Introduction.

Cholangiocarcinoma (CCA) is a lethal cancer arising in the bile ducts within and just outside the liver. It occurs worldwide and falls into two etiologically defined groups, one related to chronic liver fluke infection and the other not. Liver fluke-related CCA is found in continental Southeast Asia (caused by Opisthorchis viverrini with infection leading to opisthorchiasis), East Asia (Clonorchis sinensis), and Eastern Europe and Russia (Opisthorchis felineus). Both O. viverrini and C. sinensis are classified as group one carcinogens, while recent data from O. felineus suggest the same. In Southeast Asia, an estimated 67.3 million people are at risk of O. viverrini infection and subsequently developing CCA. When the three liver fluke species are considered, an estimated 700 million people are at risk of infection and developing CCA globally. The northeast of Thailand (Isan) is the world's hot spot of liver fluke infection and CCA. Early detection, diagnosis, and surgical intervention/curative treatment of CCA are critical to increase life expectancy and quality of life of people in the region and globally. Despite concentrated recent efforts focusing on a multidisciplinary approach to understand the ecology, epidemiology, biology, public health, and social significance of infection by cancer causing liver flukes, it remains an underestimated and under-resourced public health problem. In addition, it is still believed to be a regional problem without global significance-this is not the case. This book focuses on O. viverrini as the main causative agent of CCA in Southeast Asia, but many aspects detailed in the following chapters also relate to the two other liver fluke species. Our aim is to produce a holistic framework including the basic biology of O. viverrini and its relation to the epidemiology of the disease through diagnosis to treatment, including palliative methods, pathology, and control.

Epidemiology and Control of Opisthorchis viverrini Infection: Implications for Cholangiocarcinoma Prevention.

It is known that Opisthorchis viverrini (OV) is the most significant risk factor for the development of cholangiocarcinoma (CCA); hence, it is also known as carcinogenic parasite. Effective control and elimination of OV infection should significantly reduce O. viverrini-related CCA. This chapter includes details of the three recently developed innovative tools, namely the Isan cohort database software, an OV-RDT for screening of O. viverrini, and an ultrasound telecommunication system. Past and current control programs, i.e., education, medication, and sanitation were discussed and stressed the need for a comprehensive control program which encompasses primary, secondary, and tertiary patient care programs for confirmation and management of suspected CCA cases. The approach of mathematical modeling for control of OV and CCA was also briefly described. Additionally, we highlighted the current progress toward control of OV and CCA in Thailand and potential for expansion into nearby countries in Southeast Asia.

Palliative Care in Cholangiocarcinoma.

This chapter details all aspects of the general principles of palliative care for advanced stage cholangiocarcinoma patients. These include symptoms management, communication guide, advance care planning, and management for bereavement. Surgical and intervention techniques of palliative biliary drainage are described in detail for patients with obstructive jaundice with advanced stage CCA. Additionally, details are provided regarding the establishment of a multidisciplinary palliative care team which is critical to provide the most appropriate multimodal treatment for good quality of life and survival of patients.

Community Awareness and Education: In the West and Southeast Asia.

Although cholangiocarcinoma (CCA) or bile duct cancer is considered rare, worldwide it is the second most common primary liver cancer. The incidence is increasing globally, and mortality is high owing to its aggressiveness, late diagnosis, and refractory nature. In this chapter, the awareness of cholangiocarcinoma in the West and in Southeast Asia, particularly Thailand, is explored. The background to this cancer in each region is described, and the challenges faced by both by healthcare professionals and patients are uncovered. Although there is a growing number of organisations working at every level in each region to improve the situation for those with cholangiocarcinoma, there remains little awareness of the public health importance of this cancer. However, it is with health agencies and those at government level that hopes for an improved future for all those with cholangiocarcinoma must lie.

