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.

Characterization of tumor evolution by functional clonality and phylogenetics in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy, and its fitness may be shaped by how its tumor cells evolve. However, ability to monitor tumor cell evolution is hampered by the presence of numerous passenger mutations that do not provide any biological consequences. Here we develop a strategy to determine the tumor clonality of three independent HCC cohorts of 524 patients with diverse etiologies and race/ethnicity by utilizing somatic mutations in cancer driver genes. We identify two main types of tumor evolution, i.e., linear, and non-linear models where non-linear type could be further divided into classes, which we call shallow branching and deep branching. We find that linear evolving HCC is less aggressive than other types. GTF2IRD2B mutations are enriched in HCC with linear evolution, while TP53 mutations are the most frequent genetic alterations in HCC with non-linear models. Furthermore, we observe significant B cell enrichment in linear trees compared to non-linear trees suggesting the need for further research to uncover potential variations in immune cell types within genomically determined phylogeny types. These results hint at the possibility that tumor cells and their microenvironment may collectively influence the tumor evolution process.

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.

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.

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.

The Impact of Prehospital Point of Care Ultrasounds on Emergency Patients Length of Stay in Thailand.

Purpose: Globally, emergency departments (ED) are faced with an overcrowding problem. This issue is further compounded due to the multitude of contributing factors. Point of Care ultrasound (POCUS), especially when performed in prehospital care, that is before the patient is admitted to the ED has a high potential to reduce time of diagnosis and time of investigation which leads to shorter ED length of stay (LOS). The primary focus was on variances in ED LOS between the prehospital POCUS group and the standard care group. Patients and Methods: A cross-sectional study was conducted on prehospital patients who were admitted to the ED at Srinagarind Hospital, Thailand, from January to December 2021. We divided patients into two groups including patients who obtained prehospital POCUS (the prehospital POCUS group) and patients who received standard care treatment in which there was no prehospital POCUS performed (the standard care group). POCUS and ED medical records were documented and submitted for analysis. Results: Of 1348 prehospital patients, 840 were enrolled in this study: 169 with prehospital POCUS and 671 with standard care. Median LOS in the prehospital POCUS group was 159 min (IQR 89,289) versus 165 (IQR 102,330) in the standard care group (p = 0.125). Further imaging diagnostic test which affected ED LOS more than four hours was lower in the prehospital POCUS group (adjusted odds ratio [OR], 0.92; 95% confidence intervals [CI], 0.729-1.666) than in the standard care group. The factor associated with increased odds of ED LOS more than four hour in the prehospital POCUS group was admission to hospital (adjusted OR 1.88; 95% CI, 1.230-2.239). Conclusion: Patients evaluated with prehospital POCUS had a shorter LOS than the only standard care treatment without statistical significance.

The diagnostic capabilities of the combined cardiac and lung point of care ultrasound in shocked patients at the emergency department - Resourced limited country.

Purpose: Cardiac, lung, and inferior vena cava (IVC) ultrasound are commonly performed in the care of emergency patients especially patient presented with hypotension or shock. However, the literature indicated the limitation of IVC to assess shocked patients. This study aims to determine the efficacy of combined cardiac and lung ultrasound for evaluation the etiology of shock. Materials and Methods: A cross-sectional study was conducted on patient with shock at emergency department, Srinagarind Hospital, Thailand, from January to December 2021. Adult shocked patients who met the criteria were included in this study. Ultrasound and emergency department medical records were documented and analyzed as sensitivity, specificity, predictive value, negative predictive value, diagnostic accuracy, and Cohen's kappa coefficient (κ). Results: One hundred and two who met the criteria were enrolled. Combined cardiac and lung scans were found to be accurate 99.02% and 93.04% in obstructive and cardiogenic shock. In patients with obstructive shock was the almost perfect agreement, (κ) = 0.85. However, distributive, and hypovolemic shock had the low concordance with the final hospital diagnosis, (κ) = 0.37 and 0.43, respectively. Conclusions: The integration of cardiac and lung ultrasound can be effectively used to narrow differential diagnosis of shock.

Integrating Point of Care Ultrasound Education into Clinical Practice at the Emergency Department.

