce the risk of cancer recurrence by eradicating residual cancer and micrometastatic lesions. The benefits and harms of postoperative adjuvant chemotherapy versus placebo, no intervention, or other adjuvant chemotherapies are unclear. OBJECTIVES: To assess the benefits and harms of postoperative adjuvant chemotherapy versus placebo, no intervention, or other adjuvant chemotherapies for people with cholangiocarcinoma after curative-intent resection. SEARCH METHODS: We performed electronic searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science for trials that met the inclusion criteria up to 28 April 2021. SELECTION CRITERIA: Randomised clinical trials irrespective of blinding, publication status, or language comparing postoperative adjuvant chemotherapy versus placebo, no intervention, or a different postoperative adjuvant chemotherapy regimen for participants with curative-intent resection for cholangiocarcinoma. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods to develop and conduct the review. We conducted meta-analyses and presented results, where feasible, using a random-effects model and risk ratios (RR) with 95% confidence intervals (CI). We assessed risk of bias according to predefined domains suggested by Cochrane. We rated the certainty of evidence using the GRADE approach and presented outcome results in a summary of findings table. MAIN RESULTS: We included five published randomised clinical trials. The trials included 931 adults (18 to 83 years old) who underwent curative-intent resection for cholangiocarcinoma. Four trials compared postoperative adjuvant chemotherapy (mitomycin-C and 5-fluorouracil (5-FU); gemcitabine; gemcitabine plus oxaliplatin; or capecitabine) versus no postoperative adjuvant chemotherapy (surgery alone) in 867 participants with cholangiocarcinoma only. A fifth trial compared postoperative adjuvant S-1 (a novel oral fluoropyrimidine derivative) chemotherapy versus gemcitabine in 70 participants with intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma (64 participants), and gallbladder carcinoma (6 participants). We assessed all of the included trials at overall high risk of bias. One trial was conducted in France, three in Japan, and one in the United Kingdom. We could not perform all planned comparison analyses due to lack of data. Three trials used intention-to-treat analyses. Another trial used per-protocol analysis. In the remaining trial one participant in the intervention group and one in the control group were lost to follow-up. However, the outcomes of these two participants were not described. Postoperative adjuvant chemotherapy versus no postoperative adjuvant chemotherapy We are very uncertain as to whether postoperative adjuvant chemotherapy has little to no effect on all-cause mortality versus no postoperative adjuvant chemotherapy (RR 0.92, 95% CI 0.84 to 1.01; 4 trials, 867 participants, very low-certainty evidence). We are very uncertain of the effect of postoperative adjuvant chemotherapy on serious adverse events (RR 17.82, 95% CI 2.43 to 130.82; 1 trial, 219 participants, very low-certainty evidence). The trial indicated that postoperative adjuvant chemotherapy could increase serious adverse events, as 19/113 (20.5%) of participants developed an adverse event, compared to 1/106 (1.1%) of participants in the no-postoperative adjuvant chemotherapy group. None of the included trials reported data on health-related quality of life, cancer-related mortality, time to recurrence of the tumour, and non-serious adverse events in participants with only cholangiocarcinoma. Adjuvant S-1 chemotherapy (fluoropyrimidine derivative) versus adjuvant gemcitabine-based chemotherapy The only available trial analysed all participants with intrahepatic, perihilar cholangiocarcinoma and gallbladder carcinoma together, with data on participants with cholangiocarcinoma not provided separately. The authors reported that one-year overall mortality after adjuvant S-1 therapy was lower than with adjuvant gemcitabine-based therapy following major hepatectomy for biliary tract cancer. There were no differences in two-year overall mortality. FUNDING: two trials received support from drug companies; one trial received funding from the Japan Society of Clinical Oncology; one trial received support from "Programme Hospitalier de Recherche Clinique (PHRC2009) and Ligue Nationale Contre le Cancer"; and one trial did not provide information on support or sponsorship. We identified six ongoing randomised clinical trials. AUTHORS' CONCLUSIONS: Based on the very low-certainty evidence found in four trials in people with curative-intent resection for cholangiocarcinoma, we are very uncertain of the effects of postoperative adjuvant chemotherapy (mitomycin-C and 5-FU; gemcitabine; gemcitabine plus oxaliplatin; or capecitabine) versus no postoperative adjuvant chemotherapy on mortality. The effects of postoperative adjuvant chemotherapy compared with no postoperative adjuvant chemotherapy on serious adverse events are also very uncertain, but the result of the single trial showed 20% higher occurrences of haematologic adverse events. We assessed the certainty of the evidence as very low due to overall high risk of bias, and imprecision. Due to insufficient power of the only identified trial, the best postoperative adjuvant chemotherapy regimen in people with only cholangiocarcinoma could not be established. We also lack randomised clinical trials with outcome data on adjuvant S-1 chemotherapy versus adjuvant gemcitabine-based chemotherapy in people with cholangiocarcinoma alone. There is a need for further randomised clinical trials designed to be at low risk of bias and with adequate sample size exploring the best adjuvant chemotherapy treatment after surgery in people with cholangiocarcinoma.

