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Zhao CH, Liu H, Pan T, Xiang ZW, Mu LW, Luo JY, Zhou CR, Li MA, Liu MM, Yan HZ, Huang MS. Idarubicin-transarterial chemoembolization combined with gemcitabine plus cisplatin for unresectable intrahepatic cholangiocarcinoma. World J Gastrointest Oncol 2025; 17:103776. [PMID: 40235888 PMCID: PMC11995345 DOI: 10.4251/wjgo.v17.i4.103776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/12/2025] [Accepted: 02/07/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) is the second most common liver malignancy with poor prognosis and limited treatment options. AIM To identify the most effective drug for transarterial chemoembolization (TACE) in cholangiocarcinoma and evaluate the efficacy and safety of combining it with gemcitabine and cisplatin (GemCis) for unresectable iCCA. METHODS Cholangiocarcinoma cell lines (RBE, HuCC-T1) were treated with 10 chemotherapeutic drugs, and cytotoxicity was assessed by cell counting kit-8 assays. Tumor-bearing nude mice were treated with idarubicin or GemCis, and tumor growth was monitored. Clinical data from 85 iCCA patients were analyzed to evaluate the efficacy and safety of idarubicin-TACE combined with GemCis. RESULTS Idarubicin demonstrated the highest cytotoxicity, significantly outperforming GemCis, the standard first-line therapies. In tumor-bearing mouse models, idarubicin and GemCis treatments significantly slowed tumor growth, with idarubicin showing particularly pronounced effects on days 12 and 15 (P < 0.05). In retrospective analysis, the median overall survival (OS) and progression-free survival (PFS) in the combination therapy group were significantly longer than those in the GemCis alone group (median OS, 16.23 months vs 10.07 months, P = 0.042; median PFS, 7.73 months vs 6.30 months, P = 0.023). Additionally, major grade 3/4 adverse events (AEs) in the combination therapy group were abdominal pain (26.3% vs 6.5%, P = 0.049) and elevated transaminases (42.1% vs 12.9%, P = 0.038). Most AEs were mild to moderate and manageable. CONCLUSION Idarubicin demonstrated higher cytotoxicity than GemCis, significantly inhibiting tumor growth in tumor-bearing mouse models. Preliminary clinical results suggest that local idarubicin-TACE combined with GemCis may offer improved survival outcomes for iCCA patients with a manageable safety profile.
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Affiliation(s)
- Cheng-Hao Zhao
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Huan Liu
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Tao Pan
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Zhan-Wang Xiang
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Lu-Wen Mu
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Jun-Yang Luo
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Chu-Ren Zhou
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Ming-An Li
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Ming-Ming Liu
- Department of Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Hu-Zheng Yan
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Ming-Sheng Huang
- Department of Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
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Sahat O, Bilheem S, Lim A, Kamsa-ard S, Suwannatrai AT, Uadrang S, Leklob A, Chansaard W, Sriket N, Santong C, Daoprasert K, Kamsa-ard S. Updated cholangiocarcinoma incidence trends and projections in Thailand by region based on data from four population-based cancer registries. THE LANCET REGIONAL HEALTH. SOUTHEAST ASIA 2025; 35:100569. [PMID: 40230445 PMCID: PMC11994960 DOI: 10.1016/j.lansea.2025.100569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 04/16/2025]
Abstract
Background Cholangiocarcinoma (CCA) is a significant health concern in Thailand, as the age-standardized rates (ASR) and other trends fluctuate across different regions. However, comprehensive national estimates are lacking. This study examined the Thai ASR of CCA trends from 2012 to 2021 and projected the incidence rates to 2026. Methods This retrospective cohort analysis examined 6379 CCA cases from population-based cancer registries (PBCRs) in the northern, central, northeastern, and southern regions for the time period January 1, 2012, to December 31, 2021. The Joinpoint, age-period-cohort, and Nordpred models were used to assess CCA incidence trends and predictions. Findings CCA incidence trends in Thailand showed a decrease, with an average annual percentage change (AAPC) of -7.20% (95% CI: -11.04 to -3.19) for males, and -5.81% (95% CI: -10.81 to -0.54) for females. The projected incidence rate per 100,000 person-years for 2026 varied slightly according to the model: Joinpoint (males: 6.1, females: 3.4), age-period-cohort (males: 6.0, females: 3.3), and Nordpred (males: 5.5, females: 3.4). Regional analyses revealed decreasing trends in the northern and northeastern regions, with 2026 projections indicating further declines exceeding the 10-year trends. Owing to the small sample size, trends in the central and southern regions could not be determined. Interpretation Thailand's CCA rate has generally decreased but varies geographically; the northern and northeastern regions remain at high risk. To minimize CCA nationally, initiatives should be maintained, new risk factors explored, diagnostics improved, and regional variances addressed. Funding The Graduate School of Khon Kaen University.
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Affiliation(s)
- Oraya Sahat
- Student of Doctor of Public Health Program, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand
| | - Surichai Bilheem
- Sirindhorn College of Public Health Yala, Faculty of Public Health and Allied Health Sciences, Praboromarajchanok Institute, Yala, Thailand
| | - Apiradee Lim
- Department of Science in Mathematics with Computer Science, Faculty of Science and Technology, Prince of Songkhla University Pattani Campus, Pattani, Thailand
| | - Siriporn Kamsa-ard
- Department of Epidemiology and Biostatistics, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand
| | | | | | - Atit Leklob
- Lop Buri Cancer Hospital, Lop Buri, Thailand
| | | | | | - Chalongpon Santong
- Cancer Unit, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | - Supot Kamsa-ard
- Department of Epidemiology and Biostatistics, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand
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Kuo YH, Ong KH, Sun DP, Tian YF, Chou CL, Chan TC, Hsing CH, Li WS, Li CF, Shiue YL. Prognostic role of claudin-18.2 in intrahepatic cholangiocarcinoma. Virchows Arch 2025:10.1007/s00428-025-04081-x. [PMID: 40153004 DOI: 10.1007/s00428-025-04081-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/13/2025] [Accepted: 03/15/2025] [Indexed: 03/30/2025]
Abstract
Claudins are key components of tight junctions, essential for maintaining cellular adhesion, regulating intercellular molecule transport, and preserving cell polarity. Altered claudin expression can lead to tight junction dysfunction, potentially disrupting signaling pathways and contributing to the development of epithelial cancers. This study aims to explore the understudied role of CLDN18.2 in intrahepatic cholangiocarcinoma and its relationship with clinical outcomes. We analyzed tissue samples from 182 patients who underwent curative surgery for intrahepatic cholangiocarcinoma. Our research examined the relationship between CLDN18.2 expression and various clinical factors, including patient characteristics, pathological findings, and survival metrics such as overall survival (OS), disease-free survival (DFS), metastasis-free survival (MeFS), and local recurrence-free survival (LRFS). Overexpression of CLDN18.2 showed significant associations with R1 resection (p = 0.032) and advanced T stage (p = 0.043). Univariate analysis revealed that high CLDN18.2 expression was correlated with poorer OS (p = 0.0002), DFS (p < 0.0001), LRFS (p < 0.0001), and MeFS (p < 0.0001). Multivariate analysis further confirmed that high CLDN18.2 expression was independently associated with worse OS (p = 0.015), DFS (p < 0.001), LRFS (p < 0.001), and MeFS (p < 0.001). Overexpression of CLDN18.2 was associated with unfavorable clinical prognosis and adverse pathological features in intrahepatic cholangiocarcinoma. These findings suggest that CLDN18.2 could serve as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Yu-Hsuan Kuo
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, 71004, Taiwan
- College of Pharmacy and Science, Chia Nan University, Tainan, 71710, Taiwan
- Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
| | - Khaa Hoo Ong
- Division of Gastroenterology & General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
| | - Ding-Ping Sun
- Division of Gastroenterology & General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan
| | - Yu-Feng Tian
- Division of Gastroenterology & General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan
| | - Chia-Ling Chou
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan
| | - Ti-Chun Chan
- Department of Medical Research, Chi Mei Medical Center, Tainan, 710, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
| | - Chung-Hsi Hsing
- Department of Anesthesiology, Chi Mei Medical Center, Tainan, 710, Taiwan
- Department of Medical Research, Chi Mei Medical Center, Tainan, 710, Taiwan
| | - Wan-Shan Li
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
- Department of Clinical Pathology, Chi Mei Medical Center, Tainan, 710, Taiwan
- Trans-Omic Laboratory for Precision Medicine, Chi Mei Medical Center, Tainan, 710, Taiwan
| | - Chien-Feng Li
- Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
- Department of Medical Research, Chi Mei Medical Center, Tainan, 710, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
- Trans-Omic Laboratory for Precision Medicine, Chi Mei Medical Center, Tainan, 710, Taiwan
| | - Yow-Ling Shiue
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
- Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
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Putatunda V, Jusakul A, Roberts L, Wang XW. Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:362-377. [PMID: 39532242 PMCID: PMC11841490 DOI: 10.1016/j.ajpath.2024.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 10/07/2024] [Accepted: 10/10/2024] [Indexed: 11/16/2024]
Abstract
Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree that carries a poor prognosis. Multiple features at the genetic, epigenetic, and microenvironmental levels have been identified to better characterize CCA carcinogenesis. Genetic alterations, such as mutations in IDH1/2, BAP1, ARID1A, and FGFR2, play significant roles in CCA pathogenesis, with variations across different subtypes, races/ethnicities, and causes. Epigenetic dysregulation, characterized by DNA methylation and histone modifications, further contributes to the complexity of CCA, influencing gene expression and tumor behavior. Furthermore, CCA cells exchange autocrine and paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment, including cancer-associated fibroblasts and tumor-associated macrophages, further contributing to an immunosuppressive niche that supports tumorigenesis. This review explores the multifaceted genetic, epigenetic, and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.
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Affiliation(s)
- Vijay Putatunda
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Lewis Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Xin Wei Wang
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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Zou RQ, Dai YS, Liu F, Yang SQ, Hu HJ, Li FY. Hepatobiliary organoid research: the progress and applications. Front Pharmacol 2025; 16:1473863. [PMID: 40008122 PMCID: PMC11850396 DOI: 10.3389/fphar.2025.1473863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
Organoid culture has emerged as a forefront technology in the life sciences field. As "in vitro micro-organs", organoids can faithfully recapitulate the organogenesis process, and conserve the key structure, physiological function and pathological state of the original tissue or organ. Consequently, it is widely used in basic and clinical studies, becoming important preclinical models for studying diseases and developing therapies. Here, we introduced the definition and advantages of organoids and described the development and advances in hepatobiliary organoids research. We focus on applying hepatobiliary organoids in benign and malignant diseases of the liver and biliary tract, drug research, and regenerative medicine to provide valuable reference information for the application of hepatobiliary organoids. Despite advances in research and treatment, hepatobiliary diseases including carcinoma, viral hepatitis, fatty liver and bile duct defects have still been conundrums of the hepatobiliary field. It is necessary and crucial to study disease mechanisms, establish efficient and accurate research models and find effective treatment strategies. The organoid culture technology shed new light on solving these issues. However, the technology is not yet mature, and many hurdles still exist that need to be overcome. The combination with new technologies such as CRISPR-HOT, organ-on-a-chip may inject new vitality into future development.
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Affiliation(s)
- Rui-Qi Zou
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu-Shi Dai
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fei Liu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Si-Qi Yang
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hai-Jie Hu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fu-Yu Li
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
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Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Thongyoo P, Chindaprasirt J, Aphivatanasiri C, Intarawichian P, Kunprom W, Kongpetch S, Techasen A, Loilome W, Namwat N, Titapun A, Jusakul A. KRAS Mutations in Cholangiocarcinoma: Prevalence, Prognostic Value, and KRAS G12/G13 Detection in Cell-Free DNA. Cancer Genomics Proteomics 2025; 22:112-126. [PMID: 39730186 PMCID: PMC11696325 DOI: 10.21873/cgp.20492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/23/2024] [Accepted: 10/01/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND/AIM Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy characterized by genomic heterogeneity. KRAS mutations play a significant role in influencing patient prognosis and guiding therapeutic decision-making. This study aimed to determine the prevalence and prognostic significance of KRAS mutations in CCA, asses the detection of KRAS G12/G13 mutations in plasma cell-free DNA (cfDNA), and evaluate the prognostic value of KRAS G12/G13 mutant allele frequency (MAF) in cfDNA in relation to clinicopathological data and patient survival. MATERIALS AND METHODS A retrospective analysis of 937 CCA patients was performed using data from cBioPortal to examine KRAS mutation profiles and their association with survival. Plasma from 101 CCA patients was analyzed for KRAS G12/G13 mutations in the cfDNA using droplet digital PCR, and the results were compared with tissue-based sequencing from 78 matched samples. RESULTS KRAS driver mutations were found in 15.6% of patients, with common variants being G12D (37.0%), G12V (24.0%) and Q61H (8.2%). Patients harboring KRAS mutations exhibited decreased overall and recurrence-free survival. KRAS G12/G13 mutations were detected in 14.9% of cfDNA samples, showing moderate concordance with tissue sequencing, and achieving 80% sensitivity and 93% specificity. Elevated KRAS G12/G13 MAF in cfDNA, combined with high CA19-9 levels, correlated with poorer survival outcomes. CONCLUSION The presence of KRAS mutations was associated with poor survival in CCA, underscoring the importance of KRAS mutations as prognostic markers. The detection of KRAS mutations in cfDNA demonstrated potential as a promising non-invasive alternative for mutation detection and, when combined with CA19-9 levels, may improve prognostic efficacy in CCA.
