Factors Associated with Periductal Fibrosis Diagnosed by Ultrasonography Screening among a High Risk Population for Cholangiocarcinoma in Northeast Thailand

Intajarurnsan, Sutheera,Khuntikeo, Narong,Chamadol, Nittaya,Thinkhamrop, Bandit,Promthet, Supannee Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.8

Background: The population in northeast Thailand continues to present with hepatobiliary abnormalities, particularly periductal fibrosis (PDF) which is the result of chronic infection with liver fluke (Opisthorchis viverini; OV) and may lead to the development of cholangiocarcinoma (CCA). Although the prevalence of OV infection has been decreased due to a liver fluke control program over decades, the prevalence of PDF remains high. This study aimed to investigate demographic factors associated with PDF risk based on ultrasonography (US) screening. Materials and Methods: This cross-sectional study is part of the Cholangiocarcinoma Screening and Care Program (CASCAP), a prospective cohort study. Multiple logistic regression was used for data analysis. Results: In 55,246 subjects, the overall prevalence of PDF was 33.0% (95%CI: 32.6 - 33.4). Males (33.9 %) were at higher risk for developing PDF than females (32.2 %) (ORcrude = 0.93; 95%CI: 0.89 - 0.96; p-value < 0.001). Factors associated with an increased PDF risk, in addition to OV infection, included old age (${\geq}70$ years) (ORadj = 1.28, 95% CI: 1.14 - 1.44, p < 0.001) and hepatitis B infection (ORadj = 1.31, 95% CI: 1.11 - 1.55, p = 0.001). In contrast, number of praziquantel treatments (> 2 times) (ORadj = 0.54, 95% CI: 0.47 - 0.63, p < 0.001) and diabetes mellitus (ORadj = 0.57, 95% CI: 0.49 - 0.65, p < 0.001) were significantly associated with a decreased PDF risk. Conclusions: Future US screening should closely examine older people and hepatitis B subjects for the purpose of PDF surveillance among high risk groups for CCA. However, the results of inverse associations require further investigation in order to confirm our findings.

Survival Rate of Intrahepatic Cholangiocarcinoma Patients after Surgical Treatment in Thailand

Sriputtha, Sudarat,Khuntikeo, Narong,Promthet, Supannee,Kamsaard, Supot Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.2

Intrahepatic cholangiocarcinoma (ICC), one of the primary liver cancers, is frequent in the northeastern part of Thailand. Surgical resection remains the best method of treatment, but patients suffering from ICC usually present at a late stage of the disease. Studies of survival and prognostic factors after surgery remain rare. The aim here was to evaluate the survival rate and factors affecting the survival of patients with intrahepatic cholangiocarcinoma after surgery. The study used a retrospective cohort design. The subjects were 73 consecutive patients with ICC, who were admitted for surgery to Srinagarind Hospital, Khon Kaen University, during the period 2005-2009. The censoring date was 31 December, 2011, data being evaluated using uni- and multivariate analyses. Postoperative survival analysis was performed by the Kaplan-Meier method, and the Cox proportional hazard model was used to identify independent prognostic factors. The total follow-up time was 99 person-years. The total number of deaths was 59, giving a mortality rate of 59 per 100 person-years. The cumulative 1-, 3-, and 5-year survival rates were 52.1%, 21.7%, and 11.2%, respectively. The median duration of survival after resection was 12.4 months. Univariate analysis revealed stage of disease, lymph node metastasis, histological type, histological grade and macroscopic classification to be statistically significant (p-value<0.05) prognostic factors. In the multivariate analysis, only macroscopic classification was statistically significant (p-value<0.05). In conclusion, macroscopic classification was the only independent factor found to be significantly associated with survival following surgical treatment of ICC.

Survival Rate of Extrahepatic Cholangiocarcinoma Patients after Surgical Treatment in Thailand

Pattanathien, Pisit,Khuntikeo, Narong,Promthet, Supannee,Kamsa-ard, Supot Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.1

Background: Intra- and extrahepatic cholangiocarcinoma (CCA) is the most common cancer in Thailand, especially in the northeast region. Most extrahepatic CCA patients consult a doctor at a late stage. Surgery is still the best treatment. Objectives: The aim of this study was to evaluate survival rates and factors affecting survival in extrahepatic CCA patients following surgery at Srinagarind Hospital, Khon Kaen University, Thailand. Materials and Methods: A retrospective cohort study was conducted with 58 patients who were diagnosed and treated by surgical resection by the same surgeon at Srinagarind Hospital between 2005 and 2009. The patients were followed up until death or the end of the study (31 December, 2011). Survival rates were calculated by the Kaplan-Meier method, and the Cox proportional hazard model was used to identify independent prognostic factors. Results: The total follow-up time was 1,215 person-months, and the mortality rate was 50 per 100 person-years. The cumulative 1-, 3-, and 5-year survival rates were 62.1%, 21.7% and 10.8%, respectively. The median survival time after resection was 15 months. After adjusting for age, gender, lymph node metastasis and histological type, resection margin remained as a statistically significant prognostic factor for survival following surgery. A positive resection margin was associated with a 2.3-fold higher mortality rate than a negative margin. Conclusions: Resection margins are important prognostic factors affecting survival of extrahepatic CCA patients after surgery. A negative resection margin can reduce the mortality rate by 56%.

