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Zhang P, Liu X, Liu Y, Zhu H, Zheng C, Ling Q, Yan F, He Q, Zhu H, Yuan T, Yang B. VCP Promotes Cholangiocarcinoma Development by Mediating BAP1 Ubiquitination-Dependent Degradation. Cancer Sci 2025. [PMID: 40122668 DOI: 10.1111/cas.70061] [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: 10/31/2024] [Revised: 03/07/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025] Open
Abstract
Cholangiocarcinoma (CCA), recognized for its high malignancy, has been an enormous challenge due to lacking effective treatment therapy over the past decades. Recently, the targeted therapies, such as Pemigatinib and Ivosidenib, have provided new treatment options for patients carrying fibroblast growth factor receptor (FGFR) and isocitrate dehydrogenase 1/2 (IDH1/2) mutations, but only ~30% of patients harbor these mutants; it is urgent to explore novel targets and therapeutic therapies. The frequent downregulation of BAP1 has been observed in CCA, and the low expression of BAP1 is closely related to the poor prognosis of CCA. However, there are no effective interventions to re-activate BAP1 protein; blocking its degradation may provide a feasible strategy for BAP1-downregulation CCA treatment. In this study, we demonstrated the tumor-suppressive roles of BAP1 in CCA and identified VCP functions as the key upstream regulator mediated by BAP1 protein homeostasis. Mechanistically, VCP binds to BAP1 and promotes the latter's ubiquitination degradation via the ubiquitin-proteasome pathway, thus promoting cell proliferation and inhibiting cell apoptosis. Moreover, we found that VCP inhibitors inhibited CCA cell growth and promoted cell apoptosis by blocking BAP1 ubiquitination degradation. Collectively, our findings not only provided a novel mechanism underlying the aberrant low expression of BAP1 in CCA but also verified the anti-tumor effect of VCP inhibitors in CCA, offering a novel therapeutic target for CCA treatment.
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Affiliation(s)
- Peiying Zhang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiangning Liu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yue Liu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hongdao Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Churun Zheng
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qi Ling
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fangjie Yan
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Tao Yuan
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
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Armartmuntree N, Kittirat Y, Promraksa B, Loilome W, Dokduang H, Techasen A, Sansomchai P, Thanee M, O’Connor T, Kongthitilerd P, Padthaisong S. Antioxidative and anticancer effects of Tacca chantrieri extract enhancing cisplatin sensitivity in cholangiocarcinoma cells. PLoS One 2025; 20:e0317111. [PMID: 39820585 PMCID: PMC11737735 DOI: 10.1371/journal.pone.0317111] [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: 06/20/2024] [Accepted: 12/22/2024] [Indexed: 01/19/2025] Open
Abstract
Cholangiocarcinoma (CCA) poses a significant healthcare challenge due to the limited effects of chemotherapeutic drugs. Natural products have gained widespread attention in cancer research according to their promising anti-cancer effects with minimal adverse side effects. This study explored the potential of Tacca chantrieri (TC), a plant rich in bioactive compounds, as a therapeutic agent for CCA. TC, a traditional remedy in Southeast Asia, exhibits anti-inflammatory and cytotoxic properties against cancer cells. Ethanol extraction of TC's rhizome was conducted, and antioxidant activities were assessed through various assays, including total phenolic and flavonoid contents, DPPH radical scavenging, and FRAP assays. The cytotoxic effects of TC extracts on CCA cell lines (KKU-213A and KKU-213C) were evaluated using MTT assays and flow cytometry. Protein levels of Bax and Bcl-2 were determined through western blot analysis. Additionally, the study investigated whether the combined impact of TC extract and cisplatin on CCA cells enhanced cisplatin's efficacy as an anti-cancer treatment. Results indicated that ethanolic extracts from TC contained phenolic and flavonoid compounds with robust antioxidant activity. TC treatments reduce CCA cell viability, inhibiting growth and inducing apoptosis in a dose-dependent manner. The Bax/Bcl-2 ratio increases, signifying a pro-apoptotic shift. Importantly, TC extract not only decreases cell viability but also augments the inhibitory effect of cisplatin in CCA cells. These results provide valuable insights into TC's therapeutic mechanisms and its potential to synergize with conventional chemotherapeutic agents, offering a promising avenue for the development of alternative and more effective strategies for CCA treatment.
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Affiliation(s)
- Napat Armartmuntree
- Department of Medical Science, Amnatcharoen Campus, Mahidol University, Amnat Charoen, Thailand
| | - Yingpinyapat Kittirat
- Department of Medical Sciences, Regional Medical Sciences Center 2 Phitsanulok, Ministry of Public Health, Mueang District, Phitsanulok Province, Thailand
| | - Bundit Promraksa
- Department of Medical Sciences, Regional Medical Sciences Center 2 Phitsanulok, Ministry of Public Health, Mueang District, Phitsanulok Province, Thailand
| | - Watcharin Loilome
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
| | - Hasaya Dokduang
- Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
- Faculty of Medicine, Mahasarakham University, Mahasarakham, Thailand
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
- Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | | | - Malinee Thanee
- Cholangiocarcinoma Research Institute (CARI), Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Thomas O’Connor
- School of Physiology, Pharmacology and Neuroscience, Bristol University, Bristol, United Kingdom
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Filippi R, Brandi G, Casadei-Gardini A, Leone F, Silvestris N, Satolli MA, Salani F, Sperti E, Lutrino SE, Aprile G, Santini D, Scartozzi M, Faloppi L, Palloni A, Deserti M, Tavolari S, Rimini M, Brunetti O, Spadi R, Ilaria D, Di Maio M. Viral Hepatitis in Western Patients with Advanced Intrahepatic Cholangiocarcinoma: Retrospective Assessment of Prevalence, Prognostic and Predictive Significance. Cancer Invest 2025; 43:59-69. [PMID: 39601419 DOI: 10.1080/07357907.2024.2432013] [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: 03/14/2024] [Revised: 10/29/2024] [Accepted: 11/17/2024] [Indexed: 11/29/2024]
Abstract
Despite a biologically established causative role of viral hepatitis (VH), i.e. HBV and HCV infections, on intrahepatic cholangiocarcinoma (ICC), only few large Western cohorts exploring the association between VH and ICC development are available. The prognostic significance of VH in ICC is debated, and no data are available regarding a predictive role for standard first-line CT (CT1), consisting of gemcitabine +/- platinoids. VH-positivity definition is often clinically incomplete and inconsistent among studies. Five different VH conditions, based on laboratory and anamnestic data, were investigated in a multicentric retrospective cohort of advanced ICC cases. Depending on the specific VH condition considered, 139-194 of 472 ICC cases could be categorized according to the presence of the mentioned VH conditions. VH prevalence ranged from 9.3 to 25.3%. No VH condition showed an impact on survival, although a non-significant worse outcome was observed for some HBV-related conditions. HCV-related conditions were associated to lower pre-CT1 biomarkers of inflammation, markedly higher disease control, and numerically longer time-to-progression with CT1. No benefit on time-to-progression was demonstrated for the addition of platinoids to gemcitabine in VH-positive patients (HR 0.77, CI95% 0.41-1.45), at least in HBV-related cases. These findings are clinically relevant and deserve further investigation.
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Affiliation(s)
- Roberto Filippi
- Department of Oncology, University of Turin, Torino, Italy
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesco Leone
- Department of Oncology, ASL BI, Ospedale degli Infermi di Biella, Ponderano, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - Maria Antonietta Satolli
- Department of Oncology, University of Turin, Torino, Italy
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Francesca Salani
- Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Pisa, Italy
- Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy
| | - Elisa Sperti
- Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy
| | | | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | - Daniele Santini
- Medical Oncology A, Policlinico Umberto I, La Sapienza Università di Roma, Rome, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital, Cagliari, Italy
| | - Luca Faloppi
- Medical Oncology Unit, Ospedali "Santa Maria della Pietà" e "Bartolomeo Eustachio", AST di Macerata, Camerino, Italy
| | - Andrea Palloni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marzia Deserti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Simona Tavolari
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Margherita Rimini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Rosella Spadi
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Depetris Ilaria
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Torino, Italy
- Medical Oncology 1U, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
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Shi H, Li Z, Zhu M. Circulating Immune Cells Predict Prognosis and Clinical Response to Chemotherapy in Cholangiocarcinoma. Curr Med Chem 2025; 32:595-607. [PMID: 38698750 DOI: 10.2174/0109298673296618240424095548] [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: 01/04/2024] [Revised: 03/11/2024] [Accepted: 03/18/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND The immune system is linked to the prognosis and response to treatment of patients with cancer. However, the clinical implication of peripheral blood immune cells in cholangiocarcinoma (CCA) remains vague. Thus, we aimed to assess whether peripheral circulating immune cells could be used as an indicator for prognosis and chemotherapeutic efficacy in CCA. METHODS The distributions of immune subsets were analyzed in peripheral blood samples from 141 patients with CCA and 131 healthy volunteers by using flow cytometry. The variation in the subset distribution in the two groups and the relationship between clinicopathological features and the subpopulations were investigated. Meanwhile, we assessed the implications of lymphocyte subsets as predictors of chemotherapy outcomes and overall survival (OS). RESULTS The proportion of total lymphocytes decreased, while the percentages of activated T cells as well as CD4+CD25+ regulatory T cells (Tregs) increased in CCA. Notably, lymphocyte proportion decreased in patients with regional lymph node (N) (p=0.016) and distant metastasis (M) (p= 0.001). Furthermore, our study showed that peripheral blood lymphocyte subsets were significantly correlated with chemotherapy efficacy, with increased proportions of CD3+ cells (p=0.021) and CD4+ cells (p=0.016) in the effective group. Finally, the Kaplan-Meier analysis indicated that patients with high natural killer (NK) cell proportion might have prolonged OS (p = 0.028). CONCLUSION The relationship between circulating immune cells with prognosis and chemotherapy response in patients with CCA highlights their potential application as an indicator of CCA prognosis and stratification of chemotherapy response.