Synopsis.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer worldwide. Despite the severity of the disease and its impact on individuals, families, and communities, there remains an overall lack of awareness and interest in this disease. The information contained in the chapters of this book shows that this is indeed a significant public health and socioeconomic problem with varying levels of country-specific awareness. In Southeast Asia liver fluke, O. viverrini related CCA is endemic with the highest incidence worldwide in northeast Thailand, yet it is treatable and preventable. The chapters highlight significant advances in our knowledge of the biology and epidemiology of the O. viverrini species complex, intermediate hosts, systematics, population genetics, and the complexity of the three-host life cycle. A comprehensive conceptual framework has been developed to assist in understanding the complexity of molecular mechanisms of CCA carcinogenesis and cancer development which can result in improvement of targeted CCA therapy. There have been many advances in understanding the pathology of CCA in the biliary tract, including advances in prognosis and molecular pathogenesis. The development of different modalities and their advantages for diagnosis have increased diagnostic accuracy, providing reliable information allowing appropriate treatment and management programs to be selected for each patient. Particularly exciting is the recent development of a urine antigen assay which has revolutionized the diagnostic approach of opisthorchiasis due to its simplicity, the non-invasive nature of sample collection, and its ease of use in field settings. Significant in-roads and advances have been made in the surgical and systemic treatment of CCA patients. Additionally, a sophisticated data collection and analysis system, the Isan Cohort, has been developed and established for the treatment and control of CCA. Importantly, a greater understanding has been made of the social, community, religious, and anthropological issues initiating and sustaining the eating behavior of raw, partially cooked, and/or fermented fresh water fish. Specially designed education programs/curricula, based on currently available multidisciplinary hard data targeting school children, have been introduced since the inception of the Cholangiocarcinoma Screening and Care Program (CASCAP) and the subsequent strategic Fluke Free Thailand Model. The education program is being expanded to other provinces in Thailand and in the near future to other Southeast Asian countries, initially to Lao PDR, where the Fluke Free Lao PDR program has already been implemented. Despite advances that have been made in many disciplines focused on O. viverrini related CCA, raising awareness of CCA at all levels, particularly across endemic regions, is still needed, as is raising the awareness of CCA globally. As parasites and parasite related diseases have no borders, it is critical that an effective common strategic plan is instigated and established between all countries where liver fluke, O. viverrini related CCA is a significant public health problem, thereby increasing the quality of life and life expectancy of millions of people who suffer from this insidious disease.

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.

RAW ATTITUDES: Socio-Cultures, Altered Landscapes, and Changing Perceptions of an Underestimated Disease.

Raw attitudes relate to the food cultures, eating habits, and behaviours of people in relation to the consumption of raw, partially cooked, and fermented freshwater fish dishes, which puts people at risk of Ophistochis viverrini and other parasitic infections. The chapter reviews raw attitudes within the countries and across the borders of the greater Mekong region, particularly northeast Thailand, Lao PDR, Vietnam, and Cambodia. Rather than treat each nation-state as an isolated epidemiological box, the chapter explores transborder complexity in relation to multiple anthropogenic transformations to the landscapes of the region and developmental impacts upon ecosystems and life cycles. Economic projects such as multiple hydropower dams, irrigation schemes, water-diversions, roads, and aquaculture ponds have significant impacts on FTZ life-cycle dynamics. In addition, many ecological changes are transboundary ones, and there are added complications relating human mobility, altered agrarian landscapes, and significant numbers of migrant workers. The chapter also examines public health programmes and educational interventions which are altering perceptions of O. viverrini and cholangiocarcinoma over time. A key argument is the need for transdisciplinary scientific and social science strategies alongside multi-pronged health interventions, such as 'the CASCAP model'. There exist many unknowns and gaps relating to widespread anthropogenic modifications upon life cycles, upon lifestyles, livelihoods, and human behaviours, which require research projects that span socio-economic, ecological, geographical, and public health dynamics of disease.

1H NMR fecal metabolic phenotyping of periductal fibrosis- and cholangiocarcinoma-specific metabotypes defining perturbation in gut microbial-host co-metabolism.