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Affiliation(s)
- Pitchasak Thongyoo
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Jarin Chindaprasirt
- Medical Oncology Program, Department of Internal Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | | | - Waritta Kunprom
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sarinya Kongpetch
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Anchalee Techasen
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Nisana Namwat
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Apinya Jusakul
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand;
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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Sahat O, Kamsa-ard S, Suwannatrai AT, Lim A, Kamsa-ard S, Bilheem S, Daoprasert K, Leklob A, Uadrang S, Santong C, Sriket N, Chansaard W. Spatial analysis of cholangiocarcinoma in Thailand from 2012 to 2021; a population-based cancer registries study. PLoS One 2024; 19:e0311035. [PMID: 39661606 PMCID: PMC11633966 DOI: 10.1371/journal.pone.0311035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 09/10/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is major health issue in Thailand, with high incidences in different parts of country. This study examines the association between spatial variables and CCA in Thailand. METHODS Thailand's four population-based cancer registries provided data for this retrospective cohort analysis between January 1, 2012, and December 31, 2021. 6,379 diagnosed CCA cases were found in 554 sub-districts. Moran's I and Local Indicators of Spatial Association (LISA) measured geographic dispersion and estimated sex age-standardized rates (ASRs). Multivariable log-linear regression assessed geography and CCA, calculating adjusted incidence rate ratios (IRRs) and 95% confidence interval (CI). RESULTS Of 6,379 CCA cases, 63.9% were male, and the mean age at diagnosis was 66.2 years (standard deviation = 11.07 years). CCA ASRs for both sexes in Thailand was 8.9 per 100,000 person-years. The northeastern region had the greatest ASR at 13.4 per 100 000 person-years. Moran's I and LISA studies grouped regions by spatial variables. The association between spatial variables and CCA demonstrated that the northern region exhibited elevation (adjusted IRRs = 0.82, 95%CI: 0.78 to 0.87) and distance from water sources variable (adjusted IRRs = 0.91, 95%CI: 0.82 to 0.99). The central region elevation variable (adjusted IRRs = 0.85, 95%CI: 0.76 to 0.94). This was the distance from water sources (adjusted IRRs = 0.96, 95%CI: 0.93 to 0.99) and population density variable (adjusted IRRs = 0.94, 95%CI: 0.93 to 0.96) in the northeastern region. Population density (adjusted IRRs = 1.09, 95%CI: 1.02 to 1.15) and average temperature variable (adjusted IRRs = 1.05, 95%CI: 1.02 to 1.09) were significant in the southern region. CONCLUSION Spatial variables associated with CCA indicate that ASR differs across Thailand. So environmental and climate factors can inform targeted public health strategies to address CCA in high-risk areas throughout Thailand.
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Affiliation(s)
- Oraya Sahat
- Student of Doctor of Public Health Program, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand
| | - Supot Kamsa-ard
- Department of Epidemiology and Biostatistics, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand
| | | | - Apiradee Lim
- Department of Science in Mathematics with Computer Science, Faculty of Science and Technology, Prince of Songkla University, Pattani Campus, Pattani, Thailand
| | - Siriporn Kamsa-ard
- Department of Epidemiology and Biostatistics, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand
| | - Surichai Bilheem
- Department of Occupational Health and Safety, Sirindhorn College of Public Health, Yala, Yala, Thailand
| | | | - Atit Leklob
- Lop Buri Cancer Hospital, Lop Buri, Thailand
| | | | - Chalongpon Santong
- Cancer Unit, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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Thanakijsombat N, Soonklang K, Hiranrat P, Limpisook P, Siripongsakun S. Sonographic Predictors for Developing Cholangiocarcinoma: A Cohort Study from an Endemic Area. Asian Pac J Cancer Prev 2024; 25:4229-4236. [PMID: 39733414 PMCID: PMC12008351 DOI: 10.31557/apjcp.2024.25.12.4229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 12/18/2024] [Indexed: 12/31/2024] Open
Abstract
BACKGROUND AND AIM Cholangiocarcinoma (CCA) is an aggressive malignancy with a poor prognosis. Bile duct and peribiliary changes related to CCA may present on ultrasound (US) findings. This study aims to evaluate US findings that could be used as predictors for developing CCA through our surveillance program in an endemic area of Thailand. METHODS The study population was 4,337 villagers in Northern Thailand with a 5-year abdominal US surveillance. Patient demographics data and ultrasound findings of calcifications/granulomas, periductal fibrosis, and diffuse bile duct dilatation were included. A logistic regression model was used to determine significant predictors. RESULTS There were 4,225 people included with an average age of 45.49±7.66 years. Prevalence of calcifications/granulomas, periductal fibrosis, and diffuse bile duct dilatation detected on baseline sonographic surveillance was 11.7%, 20.5%, and 11.3%, respectively. The univariate analysis for significant predictors for CCA include age (Relative Risk; RR = 1.12), family history of CCA (RR = 2.29), periductal fibrosis (RR=2.38), and diffuse bile duct dilatation (RR = 7.59). The multivariate analysis the independent predictors were age (RR = 1.12), family history of CCA (RR = 1.92), and diffuse bile duct dilatation (RR = 5.94), respectively. CONCLUSIONS The sonographic predictor for CCA surveillance in endemic areas is diffuse bile duct dilatation. Age and family history of CCA are also helpful clinical markers.
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Affiliation(s)
- Natcha Thanakijsombat
- Sonographer School, Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, Thailand.
- Department of Emergency Medicine, Police General Hospital, Bangkok, Thailand.
| | - Kamonwan Soonklang
- Data Management Unit, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Pantajaree Hiranrat
- Sonographer School, Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Poemporn Limpisook
- Sonographer School, Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Surachate Siripongsakun
- Sonographer School, Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, Thailand.
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Sun Q, Lei X, Meng X, Zha C, Yan L, Zhang W. Bioinformatics analysis identifies WNK1 gene as a potential biomarker for cholangiocarcinoma diagnosis and immune infiltration. J Genet Eng Biotechnol 2024; 22:100426. [PMID: 39674642 PMCID: PMC11465147 DOI: 10.1016/j.jgeb.2024.100426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 09/19/2024] [Accepted: 09/19/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND Cholangiocarcinoma (CHOL) is a malignant epithelial carcinoma of the digestive system with poor prognosis and high mortality. WNK lysine deficient protein kinase 1 (WNK1) is known to be associated with tumorigenesis in various cancers. However, the relationship between WNK1 and CHOL development, as well as the potential mechanisms involved, remains poorly understood. METHODS Microarray datasets of CHOL (GSE22633 and GSE32879) were retrieved from the Gene Expression Omnibus (GEO) database. Functional enrichment and immunoinfiltration analyses were performed for genes co-expressed with WNK1. GraphPad Prism 9 was utilized for statistical data analysis and the construction of receiver operating characteristic (ROC) curves. The impact of WNK1 on the CHOL tumor microenvironment was analyzed using Tumor Immune Estimation Resource (TIMER), Venn diagrams, STRING, and TISIDB database for information on WNK1-related chemokines and chemokine receptors. Protein-protein interaction (PPI) networks were used to predict transcription factors and microRNAs interacting with WNK1 and the associated hub genes. RESULTS Differential expression of WNK1 was observed between CHOL and normal samples, suggesting its diagnostic value. Functional analysis showed that WNK1 and its associated genes were primarily enriched in pathways such as leukocyte transendothelial migration and chemokine signaling. Neutrophils were the only type of infiltrating immune cells associated with WNK1 in the CHOL tumor microenvironment (TME). VEGFA and ALB were identified as hub genes, and X-C motif chemokine receptor 1 (XCR1) and C-X-C motif chemokine ligand 5 (CXCL5) were identified as core chemokines and chemokine receptors related to WNK1 and neutrophil infiltration in CHOL. CONCLUSIONS Based on network analysis and the summary of previous studies, it was proposed that CHOL tumor cells secrete CXCL5, leading to neutrophil recruitment to the tumor microenvironment. Vascular endothelial growth factor A (VEGFA) released by the infiltrating neutrophils is suggested to promote overexpression of WNK1 by tumor cells, activating the VEGFA downstream pathway to promote angiogenesis and tumor progression.
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Affiliation(s)
- Qi Sun
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Heilong Jiang University of Chinese Medicine, Harbin, China
| | - Xianli Lei
- Clinical Medicine, Harbin Medical University, Harbin, China
| | - Xiangrong Meng
- Department of Laboratory Diagnosis, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Caijun Zha
- Scientific Research Center of Baoshan People's Hospital, Baoshan, China
| | - Lei Yan
- Department of Laboratory Diagnosis, the Sixth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenjing Zhang
- Department of Laboratory Diagnosis, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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11
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Orzan RI, Țigu AB, Nechita VI, Nistor M, Agoston R, Gonciar D, Pojoga C, Seicean A. Circulating miR-18a and miR-532 Levels in Extrahepatic Cholangiocarcinoma. J Clin Med 2024; 13:6177. [PMID: 39458127 PMCID: PMC11509052 DOI: 10.3390/jcm13206177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/09/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Cholangiocarcinoma (CCA) is a highly aggressive cancer of the bile ducts with a poor prognosis and limited diagnostic markers. This study aims to investigate the potential of miR-18a and miR-532 as biomarkers for CCA by exploring their correlations with clinical parameters and traditional tumor markers such as CA19.9, CEA, and AFP. Methods: This study involved a cohort of patients diagnosed with CCA. Serum levels of miR-18a and miR-532 were measured and analyzed in relation to various clinical parameters, including age, tumor markers, and histological features. Results: Serum levels of miR-18a and miR-532 were upregulated in patients with extrahepatic cholangiocarcinoma (eCCA) compared to healthy controls (p < 0.05). MiR-18a and miR-532 levels were correlated with each other (p = 0.011, Spearman's rho = 0.482) but showed no significant correlation with age or traditional tumor markers (CA19.9, CEA, AFP). No significant differences in miR-18a and miR-532 levels were observed concerning tumor localization or histological grading. For predicting tumor resectability, miR-532 at a cut-off point of 2.12 showed a sensitivity of 72.73%, specificity of 81.25%, and an AUC of 71.3%, while miR-18a, at a cut-off of 1.83, had a sensitivity of 63.64%, specificity of 75%, and an AUC of 59.7%. ROC curve analysis suggested moderate diagnostic potential for miR-18a and miR-532, with AUC values of 0.64 and 0.689, respectively. Conclusions: Although miR-18a and miR-532 showed significant upregulation in eCCA patients compared to healthy controls, they did not demonstrate significant associations with key clinical parameters, limiting their effectiveness as standalone diagnostic biomarkers. Further research involving larger, multi-center cohorts and additional molecular markers is necessary to validate these findings and explore the broader diagnostic potential of miRNAs in CCA.
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Affiliation(s)
- Rares Ilie Orzan
- 3rd Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Victor Babes Street, No. 8, 400347 Cluj-Napoca, Romania
- Regional Institute of Gastroenterology and Hepatology, Croitorilor Street, No. 19–21, 400394 Cluj-Napoca, Romania
| | - Adrian Bogdan Țigu
- Department of Translational Medicine, Institute of Medical Research and Life Sciences—MEDFUTURE, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Vlad-Ionuț Nechita
- Department of Medical Informatics and Biostatistics, “Iuliu Hațieganu” University of Medicine and Pharmacy, Louis Pasteur Street, No. 6, 400349 Cluj-Napoca, Romania
| | - Madalina Nistor
- Department of Translational Medicine, Institute of Medical Research and Life Sciences—MEDFUTURE, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Renata Agoston
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Victor Babes Street, No. 8, 400347 Cluj-Napoca, Romania
| | - Diana Gonciar
- Pathological Anatomy Discipline, Department of Morphological Sciences, “Iuliu Hatieganu” University of Medicine and Pharmacy, Clinicilor Street, No. 3–5, 400006 Cluj-Napoca, Romania
| | - Cristina Pojoga
- Regional Institute of Gastroenterology and Hepatology, Croitorilor Street, No. 19–21, 400394 Cluj-Napoca, Romania
- Department of Clinical Psychology and Psychotherapy, Babeș-Bolyai University, Sindicatelor Street, No. 7, 400029 Cluj-Napoca, Romania
| | - Andrada Seicean
- 3rd Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Victor Babes Street, No. 8, 400347 Cluj-Napoca, Romania
- Regional Institute of Gastroenterology and Hepatology, Croitorilor Street, No. 19–21, 400394 Cluj-Napoca, Romania
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12
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Lin D, Deng Z, Chen Z, Jiang K, Zhang Q, Zhou W, Zhang Q, Liu J, Wu Z, Guo L, Sun X. The disease burden and its distribution characteristics of clonorchiasis in Guangdong Province, Southern China. Parasit Vectors 2024; 17:353. [PMID: 39169431 PMCID: PMC11340111 DOI: 10.1186/s13071-024-06425-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/25/2024] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND Clonorchiasis has significant socioeconomic importance in endemic areas; however, studies investigating the disease burden in specific sub-regions are lacking. This study aims to address the gap by quantifying the current disease burden caused by clonorchiasis in Guangdong province and assessing its distribution characteristics. METHODS Comprehensive measures, including prevalence rates, disability-adjusted life years (DALYs), and direct medical costs, were used to assess the disease burden of clonorchiasis. To estimate the prevalence rate, the number of infections was divided by the examined population, based on the annual surveillance data on clonorchiasis cases during 2016-2021. The calculation of DALYs was based on the epidemiological parameters according to the definition issued by the World Health Organization. Cost data of clonorchiasis were utilized to quantify the direct medical costs. The distribution characteristics of disease burden were assessed through comparisons of groups of population defined by geographic area, time, and characteristics of people. RESULTS In 2021, clonorchiasis posed a significant disease burden in Guangdong Province. The prevalence rate was found to be 4.25% [95% CI (4.02%, 4.49%)], with an associated burden of DALYs of 406,802.29 [95% CI (329,275.33, 49,215,163.78)] person-years. The per-case direct medical costs of patients with clonorchiasis were estimated to be CNY 7907.2 (SD = 5154.4). Notably, while the prevalence rate and DALYs showed a steady decrease from 2016 to 2020, there was a rising trend in 2021. Spatial clustering of clonorchiasis cases and DALYs was also observed, particularly along the Pearl River and Han River. This suggests a concentration of the disease in these regions. Furthermore, significant differences in prevalence rates were found among various demographic groups, including sex, age, occupation, and education level. Additionally, patients with longer hospital stays were more likely to incur higher direct medical costs. CONCLUSIONS The burden of clonorchiasis in Guangdong Province remains high, despite significant progress achieved through the implementation of the prevention and control programs. It is suggested that measures should be taken based on the distribution characteristics to maximize the effectiveness of prevention and control, with a primary focus on key populations and areas.