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Affiliation(s)
- Huina Shi
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zhaosheng Li
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Mingchen Zhu
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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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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Sungwan P, Kidoikhammouan S, Thonsri U, Saengboonmee C, Wongkham S, Okada S, Seubwai W. Anti-Tumor and Chemosensitizing Effects of the CDK Inhibitor Dinaciclib on Cholangiocarcinoma In Vitro and In Vivo. In Vivo 2024; 38:2284-2293. [PMID: 39187317 PMCID: PMC11363801 DOI: 10.21873/invivo.13693] [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: 04/17/2024] [Revised: 05/19/2024] [Accepted: 05/29/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND/AIM Cholangiocarcinoma (CCA) is a highly aggressive disease. Most of CCA patients are diagnosed in an advanced stage of the disease, when it is unresectable and there is chemoresistance, resulting in poor prognosis. However, effective therapeutic regimens and molecular targets for CCA remain poor. Cyclin-dependent kinases (CDKs) are key regulatory enzymes in cell cycle progression. Aberrant CDK activation is a hallmark of cancer. Dinaciclib is a small molecule inhibitor of multiple CDKs, currently under clinical evaluation for treating advanced malignancies. The efficacy of anti-tumor activity of dinaciclib against chemotherapy resistant CCA cells was examined in vitro and in vivo. MATERIALS AND METHODS In this study, the effect of dinaciclib on growth and cell cycle in CCA cell lines were determined using the MTT assay and cell cycle analysis. The anti-tumor activity of dinaciclib was investigated in CCA-inoculated mice. In addition, the chemosensitizing effect of dinaciclib was investigated in gemcitabine-treated CCA cell lines. RESULTS Dinaciclib significantly suppressed cell proliferation, induced G1/S phase cell cycle arrest and apoptosis of CCA cell lines. It significantly suppressed the growth of CCA cells in xenograft mouse models. We also found that dinaciclib significantly inhibited the growth of gemcitabine-resistant CCA cell lines (KKU-213A-GemR and KKU-100-GemR). Furthermore, dinaciclib significantly enhanced the anti-tumor activity of gemcitabine in CCA cell lines. CONCLUSION Dinaciclib has the potential to be an effective therapeutic agent to control tumor cell growth of both parental and gemcitabine-resistant CCA cells.
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Affiliation(s)
- Prin Sungwan
- Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | | | - Unchalee Thonsri
- Department of Biochemistry, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan;
| | - Wunchana Seubwai
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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Porreca V, Barbagallo C, Corbella E, Peres M, Stella M, Mignogna G, Maras B, Ragusa M, Mancone C. Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches. Cancers (Basel) 2024; 16:2889. [PMID: 39199659 PMCID: PMC11352949 DOI: 10.3390/cancers16162889] [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: 07/24/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/01/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is recognized worldwide as the second leading cause of morbidity and mortality among primary liver cancers, showing a continuously increasing incidence rate in recent years. iCCA aggressiveness is revealed through its rapid and silent intrahepatic expansion and spread through the lymphatic system leading to late diagnosis and poor prognoses. Multi-omics studies have aggregated information derived from single-omics data, providing a more comprehensive understanding of the phenomena being studied. These approaches are gradually becoming powerful tools for investigating the intricate pathobiology of iCCA, facilitating the correlation between molecular signature and phenotypic manifestation. Consequently, preliminary stratifications of iCCA patients have been proposed according to their "omics" features opening the possibility of identifying potential biomarkers for early diagnosis and developing new therapies based on personalized medicine (PM). The focus of this review is to provide new and advanced insight into the molecular pathobiology of the iCCA, starting from single- to the latest multi-omics approaches, paving the way for translating new basic research into therapeutic practices.
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Affiliation(s)
- Veronica Porreca
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Cristina Barbagallo
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Eleonora Corbella
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Marco Peres
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Michele Stella
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Giuseppina Mignogna
- Department of Biochemistry Science, Sapienza University of Rome, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Bruno Maras
- Department of Biochemistry Science, Sapienza University of Rome, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Marco Ragusa
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Carmine Mancone
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
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Hansen FJ, David P, Weber GF. The Multifaceted Functionality of Plasmacytoid Dendritic Cells in Gastrointestinal Cancers: A Potential Therapeutic Target? Cancers (Basel) 2024; 16:2216. [PMID: 38927922 PMCID: PMC11201847 DOI: 10.3390/cancers16122216] [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: 05/08/2024] [Revised: 06/06/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Gastrointestinal (GI) tumors pose a significant global health burden, necessitating the exploration of novel therapeutic approaches. Plasmacytoid dendritic cells (pDCs) play a crucial role in tumor immunity, exhibiting both anti-tumor and pro-tumor effects. This review aims to summarize the role of pDCs in different types of GI tumors and assess their potential as therapeutic targets. In gastric cancer, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma, increased infiltration of pDCs was associated with a worse outcome, whereas in esophageal cancer, pancreatic cancer, and colorectal cancer, pDC infiltration improved the outcome. Initial animal studies of gastric cancer and hepatocellular carcinoma showed that pDCs could be a successful therapeutic target. In conclusion, pDCs play a multifaceted role in GI tumors, influencing both anti-tumor immunity and tumor progression. Further research is needed to optimize their clinical application and explore combinatorial approaches.
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Affiliation(s)
| | - Paul David
- Department of General and Visceral Surgery, Medical Faculty of Friedrich-Alexander-University Erlangen, University Hospital Erlangen, 91054 Erlangen, Germany;
| | - Georg F. Weber
- Department of General and Visceral Surgery, Medical Faculty of Friedrich-Alexander-University Erlangen, University Hospital Erlangen, 91054 Erlangen, Germany;
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Liu Y, Shen T, Liu J, Yu X, Li Q, Chen T, Jiang T. CFHR1 involvement in bile duct carcinoma: Insights from a data mining study. Anal Biochem 2024; 688:115474. [PMID: 38286352 DOI: 10.1016/j.ab.2024.115474] [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: 09/27/2023] [Revised: 01/25/2024] [Accepted: 01/26/2024] [Indexed: 01/31/2024]
Abstract
The aim of this study is to investigate the role of CFHR1 in bile duct carcinoma (BDC) and its mechanism of action, and we hope that our analysis and research will contribute to a better understanding of cholangiocarcinoma (BDC) disease genesis, progression and the development of new therapeutic strategies. The prognostic receiver operating characteristic curve of CFHR1 was generated using survival ROC. The ROC curve for CFHR1 showed that there is a correlation between CFHR1 expression and clinicopathological parameters and has an impact on poor prognosis. STRING was used to predict the protein-protein interaction network of the identified genes, and the Microenvironment Cell Populations counter algorithm was used to analyze immune cell infiltration within the BDC. The combined analysis showed that CFHR1 was found to be upregulated in BDC tissues, along with a total of 20 related differentially expressed genes (DEGs) (8 downregulated and 12 upregulated genes). Also, the results showed that the expression of CFHR1 is correlated with immune cell infiltration in tumor and immune cell markers in BDC (P < 0.05). In addition, we have verified experimentally the biological function of CFHR1. These findings suggest that CFHR1 may be a prognostic marker and a potential therapeutic target for BDC. Information regarding the detailed roles of CFHR1 in BDC could be valuable for improving the diagnosis and treatment of this rare cancer.