Background: The liver fluke Opisthorchis viverrini (OV), which subsequently inhabits the biliary system and results in periductal fibrosis (PDF), is one of the primarily causes of cholangiocarcinoma (CCA), a bile duct cancer with an exceptionally high incidence in the northeast of Thailand and other Greater Mekong Subregion (GMS) countries. Insights in fecal metabolic changes associated with PDF and CCA are required for further molecular research related to gut health and potential diagnostic biological marker development. Methods: In this study, nuclear magnetic resonance (NMR) metabolomics was applied for fecal metabolic phenotyping from 55 fecal water samples across different study groups including normal bile duct, PDF and CCA groups. Results: By using NMR spectroscopy-based metabolomics, fecal metabolic profiles of patients with CCA or PDF and of individuals with normal bile duct have been established with a total of 40 identified metabolites. Further multivariate statistical analysis and hierarchical clustering heat map have demonstrated the PDF- and CCA-specific metabotypes through various altered metabolite groups including amino acids, alcohols, amines, anaerobic glycolytic metabolites, fatty acids, microbial metabolites, sugar, TCA cycle intermediates, tryptophan catabolism substrates, and pyrimidine metabolites. Compared to the normal bile duct group, PDF individuals showed the significantly elevated relative concentrations of fecal ethanol, glycine, tyrosine, and N-acetylglucosamine whereas CCA patients exhibited the remarkable fecal metabolic changes that can be evident through the increased relative concentrations of fecal uracil, succinate, and 5-aminopentanoate. The prominent fecal metabolic alterations between CCA and PDF were displayed by the reduction of relative concentration of methanol observed in CCA. The metabolic alterations associated with PDF and CCA progression have been proposed with the involvement of various metabolic pathways including TCA cycle, ethanol biogenesis, hexamine pathway, methanol biogenesis, pyrimidine metabolism, and lysine metabolism. Among them, ethanol, methanol, and lysine metabolism strongly reflect the association of gut-microbial host metabolic crosstalk in PDF and/or CCA patients. Conclusion: The PDF- and CCA-associated metabotypes have been investigated displaying their distinct fecal metabolic patterns compared to that of normal bile duct group. Our study also demonstrated that the perturbation in co-metabolism of host and gut bacteria has been involved from the early step since OV infection to CCA tumorigenesis.

BiTNet: Hybrid deep convolutional model for ultrasound image analysis of human biliary tract and its applications.

Certain life-threatening abnormalities, such as cholangiocarcinoma, in the human biliary tract are curable if detected at an early stage, and ultrasonography has been proven to be an effective tool for identifying them. However, the diagnosis often requires a second opinion from experienced radiologists, who are usually overwhelmed by many cases. Therefore, we propose a deep convolutional neural network model, named biliary tract network (BiTNet), developed to solve problems in the current screening system and to avoid overconfidence issues of traditional deep convolutional neural networks. Additionally, we present an ultrasound image dataset for the human biliary tract and demonstrate two artificial intelligence (AI) applications: auto-prescreening and assisting tools. The proposed model is the first AI model to automatically screen and diagnose upper-abdominal abnormalities from ultrasound images in real-world healthcare scenarios. Our experiments suggest that prediction probability has an impact on both applications, and our modifications to EfficientNet solve the overconfidence problem, thereby improving the performance of both applications and of healthcare professionals. The proposed BiTNet can reduce the workload of radiologists by 35% while keeping the false negatives to as low as 1 out of every 455 images. Our experiments involving 11 healthcare professionals with four different levels of experience reveal that BiTNet improves the diagnostic performance of participants of all levels. The mean accuracy and precision of the participants with BiTNet as an assisting tool (0.74 and 0.61, respectively) are statistically higher than those of participants without the assisting tool (0.50 and 0.46, respectively (p<0.001)). These experimental results demonstrate the high potential of BiTNet for use in clinical settings.

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.

Urinary Metabolic Profiling of Liver Fluke-Induced Cholangiocarcinoma-A Follow-Up Study.

Background/Aims: Global liquid chromatography mass spectrometry (LC-MS) profiling in a Thai population has previously identified a urinary metabolic signature in Opisthorchis viverrini-induced cholangiocarcinoma (CCA), primarily characterised by disturbance in acylcarnitine, bile acid, steroid, and purine metabolism. However, the detection of thousands of analytes by LC-MS in a biological sample in a single experiment potentially introduces false discovery errors. To verify these observed metabolic perturbations, a second validation dataset from the same population was profiled in a similar fashion. Methods: Reverse-phase ultra-performance liquid-chromatography mass spectrometry was utilised to acquire the global spectral profile of 98 spot urine samples (from 46 healthy volunteers and 52 CCA patients) recruited from Khon Kaen, northeast Thailand (the highest incidence of CCA globally). Results: Metabolites were differentially expressed in the urinary profiles from CCA patients. High urinary elimination of bile acids was affected by the presence of obstructive jaundice. The urine metabolome associated with non-jaundiced CCA patients showed a distinctive pattern, similar but not identical to published studies. A panel of 10 metabolites achieved a diagnostic accuracy of 93.4% and area under the curve value of 98.8% (CI = 96.3%-100%) for the presence of CCA. Conclusions: Global characterisation of the CCA urinary metabolome identified several metabolites of biological interest in this validation study. Analyses of the diagnostic utility of the discriminant metabolites showed excellent diagnostic potential. Further larger scale studies are required to confirm these findings internationally, particularly in comparison to sporadic CCA, not associated with liver fluke infestation.