Association between Diabetes Mellitus and Fatty Liver Based on Ultrasonography Screening in the World's Highest Cholangiocarcinoma Incidence Region, Northeast Thailand

Thinkhamrop, Kavin,Khuntikeo, Narong,Phonjitt, Pichai,Chamadol, Nittaya,Thinkhamrop, Bandit,Moore, Malcolm Anthony,Promthet, Supannee Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.9

Fatty liver disease (FLD) can be a precondition for other liver pathology including cholangiocarcinoma (CCA). Diabetes mellitus (DM) has been suggested in some studies to be a risk factor for FLD as well as cancers, including cholangiocellular carcinoma; however, there are currently very few studies on FLD in DM subjects, although the rate of FLD continues to increase annually. To determine the association between DM and FLD ultrasonographic data were analyzed from the Cholangiocarcinoma Screening and Care Program (CASCAP), in northeast Thailand. DM was reported by the subjects based on the CASCAP health questionnaire. Factors that were associated with FLD were determined by prevalence, odds ratio (ORs) and its 95% confidence intervals (CIs) using multiple logistic regression. There were 45,263 subjects with a mean age of 53.46 (${\pm}9.25$) years. FLD was found in 36.3% of DM subjects but only in 20.7% of non-DM subjects. The association between DM and FLD was adjusted for all other factors including gender, age, education level, relatives diagnosed with CCA, smoking, alcohol consumption, and hepatitis B and C. The risk of DM in subjects having FLD was highly significant compared with the non-DM subjects (OR 2.13; 95%CI: 1.92 to 2.35; p-value < 0.001). Thus DM is significantly associated with FLD which in turn may facilitate the development of several diseases including CCA. DM should be taken into consideration in future ultrasonic investigations of FLD and CCA.

Transcriptional Profiles of Peripheral Blood Leukocytes Identify Patients with Cholangiocarcinoma and Predict Outcome

Subimerb, Chutima,Wongkham, Chaisiri,Khuntikeo, Narong,Leelayuwat, Chanvit,McGrath, Michael S.,Wongkham, Sopit Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.10

Cholangiocarcinoma (CCA), a slow growing but highly metastatic tumor, is highly prevalent in Northeast Thailand. Specific tests that predict prognosis of CCA remain elusive. The present study was designed to investigate whether peripheral blood leukocyte (PBL) transcriptional profiles might be of use as a prognostic test in CCA patients. Gene expression profiles of PBLs from 9 CCA and 8 healthy subjects were conducted using the Affymetrix HG_U133 Plus 2.0 GeneChip. We indentified informative PBLs gene expression profiles that could reliably distinguish CCA patients from healthy subjects. Of these CCA specific genes, 117 genes were up regulated and 60 were down regulated. The molecular and cellular functions predicted for these CCA specific genes according to the Gene Ontology database indicated differential PBL expression of host immune response and tumor progression genes (EREG, TGF ${\beta}1$, CXCL2, CXCL3, IL-8, and VEGFA). The expression levels of 9 differentially expressed genes were verified in 36 CCA vs 20 healthy subjects. A set of three tumor invasion related genes (PLAU, CTSL and SERPINB2) computed as "prognostic index" was found to be an independent and statistically significant predictor for CCA patient survival. The present study shows that CCA PBLs may serve as disease predictive clinically accessible surrogates for indentifying expressed genes reflective of CCA disease severity.

Association of NRF2 Polymorphism with Cholangiocarcinoma Prognosis in Thai Patients

Khunluck, Tueanjai,Kukongviriyapan, Veerapol,Puapairoj, Anucha,Khuntikeo, Narong,Senggunprai, Laddawan,Zeekpudsa, Ponsilp,Prawan, Auemduan Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.1