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Affiliation(s)
- Yan Liu
- Oncology Intervention Department, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China; Institute of Tumor Intervention, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 20062, China
| | - Tianhao Shen
- Oncology Intervention Department, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Jianming Liu
- Oncology Intervention Department, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Xue Yu
- Oncology Intervention Department, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Qiuying Li
- Oncology Intervention Department, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Tingsong Chen
- Department of Oncology, Shanghai Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.
| | - Tinghui Jiang
- Oncology Intervention Department, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
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10
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Fu S, Li J, Fan H, Zheng K, Leng B, Cao G, Xu L, Zhong Y, Niu C, Wang X. NLCECA score: a serum inflammatory-tumor biomarker score to predict survival of advanced perihilar cholangiocarcinoma after hepatic arterial infusion chemotherapy. Sci Rep 2024; 14:4466. [PMID: 38395994 PMCID: PMC10891088 DOI: 10.1038/s41598-024-53883-7] [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: 01/18/2023] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Prognostic features in advanced perihilar cholangiocarcinoma (pCCA) patients who received first-line hepatic arterial infusion chemotherapy (HAIC) are unknown. The purpose of our study was to develop an applicable score based on serum inflammatory-tumor biomarkers to predict the survival of advanced pCCA patients who received first-line HAIC. In total, 106 advanced pCCA patients were enrolled as the training cohort. The optimal cutoff values of baseline variables were defined by the receiver operating characteristic method or according to previous publications. According to the results of Cox regression analysis, baseline neutrophil-to-lymphocyte ratio (NLR) > 3.19, carcinoembryonic antigen (CEA) > 10 ng/mL, and carbohydrate antigen 19-9 (CA19-9) > 200 U/mL were identified as independent survival predictors, which were used to develop the NLCECA score (NLR, CEA, and CA19-9). When including the NLCECA score in the multivariate analysis, the NLCECA score was the only independent predictor of survival. The risk of survival decreased by 111.9% for each 1-point increase in the NLCECA score. Additionally, the NLCECA score could also predict survival in another 33 patients in the validation cohort (P < 0.001). In summary, the NLCECA score is a potential biomarker system for predicting the survival of advanced pCCA patients who received first-line HAIC.
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Affiliation(s)
- Shjie Fu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jie Li
- Center for Medical Device Evaluation, National Medical Products Administration, Beijing, 100053, China
| | - Hua Fan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Kanglian Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Boyu Leng
- Hebei North University, Hebei, 075000, China
| | - Guang Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Liang Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yujie Zhong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Chuanxin Niu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xiaodong Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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11
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Sawaisorn P, Gaballa A, Saimuang K, Leepiyasakulchai C, Lertjuthaporn S, Hongeng S, Uhlin M, Jangpatarapongsa K. Human Vγ9Vδ2 T cell expansion and their cytotoxic responses against cholangiocarcinoma. Sci Rep 2024; 14:1291. [PMID: 38221530 PMCID: PMC10788337 DOI: 10.1038/s41598-024-51794-1] [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: 02/13/2023] [Accepted: 01/09/2024] [Indexed: 01/16/2024] Open
Abstract
Human Vγ9Vδ2 T lymphocytes are regarded as promising effector cells for cancer immunotherapy since they have the ability to eliminate several tumor cells through non-peptide antigen recognition. However, the cytotoxic function and the mechanism of Vγ9Vδ2 T cells leading to specific killing of cholangiocarcinoma cells are yet to be confirmed. In this study, we established a protocol for ex vivo expansion of Vγ9Vδ2 T cells from healthy donors' peripheral blood mononuclear cells by culture with zoledronate and addition of IL-2, and IL-15 or IL-18 or neither. Testing the cytotoxic capacity of cultured Vγ9Vδ2 T cells against cholangiocarcinoma cell lines showed higher reactivity than against control cells. Surface expression of CD107 was detected on the Vγ9Vδ2 T cells, suggesting that these cells limit in vitro growth of cholangiocarcinoma cells via degranulation of the perforin and granzyme pathway. Analysis of molecular signaling was used to demonstrate expression of pro- and anti-survival genes and a panel of cytokine genes in Vγ9Vδ2 T cells. We found that in the presence of either IL-15 or IL-18, levels of caspase 3 were significantly reduced. Also, IL-15 and IL-18 stimulated cells contained cytotoxicity against cholangiocarcinoma cells, suggesting that stimulated Vγ9Vδ2 T cells may provide a feasible therapy for cholangiocarcinoma.
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Affiliation(s)
- Piamsiri Sawaisorn
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Ahmed Gaballa
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Kween Saimuang
- Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Chaniya Leepiyasakulchai
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Sakaorat Lertjuthaporn
- Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Suradej Hongeng
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Michael Uhlin
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
- Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Huddinge, Sweden.
| | - Kulachart Jangpatarapongsa
- Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand.
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12
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Wang J, Xia Y, Cao Y, Zeng X, Luo H, Cai X, Shi M, Luo H, Wang D. Safety and feasibility of laparoscopic radical resection for bismuth types III and IV hilar cholangiocarcinoma: a single-center experience from China. Front Oncol 2023; 13:1280513. [PMID: 38188306 PMCID: PMC10766688 DOI: 10.3389/fonc.2023.1280513] [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: 08/20/2023] [Accepted: 11/29/2023] [Indexed: 01/09/2024] Open
Abstract
Background Surgery represents the only cure for hilar cholangiocarcinoma (HC). However, laparoscopic radical resection remains technically challenging owing to the complex anatomy and reconstruction required during surgery. Therefore, reports on laparoscopic surgery (LS) for HC, especially for types III and IV, are limited. This study aimed to evaluate the safety and feasibility of laparoscopic radical surgery for Bismuth types III and IV HC. Methods The data of 16 patients who underwent LS and 9 who underwent open surgery (OS) for Bismuth types III and IV HC at Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, between December 2017 and January 2022 were analyzed. Basic patient information, Bismuth-Corlette type, AJCC staging, postoperative complications, pathological findings, and follow-up results were evaluated. Results Sixteen patients underwent LS and 9 underwent OS for HC. According to the preoperative imaging data, there were four cases of Bismuth type IIIa, eight of type IIIb, and four of type IV in the LS group and two of type IIIa, four of type IIIb, and three of type IV in the OS group (P>0.05). There were no significant differences in age, sex, ASA score, comorbidity, preoperative percutaneous transhepatic biliary drainage rate, history of abdominal surgery, or preoperative laboratory tests between the two groups (P>0.05). Although the mean operative time and mean intraoperative blood loss were higher in the LS group than in OS group, the differences were not statistically significant (P=0.121 and P=0.115, respectively). Four patients (25%) in the LS group and two (22.2%) in the OS group experienced postoperative complications (P>0.05). No significant differences were observed in other surgical outcomes and pathologic findings between the two groups. Regarding the tumor recurrence rate, there was no difference between the groups (P>0.05) during the follow-up period (23.9 ± 13.3 months vs. 17.8 ± 12.3 months, P=0.240). Conclusion Laparoscopic radical resection of Bismuth types III and IV HC remains challenging, and extremely delicate surgical skills are required when performing extended hemihepatectomy followed by complex bilioenteric reconstructions. However, this procedure is generally safe and feasible for hepatobiliary surgeons with extensive laparoscopy experience.
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Affiliation(s)
- Jianjun Wang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yang Xia
- Department of Neurosurgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yuan Cao
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Hua Luo
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xianfu Cai
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Mingsong Shi
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Huiwen Luo
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Decai Wang
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
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13
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Detarya M, Mahalapbutr P, Waenphimai O, Kidoikhammouan S, Janeklang S, Sawanyawisuth K, Vaeteewoottacharn K, Seubwai W, Saengboonmee C, Thothaisong T, Pabuprapap W, Suksamrarn A, Wongkham S. Induction of apoptotic cell death of cholangiocarcinoma cells by tiliacorinine from Tiliacora triandra: A mechanistic insight. Biochim Biophys Acta Gen Subj 2023; 1867:130486. [PMID: 37813201 DOI: 10.1016/j.bbagen.2023.130486] [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: 07/01/2023] [Revised: 09/06/2023] [Accepted: 10/05/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) exhibits poor response to the present chemotherapeutic agents and frequently develops drug resistance. Finding novel anticancer drugs might enhance patient outcomes. Tiliacorinine, a bisbenzylisoquinoline alkaloid from the Thai medicinal plant Tiliacora triandra, effectively induced apoptosis of human CCA cell lines and inhibited tumor growth in mice. Here, we elucidate further the molecular mechanisms underlining the cytotoxicity of tiliacorinine and its implication in overcoming gemcitabine-resistance of CCA cells. METHODS Cytotoxicity of tiliacorinine against CCA cell lines was assessed using MTT assay. The molecular signaling was determined using Western blot analysis. Molecular docking simulations were applied to predict the binding affinity and orientation of tiliacorinine to the possible binding site(s) of the target proteins. RESULTS Tiliacorinine induced apoptotic cell death of CCA cells in a dose- and time-dependent manner. Tiliacorinine significantly suppressed the expression of anti-apoptotic proteins, Bcl-xL and XIAP; activated apoptotic machinery proteins, caspase-3, caspase-9, and PARP; and decreased the levels of pAkt and pSTAT3. EGF/EGFR activation model and molecular docking simulations revealed EGFR, Akt, and STAT3 as potent targets of tiliacorinine. Molecular docking simulations indicated a strong binding affinity of tiliacorinine to the ATP-binding pockets of EGFR, PI3K, Akt, JAK2, and SH2 domain of STAT3. Tiliacorinine could synergize with gemcitabine and restore the cytotoxicity of gemcitabine against gemcitabine-resistant CCA cells. CONCLUSION Tiliacorinine effectively induced apoptosis via binding and blocking the actions of EGFR, Akt, and STAT3. GENERAL SIGNIFICANCE Tiliacorinine is a novel multi-kinase inhibitor and possibly a potent anti-cancer agent, in cancers with high activation of EGFR.