The impact of hypoxia and oxidative stress on proteo-metabolomic alterations of 3D cholangiocarcinoma models.

The three-dimensional multicellular spheroid (3D MCS) model has been employed in cholangiocarcinoma research as it generates 3D architecture and includes more physiological relevance with the multicellular arrangement. However, it is also essential to explain the molecular signature in this microenvironment and its structural complexity. The results indicated that poorly differentiated CCA cell lines were unable to form 3D MCS due to the lack of cell adhesion molecules with more mesenchymal marker expression. The well-differentiated CCA and cholangiocyte cell lines were able to develop 3D MCSs with round shapes, smooth perimeter, and cell adhesion molecules that led to the hypoxic and oxidative microenvironment detected. For MMNK-1, KKU-213C, and KKU-213A MCSs, the proteo-metabolomic analysis showed proteins and metabolic products altered compared to 2D cultures, including cell-cell adhesion molecules, energy metabolism-related enzymes and metabolites, and oxidative-related metabolites. Therefore, the 3D MCSs provide different physiological states with different phenotypic signatures compared to 2D cultures. Considering the 3D model mimics more physiological relevance, it might lead to an alternate biochemical pathway, targeting to improve drug sensitivity for CCA treatment.

Prognostic significance of tumor-infiltrating lymphocytes in predicting outcome of distal cholangiocarcinoma in Thailand.

Patients with distal cholangiocarcinoma (dCCA) generally have poor outcomes because of late presentation and diagnosis. Therefore, prognostic factors for predicting outcomes are essential to improve therapeutic strategies and quality of life. Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic predictor in several cancers. However, their role in dCCA is still unclear. This study aimed to evaluate the association of TILs with outcome in patients with dCCA. Fifty-two patients were evaluated for the percentage rate of TILs in their cancers, and a median TIL level was used to divide the patients into two groups. Survival, multivariate, and correlation analyses were performed to determine the prognostic factors. Results showed that a low TIL level was associated with poor survival. Multivariate analysis revealed TILs as an independent factor for poor outcome. Moreover, TILs were markedly correlated with growth patterns, and both were applied to classify patients with dCCA. Subgroups of TILs with growth pattern incorporation improved stratification performance in separating good from poor patient outcomes. This study suggested that TILs could be a prognostic factor for predicting survival and for clustering patients with dCCA to improve prognostication capability. This finding may be incorporated into a new staging system for stratifying dCCA in Thailand.

Modification of the eighth AJCC/UICC staging system for perihilar cholangiocarcinoma: An alternative pathological staging system from cholangiocarcinoma-prevalent Northeast Thailand.

Aim: This study aims to improve the classification performance of the eighth American Joint Committee on Cancer (AJCC) staging system for perihilar cholangiocarcinoma (pCCA) by proposing the Khon Kaen University (KKU) staging system developed in cholangiocarcinoma-prevalent Northeast Thailand. Method: Four hundred eighty-eight patients with pCCA who underwent partial hepatectomy between 2002 and 2017 at the Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand, were included. Overall survival (OS) related to clinicopathological features was analyzed using the Kaplan-Meier method. Logrank test was performed in univariate analysis to compare OS data of clinicopathological features to determine risk factors for poor survival. Significant features were further analyzed by multivariate analysis (Cox regression) to identify prognostic factors which were then employed to modify the eighth AJCC staging system. Results: Multivariate analysis showed that growth pattern (HR = 4.67-19.72, p < 0.001), moderately and poorly differentiated histological grades (HR = 2.31-4.99, p < 0.05 and 0.001, respectively), lymph node metastasis N1 and N2 (HR = 1.37 and 2.18, p < 0.05 and 0.01, respectively), and distant metastasis (HR = 2.11, p < 0.001) were independent factors when compared to their respective reference groups. There was a clear separation of patients with pCCA into KKU stage: I [OS = 116 months (mo.)], II (OS = 46 mo.), IIIA (OS = 24 mo.), IIIB (11 mo.), IVA (OS = 7 mo.), and IVB (OS = 6 mo.). Conclusion: The new staging system was based on the incorporation of growth patterns to modify the eighth AJCC staging system. The classification performance demonstrated that the KKU staging system was able to classify and distinctly separate patients with pCCA into those with good and poor outcomes. It was also able to improve the stratification performance and discriminative ability of different stages of pCCA classification better than the eighth AJCC staging system. Hence, the KKU staging system is proposed as an alternative model to augment the accuracy of survival prognostication and treatment performance for patients with pCCA.

