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Abstract 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.

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.

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 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.

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.

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.

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

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.

Objectives: To analyze the medical diagnosis that led to payments of the first aid solatiums (FAS) regarding Section 41 of 2002 National Health Security Act (S41NHSA) in the region 7 of NHS Office (R7NHSO) and the magnitude in both number of cases and amount of money paid. To focus FAS cases and payment in the obstetric specialty which had the greatest part of FAS payment, and to find out the quality improvement for reducing the problems in obstetric and gynecological cases. The study was done for only during 2012-2014.Materials and Methods:All of the FAS medical cases records regarding S41NHSA in the R7NHSO during 2012-2014 were collected. The medical diagnosis that led to the final approval of FAS payment by NHSO was reviewed. The working group of the Sub-Committee to Control the Quality and Standard of the Public Health Service of the R7NHSO had created the guideline to minimize the problems in obstetric and gynecological cases.Results: The R7NHSO included 4 provinces in the Northeast which are Khon Kaen, Kalasin, Roi Et, and Maha Sarakham. The numbers of FAS payment cases during 2012-2014 were 79, 106, and 110 cases or 295 cases in 3 years. The ratio of S41NHSA complaint per total number of in-patients was low but increasing yearly during this 3 years period. The province with more number of in-patients had a more FAS cases and a more FAS payment. The five most common FAS payment cases in descending rate were from department of obstetrics (54.38%), surgery (13.9%), medicine (10.5%) pediatric (7.4%) and orthopedics (3.73%). The obstetric department shared the greatest part of FAS payment cases and money. The top five number of cases (percentage) FAS payment in obstetrics were neonatal death 59 (30.73%), shoulder dystocia 41 (21.35%), unintended pregnancy after tubal ligation 40 (20.83%), maternal death 20 (10.42%) and cerebral palsy 6 (3.13%). The total amount of FAS money paid during the 2012-2014 was 54.68 million Baht for the whole R7NHSO, of which was from Khon Kaen 22.99 million Baht, Kalasin 12.89 million Baht, Roi Et 12.30 million Baht, and Maha Sarakham 6.49 million Baht. The average FAS payment was 185,361.36 Baht/case. The authors suggested 5 items of quality improvement methods to reduce obstetric loss. Conclusion: The FAS cases and FAS payment in R7NHSO were rising. Most of the FAS cases and payment were from the department of obstetrics. Many diagnoses that caused FAS cases and payments were preventable. A good policy of man power arrangement of obstetricians, a continuously in-service training, and a better incentive for the service providers, the consultation and transferring system of the risky patients should be revised.

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

Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer, arising in the biliary ducts that extend into the liver. The highest incidence of ICC occurs in Southeast Asia, particularly in the Mekong River Basin countries of Thailand, Laos, Cambodia, and Vietnam, where it is strongly associated with chronic infection by the food-borne liver fluke Opisthorchis viverrini (OV), one of only three eukaryote pathogens considered Group one carcinogens. Intrahepatic cholangiocarcinoma is usually diagnosed at an advanced stage, with a poor prognosis and survival often less than 24 months. Hence, biomarkers that enable the early detection of ICC would be desirable and have a potentially important impact on the public health in the resource-poor regions where this cancer is most prevalent. As microRNAs (miRNAs) remain well preserved after formalin fixation, there is much interest in developing them as biomarkers that can be investigated using tumor biopsy samples preserved in formalin fixed paraffin embedded (FFPE) tumor blocks. Recently, we reported the first comprehensive profiling of tissue-based miRNA expression using FFPE from the three most common subtypes of OV-induced ICC tumors: moderately differentiated ICC, papillary ICC, and well-differentiated ICC. We observed that each subtype of OV-induced ICC exhibited a distinct miRNA profile, which suggested the involvement of specific sets of miRNAs in the progression of this cancer. In addition, non-tumor tissue adjacent to ICC tumor tissue on the same FFPE block shared a similar miRNA dysregulation profile with the tumor tissue than with normal (non-tumor) liver tissue (individuals without ICC or OV infection). Herein, we provide a detailed description of the microarray analysis procedures used to derive these findings.

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.

Intraductal papillary neoplasm of the bile duct (IPNB) is a specific type of bile duct tumor. It has been proposed that it could be the biliary counterpart of the intraductal papillary neoplasm of the pancreas (IPMN-P). This hypothesis is supported by the presence of simultaneous intraductal tumors of both the bile duct and pancreas. There have been five reports of patients with simultaneous IPNB and IPMN-P. In all of these cases, biliary involvement was limited to the intrahepatic and perihilar bile duct, which had characteristics similar to IPMN-P and usually had slow progression in nature. Herein, we present the first case of extensive intraductal neoplasm involving the extrahepatic bile duct, intrahepatic bile duct, and entire length of the pancreas with a poor outcome, even after being treated aggressively with radical surgery and adjuvant chemotherapy. Additionally, we summarize previous case reports of simultaneous intraductal lesions of the bile duct and pancreas.