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Affiliation(s)
- Datao Lin
- Department of Parasitology, Key Laboratory of Tropical Disease Control (Ministry of Education), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhuohui Deng
- Guangdong Provincial Center for Disease Control and Prevention, WHO Collaborating Centre for Surveillance, Research and Training of Emerging Infectious Diseases, Guangzhou, 511430, China.
| | - Zebin Chen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Kefeng Jiang
- Department of Parasitology, Key Laboratory of Tropical Disease Control (Ministry of Education), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Qiming Zhang
- Guangdong Provincial Center for Disease Control and Prevention, WHO Collaborating Centre for Surveillance, Research and Training of Emerging Infectious Diseases, Guangzhou, 511430, China
| | - Wenjing Zhou
- Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Qixian Zhang
- Department of Gastroenterology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Jun Liu
- Guangdong Provincial Center for Disease Control and Prevention, WHO Collaborating Centre for Surveillance, Research and Training of Emerging Infectious Diseases, Guangzhou, 511430, China
| | - Zhongdao Wu
- Department of Parasitology, Key Laboratory of Tropical Disease Control (Ministry of Education), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Lan Guo
- Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Xi Sun
- Department of Parasitology, Key Laboratory of Tropical Disease Control (Ministry of Education), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
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13
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Wang Y, Liu Y, Chen H, Xu Z, Jiang W, Xu X, Shan J, Chang J, Zhou T, Wang J, Chenyan A, Fan S, Tao Z, Shao K, Li X, Chen X, Ji G, Wu X. PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2. Cell Oncol (Dordr) 2024; 47:1233-1252. [PMID: 38386231 DOI: 10.1007/s13402-024-00924-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood. METHODS In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques. RESULTS Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model. CONCLUSION Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.
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Affiliation(s)
- Yuming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Yiwei Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Hairong Chen
- Department of Occupational Medicine and Environmental Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhenggang Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Wangjie Jiang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Xiao Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Jijun Shan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Jiang Chang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Tao Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Jifei Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Anlan Chenyan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Shilong Fan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Zifan Tao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Ke Shao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Xiangcheng Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Xiaofeng Chen
- Department of Oncology, Jiangsu Province Hospital, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, China.
| | - Guwei Ji
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China.
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China.
| | - Xiaofeng Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China.
- Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China.
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Suwanprinya C, Luvira V, Winaikosol K, Surakunprapha P, Punyavong P, Jenwitheesuk K, Pugkhem A, Pairojkul C. En bloc groin node resection reconstructed with external oblique flap for solitary metastatic cholangiocarcinoma: a case report. Clin J Gastroenterol 2024; 17:543-550. [PMID: 38517592 DOI: 10.1007/s12328-024-01943-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 02/24/2024] [Indexed: 03/24/2024]
Abstract
Cholangiocarcinoma requires complete surgical resection for cure. Even so, the recurrence and metastasis rates are high, and further treatment is typically through palliative systemic chemotherapy. Curative-intent resection of metastatic site may provide survival benefit in selected cases. However, there were no previous reports of groin node dissection in cholangiocarcinoma. We have reported the first case of intrahepatic mass-forming cholangiocarcinoma with isolated synchronous groin node metastasis, successfully treated with resection of the liver mass followed by groin node resection, reconstructed with musculofascial flap. A 73-year-old man presented with right upper quadrant abdominal pain radiating to the right groin for two months. Magnetic resonance cholangiopancreatography revealed a 3.1 × 1.2 cm enhancing mass between hepatic segment 4 and the anterior peritoneum, invading the abdominal wall. Computed tomography of the abdomen revealed a 2.4 × 2.2 cm focal enhancing mass at the anterior aspect of the right lower abdominal wall, just anterior to the right inguinal ligament and iliac vessel. He underwent en bloc resection of hepatic segment 4, gallbladder, and anterior abdominal wall, and the histology result is cholangiocarcinoma. After systemic chemotherapy, he underwent en bloc resection of the right groin mass, reconstructed with external oblique musculofascial flap. The patient was able to achieve a 20-month recurrence free survival after the final operation. This case has demonstrated that in a carefully selected case, resection of distant metastasis cholangiocarcinoma can provide survival benefits, even in the rare site of metastasis.
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Affiliation(s)
- Chalisa Suwanprinya
- General Surgery Unit, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Vor Luvira
- General Surgery Unit, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Kengkart Winaikosol
- Plastic & Reconstructive Surgery Unit, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Palakorn Surakunprapha
- Plastic & Reconstructive Surgery Unit, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Pattama Punyavong
- Plastic & Reconstructive Surgery Unit, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Kamonwan Jenwitheesuk
- Plastic & Reconstructive Surgery Unit, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Ake Pugkhem
- General Surgery Unit, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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15
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Yang Z, Wang L, Zhai Y, Zhao J, Ye F, Wang S, Jiang L, Song Y, Sun Y, Zhu J, Tang Y, Liu Y, Song Y, Fang H, Li N, Qi S, Lu N, Li YX, Zhao H, Chen B. Nodal recurrence mapping and clinical target volumes after resection of intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma. Clin Transl Radiat Oncol 2024; 45:100749. [PMID: 38425471 PMCID: PMC10904232 DOI: 10.1016/j.ctro.2024.100749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 01/29/2024] [Accepted: 02/15/2024] [Indexed: 03/02/2024] Open
Abstract
Background Scarce evidence exists for clinical target volume (CTV) definitions of regional lymph nodes (LNs) in intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We investigated the mapping pattern of nodal recurrence after surgery for iCCA and cHCC-CCA and provided evidence for the nodal CTV definition. Methods We retrospectively reviewed the medical records of patients with iCCA or cHCC-CCA who underwent surgery between 2010 and 2020. Eligibility criteria included patients pathologically diagnosed with iCCA or cHCC-CCA after surgery and a first recurrent event in regional LNs during follow-up. All recurrent LNs were registered onto reference computed tomography images based on the vascular structures to reconstruct the node mapping. Fifty-three patients were eligible. LN regions were classified into four risk groups. Results Hepatic hilar and portal vein-vena cava were the most common recurrent regions, with recurrence rates of 62.3 % and 39.6 % (high-risk regions), respectively. Recurrence rates in the left gastric, diaphragmatic, common hepatic, superior mesenteric vessels, celiac trunk, and paracardial regions ranged from 15.1 % to 30.2 % (intermediate-risk regions). There were fewer recurrences in the para-aortic (16a1, a2, b1) and splenic artery and hilum regions, with rates <10 % (low-risk regions). No LN recurrence was observed in the para-oesophageal or para-aortic region (16b2) (very low-risk regions). Based on node mapping, the CTV should include high- and intermediate-risk regions for pathologically negative LN patients during postoperative radiotherapy. Low-risk regions should be included for pathologically positive LN patients. Conclusion We provide evidence for CTV delineation in patients with iCCA and cHCC-CCA based on recurrent LN mapping.
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Affiliation(s)
- Zhuanbo Yang
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yirui Zhai
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Feng Ye
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Shulian Wang
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Liming Jiang
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yan Song
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yongkun Sun
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Ji Zhu
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yuan Tang
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yueping Liu
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yongwen Song
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Hui Fang
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Ning Li
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Shunan Qi
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Ningning Lu
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Ye-Xiong Li
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Bo Chen
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
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16
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Thongchot S, Ferraresi A, Vidoni C, Salwa A, Vallino L, Kittirat Y, Loilome W, Namwat N, Isidoro C. Preclinical evidence for preventive and curative effects of resveratrol on xenograft cholangiocarcinogenesis. Cancer Lett 2024; 582:216589. [PMID: 38097133 DOI: 10.1016/j.canlet.2023.216589] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/11/2023] [Accepted: 12/05/2023] [Indexed: 12/21/2023]
Abstract
Cholangiocarcinoma (CCA), the malignant tumor of bile duct epithelial cells, is a relatively rare yet highly lethal cancer. In this work, we tested the ability of Resveratrol (RV) to prevent and cure CCA xenograft in nude mice and investigated molecular mechanisms underpinning such anticancer effect. Human CCA cells were xenografted in mice that were or not treated prior to or after to transplantation with RV. Tumor growth was monitored and analyzed for the markers of cell proliferation, apoptosis, and autophagy. TCGA was interrogated for the molecules possibly targeted by RV. RV could inhibit the growth of human CCA xenograft when administered after implantation and could reduce the growth or even impair the implantation of the tumors when administered prior the transplantation. RV inhibited CCA cell proliferation, induced apoptosis with autophagy, and strongly reduced the presence of CAFs and production of IL-6. Interrogation of CCA dataset in TCGA database revealed that the expression of IL-6 Receptor (IL-6R) inversely correlated with that of MAP-LC3 and BECLIN-1, and that low expression of IL-6R and of MIK67, two pathways downregulated by RV, associated with better survival of CCA patients. Our data demonstrate that RV elicits a strong preventive and curative anticancer effect in CCA by limiting the formation of CAFs and their release of IL-6, and this results in up-regulation of autophagy and apoptosis in the cancer cells. These findings support the clinical use of RV as a primary line of prevention in patients exposed at risk and as an adjuvant therapeutics in CCA patients.
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Affiliation(s)
- Suyanee Thongchot
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand; Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy; Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Alessandra Ferraresi
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Chiara Vidoni
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Amreen Salwa
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Letizia Vallino
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Yingpinyapat Kittirat
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand; Department of Medical Sciences, Regional Medical Sciences Center 2 Phitsanulok, Ministry of Public Health, Phitsanulok, Thailand
| | - Watcharin Loilome
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand
| | - Nisana Namwat
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand.
| | - Ciro Isidoro
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy.
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17
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Anchalee N, Thinkhamrop K, Suwannatrai AT, Titapun A, Loilome W, Kelly M. Spatio-Temporal Analysis of Cholangiocarcinoma in a High Prevalence Area of Northeastern Thailand: A 10-Year Large Scale Screening Program. Asian Pac J Cancer Prev 2024; 25:537-546. [PMID: 38415540 PMCID: PMC11077099 DOI: 10.31557/apjcp.2024.25.2.537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 02/11/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is experiencing a global increase, particularly in Northeast Thailand, which has the highest global incidence rates. However, there is a paucity of studies on CCA screening, especially in high-risk populations. This study aimed to investigate the distribution and spatial patterns of CCA in Northeast Thailand over a ten-year screening period. METHODS The study included CCA patients from the Cholangiocarcinoma Screening and Care Program (CASCAP) between 2013 and 2022, which encompasses 20 provinces and 282 districts in Northeast of Thailand. CCA data were based on pathological diagnosis to determine the distribution and spatial patterns. RESULTS Of the 2,515 CCA patients, approximately two-thirds were males (63.98%), and the majority were aged over 55 years (72.72%), with a mean age of 61.12 ± 9.13 years. The highest percentage of CCA cases occurred in 2014 at 19.01% of all patients, followed by 2018 at 15.23%. The overall CCA incidence rate in Northeast Thailand over ten years was 32 per 100,000 population. Hotspot statistical analysis identified high-scoring geographic clusters in the upper and middle regions, showing a tendency to expand from hotspot areas into nearby areas. CONCLUSION The distribution of CCA in Northeast Thailand has continued to rise over the past decade, particularly in the upper and middle regions. Targeted screening in high-risk areas and increased awareness of CCA risks are crucial to mitigate its impact.
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Affiliation(s)
- Nattapong Anchalee
- Doctor of Public Health Program, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand.
| | - Kavin Thinkhamrop
- Cholangiocarcinoma Research Institute (CARI), Khon Kaen, Thailand.
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- Health and Epidemiology Geoinformatics Research (HEGER), Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand.
| | - Apiporn T. Suwannatrai
- Cholangiocarcinoma Research Institute (CARI), Khon Kaen, Thailand.
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute (CARI), Khon Kaen, Thailand.
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute (CARI), Khon Kaen, Thailand.
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Matthew Kelly
- Department of Applied Epidemiology, National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australia.
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18
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Ong KH, Hsieh YY, Lai HY, Sun DP, Chen TJ, Huang SKH, Tian YF, Chou CL, Shiue YL, Wu HC, Chan TC, Tsai HH, Li CF, Su PA, Kuo YH. Cartilage oligomeric matrix protein overexpression is an independent poor prognostic indicator in patients with intrahepatic cholangiocarcinoma. Sci Rep 2023; 13:17444. [PMID: 37838792 PMCID: PMC10576746 DOI: 10.1038/s41598-023-43006-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 09/18/2023] [Indexed: 10/16/2023] Open
Abstract
Cartilage oligomeric matrix protein (COMP) interacts with various extracellular matrix proteins in tissues. Elevated COMP levels recently linked to worse overall survival in multiple cancer types. COMP's significance in intrahepatic cholangiocarcinoma (iCCA) remains uncertain. Here we report a retrospective study to explore COMP's impact on iCCA outcomes. We collected 182 patients' iCCA tumor tissues. COMP overexpression was associated with adverse factors like R1 resection (p = 0.008), advanced T stage (p < 0.001), large duct type (p = 0.004), and poorly differentiated histology (p = 0.002). COMP overexpression correlates with poorer DFS (HR, 3.651; p = 0.001), OS (HR, 1.827; p = 0.023), LRFS (HR, 4.077; p < 0.001), and MFS (HR, 3.718; p < 0.001). High COMP expression ties to worse overall survival (p = 0.0001), DSS (p < 0.0001), LRFS (p < 0.0001), and MFS (p < 0.0001). In conclusion, COMP overexpression links to poor prognosis and pathological features in iCCA, indicating its potential as a biomarker.
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Affiliation(s)
- Khaa Hoo Ong
- Division of Gastroenterology and General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan, ROC
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan, ROC
| | - Yao-Yu Hsieh
- Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan, ROC
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan, ROC
| | - Hong-Yue Lai
- Department of Pharmacology, School of Medicine, College of Medicine, China Medical University, Taichung, 404, Taiwan, ROC
| | - Ding-Ping Sun
- Division of Gastroenterology and General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
| | - Tzu-Ju Chen
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan, ROC
- Department of Clinical Pathology, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
| | - Steven Kuan-Hua Huang
- Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
- Department of Medical Science Industries, College of Health Sciences, Chang Jung Christian University, Tainan, 711, Taiwan, ROC
| | - Yu-Feng Tian
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
| | - Chia-Ling Chou
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan, ROC
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
| | - Yow-Ling Shiue
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan, ROC
- Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan, ROC
| | - Hung-Chang Wu
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, 71004, Taiwan, ROC
- College of Pharmacy and Science, Chia Nan University, Tainan, 71710, Taiwan, ROC
| | - Ti-Chun Chan
- Department of Medical Research, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan, ROC
| | - Hsin-Hwa Tsai
- Department of Laboratory Medicine, China Medical University Hospital, Taichung, 404, Taiwan, ROC
| | - Chien-Feng Li
- Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan, ROC
- Department of Medical Research, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan, ROC
- Trans-Omic Laboratory for Precision Medicine, Chi Mei Medical Center, Tainan, 710, Taiwan, ROC
| | - Po-An Su
- Department of Infectious Disease, Chi Mei Medical Center, No.901, Zhonghua Rd. Yongkang Dist, Tainan City, 71004, Taiwan, ROC.
| | - Yu-Hsuan Kuo
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan, ROC.