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Affiliation(s)
- Marutpong Detarya
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Panupong Mahalapbutr
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Orawan Waenphimai
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | - Somkid Janeklang
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Kanlayanee Sawanyawisuth
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Kulthida Vaeteewoottacharn
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Wunchana Seubwai
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Forensic Medicine, Faculty of Medicine, and Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Charupong Saengboonmee
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Teerawut Thothaisong
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Wachirachai Pabuprapap
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Sopit Wongkham
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
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14
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Coletta D, Scarinci A, Grazi GL, Patriti A. The Role of Staging Laparoscopy for Intrahepatic Cholangiocarcinoma: A Snapshot of the Current Literature. J Laparoendosc Adv Surg Tech A 2023; 33:1019-1024. [PMID: 37768853 DOI: 10.1089/lap.2023.0193] [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] [Indexed: 09/30/2023] Open
Abstract
Background: Accurate preoperative workup is crucial to identify patients with intrahepatic cholangiocarcinoma (IHC) who would have truly benefit from liver resection, avoiding it in patients with advanced disease or distant metastases. Staging laparoscopy (SL) may prevent unnecessary laparotomies in those patients with otherwise resectable disease, but evidence of its efficacy is scarce and inconclusive. We aimed to aggregate the available evidence dealing with this specific field of research to produce a snapshot of the current knowledge systematically reviewing the inherent literature. Methods: PubMed/Medline, EMBASE, and Web of Sciences electronic databases were queried through December 2022. Inclusion criteria considered all articles reporting data about the role of SL for patients with a diagnosis of IHC. The main outcomes were as follows: overall yield and sensitivity of SL. Results: A total of 5 studies including 119 patients met the inclusion criteria and were included in the analysis. Overall, the yield of SL was 19.6% (11.4%-36%), and the sensitivity was 65.2% (55%-71%). Conclusions: The role of SL for patients with a preoperative diagnosis of IHC remains unclear. The lack of criteria and indications to perform SL for IHC raises the need for international consensus on this specific field of research.
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Affiliation(s)
- Diego Coletta
- Department of Surgical Sciences, Policlinico Umberto I University Hospital, Sapienza University of Rome, Rome, Italy
- Department of General Surgery, San Salvatore Hospital, AST Pesaro-Urbino Pesaro, Italy
| | - Andrea Scarinci
- Hepatopancreatobiliary Surgery, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Gian Luca Grazi
- Department of Experimental and Clinical Medicine, HepatoBiliaryPancreatic Surgery, University of Florence, Florence, Italy
| | - Alberto Patriti
- Department of General Surgery, San Salvatore Hospital, AST Pesaro-Urbino Pesaro, Italy
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15
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Gandhy SU, Casak SJ, Mushti SL, Cheng J, Subramaniam S, Zhao H, Zhao M, Bi Y, Liu G, Fan J, Adeniyi O, Charlab R, Kufrin D, Thompson MD, Jarrell K, Auth D, Lemery SJ, Pazdur R, Kluetz PG, Fashoyin-Aje LA. FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements. Clin Cancer Res 2023; 29:4027-4031. [PMID: 37289037 PMCID: PMC10592512 DOI: 10.1158/1078-0432.ccr-23-1042] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/19/2023] [Accepted: 06/06/2023] [Indexed: 06/09/2023]
Abstract
On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.
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Affiliation(s)
- Shruti U. Gandhy
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Sandra J. Casak
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Sirisha L Mushti
- Office of Biostatistics, Office of Translational Sciences
(OTS), CDER, U.S. FDA
| | - Joyce Cheng
- Office of Biostatistics, Office of Translational Sciences
(OTS), CDER, U.S. FDA
| | | | - Hong Zhao
- Office of Clinical Pharmacology, OTS, CDER, U.S. FDA
| | - Miao Zhao
- Office of Clinical Pharmacology, OTS, CDER, U.S. FDA
| | - Youwei Bi
- Office of Clinical Pharmacology, OTS, CDER, U.S. FDA
| | - Guansheng Liu
- Office of Clinical Pharmacology, OTS, CDER, U.S. FDA
| | - Jianghong Fan
- Office of Clinical Pharmacology, OTS, CDER, U.S. FDA
| | | | | | - Dubravka Kufrin
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Matthew D. Thompson
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Kristin Jarrell
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Doris Auth
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Steven J. Lemery
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Richard Pazdur
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Paul G. Kluetz
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
| | - Lola A. Fashoyin-Aje
- Office of Oncologic Diseases, Center for Drug Evaluation
and Research (CDER), U.S. Food and Drug Administration (FDA)
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16
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Song Z, Lin S, Wu X, Ren X, Wu Y, Wen H, Qian B, Lin H, Huang Y, Zhao C, Wang N, Huang Y, Peng B, Li X, Peng H, Shen S. Hepatitis B virus-related intrahepatic cholangiocarcinoma originates from hepatocytes. Hepatol Int 2023; 17:1300-1317. [PMID: 37368186 PMCID: PMC10522522 DOI: 10.1007/s12072-023-10556-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 05/27/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is one of the most common risk factors for intrahepatic cholangiocarcinoma (ICC). However, there is no direct evidence of a causal relationship between HBV infection and ICC. In this study, we attempted to prove that ICC may originate from hepatocytes through a pathological study involving ICC tissue-derived organoids. METHOD The medical records and tumor tissue samples of 182 patients with ICC after hepatectomy were collected. The medical records of 182 patients with ICC were retrospectively analyzed to explore the prognostic factors. A microarray of 182 cases of ICC tumor tissue and 6 cases of normal liver tissue was made, and HBsAg was stained by immunohistochemistry (IHC) to explore the factors closely related to HBV infection. Fresh ICC tissues and corresponding adjacent tissues were collected to make paraffin sections and organoids. Immunofluorescence (IF) staining of factors including HBsAg, CK19, CK7, Hep-Par1 and Albumin (ALB) was performed on both fresh tissues and organoids. In addition, we collected adjacent nontumor tissues of 6 patients with HBV (+) ICC, from which biliary duct tissue and normal liver tissue were isolated and RNA was extracted respectively for quantitative PCR assay. In addition, the expression of HBV-DNA in organoid culture medium was detected by quantitative PCR and PCR electrophoresis. RESULTS A total of 74 of 182 ICC patients were HBsAg positive (40.66%, 74/182). The disease-free survival (DFS) rate of HBsAg (+) ICC patients was significantly lower than that of HBsAg (-) ICC patients (p = 0.0137). IF and IHC showed that HBsAg staining was only visible in HBV (+) ICC fresh tissues and organoids, HBsAg expression was negative in bile duct cells in the portal area. Quantitative PCR assay has shown that the expression of HBs antigen and HBx in normal hepatocytes were significantly higher than that in bile duct epithelial cells. Combined with the IF and IHC staining, it was confirmed that HBV does not infect normal bile duct epithelial cells. In addition, IF also showed that the staining of bile duct markers CK19 and CK7 were only visible in ICC fresh tissue and organoids, and the staining of hepatocyte markers Hep-Par1 and ALB was only visible in normal liver tissue fresh tissue. Real-time PCR and WB had the same results. High levels of HBV-DNA were detected in the culture medium of HBV (+) organoids but not in the culture medium of HBV (-) organoids. CONCLUSION HBV-related ICC might be derived from hepatocytes. HBV (+) ICC patients had shorter DFS than HBV (-) ICC patients.
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Affiliation(s)
- Zimin Song
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Shuirong Lin
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Xiwen Wu
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
- Department of Clinical Nutrition, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Xiaoxue Ren
- Department of Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Yifan Wu
- Department of Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Haoxiang Wen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Baifeng Qian
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Haozhong Lin
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Yihao Huang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Chenfeng Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Nian Wang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510030, China
| | - Yan Huang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510030, China
| | - Baogang Peng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China
| | - Xiaoxing Li
- Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China.
| | - Hong Peng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China.
| | - Shunli Shen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, China.
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17
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Nanjundappa RH, Christen U, Umeshappa CS. Distinct immune surveillance in primary biliary cholangitis and primary sclerosing cholangitis is linked with discrete cholangiocarcinoma risk. Hepatol Commun 2023; 7:e0218. [PMID: 37555943 PMCID: PMC10412426 DOI: 10.1097/hc9.0000000000000218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/10/2023] [Indexed: 08/10/2023] Open
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are 2 major liver autoimmune diseases. PBC is common in women and primarily affects intrahepatic small bile duct epithelial cells, known as cholangiocytes. In contrast, PSC is dominant in men and primarily affects medium and big intrahepatic and extrahepatic bile duct epithelial cells. Cholangiocarcinoma (CCA) is a malignancy arising from cholangiocytes, and its incidence is increasing worldwide in both men and women. Numerous retrospective and clinical studies have suggested that PBC patients rarely develop CCA compared to PSC patients. CCA is accountable for the higher deaths in PSC patients due to ineffective therapies and our inability to diagnose the disease at an early stage. Therefore, it is paramount to understand the differences in immune surveillance mechanisms that render PBC patients more resistant while PSC patients are susceptible to CCA development. Here, we review several potential mechanisms contributing to differences in the susceptibility to CCA in PBC versus PSC patients.