Point of care ultrasound (POCUS) competency is now required learning for emergency medicine trainees. However, there is a wide range of areas that need to be assessed when determining competence. Therefore, this study aims to evaluate competence levels of POCUS skill acquisition including the areas of image acquisition, image interpretation and clinical integration of the emergency medicine residents while on shift in real clinical practice situations. This was a retrospective descriptive study. This study was conducted at Srinagarind Hospital, Thailand from January 2021 through December 2021. The data were collected and reviewed from electronic medical records, ultrasound images and video clips. All POCUS competency skills were assessed by researcher staff. Our results demonstrated that our learners had overall satisfactory competence of image acquisition, satisfactory image interpretation skills, and good clinical integration skills. However, obstetrics and gynecology (OB-GYN) ultrasound scores were poor and cardiac ultrasound had the most varied score of image quality. This study clearly showed the measurable benefits of a POCUS course being integrated into real clinical practice.

The Utilization of Handheld Ultrasound Devices in a Prehospital Setting.

INTRODUCTION: Prehospital ultrasounds can be considered a new form of diagnostic tool when taking into account their small structure and due to the fact that nowadays, they are used in the care of emergency patients. However, at present, there is no study regarding the advantage of ultrasound usage in prehospital settings in Thailand. STUDY OBJECTIVE: This study aims to determine the sonographic characteristics recorded by handheld ultrasounds used in prehospital care and the diagnostic accuracy of ultrasounds for prehospital patients. METHODS: A cross-sectional study was conducted on prehospital patients who underwent point-of-care ultrasound (POCUS) examination on Emergency Medical Service (EMS) operations at Srinagarind Hospital, Thailand from January 2021 through December 2021. The ultrasound images, the electronic emergency department medical records, and the EMS database were recorded and reviewed by a team of emergency physicians. The quality of prehospital ultrasound examinations was assessed by comparing the diagnoses at the scene with those taken at the hospital. RESULTS: One hundred sixty-nine prehospital patients who received POCUS examinations were examined over a one-year period. All (100.0%) of the scans were for medical cases. No ultrasound protocol was used in the prehospital care. Two hundred eight POCUS examinations were performed in this study. The most common POCUS indication was dyspnea (45.6%), followed by hypotension/shock (30.1%), and finally syncope (8.2%). The most common area where POCUS was performed was on the lung (37.0%), followed by the inferior vena cava (30.8%), and finally for cardiac cases (26.4%). This study found that 34.9% of sonographic findings could be considered abnormal. The diagnoses of prehospital patients were confirmed by using POCUS in 66 cases (39.1%) with the accuracy of prehospital diagnosis reaching a peak of 75.8%. CONCLUSION: This study shows POCUS examinations can be effectively used in prehospital care. The prehospital diagnosis given by physicians administering treatment who used POCUS examinations correlated with the in-hospital diagnosis.

"Motorcycle Ambulance" Policy to Promote Health and Sustainable Development in Large Cities.

INTRODUCTION: Motorcycles can be considered a new form of smart vehicle when taking into account their small and modern structure and due to the fact that nowadays, they are used in the new role of ambulance to rapidly reach emergency patients in large cities with traffic congestion. However, there is no study regarding the measuring of access time for motorcycle ambulances (motorlances) in large cities of Thailand. STUDY OBJECTIVE: This study aims to compare access times to patients between motorlances and conventional ambulances, including analysis of the use of automated external defibrillators (AEDs) installed on motorlances to contribute to the sustainable development of public health policies. METHODS: A cross-sectional study was conducted on all motorlance operations in Emergency Medical Services (EMS) at Srinagarind Hospital, Thailand from January 2019 through December 2020. Data were recorded using a national standard operation record form for Thailand. RESULTS: Two hundred seventy-one motorlance operations were examined over a two-year period. A total of 52.4% (N = 142) of the patients were male. The average times from dispatch to vehicle (motorlance and traditional ambulance) being en route (activation time) for motorlance and ambulance in afternoon shift were 0.59 minutes and 1.45 minutes, respectively (P = .004). The average motorlance response time in the afternoon shift was 6.12 minutes, and ambulance response time was 9.10 minutes at the same shift. Almost all of the motorlance operations (97.8%) were found to have no access to AED equipment installed in public areas. The average time from dispatch to AED arrival on scene (AED access time) was 5.02 minutes. CONCLUSION: The response time of motorlances was shorter than a conventional ambulance, and the use of AEDs on a motorlance can increase the chances of survival for patients with cardiac arrest outside the hospital in public places where AEDs are not available.

Development and Remodeling of Point-of-Care Ultrasound Education for Emergency Medicine Residents in Resource Limited Countries during the COVID-19 Pandemic.