Re-Rising of Total Bilirubin Level after Postoperative Day 3 (The V Pattern) Predicting Liver Failure and Survival of Patients who Underwent Hepatectomy for Cholangiocarcinoma.

OBJECTIVE: All types of cholangiocarcinoma (CCA) require a major hepatectomy, which has many post-operative complications. All complications usually present with persistent hyperbilirubinemia; however, studies on the prediction of post-operative hyperbilirubinemia after hepatectomy for patients with CCA are lacking. We evaluated the causes and patterns of persistent hyperbilirubinemia among the patients who underwent hepatectomy for CCA. METHODS: We retrospectively reviewed the records of 216 CCA patients who underwent curative-intent hepatic resection between January 2015 and December 2016. We identified five patterns of hyperbilirubinemia for predicting the cause of persistent hyperbilirubinemia and the respective patient outcome. All clinical parameters and outcomes were analyzed for any significant associations. RESULTS: Twenty-eight patients (24%) had post-operative persistent hyperbilirubinemia. Of these, liver failure was the most common cause (42.9%), followed by bile leakage (14.3%), then cholangitis (3.6%). Re-rising of the bilirubin level after post-operative day 3(the 'V' pattern), very well predicted liver failure. Moreover, this pattern was associated with poor survival of the patient. CONCLUSION: The current study provided a picture of persistent hyperbilirubinemia after hepatectomy for CCA. The proportion of post-operative liver failure was 12 percent. The pattern of serum bilirubin level could be used as a predictor of liver failure and long-term outcomes of CCA patients. The 'V' pattern was significantly associated with a high rate of liver failure and poor survival.

Predictive utility of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in intraductal papillary neoplasm of the bile duct.

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.

Establishment of Highly Transplantable Cholangiocarcinoma Cell Lines from a Patient-Derived Xenograft Mouse Model.

Cholangiocarcinoma (CCA) is a deadly malignant tumor of the liver. It is a significant health problem in Thailand. The critical obstacles of CCA diagnosis and treatment are the high heterogeneity of disease and considerable resistance to treatment. Recent multi-omics studies revealed the promising targets for CCA treatment; however, limited models for drug discovery are available. This study aimed to develop a patient-derived xenograft (PDX) model as well as PDX-derived cell lines of CCA for future drug screening. From a total of 16 CCA frozen tissues, 75% (eight intrahepatic and four extrahepatic subtypes) were successfully grown and subpassaged in Balb/c Rag-2-/-/Jak3-/- mice. A shorter duration of PDX growth was observed during F0 to F2 transplantation; concomitantly, increased Oct-3/4 and Sox2 were evidenced in 50% and 33%, respectively, of serial PDXs. Only four cell lines were established. The cell lines exhibited either bile duct (KKK-D049 and KKK-D068) or combined hepatobiliary origin (KKK-D131 and KKK-D138). These cell lines acquired high transplantation efficiency in both subcutaneous (100%) and intrasplenic (88%) transplantation models. The subcutaneously transplanted xenograft retained the histological architecture as in the patient tissues. Our models of CCA PDX and PDX-derived cell lines would be a useful platform for CCA precision medicine.