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Affiliation(s)
- Roopa H. Nanjundappa
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Urs Christen
- Department of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Channakeshava S. Umeshappa
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Pediatrics, IWK Health Center, Halifax, Nova Scotia, Canada
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18
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Gao L, Lin Y, Yue P, Li S, Zhang Y, Mi N, Bai M, Fu W, Xia Z, Jiang N, Cao J, Yang M, Ma Y, Zhang F, Zhang C, Leung JW, He S, Yuan J, Meng W, Li X. Identification of a novel bile marker clusterin and a public online prediction platform based on deep learning for cholangiocarcinoma. BMC Med 2023; 21:294. [PMID: 37553571 PMCID: PMC10408060 DOI: 10.1186/s12916-023-02990-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 07/20/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor, and its diagnosis is still a challenge. This study aimed to identify a novel bile marker for CCA diagnosis based on proteomics and establish a diagnostic model with deep learning. METHODS A total of 644 subjects (236 CCA and 408 non-CCA) from two independent centers were divided into discovery, cross-validation, and external validation sets for the study. Candidate bile markers were identified by three proteomics data and validated on 635 clinical humoral specimens and 121 tissue specimens. A diagnostic multi-analyte model containing bile and serum biomarkers was established in cross-validation set by deep learning and validated in an independent external cohort. RESULTS The results of proteomics analysis and clinical specimen verification showed that bile clusterin (CLU) was significantly higher in CCA body fluids. Based on 376 subjects in the cross-validation set, ROC analysis indicated that bile CLU had a satisfactory diagnostic power (AUC: 0.852, sensitivity: 73.6%, specificity: 90.1%). Building on bile CLU and 63 serum markers, deep learning established a diagnostic model incorporating seven factors (CLU, CA19-9, IBIL, GGT, LDL-C, TG, and TBA), which showed a high diagnostic utility (AUC: 0.947, sensitivity: 90.3%, specificity: 84.9%). External validation in an independent cohort (n = 259) resulted in a similar accuracy for the detection of CCA. Finally, for the convenience of operation, a user-friendly prediction platform was built online for CCA. CONCLUSIONS This is the largest and most comprehensive study combining bile and serum biomarkers to differentiate CCA. This diagnostic model may potentially be used to detect CCA.
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Affiliation(s)
- Long Gao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yanyan Lin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China
| | - Ping Yue
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China
| | - Shuyan Li
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Yong Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China
| | - Ningning Mi
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Mingzhen Bai
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Wenkang Fu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Zhili Xia
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Ningzu Jiang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Jie Cao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Man Yang
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Yanni Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Fanxiang Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Chao Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Joseph W Leung
- Division of Gastroenterology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, 95817, USA
| | - Shun He
- Department of Endoscopy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
| | - Wenbo Meng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China.
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China
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19
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Wang X, Golino JL, Hawk NV, Xie C. Reciprocal Interaction of Cancer Stem Cells of Cholangiocarcinoma with Macrophage. Stem Cell Rev Rep 2023; 19:2013-2023. [PMID: 37249733 PMCID: PMC10390592 DOI: 10.1007/s12015-023-10557-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2023] [Indexed: 05/31/2023]
Abstract
Cholangiocarcinoma is an aggressive type of liver cancer with few effective treatment options. Therefore, there is great need to better understand the biology of this malignancy to further development of novel treatment options. Cancer stem cells (CSCs) are thought to the underlying reason for cancer initiation, metastasis, and relapse. However, due to their elusive character and differences in identification among different types of cancer, it remains a challenge to study such cells. Additionally, characterization of the tumor microenvironment such as interactions with immune cells remain largely unknown. Here, we employ a fluorescent reporter system to track and isolate stem-like cancer cells of cholangiocarcinoma cell lines. Following verification of a stem-like signature (upregulated expression of stemness markers, resistance to chemotherapy, increased spheroid formation, and tumorigenesis capabilities despite inoculation of a small number of cells), we analyzed the interaction of these cells with macrophages via direct and indirect coculture assays. We noted direct coculturing increased stemness among CSC populations and induced both M1 (CD80 and HLA-DR) and M2 (CD163) tumor associated macrophage polarization. These studies suggest that there is a bi-directional crosstalk between macrophages and CSCs that promotes stemness renewal and tumor associated macrophage polarization.
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Affiliation(s)
- Xin Wang
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Jihye L Golino
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Nga Voong Hawk
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Changqing Xie
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA.
- NCI CCR Liver Cancer Program, National Institutes of Health, 10 Center Drive, Building 10 3B43, Bethesda, MD, 20892, USA.
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20
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Hassan MS, Awasthi N, Ponna S, von Holzen U. Nab-Paclitaxel in the Treatment of Gastrointestinal Cancers-Improvements in Clinical Efficacy and Safety. Biomedicines 2023; 11:2000. [PMID: 37509639 PMCID: PMC10377238 DOI: 10.3390/biomedicines11072000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/03/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.
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Affiliation(s)
- Md Sazzad Hassan
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
- Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
- Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Saisantosh Ponna
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN 46556, USA
| | - Urs von Holzen
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
- Harper Cancer Research Institute, South Bend, IN 46617, USA
- Goshen Center for Cancer Care, Goshen, IN 46526, USA
- Department of Surgery, University of Basel School of Medicine, 4001 Basel, Switzerland
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21
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Moroney J, Trivella J, George B, White SB. A Paradigm Shift in Primary Liver Cancer Therapy Utilizing Genomics, Molecular Biomarkers, and Artificial Intelligence. Cancers (Basel) 2023; 15:2791. [PMID: 37345129 PMCID: PMC10216313 DOI: 10.3390/cancers15102791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/02/2023] [Accepted: 05/10/2023] [Indexed: 06/23/2023] Open
Abstract
Primary liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Conventional therapies offer limited survival benefit despite improvements in locoregional liver-directed therapies, which highlights the underlying complexity of liver cancers. This review explores the latest research in primary liver cancer therapies, focusing on developments in genomics, molecular biomarkers, and artificial intelligence. Attention is also given to ongoing research and future directions of immunotherapy and locoregional therapies of primary liver cancers.
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Affiliation(s)
- James Moroney
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Juan Trivella
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ben George
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Sarah B. White
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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22
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Takagi C, Sato M, Tomita M, Sugita A, Tokuda T, Fujiwara K, Ando N. Induction chemotherapy and hepatic artery embolization followed by extended resection for locally advanced gallbladder cancer: a case report. Surg Case Rep 2023; 9:79. [PMID: 37184729 DOI: 10.1186/s40792-023-01664-1] [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: 03/13/2023] [Accepted: 05/08/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND Surgical resection plays a critical role in the curative therapy of patients with gallbladder cancer. However, extended resection for locally advanced gallbladder cancer is a controversial procedure because of the high operative morbidity, mortality, and poor prognosis after surgery, without consensus of its suitability. Several reports have described preoperative treatment modalities to reduce the risk of mortality and morbidity and improve the curability of surgery for locally advanced GBCA. However, only a few well-designed studies have verified the benefits of these preoperative strategies. CASE PRESENTATION A 62-year-old male patient presented to our department with a gallbladder tumor detected on abdominal ultrasound during an annual medical checkup. Multi-phase enhanced CT revealed a gallbladder tumor with a maximum diameter of 34 mm, invading the right hepatic artery, pancreatic head, hepatic flexure of the colon, and first portion of the duodenum. We diagnosed gallbladder carcinoma as cT4 cN0 cM0 cStage IVA in the Union for International Cancer Control (UICC) classification 8th edition. After administration of 12 cycles of gemcitabine and cisplatin plus S-1 regimen, tumor shrinkage was observed on computed tomography, and elevated serum CA19-9 levels were reduced to normal limits. After preoperative hepatic artery embolization, we performed gallbladder bed resection with pancreaticoduodenectomy (minor hepatopancreatoduodenectomy) and combined resection of the right hepatic artery and hepatic flexure of the colon. Histological examination revealed no evidence of lymph node metastasis (ypT4 ypN0 ycM0 yp Stage IVA in the 8th edition of the UICC). The proximal bile duct and dissected margins were negative. CONCLUSIONS The combination of induction chemotherapy and preoperative hepatic artery embolization, followed by minor hepatopancreatoduodenectomy and combined resection of the involved arteries and partial colon, could be a feasible treatment strategy for patients with locally advanced gallbladder cancer invading neighboring organs.