Cholangiocarcinoma (CCA), a malignancy of biliary duct with a very poor prognosis, is the leading cause of cancer death in countries of the Mekong subregion. Liver fluke infection is the main etiological factor, but genetic variation has been recognized as also important in conferring susceptibility to CCA risk. Nuclear factor (erythroid derived 2)-like 2 (NRF2) is a key transcription factor in detoxification and antioxidant defense. Emerging evidence has demonstrated that genetic polymorphisms in the NRF2 gene may be associated with cancer development. The objectives of this study were to investigate the association of NRF2 genetic polymorphism with CCA risk and to evaluate the influence of the NRF2 genotype on survival time of affected patients. Single nucleotide polymorphisms (SNPs) of the NRF2 gene, including rs6726395: A/G, rs2886161: C/T, rs1806649: C/T, and rs10183914: C/T, were analyzed using TaqMan$^{(R)}$ SNP genotyping assays. Among 158 healthy northeastern Thai subjects, the allele frequencies were 41, 62, 94, and 92%, respectively. The correlation of NRF2 SNPs and CCA risk was analyzed in the 158 healthy subjects and 198 CCA patients, using unconditional logistic regression. The results showed that whereas the NRF2 SNPs were not associated with CCA risk (p>0.05), Kaplan-Meier analysis of 88 intrahepatic CCA patients showed median survival time with rs6726395 genotypes of GG and AA/AG to be $344{\pm}138$ (95%CI: 73-615) days and $172{\pm}37$ (95%CI: 100-244) days, respectively, (p<0.006). On multivariate Cox proportional hazard analysis, the GG genotype of rs6726395 was found to be associated with longer survival with a hazard ratio of 0.54 (95%CI: 0.31-0.94). In addition, non-papillary adenocarcinoma was associated with poor survival with a hazard ratio of 2.09 (95%CI: 1.16-3.75). The results suggest that the NRF2 rs6726395 polymorphism can be a potential prognostic biomarker for CCA patients.

Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma

Arpa Surapaitoon,Sutas Suttiprapa,Eimorn Mairiang,Narong Khuntikeo,Chawalit Pairojkul,Jeffrey Bethony,Paul J. Brindley,Banchob Sripa 대한기생충학열대의학회 2017 The Korean Journal of Parasitology Vol.55 No.3

Trends in Incidence of Hepatocellular Carcinoma, 1990 - 2009, Khon Kaen, Thailand

Wiangnon, Surapon,Kamsa-Ard, Supot,Suwanrungruang, Krittika,Promthet, Supannee,Kamsa-Ard, Siriporn,Mahaweerawat, Suwannee,Khuntikeo, Narong Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.3

Background: Liver cancer is the most frequent cancer among Thais especially people in northeastern Thailand, but there has as yet been no assessment of trend. The data of all cancers in Khon Kaen can be retrieved from data base of the Khon Kaen Cancer Registry (KKCR) which was established in 1984. Objective: To assess the incidence trend of hepatocellular carcinoma in Khon Kaen, Thailand, between 1990 and 2009. Methods: Population-based cases of liver cancer registered between 1985 and 2009 were retrieved from the KKCR data base and cases with diagnosis of hepatocellular carcinoma (HCC) with the coding C22.0 according to ICD-O were selected. Incidence trends were calculated using the Jointpoint analysis. Results: There were 7,859 cases of HCC during the study period. Males were affected two times more frequently than females. The most common age group of cases was 50 and 69 years (60.3%). Most patients were diagnosed based on radiology imaging (40.6%) while the morphology verification was 7%. The age-standardized rates (ASR) were 13.1 to 49.8 per 100,000 among males and 4.8 to 38.4 per 100,000 among females depending on year of diagnosis since 1985. Remarkably, the ASRs were clearly low during first few years of starting the registration. The overall ASRs of HCC were 30.3 per 100,000 in males (95% CI: 25.9 to 34.6) and 13.1 per 100,000 (95% CI: 10.4 to 15.8) in females. During 1990-2009, the trends in incidences have been decreasing significantly with the annual percent change (APC) of 6.2% per year (95% CI: -7.6 to -4.8) in males and by 6.5% per year in females (95% CI: -8.4 to -4.9). Conclusions: The incidence trends have been decreasing in both sexes. The recent decline in incidence may represent a falling risk.

Altered Expression of Oxidative Metabolism Related Genes in Cholangiocarcinomas

Aukkanimart, Ratchadawan,Boonmars, Thidarut,Juasook, Amornrat,Sriraj, Pranee,Boonjaraspinyo, Sirintip,Wu, Zhiliang,Laummuanwai, Porntip,Pairojkul, Chawalit,Khuntikeo, Narong,Rattanasuwan, Panaratana Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.14

Cholangiocarcinoma (CCA) is a rare but highly fatal cancer for which the molecular mechanisms and diagnostic markers are obscure. We therefore investigated the kinetic expression of isocitrate dehydrogenase-1 (IDH1), isocitrate dehydrogenase-2 (IDH2) and homogentisate 1,2-dioxygenase (HGD) during the tumorigenesis of O. viverrini infection-associated CCA in an animal model, and confirmed down-regulation of expression in human cases of opisthorchiasis-associated CCA through real time PCR. Kinetic expression of HGD, IDH1 and IDH2 in the animal model of O. viverrini infection-induced CCA was correlated with human CCA cases. In the animal model, expression of HGD was decreased at all time points (p<0.01) and expression of both IDH1 and IDH2 was decreased in the CCA group. In human cases, expression of HGD, IDH1 and IDH2 was decreased more than 2 fold in 55 cases (70.5%), 25 cases (32.1%) and 24 cases (30.8%) respectively. The present study suggests that reduction of HGD, IDH1 and IDH2 may be involve in cholangiocarcinoma genesis and may be useful for molecular diagnosis.