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, 71004, Taiwan, ROC.
- College of Pharmacy and Science, Chia Nan University, Tainan, 71710, Taiwan, ROC.
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19
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Borlase A, Prada JM, Crellen T. Modelling morbidity for neglected tropical diseases: the long and winding road from cumulative exposure to long-term pathology. Philos Trans R Soc Lond B Biol Sci 2023; 378:20220279. [PMID: 37598702 PMCID: PMC10440174 DOI: 10.1098/rstb.2022.0279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 07/13/2023] [Indexed: 08/22/2023] Open
Abstract
Reducing the morbidities caused by neglected tropical diseases (NTDs) is a central aim of ongoing disease control programmes. The broad spectrum of pathogens under the umbrella of NTDs lead to a range of negative health outcomes, from malnutrition and anaemia to organ failure, blindness and carcinogenesis. For some NTDs, the most severe clinical manifestations develop over many years of chronic or repeated infection. For these diseases, the association between infection and risk of long-term pathology is generally complex, and the impact of multiple interacting factors, such as age, co-morbidities and host immune response, is often poorly quantified. Mathematical modelling has been used for many years to gain insights into the complex processes underlying the transmission dynamics of infectious diseases; however, long-term morbidities associated with chronic or cumulative exposure are generally not incorporated into dynamic models for NTDs. Here we consider the complexities and challenges for determining the relationship between cumulative pathogen exposure and morbidity at the individual and population levels, drawing on case studies for trachoma, schistosomiasis and foodborne trematodiasis. We explore potential frameworks for explicitly incorporating long-term morbidity into NTD transmission models, and consider the insights such frameworks may bring in terms of policy-relevant projections for the elimination era. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.
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Affiliation(s)
- Anna Borlase
- Department of Biology, University of Oxford, Oxford OX1 3SZ, UK
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK
| | - Joaquin M. Prada
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Thomas Crellen
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK
- School of Biodiversity, One Health & Veterinary Medicine, Graham Kerr Building, University of Glasgow, Glasgow G12 8QQ, UK
- Wellcome Centre for Integrative Parasitology, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, UK
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20
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Khuntikeo N, Padthaisong S, Loilome W, Klanrit P, Ratchatapusit S, Techasen A, Jareanrat A, Thanasukarn V, Srisuk T, Luvira V, Chindaprasirt J, Sa-ngiamwibool P, Aphivatanasiri C, Intarawichian P, Koonmee S, Prajumwongs P, Titapun A. Mismatch Repair Deficiency Is a Prognostic Factor Predicting Good Survival of Opisthorchis viverrini-Associated Cholangiocarcinoma at Early Cancer Stage. Cancers (Basel) 2023; 15:4831. [PMID: 37835526 PMCID: PMC10572072 DOI: 10.3390/cancers15194831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/13/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND The mismatch repair (MMR) system prevents DNA mutation; therefore, deficient MMR protein (dMMR) expression causes genetic alterations and microsatellite instability (MSI). dMMR is correlated with a good outcome and treatment response in various cancers; however, the situation remains ambiguous in cholangiocarcinoma (CCA). This study aims to evaluate the prevalence of dMMR and investigate the correlation with clinicopathological features and the survival of CCA patients after resection. MATERIALS AND METHODS Serum and tissues were collected from CCA patients who underwent resection from January 2005 to December 2017. Serum OV IgG was examined using ELISA. The expression of MMR proteins MLH1, MSH2, MSH6 and PMS2 was investigated by immunohistochemistry; subsequently, MMR assessment was evaluated as either proficient or as deficient by pathologists. The clinicopathological features and MMR status were compared using the Chi-square test. Univariate and multivariate analyses were conducted to identify prognostic factors. RESULTS Among the 102 CCA patients, dMMR was detected in 22.5%. Survival analysis revealed that dMMR patients had better survival than pMMR (HR = 0.50, p = 0.008). In multivariate analysis, dMMR was an independent factor for a good prognosis in CCA patients (HR = 0.58, p = 0.041), especially at an early stage (HR = 0.18, p = 0.027). Moreover, subgroup analysis showed dMMR patients who received adjuvant chemotherapy had better survival than surgery alone (HR = 0.28, p = 0.012). CONCLUSION This study showed a high prevalence of dMMR in cholangiocarcinoma with dMMR being the independent prognostic factor for good survival, especially in early-stage CCA and for patients who received adjuvant chemotherapy. dMMR should be the marker for selecting patients to receive a specific adjuvant treatment after resection for CCA.
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Affiliation(s)
- Natcha Khuntikeo
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Sureerat Padthaisong
- Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand;
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Poramate Klanrit
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Soontaree Ratchatapusit
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Apiwat Jareanrat
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Vasin Thanasukarn
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Tharatip Srisuk
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Vor Luvira
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Jarin Chindaprasirt
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Medical Oncology Program, Department of Medicine Srinagarind Hospital, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Prakasit Sa-ngiamwibool
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chaiwat Aphivatanasiri
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Piyapharom Intarawichian
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Supinda Koonmee
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Piya Prajumwongs
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Attapol Titapun
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
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21
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Taghizadeh H, Djanani A, Eisterer W, Gerger A, Gruenberger B, Gruenberger T, Rumpold H, Weiss L, Winder T, Wöll E, Prager GW. Systemic treatment of patients with locally advanced or metastatic cholangiocarcinoma - an Austrian expert consensus statement. Front Oncol 2023; 13:1225154. [PMID: 37711201 PMCID: PMC10499516 DOI: 10.3389/fonc.2023.1225154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/11/2023] [Indexed: 09/16/2023] Open
Abstract
Locally advanced or metastatic cholangiocarcinoma is an aggressive carcinoma with a dismal prognosis. For the first-line treatment of locally advanced or metastatic cholangiocarcinoma, cisplatin/gemcitabine has been the standard of care for more than 10 years. Its combination with the immune checkpoint inhibitor durvalumab resulted in an efficiency improvement in the phase III setting. Regarding the use of chemotherapy in the second line, positive phase III data could only be generated for FOLFOX. The evidence base for nanoliposomal irinotecan (Nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) is contradictory. After the failure of first-line treatment, targeted therapies can be offered if the molecular targets microsatellite instability-high (MSI-H), IDH1, FGFR2, BRAF V600E, and NTRK are detected. These targeted agents are generally preferable to second-line chemotherapy. Broad molecular testing should be performed, preferably from tumor tissue, at the initiation of first-line therapy to timely identify potential molecular targets.
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Affiliation(s)
- Hossein Taghizadeh
- Department of Internal Medicine I, University Hospital St. Pölten, St. Pölten, Austria
- Karl Landsteiner University of Health Sciences, Krems, Austria
| | - Angela Djanani
- Clinical Division of Gastroenterology, Hepatology and Metabolism, Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Wolfgang Eisterer
- Department of Internal Medicine, Klagenfurt Hospital, Klagenfurt am Wörthersee, Austria
| | - Armin Gerger
- Department of Internal Medicine, Clinical Division of Oncology, Medical University of Graz, Graz, Austria
| | - Birgit Gruenberger
- Department of Internal Medicine and Hematology and Internal Oncology, Landesklinikum Wiener Neustadt, Wiener Neustadt, Austria
| | - Thomas Gruenberger
- Department of Surgery, Clinic Favoriten, Hepatopancreatobiliary Center (HPB) Center, Health Network Vienna, and Sigmund Freud Private University, Vienna, Austria
| | - Holger Rumpold
- Visceral Oncology Center, Ordensklinikum Linz, Linz, Austria
| | - Lukas Weiss
- Department of Internal Medicine III, Paracelsus Medical University, Salzburg, Austria
| | - Thomas Winder
- Department of Internal Medicine II, Hospital Feldkirch, Feldkirch, Austria
| | - Ewald Wöll
- Department of Internal Medicine, Saint Vincent Hospital Zams, Zams, Austria
| | - Gerald W. Prager
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria
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22
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Möhring C, Khan O, Zhou T, Sadeghlar F, Mahn R, Kaczmarek DJ, Dold L, Toma M, Marinova M, Glowka TR, Matthaei H, Manekeller S, Kalff JC, Strassburg CP, Weismüller TJ, Gonzalez-Carmona MA. Comparison between regular additional endobiliary radiofrequency ablation and photodynamic therapy in patients with advanced extrahepatic cholangiocarcinoma under systemic chemotherapy. Front Oncol 2023; 13:1227036. [PMID: 37711210 PMCID: PMC10497756 DOI: 10.3389/fonc.2023.1227036] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/31/2023] [Indexed: 09/16/2023] Open
Abstract
Background and aims Extrahepatic cholangiocarcinoma (eCCA) remains a malignancy with a dismal prognosis. The first-line standard of care includes systemic chemotherapy (SC) and biliary drainage through stenting. Endobiliary ablative techniques, such as photodynamic therapy (ePDT) and radio-frequency ablation (eRFA), have demonstrated feasibility and favorable survival data. This study aimed to compare the oncologic outcome in patients treated with SC and concomitant eRFA or ePDT. Method All patients with eCCA were evaluated for study inclusion. Sixty-three patients receiving a combination of SC and at least one endobiliary treatment were retrospectively compared. Results Patients were stratified into three groups: SC + ePDT (n = 22), SC + eRFA (n = 28), and SC + ePDT + eRFA (n = 13). The median overall survival (OS) of the whole cohort was 14.2 months with no statistically significant difference between the three therapy groups but a trend to better survival for the group receiving ePDT as well as eRFA, during SC (ePDT + SC, 12.7 months; eRFA + SC, 13.8 months; ePDT + eRFA + SC, 20.2 months; p = 0.112). The multivariate Cox regression and subgroup analysis highlighted the beneficial effect of eRFA on OS. Overall, combined therapy was well tolerated. Only cholangitis occurred more often in the SC + eRFA group. Conclusion Additional endobiliary ablative therapies in combination with SC were feasible. Both modalities, eRFA and ePDT, showed a similar benefit in terms of survival. Interestingly, patients receiving both regimes showed the best OS indicating a possible synergism between both ablative therapeutic techniques.
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Affiliation(s)
- Christian Möhring
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Oliver Khan
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Taotao Zhou
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | | | - Robert Mahn
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | | | - Leona Dold
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Marieta Toma
- Department of Pathology, University Hospital of Bonn, Bonn, Germany
| | - Milka Marinova
- Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany
| | - Tim R. Glowka
- Department of Surgery, University Hospital of Bonn, Bonn, Germany
| | - Hanno Matthaei
- Department of Surgery, University Hospital of Bonn, Bonn, Germany
| | | | - Jörg C. Kalff
- Department of Surgery, University Hospital of Bonn, Bonn, Germany
| | | | - Tobias J. Weismüller
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
- Department of Gastroenterology and Oncology, Vivantes Humboldt Hospital, Berlin, Germany
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23
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Kuwatani M, Sakamoto N. Promising Highly Targeted Therapies for Cholangiocarcinoma: A Review and Future Perspectives. Cancers (Basel) 2023; 15:3686. [PMID: 37509347 PMCID: PMC10378186 DOI: 10.3390/cancers15143686] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/16/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
To overcome the poor prognosis of cholangiocarcinoma (CCA), highly targeted therapies, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and experimental photoimmunotherapy (PIT), have been developed. Three preclinical trials have investigated the use of ADCs targeting specific antigens, namely HER2, MUC1, and glypican-1 (GPC1), for CCA. Trastuzumab emtansine demonstrated higher antiproliferative activity in CCA cells expressing higher levels of HER2. Similarly, "staphylococcal enterotoxin A-MUC1 antibody" and "anti-GPC1 antibody-monomethyl auristatin F" conjugates showed anticancer activity. PDT is effective in areas where appropriate photosensitizers and light coexist. Its mechanism involves photosensitizer excitation and subsequent reactive oxygen species production in cancer cells upon irradiation. Hematoporphyrin derivatives, temoporfin, phthalocyanine-4, talaporfin, and chlorine e6 derivatives have mainly been used clinically and preclinically in bile duct cancer. Currently, new forms of photosensitizers with nanotechnology and novel irradiation catheters are being developed. PIT is the most novel anti-cancer therapy developed in 2011 that selectively kills targeted cancer cells using a unique photosensitizer called "IR700" conjugated with an antibody specific for cancer cells. PIT is currently in the early stages of development for identifying appropriate CCA cell targets and irradiation devices. Future human and artificial intelligence collaboration has potential for overcoming challenges related to identifying universal CCA cell targets. This could pave the way for highly targeted therapies for CCA, such as ADC, PDT, and PIT.
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Affiliation(s)
- Masaki Kuwatani
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, North 14, West 5, Kita-ku, Sapporo 060-8648, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, North 14, West 5, Kita-ku, Sapporo 060-8648, Japan
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24
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Scimeca M, Rovella V, Palumbo V, Scioli MP, Bonfiglio R, Tor Centre, Melino G, Piacentini M, Frati L, Agostini M, Candi E, Mauriello A. Programmed Cell Death Pathways in Cholangiocarcinoma: Opportunities for Targeted Therapy. Cancers (Basel) 2023; 15:3638. [PMID: 37509299 PMCID: PMC10377326 DOI: 10.3390/cancers15143638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Cholangiocarcinoma is a highly aggressive cancer arising from the bile ducts. The limited effectiveness of conventional therapies has prompted the search for new approaches to target this disease. Recent evidence suggests that distinct programmed cell death mechanisms, namely, apoptosis, ferroptosis, pyroptosis and necroptosis, play a critical role in the development and progression of cholangiocarcinoma. This review aims to summarize the current knowledge on the role of programmed cell death in cholangiocarcinoma and its potential implications for the development of novel therapies. Several studies have shown that the dysregulation of apoptotic signaling pathways contributes to cholangiocarcinoma tumorigenesis and resistance to treatment. Similarly, ferroptosis, pyroptosis and necroptosis, which are pro-inflammatory forms of cell death, have been implicated in promoting immune cell recruitment and activation, thus enhancing the antitumor immune response. Moreover, recent studies have suggested that targeting cell death pathways could sensitize cholangiocarcinoma cells to chemotherapy and immunotherapy. In conclusion, programmed cell death represents a relevant molecular mechanism of pathogenesis in cholangiocarcinoma, and further research is needed to fully elucidate the underlying details and possibly identify therapeutic strategies.