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Affiliation(s)
- Chisato Takagi
- Department of Surgery, International Goodwill Hospital, 1-28-1, Nishigaoka, Izumi-Ku, Yokohama-City, Kanagawa, 245-0006, Japan.
| | - Michio Sato
- Department of Surgery, International Goodwill Hospital, 1-28-1, Nishigaoka, Izumi-Ku, Yokohama-City, Kanagawa, 245-0006, Japan
| | - Masato Tomita
- Department of Surgery, International Goodwill Hospital, 1-28-1, Nishigaoka, Izumi-Ku, Yokohama-City, Kanagawa, 245-0006, Japan
| | - Atsushi Sugita
- Department of Surgery, International Goodwill Hospital, 1-28-1, Nishigaoka, Izumi-Ku, Yokohama-City, Kanagawa, 245-0006, Japan
| | - Toshiki Tokuda
- Department of Surgery, International Goodwill Hospital, 1-28-1, Nishigaoka, Izumi-Ku, Yokohama-City, Kanagawa, 245-0006, Japan
| | - Koki Fujiwara
- Department of Surgery, International Goodwill Hospital, 1-28-1, Nishigaoka, Izumi-Ku, Yokohama-City, Kanagawa, 245-0006, Japan
| | - Nobutoshi Ando
- Department of Surgery, International Goodwill Hospital, 1-28-1, Nishigaoka, Izumi-Ku, Yokohama-City, Kanagawa, 245-0006, Japan
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23
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Thakral N, Gonzalez T, Nano O, Shin SH, Samuels S, Hussein A. Cirrhosis in intrahepatic cholangiocarcinoma: prognostic importance and impact on survival. BMC Gastroenterol 2023; 23:151. [PMID: 37179301 PMCID: PMC10183123 DOI: 10.1186/s12876-023-02710-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 03/03/2023] [Indexed: 05/15/2023] Open
Abstract
CONTEXT Cholangiocarcinoma (CCA), a malignancy of the biliary tract epithelium is of increasing importance due to its rising incidence worldwide. There is a lack of data on cirrhosis in intrahepatic CCA (iCCA) and how it affects overall survival and prognosis. OBJECTIVES The primary objective of this study was to examine if there were differences in survival outcomes between iCCA patients with concomitant cirrhosis and those without cirrhosis. METHODS The National Cancer Database (NCDB) was used to identify and study patients with iCCA from 2004 to 2017. The presence of cirrhosis was defined using CS Site-Specific Factor 2 where 000 indicated no cirrhosis and 001 indicated the presence of cirrhosis. Descriptive statistics were utilized for patient demographics, disease staging, tumor, and treatment characteristics. Kaplan-Meier (KM) method with log-rank test and a multivariate logistic regression model was used to assess if the presence of cirrhosis in iCCA was associated with survival status and long-term survival (60 or more months after diagnosis). RESULTS There were 33,160 patients with CCA in NCDB (2004-2017), of which 3644 patients were diagnosed with iCCA. One thousand fifty-two patients (28.9%) had cirrhosis as defined by Ishak Fibrosis score 5-6 on biopsy and 2592 patients (71.1%) did not meet the definition for cirrhosis. Although in univariate analyses using KM/log-rank tests showed a survival advantage for non-cirrhotic patients, there was no statistically significant association found between cirrhosis and survival status (OR = 0.82, p = 0.405) or long-term survival (OR = 0.98, p = 0.933) when multivariate analysis was used. iCCA patients with cirrhosis and Stage 1 tumor had the highest median OS (132 months) vs 73.7 months in the non-cirrhotic arm, while patients with stage IV disease who had cirrhosis had half the survival time of those without. Our data thus indicates that the presence of cirrhosis is not an independent prognostic factor for survival.
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Affiliation(s)
- Nimish Thakral
- Department of Hepatology, University of Kentucky, 740 S. Limestone, Medicine Specialties, Kentucky Clinic Wing C, Room 211, Floor, 2, Lexington, KY, 40536, USA.
| | | | - Olger Nano
- Memorial Healthcare System, Hollywood, USA
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He Q, Pan X, Yin Y, Xu A, Yi X, Wu Y, Li X. Clonorchis sinensis granulin promotes malignant transformation of human intrahepatic biliary epithelial cells through interaction with M2 macrophages via regulation of STAT3 phosphorylation and the MEK/ERK pathway. Parasit Vectors 2023; 16:139. [PMID: 37095578 PMCID: PMC10124682 DOI: 10.1186/s13071-023-05765-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/03/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Clonorchis sinensis granulin (CsGRN), a component of the excretory/secretory products of this species, is a multifunctional growth factor that can promote the metastasis of cholangiocarcinoma cells. However, the effect of CsGRN on human intrahepatic biliary epithelial cells (HIBECs) is unclear. Here, we investigated the effect of CsGRN on the malignant transformation of HIBECs and its possible underlying mechanism. METHODS The malignant transformation phenotypes of HIBECs after CsGRN treatment were estimated by EdU-488 incorporation assay, colony formation assay, wound-healing assay, Transwell assay and western blot. The biliary damage of CsGRN-treated mice was detected by western blot, immunohistochemical staining and hematoxylin and eosin staining. The phenotypes of the macrophages [human monocytic leukemia cell line (THP-1)] were analyzed by flow cytometry, immunofluorescence and immunohistochemistry, both in vitro and in vivo. A co-culture system was developed to explore the interaction between THP-1 and HIBECs in CsGRN-containing medium. Enzyme-linked immunosorbent assay and western blot were used to detected the activation of interleukin 6 (IL-6), phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. An inhibitor of the MEK/ERK pathway, PD98059, was used to determine whether this pathway is involved in CsGRN-mediated cell interactions as well as in STAT3 phosphorylation and malignant transformation of HIBECs. RESULTS Excessive hyperplasia and abnormal proliferation of HIBECs, enhanced secretion of hepatic pro-inflammatory cytokines and chemokines, as well as biliary damage, were observed in vitro and in vivo after treatment with CsGRN. The expression of the markers of M2 macrophages significantly increased in CsGRN-treated THP-1 cells and biliary duct tissues compared with the controls. Moreover, following treatment with CsGRN, the HIBECs underwent malignant transformation in the THP-1-HIBECs co-culture group. In addition, high expression of IL-6 was observed in the CsGRN-treated co-culture media, which activated the phosphorylation of STAT3, JAK2, MEK and ERK. However, treatment with an inhibitor of the MEK/ERK pathway, PD98059, decreased expression of p-STAT3 in CsGRN-treated HIBECs and further repressed the malignant transformation of HIBECs. CONCLUSIONS Our results demonstrated that, by inducing the M2-type polarization of macrophages and activating the IL-6/JAK2/STAT3 and MEK/ERK pathways in HIBECs, CsGRN promoted the malignant transformation of the latter.
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Affiliation(s)
- Qing He
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
- Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China
- China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China
| | - Xiaowen Pan
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
- Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China
- China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China
| | - Yingxuan Yin
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
- Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China
- China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China
| | - Anyuan Xu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
- Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China
- China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China
| | - Xueqing Yi
- Department of Basic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Yinjuan Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
- Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China.
- China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China.
| | - Xuerong Li
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
- Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China.
- China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China.
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25
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Impact of metformin on the incidence of human cholangiocarcinoma in diabetic patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2023; 35:241-247. [PMID: 36708293 DOI: 10.1097/meg.0000000000002503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Cholangiocarcinoma (CCA) is the second most common liver cancer. Diabetes is a well-known risk factor; however, treatment with metformin has been reported to be protective for several cancers, but data on CCA are still sparse and heterogeneous. We performed this meta-analysis to investigate the role of metformin as a potential protective factor for CCA. In this systematic review and meta-analysis, we searched PubMed/MEDLINE and EMBASE databases, from the date of inception to November 2022, for studies analyzing CCA rate in patients taking metformin. Twenty-nine articles were initially identified, of which four were eligible and included in our systematic review and meta-analysis, from which we estimated the relative risk (RR). The rate of CCA was lower for diabetic patients taking metformin than diabetic patients without metformin intake when comparing two highest quality studies [RR, 0.38; 95% confidence interval (CI), 0.290-0.508; P < 0.001], and three studies with similar inclusion criteria (RR, 0.34; 95% CI, 0.51-0.35; P < 0.001) without significant statistical heterogeneity among them (I2 = 29.83%, P = 0,2326 and I2 = 35.08%; P = 0.2143, respectively). Our study demonstrated a significant impact of metformin in reducing the risk of CCA by nearly 62-66% in diabetic patients taking metformin.