The administration of an accurate and effective POCUS course is a crucial tool in improving health education and thus the health care system in low- to middle-income countries. The development of the ultrasound curriculum in these countries during the pandemic era is a major challenge for medical educators. Therefore, this study aims to survey the learner experience after implementing the POCUS curriculum for first-year emergency medicine residents. All learners responded to the survey. Our results demonstrated that the ultrasound rotation and our ultra-sound learning materials were useful tools which showed a positive impact on POCUS knowledge for our learners. However, some obstacles of POCUS learning were identified to assist in closing faculty development gaps, including the availability of handheld devices, as well as the re-modeling of the ultrasound rotation course, which should be managed according to the feedback we received. This study demonstrated a clear need for constant updates in higher education, medical program development, accuracy of local learning materials, and the explosion of virtual and online learning platforms during this decade.

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.

Decreasing trends in cholangiocarcinoma incidence and relative survival in Khon Kaen, Thailand: An updated, inclusive, population-based cancer registry analysis for 1989-2018.

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.

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.

Use of a Motorlance to Deliver Emergency Medical Services; a Prospective Cross Sectional Study.

INTRODUCTION: Access time to patients with critical or emergent situations outside the hospital is a critical factor that affects both severity of injury and survival. This study aimed to compare the access time to the scene of an emergency situation between a traditional ambulance and motorlance. METHODS: This prospective cross sectional study was conducted on all users of emergency call, Srinagarind Hospital, Thailand, from June to December 2018, who received a registration number from the command center. RESULTS: 504 emergency-service operations were examined over a six-month period, 252 (50%) of which were carried out by motorlance. The mean activation time for motorlance and ambulance were 0.57 ± 0.22 minutes and 1.11 ± 0.18 minutes, respectively (p<0.001). Mean response time for motorlance was significantly lower (5.57 ± 1.21 versus 7.29 ± 1.32 minutes; p < 0.001). The response times during 6 a.m. to 6 p.m. were 5.26 ± 1.11 minutes for motorlance and 7.15 ± 1.39 minutes for ambulance (p < 0.001). These measures for night time (6 p.m. to 6 a.m.) were 5.58 ± 1.21 minutes and 8.01 ± 1.30 minutes, respectively (p < 0.001). The mean automated external defibrillator (AED) waiting time for motorlance and ambulance were 5.26 ± 2.36 minutes and 9.24 ± 3.30 minutes, respectively (p = 0.012). The survival rate of patients after AED use in motorlance and ambulance was 80% versus 37.5%; p<0.001. CONCLUSION: Emergency service delivery by motorlance had lower mean activation time, response time, AED time, and mortality rate of cardiac arrest patients compared to ambulance. It seems that motorlance could be considered as an effective and applicable device in emergency medical service delivery, especially in crowded cities with heavy traffic.

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.

Urinary Metabolites Diagnostic and Prognostic of Intrahepatic Cholangiocarcinoma.

BACKGROUND: Liver cancer is the second leading cause of cancer-related deaths worldwide. With a predicted 2.4-fold rise in liver cancer incidence by 2020, there is an urgent need for early, inexpensive diagnostic biomarkers to deploy in the clinic. METHODS: We employed ultraperformance liquid chromatography tandem mass-spectrometry (UPLC/MS-MS) for the quantitation of four metabolites, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and a lipid molecule designated as 561+, in urine samples from the NCI-MD cohort comprising 98 hepatocellular carcinoma (HCC) cases, 101 high-risk subjects, and 95 controls. Validation was carried out in the TIGER-LC cohort [n = 370 HCC and intrahepatic cholangiocarcinoma (ICC) cases, 471 high-risk subjects, 251 controls], where ICC, the second most common primary hepatic malignancy, is highly prevalent. Metabolite quantitation was also conducted in TIGER-LC tissue samples (n = 48 ICC; n = 51 HCC). RESULTS: All profiled metabolites were significantly increased in liver cancer when compared with high-risk subjects and controls in the NCI-MD study. In the TIGER-LC cohort, the four-metabolite profile was superior at classifying ICC than a clinically utilized marker, CA19-9, and their combination led to a significantly improved model (AUC = 0.88, P = 4E-8). Metabolites CR and NANA were significantly elevated in ICC when compared with HCC cases in both urine and tissue samples. High levels of CR were associated with poorer prognosis in ICC. CONCLUSIONS: Four metabolites are significantly increased in HCC and ICC and are robust at classifying ICC in combination with the clinically utilized marker CA19-9. IMPACT: Noninvasive urinary metabolite biomarkers hold promise for diagnostic and prognostic evaluation of ICC.

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.