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Affiliation(s)
- Manuel Scimeca
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Valentina Rovella
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Valeria Palumbo
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Maria Paola Scioli
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Rita Bonfiglio
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | | | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Mauro Piacentini
- Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Luigi Frati
- Institute Pasteur Italy-Cenci Bolognetti Foundation, Via Regina Elena 291, 00161 Rome, Italy
- IRCCS Neuromed S.p.A., Via Atinense 18, 86077 Pozzilli, Italy
| | - Massimiliano Agostini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Alessandro Mauriello
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
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25
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Samankul A, Senawong G, Utaiwat S, Prompipak J, Woranam K, Phaosiri C, Sripa B, Senawong T. Tiliacora triandra Leaf Powder Ethanolic Extract in Combination with Cisplatin or Gemcitabine Synergistically Inhibits the Growth of Cholangiocarcinoma Cells In Vitro and in Nude Mouse Xenograft Models. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1269. [PMID: 37512080 PMCID: PMC10386122 DOI: 10.3390/medicina59071269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023]
Abstract
Background and Objectives: The treatments of cholangiocarcinoma (CCA) with Cisplatin (Cis) and Gemcitabine (Gem) often cause side effects and drug resistance. This study aimed to investigate the combined effects of Tiliacora triandra leaf powder ethanolic extract (TLPE) and Cis or Gem on CCA cells in vitro and in nude mouse xenografts. Materials and Methods: Antiproliferative activity was evaluated using MTT assay. Drug interaction was studied by Chou-Talalay method. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. Cell cycle and apoptosis regulating proteins were evaluated by western blot analysis. Results:Treatments with Cis or Gem in combination with TLPE significantly inhibited the growth of KKU-M213B and KKU-100 cells compared with single drug treatments. Synergistic drug interactions were observed with the dose reduction of Cis and Gem treatments. The safety of TLPE was demonstrated in vitro by the hemolytic assay. Synergistic combination treatments down-regulated Bcl2 and reduced the ratio of Bcl2/Bax in both CCA cells. TLPE enhanced tumor suppression of both Cis and Gem in nude mouse xenograft models. Combination treatments with Cis and TLPE reduced Cis toxicity, as demonstrated by the enhanced body weight change of the treated mice compared with the treatment with Cis alone. Furthermore, TLPE reduced hepatotoxicity caused by Gem treatment and reduced kidney and spleen toxicities caused by Cis treatment. Conclusion: These findings suggest that TLPE enhances the anticancer activity of Cis and Gem and reduces their toxicity both in vitro and in nude mouse xenograft models.
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Affiliation(s)
- Arunta Samankul
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Gulsiri Senawong
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Suppawit Utaiwat
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Jeerati Prompipak
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Khanutsanan Woranam
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chanokbhorn Phaosiri
- Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Banchob Sripa
- WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Thanaset Senawong
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
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26
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You G, Zeng L, Tanaka H, Ohta E, Fujii T, Ohshima K, Tanaka M, Hamajima N, Viwatthanasittiphong C, Muangphot M, Chenvidhya D, Jedpiyawongse A, Sripa B, Miwa M, Honjo S. Polymorphism of genes encoding drug-metabolizing and inflammation-related enzymes for susceptibility to cholangiocarcinoma in Thailand. World J Gastrointest Pathophysiol 2023; 14:21-33. [PMID: 37035273 PMCID: PMC10074948 DOI: 10.4291/wjgp.v14.i2.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 02/19/2023] [Accepted: 03/15/2023] [Indexed: 03/21/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is an intractable cancer, and its incidence in northeastern Thailand is the highest worldwide. Infection with the liver fluke Opisthorchis viverrini (OV) has been associated with CCA risk. However, animal experiments have suggested that OV alone does not induce CCA, but its combination with a chemical carcinogen like nitrosamine can cause experimentally induced CCA in hamsters. Therefore, in humans, other environmental and genetic factors may also be involved.
AIM To examine relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing and inflammation-related genes.
METHODS This hospital-based case-control study enrolled 95 case-control pairs matched by age (± 5 years) and sex. We examined relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing and inflammation-related genes, serum anti-OV, alcohol consumption, and smoking. Polymorphisms of CYP2E1, IL-6 (-174 and -634), IL-10 (-819), and NF-κB (-94) and their co-occurrence with polymorphisms in the drug-metabolizing enzyme gene GSTT1 or GSTM1 were also analyzed.
RESULTS Although CCA risk was not significantly associated with any single polymorphism, persons with the GSTT1 wild-type and CYP2E1 c1/c2 + c2/c2 genotype had an increased risk (OR = 3.33, 95%CI: 1.23-9.00) as compared with persons having the GSTT1 wild-type and CYP2E1 c1/c1 wild genotype. The presence of anti-OV in serum was associated with a 7- to 11-fold increased risk, and smoking level was related to an OR of 1.5-1.8 in multivariable analyses adjusted for each of the seven genetic polymorphisms.
CONCLUSION In addition to infection with OV, gene-gene interactions may be considered as one of the risk factors for CCA development.
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Affiliation(s)
- Gyokukou You
- Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
| | - Lu Zeng
- Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
| | - Hideaki Tanaka
- Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
| | - Emi Ohta
- Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
| | - Takahiro Fujii
- Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
| | - Kazuhiko Ohshima
- Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
| | - Masakazu Tanaka
- Division of Neuroimmunology, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima 890-8544, Kagoshima, Japan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan
| | | | - Mantana Muangphot
- Department of Pathology, Ubon Cancer Centre, Ubon Ratchathani 34000, Thailand
| | | | | | - Banchob Sripa
- Department of Pathology, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Masanao Miwa
- Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
| | - Satoshi Honjo
- Department of Paediatirics, National Hospital Organization, Fukuoka National Hospital, Fukuoka 811-1394, Fukuoka, Japan
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27
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Bakrania A, Joshi N, Zhao X, Zheng G, Bhat M. Artificial intelligence in liver cancers: Decoding the impact of machine learning models in clinical diagnosis of primary liver cancers and liver cancer metastases. Pharmacol Res 2023; 189:106706. [PMID: 36813095 DOI: 10.1016/j.phrs.2023.106706] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/17/2023] [Accepted: 02/19/2023] [Indexed: 02/22/2023]
Abstract
Liver cancers are the fourth leading cause of cancer-related mortality worldwide. In the past decade, breakthroughs in the field of artificial intelligence (AI) have inspired development of algorithms in the cancer setting. A growing body of recent studies have evaluated machine learning (ML) and deep learning (DL) algorithms for pre-screening, diagnosis and management of liver cancer patients through diagnostic image analysis, biomarker discovery and predicting personalized clinical outcomes. Despite the promise of these early AI tools, there is a significant need to explain the 'black box' of AI and work towards deployment to enable ultimate clinical translatability. Certain emerging fields such as RNA nanomedicine for targeted liver cancer therapy may also benefit from application of AI, specifically in nano-formulation research and development given that they are still largely reliant on lengthy trial-and-error experiments. In this paper, we put forward the current landscape of AI in liver cancers along with the challenges of AI in liver cancer diagnosis and management. Finally, we have discussed the future perspectives of AI application in liver cancer and how a multidisciplinary approach using AI in nanomedicine could accelerate the transition of personalized liver cancer medicine from bench side to the clinic.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, ON, Canada; Ajmera Transplant Program, University Health Network, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| | | | - Xun Zhao
- Toronto General Hospital Research Institute, Toronto, ON, Canada; Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, ON, Canada; Ajmera Transplant Program, University Health Network, Toronto, ON, Canada; Division of Gastroenterology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada; Department of Medical Sciences, Toronto, ON, Canada.
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28
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Borad MJ, Bai LY, Richards D, Mody K, Hubbard J, Rha SY, Soong J, McCormick D, Tse E, O'Brien D, Bayat A, Ahn D, Davis SL, Park JO, Oh DY. Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study. Hepatology 2023; 77:760-773. [PMID: 36152015 DOI: 10.1002/hep.32804] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. APPROACH AND RESULTS This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) ( p = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. CONCLUSIONS Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma.
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Affiliation(s)
- Mitesh J Borad
- Center for Individualized Medicine, Liver and Biliary Cancer Research Program and Cancer Cell , Gene and Virus Therapy Lab, Mayo Clinic Arizona , Scottsdale , Arizona , USA
| | - Li-Yuan Bai
- China Medical University Hospital, and China Medical University , Taichung , Taiwan
| | - Donald Richards
- Texas Oncology-Tyler, US Oncology Research , Tyler , Texas , USA
| | - Kabir Mody
- Division of Hematology and Oncology , Mayo Clinic Jacksonville , Jacksonville , Florida , USA
| | - Joleen Hubbard
- Department of Medical Oncology , Mayo Clinic Rochester , Rochester , Minnesota , USA
| | - Sun Young Rha
- Yonsei Cancer Center , Yonsei University College of Medicine , Seoul , South Korea
| | - John Soong
- Clinical Operations , Senhwa Biosciences Corporation , San Diego , California , USA
| | - Daniel McCormick
- Clinical Operations , Senhwa Biosciences Corporation , San Diego , California , USA
| | - Emmett Tse
- Clinical Operations , Senhwa Biosciences Corporation , San Diego , California , USA
| | - Daniel O'Brien
- Department of Quantitative Health Sciences , Mayo Clinic , Rochester , Minnesota , USA
| | - Ahmad Bayat
- Regulatory Affairs , Amarex Clinical Research , Germantown , Maryland , USA
| | - Daniel Ahn
- Division of Hematology/Medical Oncology, Department of Internal Medicine , Mayo Clinic Arizona , Phoenix , Arizona , USA
| | - S Lindsey Davis
- Division of Medical Oncology , University of Colorado Cancer Center , Aurora , Colorado , USA
| | - Joon Oh Park
- Division of Hematology-Oncology , Samsung Medical Centre, Sungkyunkwan University School of Medicine , Seoul , South Korea
| | - Do-Youn Oh
- Cancer Research Institute , Seoul National University Hospital, Seoul National University College of Medicine, Integrated Major in Innovative Medical Science, Seoul National University Graduate School , Seoul , South Korea
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29
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Mehmood A, Nawab S, Jin Y, Kaushik AC, Wei DQ. Mutational Impacts on the N and C Terminal Domains of the MUC5B Protein: A Transcriptomics and Structural Biology Study. ACS OMEGA 2023; 8:3726-3735. [PMID: 36743039 PMCID: PMC9893249 DOI: 10.1021/acsomega.2c04871] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/18/2022] [Indexed: 06/18/2023]
Abstract
Cholangiocarcinoma (CCA) involves various epithelial tumors historically linked with poor prognosis because of its aggressive sickness course, delayed diagnosis, and limited efficacy of typical chemotherapy in its advanced stages. In-depth molecular profiling has exposed a varied scenery of genomic alterations as CCA's oncogenic drivers. Previous studies have mainly focused on commonly occurring TP53 and KRAS alterations, but there is limited research conducted to explore other vital genes involved in CCA. We retrieved data from The Cancer Genome Atlas (TCGA) to hunt for additional CCA targets and plotted a mutational landscape, identifying key genes and their frequently expressed variants. Next, we performed a survival analysis for all of the top genes to shortlist the ones with better significance. Among those genes, we observed that MUC5B has the most significant p-value of 0.0061. Finally, we chose two missense mutations at different positions in the vicinity of MUC5B N and C terminal domains. These mutations were further subjected to molecular dynamics (MD) simulation, which revealed noticeable impacts on the protein structure. Our study not only reveals one of the highly mutated genes with enhanced significance in CCA but also gives insights into the influence of its variants. We believe these findings are a good asset for understanding CCA from genomics and structural biology perspectives.
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Affiliation(s)
- Aamir Mehmood
- Department
of Bioinformatics and Biological Statistics, School of Life Sciences
and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Sadia Nawab
- State
Key Laboratory of Microbial Metabolism and School of Life Sciences
and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Yifan Jin
- Department
of Bioinformatics and Biological Statistics, School of Life Sciences
and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Aman Chandra Kaushik
- Department
of Bioinformatics and Biological Statistics, School of Life Sciences
and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Dong-Qing Wei
- State
Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade
Joint Innovation Center on Antibacterial Resistances, Joint International
Research Laboratory of Metabolic & Developmental Sciences and
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
- Zhongjing
Research and Industrialization Institute of Chinese Medicine, Zhongguancun Scientific Park, Meixi, Nanyang, Henan 473006, P. R. China
- Peng
Cheng Laboratory, Vanke
Cloud City Phase I Building 8, Xili Street, Nanshan
District, Shenzhen, Guangdong 518055, P. R. China
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Tag-Adeen M, Malak M, Abdel-Gawad M, Abu-Elfatth A, Eldamarawy RH, Alzamzamy A, Elbasiony M, Elsharkawy RM, El-Raey F, Basiony AN, Qasem A, Shady Z, Abdelmohsen AS, Abdeltawab D, Farouk M, Fouad OM, Rabie A, Erian AH, Sapra A, Shaibat-Alhamd W, Aboubakr A, Omran D, Alboraie M. Clinical characteristics, risk factors and diagnostic outcomes of patients presented with indeterminate biliary stricture: A multicenter study. Front Med (Lausanne) 2023; 9:1018201. [PMID: 36714140 PMCID: PMC9875376 DOI: 10.3389/fmed.2022.1018201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND AND AIM Indeterminate biliary stricture (IBS) is a frequently encountered clinical problem. In this study, we aimed to highlight the clinical characteristics, risk factors and diagnostic outcomes of patients presented with indeterminate biliary stricture. METHOD A Retrospective multicenter study included all patients diagnosed with IBS in the participating centers between 2017 and 2021. Data regarding IBS such as presentations, patient characteristics, diagnostic and therapeutic modalities were collected from the patients' records and then were analyzed. RESULTS Data of 315 patients with IBS were retrospectively collected from 7 medical centers with mean age: 62.6 ± 11 years, females: 40.3% and smokers: 44.8%. For diagnosing stricture; Magnetic resonance imaging/Magnetic resonance cholangiopancreatography (MRI/MRCP) was the most frequently requested imaging modality in all patients, Contrast enhanced computerized tomography (CECT) in 85% and endoscopic ultrasound (EUS) in 23.8%. Tissue diagnosis of cholangiocarcinoma was achieved in 14% only. The used therapeutic modalities were endoscopic retrograde cholangiopancreatography (ERCP)/stenting in 70.5%, percutaneous trans-hepatic biliary drainage (PTD): 17.8%, EUS guided drainage: 0.3%, and surgical resection in 8%. The most frequent type of strictures was distal stricture in 181 patients, perihilar in 128 and intrahepatic in 6. Distal strictures had significant male predominance, with higher role for EUS for diagnosis and higher role for ERCP/stenting for drainage, while in the perihilar strictures, there was higher role for CECT and MRI/MRCP for diagnosis and more frequent use of PTD for drainage. CONCLUSION Indeterminate biliary stricture is a challenging clinical problem with lack of tissue diagnosis in most of cases mandates an urgent consensus diagnostic and treatment guidelines.