Serum α2,6-sialylated glycoform of serotransferrin as a glycobiomarker for diagnosis and prediction of clinical severity in cholangiocarcinoma.

BACKGROUND: Glycoprotein sialylation changes are associated with severe development of various cancers. We previously discovered the sialylation of serotransferrin (TF) in cholangiocarcinoma (CCA) using glycoproteomics approach. However, a simple and reliable method for validating sialylation of a specific glycobiomarker is urgently needed. METHODS: We identified the altered glycosylation in CCA tissues by glycoproteomics approach using mass spectrometry. An enzyme-linked lectin assay (ELLA) was developed for determining the serum levels of sialylated TF in CCA, hepatocellular carcinoma (HCC) and healthy controls in training and validation cohorts. RESULTS: The nine highly sialylated glycoforms of TF were markedly abundant in CCA tumor tissues than in control. Serum SNA-TF and MAL1-TF were significantly higher in CCA patients. Under receiver operating characteristic curve, serum SNA-TF concentrations significantly differentiated CCA from healthy control. Higher SNA-TF were significantly correlated with severe tumor stages and lymph node metastasis. The combined SNA-TF, MAL1-TF, and CA19-9 as a novel glycobiomarkers panel demonstrated the highest specificity (96.2%) for distinguishing CCA from HCC patients. In CCA patients with low CA19-9 levels, SNA-TF in combination with CA19-9 achieved in 97% diagnostic accuracy. CONCLUSIONS: Sialylated serotransferrin glycoforms could be used as a novel glycobiomarker for diagnosis and prediction of clinical severity in CCA patients.

Chemotherapeutic resistant cholangiocarcinoma displayed distinct intratumoral microbial composition and metabolic profiles.

Background: Cholangiocarcinoma (CCA) is a malignancy of the cholangiocytes. One of the major issues regarding treatment for CCA patients is the development of chemotherapeutic resistance. Recently, the association of intratumoral bacteria with chemotherapeutic response has been reported in many cancer types. Method: In the present study, we aimed to investigate the association between the intratumoral microbiome and its function on gemcitabine and cisplatin response in CCA tissues using 16S rRNA sequencing and 1H NMR spectroscopic analysis. Result: The results of 16S rRNA sequencing demonstrated that Gammaproteobacteria were significantly higher in both gemcitabine- and cisplatin-resistance groups compared to sensitive groups. In addition, intratumoral microbial diversity and abundance were significantly different compared between gemcitabine-resistant and sensitive groups. Furthermore, the metabolic phenotype of the low dose gemcitabine-resistant group significantly differed from that of low dose gemcitabine-sensitive group. Increased levels of acetylcholine, adenine, carnitine and inosine were observed in the low dose gemcitabine-resistant group, while the levels of acetylcholine, alpha-D-glucose and carnitine increased in the low dose cisplatin-resistant group. We further performed the intergrative microbiome-metabolome analysis and revealed a correlation between the intratumoral bacterial and metabolic profiles which reflect the chemotherapeutics resistance pattern in CCA patients. Conclusion: Our results demonstrated insights into the disruption of the microbiome and metabolome in the progression of chemotherapeutic resistance. The altered microbiome-metabolome fingerprints could be used as predictive markers for drug responses potentially resulting in the development of an appropriate chemotherapeutic drug treatment plan for individual CCA patients.

Associations between ultrasound screening findings and cholangiocarcinoma diagnosis in an at-risk population.