Papillomatosis of the Biliary Tree and Gallbladder: Successful Treatment With Repeated Resection and Liver Transplant.

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.

Cholangiocarcinoma Trends, Incidence, and Relative Survival in Khon Kaen, Thailand From 1989 Through 2013: A Population-Based Cancer Registry Study.

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.

Association between Repeated Praziquantel treatment and Papillary, and Intrahepatic Cholangiocarcinoma.

INTRODUCTION AND AIM: The carcinogenesis of tubular and papillary cholangiocarcinoma (CCA) differ. The available epidemiologic studies about risk factors for CCA do not differentiate between the tubular and papillary type. The current study investigated the relationship between the number of repeated use of Praziquantel (PZQ) treatments and each type of CCA. MATERIAL AND METHODS: This was a hospital-based, matched, case-control study of patients admitted to Srinagarind Hospital, Khon Kaen University. The patients were 210 pathologically-confirmed cases of CCA, while the controls were 840 subjects diagnosed with other diseases. The 4 controls were individually matched with each case by sex, age, and date of admission. The cases were classified according to location (intrahepatic vs. extrahepatic) and cell type (papillary vs. tubular). Multivariable conditional logistic regression was used for the analysis. RESULTS: After adjusting for confounders, there were statistically significant associations between intrahepatic and papillary CCA and repeated use of PZQ treatment. The respective odds of developing intrahepatic CCA for those who used PZQ once, twice, or more was 1.54 (95%CI:0.92-2.55 ), 2.28 (95%CI:0.91-5.73), and 4.21 (95%CI:1.61-11.05). The respective odds of developing papillary CCA for those who used PZQ once, twice, or more was 1.45 (95%CI:0.80-2.63), 2.96 (95%CI:1.06-8.24), and 3.24 (95%CI:1.09-9.66). There was no association between number of uses of PZQ treatment and developing extrahepatic or tubular CCA. CONCLUSION: The current study found an association between papillary and intrahepatic CCA and repeated use of PZQ treatment. We suggest further study on the risk factors for papillary and tubular CCA should be performed separately.

Programmed Death-Ligand 1 (PD-L1) Expression Associated with a High Neutrophil/Lymphocyte Ratio in Cholangiocarcinoma

Background: Effective treatments for cholangiocarcinoma (CCA) are still lacking. There are promising results of checkpoint inhibitor programmed cell death ligand-1 (PD-L1) activities in early phase trials. This study aimed to investigate the expression of PD-L1 and its relation to possible treatments for CCA. Methods: Formalin-fixed paraffin-embedded tumor samples from 46 patients with cholangiocarcinoma were retrieved. PD-L1 expression was evaluated by immunohistochemistry using anti-PD-L1 antibody, clone 5H1. A PD-L1 positive response on tumor cells was defined as >1% of tumor cell membranes stained. The association between PD-L1, clinico-pathological characteristics was analyzed using Fisher's exact test, and survival analysis was done with the Cox regression model. Results: Out of 46 samples, 32 (70%) had positive PD-L1 expression in tumor cell membranes. The median level of PD-L1 expression was 1.75% (0-34.7). PD-L1 expression was significantly associated with stage IV disease (OR 3.98, p=0.046) and a high neutrophil/lymphocyte ratio (OR 5.36, p=0.018). PD-L1 positivity was associated with worse overall survival compared with those with a PD-L1 negative tumor but did not reach a level of significance (7.2 vs. 7.9 months, p=0.32). Conclusion: PD-L1 is widely expressed in CCA but was not predictive for overall survival. PD-L1 positivity was (7.2 and 7.9 months, p=0.32). Significantly associated with stage IV disease and a high neutrophil/lymphocyte ratio.