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Affiliation(s)
- Mohammed Tag-Adeen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Qena Faculty of Medicine, South Valley University, Qena, Egypt
| | - Mohamed Malak
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Muhammad Abdel-Gawad
- Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, Egypt
| | - Ahmed Abu-Elfatth
- Department of Tropical Medicine and Gastroenterology, Assuit University, Assiut, Egypt
| | | | - Ahmed Alzamzamy
- Department of Gastroenterology and Heptology, Maadi Armed Forces Medical Complex, Military Medical Academy, Cairo, Egypt
| | - Mohamed Elbasiony
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Dakahlya, Egypt
| | - Ramy M. Elsharkawy
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Fathiya El-Raey
- Department of Hepatogastroenterology and Infectious Diseases, Al-Azhar University, Damietta, Egypt
| | - Ahmed N. Basiony
- Department of Tropical Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed Qasem
- Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, Egypt
| | - Zakarya Shady
- Department of Internal Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed S. Abdelmohsen
- Department of Tropical Medicine and Gastroenterology, Assuit University, Assiut, Egypt
| | - Doaa Abdeltawab
- Department of Tropical Medicine and Gastroenterology, Assuit University, Assiut, Egypt
| | - Mahmoud Farouk
- Department of Tropical Medicine and Gastroenterology, Assuit University, Assiut, Egypt
| | - Ola M. Fouad
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Qena Faculty of Medicine, South Valley University, Qena, Egypt
| | - Ahmed Rabie
- Department of Pathology, Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Abdul-Hakim Erian
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Qena Faculty of Medicine, South Valley University, Qena, Egypt
| | - Ahlam Sapra
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Qena Faculty of Medicine, South Valley University, Qena, Egypt
| | - Wael Shaibat-Alhamd
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Al-Azhar Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | - Ashraf Aboubakr
- Department of Gastroenterology and Heptology, Maadi Armed Forces Medical Complex, Military Medical Academy, Cairo, Egypt
| | - Dalia Omran
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Mohamed Alboraie
- Department of Internal Medicine, Al-Azhar University, Cairo, Egypt
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Skalicky P, Urban O, Ehrmann J, Svebisova H, Klos D, Tesarikova J, Neoral C, Knapkova K, Lovecek M. The short- and long-term outcomes of pancreaticoduodenectomy for distal cholangiocarcinoma. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2022; 166:386-392. [PMID: 34467956 DOI: 10.5507/bp.2021.043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The aim of the study was to calculate the short-term and long-term outcomes of curative-intent surgery in distal cholangiocarcinoma (DCC) patients to identify potential prognostic factors. PATIENTS AND METHODS A retrospective cohort study of 32 consecutive DCC patients treated with pancreaticoduodenectomy between 2009-2017. The clinicopathological and histopathological data were evaluated for prognostic factors using the univariable Cox regression analysis. The Overall Survival (OS) was estimated using the Kaplan-Meier analysis. RESULTS The study comprised a total of 32 patients, with a mean age of 65.8 (± 9.0) years at the time of surgery. R0 resection was achieved in 25 (86.2%) patients, 19 (65.5%) patients received adjuvant oncological therapy. The OS rates at 1, 3 and 5 years were 62.5%, 37.5% and 21.9%, respectively. The 90-day mortality was 3/32 (9.4%) accounting for one-fourth of the first-year mortality rate. The median OS was 28.5 months. The only statistically significant prognostic factor was vascular resection, which was associated with worse OS in the univariable analysis (HR: 3.644; 95%-CI: 1.179-11.216, P=0.025). An age less than 65 years, ASA grade I/II, hospital stay of fewer than 15 days, R0 resection, lymph node ratio less than 0.2 and adjuvant oncological therapy tended to be associated with better OS but without statistically significant relevance. CONCLUSION The main factor directly influencing the survival of DCC patients is surgical complications. Surgical mortality comprises a significant group of patients, who die in the first year following pancreaticoduodenectomy. Vascular resection is the most important negative prognostic factor for long-term survival.
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Affiliation(s)
- Pavel Skalicky
- Department of Surgery I, University Hospital Olomouc, Czech Republic
| | - Ondrej Urban
- Department of Internal Medicine II - Gastroenterology and Geriatrics, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Jiri Ehrmann
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Hana Svebisova
- Department of Oncology, University Hospital Olomouc, Czech Republic
| | - Dusan Klos
- Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Jana Tesarikova
- Department of Surgery I, University Hospital Olomouc, Czech Republic
| | - Cestmir Neoral
- Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Katerina Knapkova
- Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Martin Lovecek
- Department of Surgery I, University Hospital Olomouc, Czech Republic
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Prevalence and Risk Factors of Opisthorchis viverrini Infection in Sakon Nakhon Province, Thailand. Trop Med Infect Dis 2022; 7:tropicalmed7100313. [PMID: 36288054 PMCID: PMC9607628 DOI: 10.3390/tropicalmed7100313] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/14/2022] [Accepted: 10/15/2022] [Indexed: 11/18/2022] Open
Abstract
Opisthorchiasis is a parasitic infection caused by the liver fluke Opisthorchis viverrini. This parasite is widely distributed and well documented in Thailand, Lao PDR, Southern Vietnam, Cambodia, and Myanmar. However, its prevalence is a major problem in these countries. Thus, the aim of this study was to determine the prevalence and risk factors of O. viverrini infection from 2017 to 2020 in Sakon Nakhon province, Thailand. Questionnaires were used to interview 320 participants (160 cases and 160 controls) in a random selection of 18 districts across Sakon Nakhon province. Univariate logistic regression was used to identify the factors associated with O. viverrini infection. The overall prevalence levels of O. viverrini infection in Sakon Nakhon province for 2018, 2019, and 2020 were 3.60%, 5.21%, and 7.01%, respectively. Raw fish consumption was a positive risk factor for its infection in endemic areas. Factors associated with O. viverrini infection were the habit of consuming unsafely prepared fish (OR = 6.33, 95%CI = 0.32–0.59), the medical history of O. viverrini examination (OR = 8.93, 95%CI = 5.15–15.47), a history of O. viverrini infection (OR = 3.64, 95%CI = 1.17–1.44), and a history of taking praziquantel (OR = 3.64, 95%CI = 1.17–1.44). These results identified gaps in the epidemiological knowledge of O. viverrini in this region that need addressing to identify and develop innovative methods for prevention, control, and support efforts to permanently overcome O. viverrini infection in endemic regions.
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Ma K, Wang Y, Zhang Y, Sun H, Zhang X, Sun C, Zhang B, Zhang Y, Cheng H, Liu A, Wang M, Han B. Clinical Practice of Targeted Capture Sequencing to Identify Actionable Alterations in Cholangiocarcinoma. Cancers (Basel) 2022; 14:cancers14205062. [PMID: 36291846 PMCID: PMC9600135 DOI: 10.3390/cancers14205062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/27/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
The early diagnosis and treatment of cholangiocarcinoma (CCA) remain a challenge worldwide. Genetic testing promises to solve these problems. Due to the different mutation landscapes across populations and the paucity of sequencing data of Chinese patients with CCA, the existing mutation landscape is insufficient to reflect the mutation characteristics of Chinese patients. Thus, we retrospectively analyzed 72 Chinese patients with CCA who had received genetic testing of targeted capture sequencing. A total of 2152 somatic mutations were detected in 56 (77.78%) patients, of which, the frequently mutated driver genes were TP53 (27.78%), KMT2D (23.81%), KMT2C (20.63%), BCOR (18.06%), APC (15.28%), BAP1 (13.89%), ARID1A (12.50%), NF1 (12.50%), PIK3CA (12.50%), KRAS (11.11%), and LRP1B (11.11%). Most mutations were enriched in NRF2, TP53, and TGF-Beta oncogenic signaling pathways and cadherin repeat domains which were associated with intercellular adhesion. Based on cancer-related public databases and multiple protein function prediction algorithms, we identified 118 novel pathogenic or likely pathogenic somatic mutations and 77 actionable alterations. Molecular analysis of tumors from a precision oncology perspective can provide potential targets for early diagnosis and treatment of CCA and assist physicians in clinical decision making.
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Affiliation(s)
- Kai Ma
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Youpeng Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Yuanzheng Zhang
- Collage of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110169, China
| | - Hongfa Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Xuhui Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Chuandong Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Bingyuan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Ying Zhang
- School of Business Administration, Northeastern University, Shenyang 110169, China
| | - Haoyue Cheng
- Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Ao Liu
- The Sixth Medical Center, Chinese PLA Medical School, Beijing 100853, China
| | - Mengyao Wang
- Department of Research and Development, Shenzhen Byoryn Technology Co., Ltd., Shenzhen 518122, China
- Correspondence: (M.W.); (B.H.); Tel.: +86-0532-96166 (B.H.)
| | - Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
- Correspondence: (M.W.); (B.H.); Tel.: +86-0532-96166 (B.H.)
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Islam MA, Barshetty MM, Srinivasan S, Dudekula DB, Rallabandi VPS, Mohammed S, Natarajan S, Park J. Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study. Biomolecules 2022; 12:biom12091279. [PMID: 36139117 PMCID: PMC9496582 DOI: 10.3390/biom12091279] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/05/2022] [Accepted: 09/08/2022] [Indexed: 11/28/2022] Open
Abstract
Biliary tract cancer (BTC) is constituted by a heterogeneous group of malignant tumors that may develop in the biliary tract, and it is the second most common liver cancer. Human ribonucleotide reductase M1 (hRRM1) has already been proven to be a potential BTC target. In the current study, a de novo design approach was used to generate novel and effective chemical therapeutics for BTC. A set of comprehensive pharmacoinformatics approaches was implemented and, finally, seventeen potential molecules were found to be effective for the modulation of hRRM1 activity. Molecular docking, negative image-based ShaEP scoring, absolute binding free energy, in silico pharmacokinetics, and toxicity assessments corroborated the potentiality of the selected molecules. Almost all molecules showed higher affinity in comparison to gemcitabine and naphthyl salicylic acyl hydrazone (NSAH). On binding interaction analysis, a number of critical amino acids was found to hold the molecules at the active site cavity. The molecular dynamics (MD) simulation study also indicated the stability between protein and ligands. High negative MM-GBSA (molecular mechanics generalized Born and surface area) binding free energy indicated the potentiality of the molecules. Therefore, the proposed molecules might have the potential to be effective therapeutics for the management of BTC.
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Affiliation(s)
- Md Ataul Islam
- 3BIGS Omicscore Private Limited, 909 Lavelle Building, Richmond Circle, Bangalore 560025, India
| | | | - Sridhar Srinivasan
- 3BIGS Omicscore Private Limited, 909 Lavelle Building, Richmond Circle, Bangalore 560025, India
| | - Dawood Babu Dudekula
- 3BIGS Omicscore Private Limited, 909 Lavelle Building, Richmond Circle, Bangalore 560025, India
| | | | - Sameer Mohammed
- 3BIGS Omicscore Private Limited, 909 Lavelle Building, Richmond Circle, Bangalore 560025, India
| | | | - Junhyung Park
- 3BIGS Co., Ltd., B-831, Geumgang Penterium IX Tower, Hwaseong 18469, Korea
- Correspondence:
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Wang J, Ge F, Yuan T, Qian M, Yan F, Yang B, He Q, Zhu H. The molecular mechanisms and targeting strategies of transcription factors in cholangiocarcinoma. Expert Opin Ther Targets 2022; 26:781-789. [PMID: 36243001 DOI: 10.1080/14728222.2022.2137020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/13/2022] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Cholangiocarcinoma consists of a cluster of malignant biliary tumors that tend to have a poor prognosis, ranking as the second most prevalent type of liver cancer, and their incidence rate has increased globally recently. The high-frequency driving mutations of cholangiocarcinoma, such as KRAS/IDH1/ARID1A/P53, imply the epigenetic instability of cholangiocarcinoma, leading to the dysregulation of various related transcription factors, thus affecting the occurrence and development of cholangiocarcinoma. Increasingly evidence indicates that the high heterogeneity and malignancy of cholangiocarcinoma are closely related to the dysregulation of transcription factors which promote cell proliferation, invasion, migration, angiogenesis, and drug resistance through reprogrammed transcriptional networks. It is of great significance to further explore and summarize the role of transcription factors in cholangiocarcinoma. AREAS COVERED This review summarizes the oncogenic or tumor suppressive roles of key transcription factors in regulating cholangiocarcinoma progression and the potential targeting strategies of transcription factors in cholangiocarcinoma. EXPERT OPINION Cholangiocarcinoma is a type of cancer highly influenced by transcriptional regulation, specifically transcription factors and epigenetic regulatory factors. Targeting transcription factors could be a potential and important strategy that is likely to impact future cholangiocarcinoma treatment.