The rate of cholangiocarcinoma (CCA) is increasing every year, especially in northeastern Thailand. Screening for CCA using ultrasonography (US) is the fastest technique to identify patients in early stage of CCA development. Currently, few studies have examined patterns of hepatobiliary abnormalities identified using US, which can be indicative of CCA. We aim to evaluate the rate of CCA and its relations to history of US findings. Our study included participants who underwent US and pathological diagnosis of CCA from the Cholangiocarcinoma Screening and Care Program, Northeast Thailand between 2013 and 2020. Data on histological findings were based on the standard protocol of the tertiary hospital at Khon Kaen University. CCA data is categorized into two groups (yes/no) to find the relationship with history of US findings. The adjusted odds ratio (AOR) and their 95% confidence intervals (CI) were used to evaluate the relationship obtained by multiple logistic regression. Of 1880 subjects who underwent US and a pathological diagnosis of CCA, the overall rate of CCA was 35.74%. CCA rate among those with liver mass (LM) was 54.85% and with dilated bile duct (DBD) was 62.01%. The relationship between DBD and CCA was highly significant (AOR = 3.46; 95% CI 2.74-4.36) followed by LM (AOR = 2.28; 95% CI 1.81-2.86) P value < 0.001. Our study reveals that US findings history have a strong association with CCA, especially in people diagnosed with DBD and LM. Therefore, these abnormalities can be indicators for suspected CCA diagnosis through US.

Association between the Number of Repeated Praziquantel Treatments and Kidney Parenchymal Change in Northeast Thailand.

BACKGROUND: In Northeast Thailand, Praziquantel (PZQ) is used to treat infection with the Opisthorchis viverrnini (OV). OV has highly prevalence in this area due to the traditional consumption of uncooked cyprinid fish. The nephrotoxic effects of PZQ metabolite excretion through the kidney have not been assessed yet. This study investigated the relationship between number of Praziquantel treatments and kidney parenchymal change. METHODS: A study was carried out on participants from the Cholangiocarcinoma Screening and Care Program (CASCAP) between 2013 - 2018. The frequency of PZQ use was reported using a standardized questionnaire. Kidney parenchymal change (KPC) was defined as having a kidney abnormality based on ultrasonography diagnosed by well-trained general practitioners. Adjusted odds ratios (ORs) measured associations between PZQ frequency and KPC controlling for the effects of other extraneous factors using multiple logistic regression. RESULTS: A total of 490,969 subjects with mean age of 55.2 (SD = 9.15) years were enrolled among them 62.1% were female. Prevalence of KPC was 1.2% while prevalence of KPC were 1.2%, 1.3%, 1.4%, and 1.5% for participants with one, two, three, and more than 3 PZQ treatment occasions respectively. Those dose-response relationship was statistically significant based on chi-square test for trend (p-value <0.001). After controlling for possible confounders, compared to non-treatment, subjects with more than 3 treatment occasions were 25% more likely to have a KPC positive result (OR = 1.25; 95% CI: 1.02 - 1.52; p-value = 0.028). CONCLUSION: The number of repeated PZQ treatments is statistically significantly related to KPC. This relationship could be included in health messaging for those who continue eating uncooked fish with an understanding that the OV infection can easily be cured by PZQ without any other health concerns. For positive OV cases, however, the known efficacy of PZQ could over-ride the small magnitude of the adverse effect.

Effects of day-to-day variation of Opisthorchis viverrini antigen in urine on the accuracy of diagnosing opisthorchiasis in Northeast Thailand.

Antigen detection in urine using an enzyme-linked immunosorbent assay (ELISA) is more sensitive than fecal examination for diagnosis of opisthorchiasis and for assessment of the effects of drug treatment. It is not known whether day-to-day variation of urine composition, including levels of Opisthorchis viverrini antigen, influences the urine assay. We investigated this topic with the cooperation of participants from two localities in Northeast Thailand. Project participants were screened for parasite infections for three consecutive days using the quantitative formalin-ethyl acetate concentration technique (FECT) to detect O. viverrini eggs and the urine ELISA for detection of O. viverrini antigen. A subset of participants (n = 801) with matched fecal and urine samples were analyzed for comparison of inter-day prevalence estimates and the performance of the urine assay compared against FECT for diagnosis of opisthorchiasis. The daily prevalence measured by the urine assay ranged between 29.0%-30.2% while those by FECT ranged between 11.9%-20.2%. The cumulative three-day prevalence estimate determined by the urine antigen assay was 30.3%, which was significantly higher than that by FECT (20.2%, p < 0.05). A significant positive correlation was found between the concentration of antigen in urine and fecal egg counts (p < 0.001). Overall, the urine assay had better diagnostic performance for opisthorchiasis than fecal examination by FECT. The high sensitivity plus negligible daily variation of O. viverrini antigen in urine indicates the utility of the urine assay for diagnosis, as well as population screening, of opisthorchiasis.

Modification of the AJCC/UICC 8th edition staging system for intrahepatic cholangiocarcinoma: proposal for an alternative staging system from cholangiocarcinoma-prevalent Northeast Thailand.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.