Argininosuccinate synthetase (ASS), a key enzyme to synthesize arginine is down regulated in many tumors including hepatocellular carcinoma (HCC). Similar to previous reports, we have found the decrease in ASS expression in poorly differentiated HCC. These ASS(-) tumors are auxotrophic for arginine. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine, has shown activity in these tumors, but the antitumor effect is not robust and hence combination treatment is needed. Herein, we have elucidated the effectiveness of ADI-PEG20 combined with 5-Fluorouracil (5-FU) in ASS(-)HCC by targeting urea cycle and pyrimidine metabolism using four HCC cell lines as model. SNU398 and SNU387 express very low levels of ASS or ASS(-) while Huh-1, and HepG2 express high ASS similar to normal cells. Our results showed that the augmented cytotoxic effect of combination treatment only occurs in SNU398 and SNU387, and not in HepG2 and Huh-1 (ASS(+)) cells, and is partly due to reduced anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP), myeloid leukemia cell differentiation protein (Mcl-1) and B-cell lymphoma-2 (Bcl-2). Importantly, lack of ASS also influences essential enzymes in pyrimidine synthesis (carbamoyl-phosphate synthetase2, aspartate transcarbamylase and dihydrooratase (CAD) and thymidylate synthase (TS)) and malate dehydrogenase-1 (MDH-1) in TCA cycle. ADI-PEG20 treatment decreased these enzymes and made them more vulnerable to 5-FU. Transfection of ASS restored these enzymes and abolished the sensitivity to ADI-PEG20 and combination treatment. Overall, our data suggest that ASS influences multiple enzymes involved in 5-FU sensitivity. Combining ADI-PEG20 and 5-FU may be effective to treat ASS(-)hepatoma and warrants further clinical investigation.

Opisthorchis viverrini is considered among the most important of the food-borne trematodes due to its strong association with advanced periductal fibrosis and bile duct cancer (cholangiocarcinoma). We investigated the relationship between plasma levels of Interleukin (IL)-6 and the risk of developing advanced fibrosis and bile duct cancer from chronic Opisthorchis infection. We show that IL-6 circulates in plasma at concentrations 58 times higher in individuals with advanced fibrosis than age, sex, and nearest-neighbor matched controls and 221 times higher in individuals with bile duct cancer than controls. We also observed a dose-response relationship between increasing levels of plasma IL-6 and increasing risk of advanced fibrosis and bile duct cancer; for example, in age and sex adjusted analyses, individuals with the highest quartiles of plasma IL-6 had a 19 times greater risk of developing advanced periductal fibrosis and a 150 times greater risk of developing of bile duct cancer than individuals with no detectable level of plasma IL-6. Finally, we show that a single plasma IL-6 measurement has excellent positive predictive value for the detection of both advanced bile duct fibrosis and bile duct cancer in regions with high O. viverrini transmission. These data support our hypothesis that common mechanisms drive bile duct fibrosis and bile duct tumorogenesis from chronic O. viverrini infection. Our study also adds a unique aspect to the literature on circulating levels of IL-6 as an immune marker of hepatobiliary pathology by showing that high levels of circulating IL-6 in plasma are not related to infection with O. viverrini, but to the development of the advanced and often lethal pathologies resulting from chronic O. viverrini infection.

Purpose Measurement of the activities of alkaline phosphatase isoenzyme has been used for the identification and monitoring of diseases associated with the isoenzyme. Biliary alkaline phosphatase (BALP), an isoform of liver-ALP, has been found in the serum of patients with biliary obstruction and metastatic liver cancer. This study compared the BALP isoform in the serum of patients with cholangiocarcinoma (CCA) with that of non-jaundiced benign hepatobiliary disease, other cancers, and healthy persons. Methods ALP isoforms were separated using cellulose acetate electrophoresis and the activity was demonstrated using indolyl blue reagent. Results The BALP isoform was demonstrated in 65% of CCA patients independently of jaundice condition or histological grading of the tumor. The level of serum BALP in non-jaundiced CCA was significantly lower than that of jaundiced CCA, and not correlated with serum bilirubin. No BALP was detected in healthy persons. In the patients with high serum ALP (>147U/l), BALP can differentiate non-jaundiced CCA patients from other non-jaundiced carcinoma patients with 85% sensitivity, 79% specificity, and positive and negative predictive values of 81% and 83%, respectively. Conclusion The demonstration of serum BALP, in particular in non-jaundiced patients with high serum ALP, may indicate the presence of tumor in the bile duct. [ABSTRACT FROM AUTHOR]