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Affiliation(s)
- Jiao Wang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fujing Ge
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tao Yuan
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Meijia Qian
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fangjie Yan
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- The Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hong Zhu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- The Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Albendazole-induced autophagy blockade contributes to elevated apoptosis in cholangiocarcinoma cells through AMPK/mTOR activation. Toxicol Appl Pharmacol 2022; 454:116214. [PMID: 36055539 DOI: 10.1016/j.taap.2022.116214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 08/17/2022] [Accepted: 08/25/2022] [Indexed: 12/09/2022]
Abstract
Albendazole (ABZ) is a broad-spectrum anti-parasitic drug that exhibits antitumor effects against several carcinomas. The effects of ABZ on cholangiocarcinoma (CCA) and its underlying mechanisms are still unclear. Our study aims to investigate the role of ABZ in inducing autophagy-mediated apoptosis of cholangiocarcinoma cells. The antitumor effects of ABZ were evaluated against CCA cells and HIBEC intrahepatic biliary epithelial cells. Furthermore, the apoptosis rates, and autophagy flux in RBE and FRH-0201 cells treated with ABZ were investigated. ABZ inhibited proliferation, induced cell death and apoptosis in CCA cells in vitro. In vivo, tumors from ABZ- treated BALB/c nude mice were significantly smaller than untreated mice. ABZ also induced the initiation of autophagy via AMPK/mTOR pathways, resulting in the formation of autophagosome. In addition, ABZ blocked autophagic flux by inhibiting the fusion of autophagosome-lysosome, which increased the apoptotic death of CCA cells. However, the apoptotic death of CCA cells induced by ABZ was reversed by 3-methyladenine (3-MA), an autophagosome formation inhibitor, but increased by chloroquine (CQ), an autophagosome-lysosome fusion inhibitor.Our work provides novel mechanisms for anti-tumor effects of ABZ on CCA, suggesting that ABZ may be used as a potent autophagy inhibitor in the treatment of CCA.
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Kang MJ, Lim J, Han SS, Park HM, Kim SW, Lee WJ, Woo SM, Kim TH, Won YJ, Park SJ. Distinct prognosis of biliary tract cancer according to tumor location, stage, and treatment: a population-based study. Sci Rep 2022; 12:10206. [PMID: 35715440 PMCID: PMC9205970 DOI: 10.1038/s41598-022-13605-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 03/29/2022] [Indexed: 01/06/2023] Open
Abstract
Biliary tract cancer (BTC) has been inconsistently identified according to its location in epidemiological and clinical studies. This study retrospectively reviewed the treatment pattern and prognosis of BTC according to tumor location using the Korea Central Cancer Registry data of 97,676 patients with BTC from 2006 to 2017. The proportion of localized and regional Surveillance, Epidemiology, and End Results (SEER) stage was the highest in ampulla of Vater (AoV, 78.2%) cancer, followed by extrahepatic bile duct (BD, 68.3%), gallbladder (GB, 52.6%), and intrahepatic BD (49.5%) cancers. Overall, the "no active anti-cancer treatment" rate was the highest in intrahepatic BD (52.8%), followed by extrahepatic BD (49.5%), GB (39.6%), and AoV cancers (28.9%). The 5-year relative survival rate was the highest in AoV (48.5%), followed by GB (28.5%), extrahepatic BD (19.9%), and intrahepatic BD (10.8%) cancers, which significantly improved over time, except for intrahepatic BD cancer. In the localized and regional stage, older patients had a higher risk of receiving no active anti-cancer treatment in each tumor location after adjusting for period and sex. BTC statistics should be reported separately according to tumor location due to its distinct SEER stage distribution, treatment pattern, and prognosis. Care should be taken in elderly patients to reduce the rate of no active anti-cancer treatment.
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Affiliation(s)
- Mee Joo Kang
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
- Division of Cancer Registration and Surveillance, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-Si, Gyeonggi-do, 10408, Republic of Korea
- Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Jiwon Lim
- Division of Cancer Registration and Surveillance, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-Si, Gyeonggi-do, 10408, Republic of Korea
| | - Sung-Sik Han
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Hyeong Min Park
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Sun-Whe Kim
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Woo Jin Lee
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Sang Myung Woo
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Tae Hyun Kim
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Young-Joo Won
- Division of Cancer Registration and Surveillance, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-Si, Gyeonggi-do, 10408, Republic of Korea.
- Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
- Division of Health Administration, Yonsei University, Wonju, Republic of Korea.
| | - Sang-Jae Park
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
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He YT, Huang XH, Fang YY, Zeng QS, Li LD, Luo L, Lai YS. Cost-effectiveness evaluation of different control strategies for Clonorchis sinensis infection in a high endemic area of China: A modelling study. PLoS Negl Trop Dis 2022; 16:e0010429. [PMID: 35605030 PMCID: PMC9166357 DOI: 10.1371/journal.pntd.0010429] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 06/03/2022] [Accepted: 04/18/2022] [Indexed: 11/21/2022] Open
Abstract
Clonorchiasis is an important food-borne parasitic disease caused by Clonorchis sinensis infection. The evaluation of long-term cost-effectiveness of control strategies is important for disease control and prevention. The present study aimed to assess the cost-effectiveness of the three recommended strategies (i.e., WHO, Chinese and Guangdong strategies) and different combinations of commonly used measures (i.e., preventive chemotherapy, information, education, and communication (IEC) and environmental improvement) on clonorchiasis. The study area, Fusha town in Guangdong Province, was a typical high endemic area in China. The analysis was based on a multi-group transmission model of C. sinensis infection. We set the intervention duration for 10 years and post-intervention period for 50 years. The corresponding costs and DALYs were estimated. Strategies with incremental cost-effectiveness ratios (ICERs) less than 1/5 of the willingness-to-pay threshold were identified as highly cost-effective strategies. The optimal control strategy was obtained using the next best comparator method. The ICERs of Guangdong strategy were $172 (95% CI: $143-$230) US for praziquantel and $106 (95% CI: $85-$143) US for albendazole, suggesting the highest cost-effectiveness among the three recommended strategies. For praziquantel, 470 sets of control strategies were identified as highly cost-effective strategies for achieving infection control (prevalence<5%). The optimal strategy consisted of chemotherapy targeted on at-risk population, IEC and environmental improvement, with coverages all being 100%, and with the ICER of $202 (95% CI: $168-$271) US. The results for transmission control (prevalence<1%) and albendazole were obtained with the same procedures. The findings may help to develop control policies for C. sinensis infection in high endemic areas. Moreover, the method adopted is applicable for assessment of optimal strategies in other endemic areas. Clonorchiasis, a food-borne trematodiases, affects millions of people in Asia. Highly cost-effective control strategies are critical for its control. Previous studies considering the economic evaluation of control strategies were rare, mostly based on interventions in practical, and not capable of evaluating long-term cost-effectiveness of strategies with possible combinations of control measures or under various coverages. Based on a dynamic, multi-group transmission model, we simulated different control strategies in a high clonorchiasis endemic area, and evaluated their cost-effectiveness. Among the three recommended strategies (i.e., WHO, Chinese and Guangdong strategies), the Guangdong strategy was the most cost-effective. For praziquantel, 470 sets of control strategies were identified as highly cost-effective strategies for achieving infection control (prevalence<5%) among the strategies of possible combinations of the three common measures (i.e., preventive chemotherapy, information, education, and communication (IEC) and environmental modification). The optimal strategy consisted of chemotherapy targeted on at-risk population, IEC and environmental improvement, with coverages all being 100%. The results for transmission control (prevalence<1%) and albendazole were obtained with the same procedures. The numerical results may help to develop control strategies for C. sinensis infection in high endemic areas. The methodology is applicable for other different endemic areas.
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Affiliation(s)
- Yun-Ting He
- Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Xiao-Hong Huang
- Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China
- Statistics Office of network data information department, the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Yue-Yi Fang
- Institute of Parasitic Diseases, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, Guangdong Province, People’s Republic of China
| | - Qing-Sheng Zeng
- Xinhui District Center for Disease Control and Prevention, Jiangmen City, Guangdong Province, People’s Republic of China
| | - Lai-De Li
- Xinhui District Center for Disease Control and Prevention, Jiangmen City, Guangdong Province, People’s Republic of China
| | - Le Luo
- Zhongshan Center for Disease Control and Prevention, Zhongshan, Guangdong Province, People’s Republic of China
| | - Ying-Si Lai
- Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China
- Sun Yat-sen Global Health Institute, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China
- * E-mail:
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Deenonpoe R, Sa-Ngiamwibool P, Watcharadetwittaya S, Thanee M, Intuyod K, Kongpan T, Padthaisong S, Nutalai R, Chamgramol Y, Pairojkul C. Fluorescence in situ hybridization detection of chromosome 7 and/or 17 polysomy as a prognostic marker for cholangiocarcinoma. Sci Rep 2022; 12:8441. [PMID: 35589822 PMCID: PMC9119972 DOI: 10.1038/s41598-022-11945-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 05/03/2022] [Indexed: 11/09/2022] Open
Abstract
Cholangiocarcinoma (CCA) is highly endemic in the Northeast Thailand. Recently, chromosome aberrations provided new insights into pathogenesis of CCA. Therefore, chromosome aberration might be used as a prognostic factor and therapeutic planning of this cancer. This aim of this study is to examine the correlation between an increase of chromosome 7 (C7) and/or 17 (C17) copy number variants (CNVs) with clinicopathological data and the overall survival time (OS) of CCA patients using fluorescence in situ hybridization (FISH) assays. C7 and C17 CNVs were examined using FISH form 157 formalin-fixed paraffin-embedded (FFPE) tissues of CCA patients from Khon Kaen, Thailand between 2011 and 2015. OS was visualized using Kaplan-Meier plot. Univariate and multivariate analyses were used to determine the ability of the clinicopathological parameters to predict OS. C17 > trisomy (odd ratio, 6.944, P < 0.001), C7/17 trisomy (odd ratio; 4.488, P = 0.019), and C7/17 > trisomy (odd ratio; 6.723, P < 0.001) were independently predictive factors for lymph node metastasis. Interestingly, an increase of C7, C17, and C7/17 CNVs in both trisomy and > trisomy was independently correlated with short median OS. An increased of C7 and/or 17 have a potential as a poor prognostic marker in CCA patients.
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Affiliation(s)
- Raksawan Deenonpoe
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand. .,Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand.
| | - Prakasit Sa-Ngiamwibool
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
| | - Sasithorn Watcharadetwittaya
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
| | - Malinee Thanee
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
| | - Kitti Intuyod
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand
| | - Thachanan Kongpan
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand
| | - Sureerat Padthaisong
- Faculty of Allied Health Sciences, Burapha University, Chonburi, 20131, Thailand
| | - Rungtiwa Nutalai
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand.,Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Yaovalux Chamgramol
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraparp Road, Muang District, Khon Kaen, 40002, Thailand
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Chen M, Li Y, Ma N, Zang J. Mesenchymal stem cell‑derived exosomes loaded with 5‑Fu against cholangiocarcinoma in vitro. Mol Med Rep 2022; 25:213. [PMID: 35543159 PMCID: PMC9133964 DOI: 10.3892/mmr.2022.12729] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 04/19/2022] [Indexed: 11/06/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an intractable malignant tumour with a high degree of malignancy that is asymptomatic in the early stages. Exosomes have been shown in numerous studies in recent years to be effective delivery vehicles for chemotherapy drugs to suppress tumour proliferation and growth in vivo and in vitro. In order to explore the inhibition of 5-fluorouracil (5-Fu)-loaded exosomes on CCA growth, the present study used human bone marrow mesenchymal stem cell-derived exosomes, as well as incubation and sonication methods for 5-Fu loading into exosomes, to treat CCA in vitro. The findings demonstrated that exosomes isolated from mesenchymal stem cells have typical exosome characteristics. Both the incubation and sonication methods successfully loaded 5-Fu into the exosomes (5-Fu-Exos), with the sonication method having a higher loading efficiency than the incubation method. When compared to the free 5-Fu group, the 5-Fu-Exos group significantly inhibited the viability of CCA cells (P<0.01), indicating that 5-Fu-Exos can be an effective chemotherapy drug for CCA treatment.
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Affiliation(s)
- Mingzheng Chen
- Department of Medicine, Graduate School, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Yangyang Li
- Department of Medicine, Graduate School, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Ningfu Ma
- Department of Medicine, Graduate School, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Jinfeng Zang
- Department of Hepatobiliary Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of The Medical School of Nantong University, Taizhou, Jiangsu 225300, P.R. China
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Baria K, De Toni EN, Yu B, Jiang Z, Kabadi SM, Malvezzi M. Worldwide Incidence and Mortality of Biliary Tract Cancer. GASTRO HEP ADVANCES 2022; 1:618-626. [PMID: 39132071 PMCID: PMC11307584 DOI: 10.1016/j.gastha.2022.04.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 04/12/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Biliary tract cancer (BTC) consists of a group of hepatic and perihepatic tumors that are in close proximity but are anatomically different, including gallbladder cancer (GBC), cholangiocarcinoma (extrahepatic and intrahepatic [ICC]), and ampulla of Vater cancer (AVC). Most epidemiologic research has focused on 1 or more anatomic subtypes, or does not differentiate BTC from hepatocellular carcinoma or other primary liver cancers. Here, we provide a descriptive update on global incidence and mortality rates for BTC, overall and by anatomic subtypes. Methods Age-standardized rates (per 100,000 person-years) were derived from the International Agency for Research on Cancer, Cancer Incidence in Five Continents, Volume XI (2008-2012; 22 countries), and the World Health Organization Mortality Database (2006-2016; 38 countries). Results BTC incidence varied by country, with the highest in Chile (14.35) and the lowest in Vietnam (1.25). Mortality rates for BTC were highest for the Republic of Korea (11.64) and lowest for the Republic of Moldova (1.65). BTC mortality rates increased over time in 24 of 34 countries. Patients aged ≥75 years had 5-10 times higher mortality rates than the overall BTC rate in all countries. In most countries, incidence rates were highest for GBC, and mortality rates highest for ICC, while both were lowest for AVC. Females had and died from GBC more frequently than males. For ICC, extrahepatic cholangiocarcinoma, and AVC, males trended toward higher incidence and mortality rates. Conclusion The increasing incidence and mortality trends reported here indicate a need for improved prevention and treatment for all BTC subtypes.