Prognostic Factors for Large Symptomatic Gists: a Pragmatic Study of Experiences From a University Hospital Over 10 Years

Background: Gastrointestinal stromal tumors (GISTs), which are mesenchymal neoplasms in the gastrointestinal (GI) tract account for 0.2% of all GI tumors. Several factors have been reported (mostly from studies conducted in Western countries) to be associated with survival in GISTs cases such as tumor site, staging, and tumor size. We conducted a pragmatic study, looking at a 10-year period, aimed at understanding the prognostic factors related to GISTs in a university hospital. The study population consisted of patients with large symptomatic GISTs. Methods: This was a retrospective study conducted at the Department of Surgery in the Khon Kaen University Hospital (Thailand). All patients diagnosed with GISTs that were treated between 2006 and 2015 were consecutively enrolled. The diagnosis of GISTs was made by examining the pathological section and immunohistochemistry results. The outcome of this study was the rate of survival after surgical treatment. Prognostic factors were determined using Cox regression analysis. Results: There were 124 GISTs patients treated at the university hospital during the 10-year period of the study. The median age of all patients was 54 years (range 24-83 years). Of those, 119 (95.9%) were symptomatic. Rectosigmoid GISTs accounted for 20.2% of all tumors. The median tumor size was 8 cm. A total of 68 patients (54.8%) died. The median survival time for all patients was 7.18 years (1st -3rd quartile range 6.48-7.89). There were three significant factors associated with death including male gender, liver metastasis, and peritoneal metastasis. Conclusion: Male gender, liver metastasis, and peritoneal metastasis were prognostic factors for large symptomatic GISTs.

Differential Protein Expression Marks the Transition From Infection With Opisthorchis viverrini to Cholangiocarcinoma.

Parts of Southeast Asia have the highest incidence of intrahepatic cholangiocarcinoma (CCA) in the world because of infection by the liver fluke Opisthorchis viverrini (Ov). Ov-associated CCA is the culmination of chronic Ov-infection, with the persistent production of the growth factors and cytokines associated with persistent inflammation, which can endure for years in Ov-infected individuals prior to transitioning to CCA. Isobaric labeling and tandem mass spectrometry of liver tissue from a hamster model of CCA was used to compare protein expression profiles from inflammed tissue (Ovinfected but not cancerous) versus cancerous tissue (Ov-induced CCA). Immunohistochemistry and immunoblotting were used to verify dysregulated proteins in the animal model and in human tissue. We identified 154 dysregulated proteins that marked the transition from Ov-infection to Ov-induced CCA, i.e. proteins dysregulated during carcinogenesis but not Ov-infection. The verification of dysregulated proteins in resected liver tissue from humans with Ov-associated CCA showed the numerous parallels in protein dysregulation between human and animal models of Ov-induced CCA. To identify potential circulating markers for CCA, dysregulated proteins were compared with proteins isolated from exosomes secreted by a human CCA cell line (KKU055) and 27 proteins were identified as dysregulated in CCA and present in exosomes. These data form the basis of potential diagnostic biomarkers for human Ov-associated CCA. The profile of protein dysregulation observed during chronic Ovinfection and then in Ov-induced CCA provides insight into the etiology of an infection-induced inflammation-related cancer.

Morphological Classification of Intraductal Papillary Neoplasm of the Bile Duct with Survival Correlation

Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a specific entity for which there has been no classification that correlates clinical presentation with patient survival. We, therefore, propose a new classification based on radio-pathological appearance correlated with clinical findings including outcome. Methods: We retrospectively reviewed the medical and pathological records of 103 IPNB patients who underwent curative-intent hepatic resection between January 2008 and December 2011. A morphological classification was then created based on the presence of (a) bile duct dilatation, (b) intraductal mass(es), (c) cystic lesion(s), and (d) macro-invasion of the liver. All clinical parameters and survival were analyzed. Results: The median survival of IPNB patients was 1,728 days (95%CI: 1,485 to 1,971 days). The proposed classification predicted survival very well (log-rank test; p < 0.01). For patients with the cystic variant and micro-papillary IPNB, there were no tumor-related deaths within 3 years of surgery and median survival was not reached during the follow-up. The respective median survival times for IPNBs with unilateral intrahepatic duct dilatation, bilateral intrahepatic duct dilatation, and macro-invasion were 1,888 days (95%CI 1,118- 2,657), 673 days (95%CI: 392- 953), and 578 days (95%CI: 285- 870). Conclusion: We propose a new classification for IPNBs which not only provides a view of patients in terms of their radio-pathologic status but also should help in guiding planning of surgical procedures.