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Wang WQ, Xu GY, Li J, Liang BY, Li J, Lin ML, Chen XP, Zhang EL, Huang ZY. HBcAb positivity increases the risk of postoperative complications after extended hemihepatectomy for hilar cholangiocarcinoma. Cancer Med 2023; 12:9627-9636. [PMID: 36847156 PMCID: PMC10166974 DOI: 10.1002/cam4.5740] [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: 09/13/2022] [Revised: 11/29/2022] [Accepted: 02/13/2023] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Hepatitis B core antibody (HBcAb) positivity is considered a prior hepatitis B virus (HBV) infection. However, little is known about the effect of HBcAb positivity on surgical safety for hilar cholangiocarcinoma (hCCA). The present study aims to investigate the role of HBcAb positivity on postoperative complications of hCCA. METHODS A retrospective analysis was performed on the status of HBcAb positivity, liver fibrosis, perioperative surgical complications, and long-term outcomes of hCCA patients with Hepatitis B surface antigen (HBsAg) negativity who underwent surgical treatment in Tongji Hospital from April 2012 to September 2019. RESULTS HBcAb positivity with negative HBsAg occurs in 137 hCCA patients (63.1%). A total of 99 hCCA patients with negative HBsAg underwent extended hemihepatectomy, of whom 69 (69.7%) and 30 (30.3%) were HBcAb-positive and HBcAb-negative, respectively. Significant fibrosis was detected in 63.8% of the patients with HBcAb-positive, which was markedly higher than those with HBcAb-negative (36.7%) (p = 0.016). The postoperative complications and 90-day mortality rates were 37.4% (37/99) and 8.1% (8/99), respectively. The incidence of postoperative complications in HBcAb-positive patients (44.9%) was significantly higher than that in HBcAb-negative patients (20.0%) (p = 0.018). All the patients who died within 30-day after surgery were HBcAb-positive. Multivariate analysis showed that the independent risk factors for complications were HBcAb positivity, preoperative cholangitis, portal occlusion >15 min, and significant fibrosis. There were no significant differences in recurrence-free survival (RFS) and overall survival (OS) between HBcAb-positive and HBcAb-negative patients (p = 0.642 and p = 0.400, respectively). CONCLUSIONS HBcAb positivity is a common phenomenon in hCCA patients from China, a country with highly prevalent HBcAb positivity. The status of HBcAb-positive markedly increases the incidence of postoperative complications after extended hemihepatectomy for hCCA patients.
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Affiliation(s)
- Wen-Qiang Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guang-Yuan Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin-Yong Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiang Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mei-Long Lin
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Er-Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi-Yong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Benson KK, Sheel A, Rahman S, Esnakula A, Manne A. Understanding the Clinical Significance of MUC5AC in Biliary Tract Cancers. Cancers (Basel) 2023; 15:cancers15020433. [PMID: 36672382 PMCID: PMC9856870 DOI: 10.3390/cancers15020433] [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: 12/19/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Biliary tract cancers (BTC) arise from biliary epithelium and include cholangiocarcinomas or CCA (including intrahepatic (ICC) and extrahepatic (ECC)) and gallbladder cancers (GBC). They often have poor outcomes owing to limited treatment options, advanced presentations, frequent recurrence, and poor response to available systemic therapy. Mucin 5AC (MUC5AC) is rarely expressed in normal biliary epithelium, but can be upregulated in tissues of benign biliary disease, premalignant conditions (e.g., biliary intraepithelial neoplasia), and BTCs. This mucin's numerous glycoforms can be divided into less-glycosylated immature and heavily-glycosylated mature forms. Reported MUC5AC tissue expression in BTC varies widely, with some associations based on cancer location (e.g., perihilar vs. peripheral ICC). Study methods were variable regarding cancer subtypes, expression positivity thresholds, and MUC5AC glycoforms. MUC5AC can be detected in serum of BTC patients at high concentrations. The hesitancy in developing MUC5AC into a clinically useful biomarker in BTC management is due to variable evidence on the diagnostic and prognostic value. Concrete conclusions on tissue MUC5AC are difficult, but serum detection might be relevant for diagnosis and is associated with poor prognosis. Future studies are needed to further the understanding of the potential clinical value of MUC5AC in BTC, especially regarding predictive and therapeutic value.
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Affiliation(s)
- Katherine K. Benson
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Ankur Sheel
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Shafia Rahman
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Ashwini Esnakula
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Correspondence: ; Tel.: +1-614-366-2982
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Liu Y, Wang B, Mo X, Tang K, He J, Hao J. A Deep Learning Workflow for Mass-Forming Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma Classification Based on MRI. Curr Oncol 2022; 30:529-544. [PMID: 36661691 PMCID: PMC9857958 DOI: 10.3390/curroncol30010042] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/21/2022] [Accepted: 12/27/2022] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVE Precise classification of mass-forming intrahepatic cholangiocarcinoma (MF-ICC) and hepatocellular carcinoma (HCC) based on magnetic resonance imaging (MRI) is crucial for personalized treatment strategy. The purpose of the present study was to differentiate MF-ICC from HCC applying a novel deep-learning-based workflow with stronger feature extraction ability and fusion capability to improve the classification performance of deep learning on small datasets. METHODS To retain more effective lesion features, we propose a preprocessing method called semi-segmented preprocessing (Semi-SP) to select the region of interest (ROI). Then, the ROIs were sent to the strided feature fusion residual network (SFFNet) for training and classification. The SFFNet model is composed of three parts: the multilayer feature fusion module (MFF) was proposed to extract discriminative features of MF-ICC/HCC and integrate features of different levels; a new stationary residual block (SRB) was proposed to solve the problem of information loss and network instability during training; the attention mechanism convolutional block attention module (CBAM) was adopted in the middle layer of the network to extract the correlation of multi-spatial feature information, so as to filter the irrelevant feature information in pixels. RESULTS The SFFNet model achieved an overall accuracy of 92.26% and an AUC of 0.9680, with high sensitivity (86.21%) and specificity (94.70%) for MF-ICC. CONCLUSION In this paper, we proposed a specifically designed Semi-SP method and SFFNet model to differentiate MF-ICC from HCC. This workflow achieves good MF-ICC/HCC classification performance due to stronger feature extraction and fusion capabilities, which provide complementary information for personalized treatment strategy.
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Affiliation(s)
- Yangling Liu
- Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Kunming 650504, China
| | - Bin Wang
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China
| | - Xiao Mo
- Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Kunming 650504, China
| | - Kang Tang
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China
| | - Jianfeng He
- Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Kunming 650504, China
| | - Jingang Hao
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China
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Tran A, Konstantinidis M, Moon J, El Sehemawi N, Ferreira K, Habibollahi P, Odisio BC, Nourouzpour S, Bassir A, Nezami N. Interventions for unresectable intrahepatic cholangiocarcinoma: a network meta‐analysis. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2022; 2022:CD015159. [PMCID: PMC9730740 DOI: 10.1002/14651858.cd015159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To establish the existence of differences in effectiveness and safety of intra‐arterial therapies (IATs) such as bland embolisation, conventional transarterial chemoembolisation (cTACE), drug‐eluting bead transarterial chemoembolisation (DEBTACE), yttrium‐90 (Y90), hepatic artery infusion (HAI), external beam radiotherapies (EBRTs), and immunotherapy versus systemic chemotherapy for unresectable intrahepatic cholangiocarcinoma through pairwise meta‐analysis and network meta‐analysis with subsequent treatment ranking.
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Affiliation(s)
| | - Andrew Tran
- UT Health McGovern Medical SchoolHoustonTexasUSA
| | - Menelaos Konstantinidis
- Institute of Health Policy, Management and Evaluation, University of TorontoTorontoCanada,Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health TorontoTorontoCanada
| | - John Moon
- Division of Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging SciencesEmory University School of MedicineAtlantaGeorgiaUSA
| | | | | | - Peiman Habibollahi
- Department of Interventional RadiologyDivision of Diagnostic Imaging, The University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Bruno C Odisio
- Department of Interventional RadiologyDivision of Diagnostic Imaging, The University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | | | - Ali Bassir
- Department of Radiological SciencesDavid Geffen School of Medicine, University of California Los AngelesLos AngelesCaliforniaUSA
| | - Nariman Nezami
- Department of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA,Experimental Therapeutics Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterBaltimoreMarylandUSA
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Wu WS, Chen RF, Cheng CC, Wei JL, Lin CF, You RI, Chen YC, Lee MC, Chen YC. Suppressing of Src-Hic-5-JNK-AKT Signaling Reduced GAPDH Expression for Preventing the Progression of HuCCT1 Cholangiocarcinoma. Pharmaceutics 2022; 14:pharmaceutics14122698. [PMID: 36559193 PMCID: PMC9784408 DOI: 10.3390/pharmaceutics14122698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/17/2022] [Accepted: 11/29/2022] [Indexed: 12/05/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant neoplasm of the bile ducts, being the second most common type of cancer in the liver, and most patients are diagnosed at a late stage with poor prognosis. Targeted therapy aiming at receptors tyrosine kinases (RTKs) such as c-Met or EGFR have been developed but with unsatisfactory outcomes. In our recent report, we found several oncogenic molecules downstream of RTKs, including hydrogen peroxide clone-5 (Hic-5), Src, AKT and JNK, were elevated in tissues of a significant portion of metastatic CCAs. By inhibitor studies and a knockdown approach, these molecules were found to be within the same signal cascade responsible for the migration of HuCCT1 cells, a conventionally used CCA cell line. Herein, we also found Src inhibitor dasatinib and Hic-5 siRNA corporately suppressed HuCCT1 cell invasion. Moreover, dasatinib inhibited the progression of the HuCCT1 tumor on SCID mice skin coupled with decreasing the expression of Hic-5 and EGFR and the activities of Src, AKT and JNK. In addition, we found a glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and several cytoskeletal molecules such as tubulin and cofilin were dramatically decreased after a long-term treatment of the HuCCT1 tumor with a high dose of dasatinib. Specifically, GAPDH was shown to be a downstream effector of the Hic-5/Src/AKT cascade involved in HuCCT1 cell migration. On the other hand, TFK1, another CCA cell line without Hic-5 expression, exhibited very low motility, whereas an ectopic Hic-5 expression enhanced the activation of Src and AKT and marginally increased TFK1 migration. In the future, it is tempting to investigate whether cotargeting Src, Hic-5 and/or GAPDH is efficient for preventing CCA progression in future clinical trials.