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Affiliation(s)
- Katherine Baria
- Global Medical Affairs, AstraZeneca Pharmaceuticals, Gaithersburg, Maryland
| | - Enrico N. De Toni
- Department of Internal Medicine II, Ludwig Maximilian University of Munich, München, Germany
| | - Binbing Yu
- Oncology Biometrics, AstraZeneca Pharmaceuticals, Gaithersburg, Maryland
| | - Zhuoxin Jiang
- Epidemiology and Real-World Evidence, AstraZeneca Pharmaceuticals, Gaithersburg, Maryland
| | - Shaum M. Kabadi
- Epidemiology and Real-World Evidence, AstraZeneca Pharmaceuticals, Gaithersburg, Maryland
| | - Matteo Malvezzi
- Department of Clinical Medicine and Community Health, University of Milan, Milan, Italy
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Progression of intraductal papillary neoplasm of the bile duct (IPNB): A proposed model through the observation of patients with non-resected tumors. Ann Hepatol 2022; 23:100299. [PMID: 33378705 DOI: 10.1016/j.aohep.2020.100299] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/11/2020] [Accepted: 11/23/2020] [Indexed: 02/04/2023]
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Dana P, Kariya R, Lert-itthiporn W, Seubwai W, Saisomboon S, Wongkham C, Okada S, Wongkham S, Vaeteewoottacharn K. Homophilic Interaction of CD147 Promotes IL-6-Mediated Cholangiocarcinoma Invasion via the NF-κB-Dependent Pathway. Int J Mol Sci 2021; 22:13496. [PMID: 34948304 PMCID: PMC8706168 DOI: 10.3390/ijms222413496] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA), an aggressive cancer of bile ducts, is a well-known chronic inflammation-related disease. The major impediment in CCA treatment is limited treatment options for advanced disease; hence, an alternative is urgently required. The role of CD147 on cytokine production has been observed in inflammation-related diseases, but not in CCA. Therefore, this study was focused on CD147-promoting proinflammatory cytokine production and functions. Proinflammatory cytokine profiles were compared between CD147 expressing CCA cells and CD147 knockout cells (CD147 KO). Three cytokines, namely interleukin (IL)-6, IL-8, and granulocyte-monocyte colony-stimulating factor (GM-CSF), were dramatically diminished in CD147 KO clones. The involvement of the CD147-related cytokines in CCA invasion was established. CD147-promoted IL-6, IL-8, and GM-CSF secretions were regulated by NF-κB nuclear translocation, Akt activation, and p38 phosphorylation. CD147-fostering IL-6 production was dependent on soluble CD147, CD147 homophilic interaction, and NF-κB function. The overexpression of specific genes in CCA tissues compared to normal counterparts emphasized the clinical importance of these molecules. Altogether, CD147-potentiated proinflammatory cytokine production leading to CCA cell invasion is shown for the first time in the current study. This suggests that modulation of CD147-related inflammation might be a promising choice for advanced CCA treatment.
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Affiliation(s)
- Paweena Dana
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Ryusho Kariya
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| | - Worachart Lert-itthiporn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Wunchana Seubwai
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Saowaluk Saisomboon
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| | - Chaisiri Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.D.); (W.L.-i.); (S.S.); (C.W.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand;
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; (R.K.); (S.O.)
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Jayaraman PS, Gaston K. Targeting protein kinase CK2 in the treatment of cholangiocarcinoma. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:434-447. [PMID: 36045705 PMCID: PMC9400764 DOI: 10.37349/etat.2021.00055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/31/2021] [Indexed: 12/23/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a disease with a very poor prognosis and limited treatment options. Although targeted therapies directed towards specific mutations found in CCA are becoming available and are showing great potential, many tumors do not carry actionable mutations and, in those that do, the emergence of drug resistance is a likely consequence of treatment. Therapeutic targeting of enzymes and other proteins that show elevated activity in CCA cells but which are not altered by mutation is a potential strategy for the treatment of target negative and drug-resistant disease. Protein kinase CK2 (CK2) is a ubiquitously expressed kinase that has increased expression and increased activity in a variety of cancer types including CCA. Several potent CK2 inhibitors are in pre-clinical development or under assessment in a variety of clinical trials often in combination with drugs that induce DNA damage. This review outlines the importance of CK2 in CCA and assesses the progress that has been made in the evaluation of CK2 inhibition as a treatment strategy in this disease. Targeting CK2 based on the expression levels or activity of this protein and/or in combination with drugs that induce DNA damage or inhibit cell cycle progression, could be a viable option for tumors that lack actionable mutations, or for tumors that develop resistance to targeted treatments.
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Affiliation(s)
- Padma-Sheela Jayaraman
- Biodiscovery Institute, University of Nottingham, NG7 2UH, UK
- Division of Translational Medical Sciences, School of Medicine, University of Nottingham, NG7 2UH, UK
| | - Kevin Gaston
- Biodiscovery Institute, University of Nottingham, NG7 2UH, UK
- Division of Translational Medical Sciences, School of Medicine, University of Nottingham, NG7 2UH, UK
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Ben Khaled N, Jacob S, Rössler D, Bösch F, De Toni EN, Werner J, Ricke J, Mayerle J, Seidensticker M, Schulz C, Fabritius MP. Current State of Multidisciplinary Treatment in Cholangiocarcinoma. Dig Dis 2021; 40:581-595. [PMID: 34695826 DOI: 10.1159/000520346] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 10/19/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a highly aggressive malignancy, and its incidence seems to be increasing over the last years. Given the high rate of irresectability at the time of initial diagnosis, new treatment approaches are important to achieve better patient outcomes. Our review provides an overview of current multimodal therapy options across different specialties of gastroenterology/oncology, surgery, and interventional radiology. SUMMARY CCA is subdivided into clinically and molecularly distinct phenotypes. Surgical treatment currently is the only potentially curative therapy, but unfortunately, the majority of all patients are not eligible for resection at the time of initial diagnosis due to anatomic location, inadequate hepatic reserve, metastatic disease, or limiting comorbidities. However, multimodal treatment options are available to prolong survival, relieve symptoms, and maintain life quality. KEY MESSAGES The treatment of CCA is complex and requires close interdisciplinary collaboration and individualized treatment planning to ensure optimal patient care at specialized centers. Molecular profiling of patients and inclusion into clinical trials is highly recommended.
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Affiliation(s)
- Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Sven Jacob
- Department of General-, Visceral- and Transplantation-Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Daniel Rössler
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Florian Bösch
- Department of General-, Visceral- and Transplantation-Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Enrico N De Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Jens Werner
- Department of General-, Visceral- and Transplantation-Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Christian Schulz
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
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Songjang W, Nensat C, Pongcharoen S, Jiraviriyakul A. The role of immunogenic cell death in gastrointestinal cancer immunotherapy (Review). Biomed Rep 2021; 15:86. [PMID: 34512974 PMCID: PMC8411483 DOI: 10.3892/br.2021.1462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/30/2021] [Indexed: 12/24/2022] Open
Abstract
Modern cancer immunotherapy techniques are aimed at enhancing the responses of the patients' immune systems to fight against the cancer. The main promising strategies include active vaccination of tumor antigens, passive vaccination with antibodies specific to cancer antigens, adoptive transfer of cancer-specific T cells and manipulation of the patient's immune response by inhibiting immune checkpoints. The application of immunogenic cell death (ICD) inducers has been proven to enhance the immunity of patients undergoing various types of immunotherapy. The dying, stressed or injured cells release or present molecules on the cell surface, which function as either adjuvants or danger signals for detection by the innate immune system. These molecules are now termed 'damage-associated molecular patterns'. The term 'ICD' indicates a type of cell death that triggers an immune response against dead-cell antigens, particularly those derived from cancer cells, and it was initially proposed with regards to the effects of anticancer chemotherapy with conventional cytotoxic drugs. The aim of the present study was to review and discuss the role and mechanisms of ICD as a promising combined immunotherapy for gastrointestinal tumors.
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Affiliation(s)
- Worawat Songjang
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Chatchai Nensat
- Biomedical Sciences, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Sutatip Pongcharoen
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand
| | - Arunya Jiraviriyakul
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
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Boottanun P, Ino Y, Shimada K, Hiraoka N, Angata K, Narimatsu H. Association between the expression of core 3 synthase and survival outcomes of patients with cholangiocarcinoma. Oncol Lett 2021; 22:760. [PMID: 34539864 PMCID: PMC8436361 DOI: 10.3892/ol.2021.13021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 08/04/2021] [Indexed: 02/04/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive and metastatic type of malignant carcinoma that is associated with high mortality rates and is difficult to detect at early stages. Core 3 structure is a mucin-type O-glycans synthesized by β1,3-N-acetylglucosaminyltransferase 6 (core 3 synthase), which plays an important role in the digestive system, in particular gastrointestinal goblet cells. It has been reported that core 3 synthase-expressing cells show lower migratory and invasive rates, and lower metastatic activity. A immunohistochemical study also showed that this enzyme was expressed in normal epithelial cells of the colon, but completely disappeared in colorectal cancer cells. The present study aimed to identify biomarkers that could be used to predict the prognosis of patients with CCA. Pathological specimens of 185 CCA tissues were immunohistochemically stained with two antibodies, G8-144 and MECA-79, which recognize core 3 synthase and 6-sulfated N-acetyllactosamine on the extended core-1 O-glycans, respectively. The association between G8-144 or MECA-79 positivity and patient prognosis was statistically analyzed. Positive expression of G8-144 was associated with improved prognosis in patients with distal CCA (dCCA). Patients with dCCA positive for G8-144 showed lower mortality rates than those with negative expression. However, the positive expression of MECA-79 was associated with CCA progression and metastasis, indicating that it is a poor prognostic marker for CCA. In conclusion, as both antibodies resulted in mirror-image staining, the involvement of G8-144 and MECA-79 in O-glycan synthesis could be considered as potential favorable and unfavorable biomarkers, respectively, for CCA prognosis.
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Affiliation(s)
- Patcharaporn Boottanun
- Graduate School of Comprehensive Human Sciences, Major in Medical Sciences, Clinical Sciences Program, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.,Molecular and Cellular Glycoproteomics Research Group, Department of Life Science and Biotechnology, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8565, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
| | - Yoshinori Ino
- Division of Molecular Pathology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
| | - Kazuaki Shimada
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan
| | - Nobuyoshi Hiraoka
- Division of Molecular Pathology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.,Department of Analytical Pathology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
| | - Kiyohiko Angata
- Molecular and Cellular Glycoproteomics Research Group, Department of Life Science and Biotechnology, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8565, Japan
| | - Hisashi Narimatsu
- Graduate School of Comprehensive Human Sciences, Major in Medical Sciences, Clinical Sciences Program, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.,Molecular and Cellular Glycoproteomics Research Group, Department of Life Science and Biotechnology, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8565, Japan
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Jala I, Almanfaluthi ML, Laha T, Kanthawong S, Tangkawattana S, Saichua P, Suttiprapa S, Sripa B. Helicobacter pylori GroEL Seropositivity Is Associated with an Increased Risk of Opisthorchis viverrini-Associated Hepatobiliary Abnormalities and Cholangiocarcinoma. THE KOREAN JOURNAL OF PARASITOLOGY 2021; 59:363-368. [PMID: 34470087 PMCID: PMC8413853 DOI: 10.3347/kjp.2021.59.4.363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/02/2021] [Indexed: 11/23/2022]
Abstract
Despite the synergistic effect of Opisthorchis viverrini and Helicobacter pylori co-infection on pathogenesis of severe hepatobiliary abnormalities (HBA) including advanced periductal fibrosis and replace with cholangiocarcinoma (CCA) have been established, the immune response to H. pylori in O. viverrini infected population has never been explored. Hence, this study aimed to investigate the antibody responses to 2 immunogenic H. pylori proteins in O. viverrini-infected patients with HBA and CCA. The risk analysis by multinomial logistic regression revealed that GroEL seropositivity was associated with higher risks of hepatobiliary abnormalities and CCA with adjusted odds ratios (95% confidence intervals) of 2.11 (95% CI=1.20-3.71, P=0.008) and 2.13 (95% CI=1.21-3.75, P=0.009), respectively. These findings indicate that GroEL seropositivity might be a biomarker for early detection of O. viverrini associated HBA and CCA.
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Affiliation(s)
- Isabelle Jala
- Tropical Medicine Graduate Program (International Program), Academic Affairs, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Muhammad Luthfi Almanfaluthi
- Tropical Medicine Graduate Program (International Program), Academic Affairs, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Thewarach Laha
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sakawrat Kanthawong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sirikachorn Tangkawattana
- WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Department of Pathobiology, Faculty of Veterinary Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Prasert Saichua
- Tropical Medicine Graduate Program (International Program), Academic Affairs, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sutas Suttiprapa
- Tropical Medicine Graduate Program (International Program), Academic Affairs, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Banchob Sripa
- WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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49
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Infrahepatic Inferior Vena Cava Clamping Reduces Blood Loss during Liver Transection for Cholangiocarcinoma. Int J Hepatol 2021; 2021:1625717. [PMID: 34484836 PMCID: PMC8413082 DOI: 10.1155/2021/1625717] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/14/2021] [Accepted: 08/04/2021] [Indexed: 11/17/2022] Open
Abstract
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.
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50
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Janthamala S, Jusakul A, Kongpetch S, Kimawaha P, Klanrit P, Loilome W, Namwat N, Techasen A. Arctigenin inhibits cholangiocarcinoma progression by regulating cell migration and cell viability via the N-cadherin and apoptosis pathway. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:2049-2059. [PMID: 34283274 DOI: 10.1007/s00210-021-02123-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/02/2021] [Indexed: 12/28/2022]
Abstract
Northeast Thailand has the highest incidence of cholangiocarcinoma (CCA) in the world. The lack of promising diagnostic markers and appropriate therapeutic drugs is the main problem for metastatic stage CCA patients who have a poor prognosis. N-cadherin, a cell adhesion molecule, is usually upregulated in cancers and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT), one of the metastasis processes. Additionally, it has been shown that arctigenin, a seed isolated compound from Arctium lappa, can inhibit cancer cell progression via suppression of N-cadherin pathway. In this study, we investigated the protein expression of N-cadherin and its correlation with clinicopathological data of CCA patients, as well as the impact of arctigenin on KKU-213A and KKU-100 CCA cell lines and its underlying mechanisms. Immunohistochemistry results demonstrated that high expression of N-cadherin was significantly associated with severe CCA stage (p = 0.027), and shorter survival time (p = 0.002) of CCA patients. The mean overall survival times between low and high expression of N-cadherin were 31.6 and 14.8 months, respectively. Wound healing assays showed that arctigenin significantly inhibited CCA cell migration by downregulating N-cadherin whereas upregulating E-cadherin expression. Immunocytochemical staining revealed that arctigenin suppressed the expression of N-cadherin in both CCA cell lines. Furthermore, flow cytometry and western blot analysis revealed that arctigenin significantly reduced CCA cell viability and induced apoptosis via the Bax/Bcl-2/caspase-3 pathway. This research supports the use of N-cadherin as a prognostic marker for CCA and arctigenin as a potential alternative therapy for improving CCA treatment outcomes.
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Affiliation(s)
- Sutthiwan Janthamala
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Sarinya Kongpetch
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Phongsaran Kimawaha
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Poramate Klanrit
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Nisana Namwat
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
- Department of Clinical Microbiology, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
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