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Affiliation(s)
- Wen-Sheng Wu
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
| | - Rui-Fang Chen
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Chuan-Chu Cheng
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Jia-Ling Wei
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Chen-Fang Lin
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Ren-In You
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Yen-Chang Chen
- Department of Anatomical Pathology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- Department of Pathology, School of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Ming-Che Lee
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Yen-Cheng Chen
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- School of Medicine, Tzu Chi University, Hualien 970, Taiwan
- Correspondence:
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Su N, Dawuti W, Hu Y, Zhao H. Noninvasive cholangitis and cholangiocarcinoma screening based on serum Raman spectroscopy and support vector machine. Photodiagnosis Photodyn Ther 2022; 40:103156. [PMID: 36252780 DOI: 10.1016/j.pdpdt.2022.103156] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/17/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022]
Abstract
The feasibility of serum Raman spectroscopy for rapid screening of cholangitis and cholangiocarcinoma (CCA) was explored Raman spectra were collected from 49 patients with cholangitis, 38 patients with CCA, and 55 healthy volunteers. Normalized mean Raman spectra and spectral attributions reveal disease-specific biomolecular differences. Support vector machine (SVM) was used to establish the two-way (cholangitis vs healthy, CCA vs healthy etc.) and 3-way (cholangitis vs CCA vs healthy) classification model, and leave-one-out cross-validation (LOOCV) was used to verify these models' performance. Based on the support vector machine algorithm, serum Raman spectroscopy could identify cholangitis and CCA. Its diagnostic sensitivity, and specificity were 89.80%, 94.55%, and 89.50%, 98.18%, respectively. This study demonstrates that label-free serum Raman spectroscopy analysis technique combined with SVM diagnostic algorithm has great potential for noninvasive cholangitis and CCA screening.
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Affiliation(s)
- Na Su
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Wubulitalifu Dawuti
- School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yan Hu
- Science and Technology Talent Development, Center of Xinjiang Uygur Autonomous Region, Urumqi, China.
| | - Hui Zhao
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
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Locoregional Approaches in Cholangiocarcinoma Treatment. Cancers (Basel) 2022; 14:cancers14235853. [PMID: 36497334 PMCID: PMC9740081 DOI: 10.3390/cancers14235853] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/20/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a rare hepatic malignant tumor with poor prognosis due to late detection and anatomic factors limiting the applicability of surgical resection. Without surgical resection, palliation is the most common approach. In non-surgical cases contained within the liver, locoregional therapies provide the best chance for increased survival and disease control. The most common methods, transarterial chemoembolization and transarterial radioembolization, target tumors by embolizing their blood supply and limiting the tumor's ability to metabolize. Other treatments induce direct damage via thermal ablation to tumor tissue to mediate their anti-tumor efficacy. Recent studies have begun to explore roles for these therapies outside their previous role of palliation. This review will outline the mechanisms of each of these treatments, along with their effects on overall survival, while comparing these to non-locoregional therapies.
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The Role of Fluorescence In Situ Hybridization in Pancreatobiliary Brushing Cytology: A Large Retrospective Review with Histologic Correlation. Diagnostics (Basel) 2022; 12:diagnostics12102486. [PMID: 36292175 PMCID: PMC9600502 DOI: 10.3390/diagnostics12102486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/24/2022] Open
Abstract
(1) Background: Although the specificity of brush cytology for the detection of malignant pancreaticobiliary strictures is high, its sensitivity is low. Fluorescence in situ hybridization (FISH) can be used to detect chromosomal aneuploidy in biliary brushing specimens, and when used as an adjunct to routine cytology, it significantly improves diagnostic sensitivity. (2) Methods: We searched our laboratory information system to identify all bile duct brush cytology cases with follow-up surgical pathology between January 2001 and September 2019. Cytologic diagnoses were classified as negative, atypical, suspicious, or malignant. Correlated surgical pathological diagnoses were classified as benign or malignant. FISH test results were obtained for a subset of cytology cases with concurrent FISH testing, and the sensitivity, specificity, positive predictive value, and negative predictive value in identifying malignancy for cytology alone, FISH alone, and combined cytology and FISH were calculated. (3) Results: A total of 1017 brushing cytology cases with histologic correlation were identified. A total of 193 FISH tests were performed concurrently with cytological specimens. Malignant diagnoses were identified in 623 of 1017 patients, while 394 patients had benign strictures. The sensitivity, specificity, positive predictive, and negative predictive rate were 65%, 78%, 83%, and 49% for cytology alone; 72%, 67%, 63%, and 68% for FISH alone; and 85%, 42%, 60%, and 74% for combined cytology and FISH, respectively. Among FISH-positive cases, the risk of malignancy for polysomy was 82% and 32% for trisomy. (4) Conclusions: FISH improves the sensitivity and negative predictive rate of bile duct brush cytology. The combination of cytology and FISH has increased the sensitivity from 65% to 85% and the negative predictive rate from 49% to 74% when compared to cytology alone. A patient with a polysomy FISH result had a significantly higher risk of malignancy than a patient with a trisomy 7 result (82% vs. 32%, p < 0.00001).
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Zhou T, Meadows V, Kundu D, Kyritsi K, Owen T, Ceci L, Carpino G, Onori P, Gaudio E, Wu N, Glaser S, Ekser B, Alpini G, Kennedy L, Francis H. Mast cells selectively target large cholangiocytes during biliary injury via H2HR-mediated cAMP/pERK1/2 signaling. Hepatol Commun 2022; 6:2715-2731. [PMID: 35799467 PMCID: PMC9512472 DOI: 10.1002/hep4.2026] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 05/28/2022] [Accepted: 06/11/2022] [Indexed: 11/11/2022] Open
Abstract
Bile ducts are heterogenous in structure and function, and primary sclerosing cholangitis (PSC) damages specific bile ducts leading to ductular reaction (DR), mast cell (MC) infiltration, increased histamine release, inflammation, and fibrosis. Bile duct ligation (BDL) induces large duct damage via cyclic adenosine monophosphate (cAMP)/extracellular signal-related protein kinase (ERK) signaling, and large cholangiocytes express H2 histamine receptor (H2HR). We evaluated how MCs interact with large cholangiocytes during cholestasis. Male wild-type (WT) and MC-deficient (KitW-sh ) mice 10-12 weeks of age were subjected to BDL for 7 days. Select KitW-sh mice were injected with MCs pretreated with control or H2HR antagonist (ranitidine, 25 μm, 48 h) via tail vein injection. In vitro, MC migration toward small mouse cholangiocytes (SMCCs) and large mouse cholangiocytes (LMCCs) treated with lipopolysaccharide or histamine (±ranitidine) was measured. LMCCs were stimulated with MC supernatants pretreated with control, α-methyl-dl-histidine (to block histamine release), or ranitidine. Liver damage, large duct DR/senescence, inflammation, fibrosis, and cAMP/ERK immunoreactivity increased in BDL WT and KitW-sh +MC mice but decreased in BDL KitW-sh and KitW-sh +MC-H2HR mice. In vitro, MCs migrate toward damaged LMCCs (but not SMCCs) blocked by inhibition of H2HR. Loss of MC histamine or MC-H2HR decreases LMCC proliferation, senescence, H2HR, and cAMP/ERK levels. Human PSC livers have increased MC number found near DR, senescent ducts, and H2HR-positive ducts. Conclusion: Infiltrating MCs preferentially interact with large ducts via H2HR signaling promoting biliary and liver damage. Mediation of MCs may be a therapeutic strategy for PSC.
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Affiliation(s)
- Tianhao Zhou
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
| | - Vik Meadows
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
| | - Debjyoti Kundu
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
| | - Konstantina Kyritsi
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
| | - Travis Owen
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
| | - Ludovica Ceci
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
| | - Guido Carpino
- Department of MovementHuman and Health SciencesUniversity of Rome “Foro Italico”RomeItaly
| | - Paolo Onori
- Department of Anatomical, HistologicalForensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly
| | - Eugenio Gaudio
- Department of Anatomical, HistologicalForensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly
| | - Nan Wu
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
| | - Shannon Glaser
- Department of Medical PhysiologyTexas A&M UniversityBryanTexasUSA
| | - Burcin Ekser
- Division of Transplant SurgeryDepartment of SurgeryIndiana University School of MedicineIndianapolisIndianaUSA
| | - Gianfranco Alpini
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
- Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA
| | - Lindsey Kennedy
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
- Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA
| | - Heather Francis
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA
- Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA
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Elshami M, Hue JJ, Ahmed FA, Kakish H, Hoehn RS, Rothermel LD, Hardacre JM, Ammori JB, Winter JM, Ocuin LM. Defining Facility Volume Threshold for Optimization of Short- and Long-Term Outcomes in Patients Undergoing Resection of Perihilar Cholangiocarcinoma. J Gastrointest Surg 2022; 27:730-740. [PMID: 36138311 DOI: 10.1007/s11605-022-05465-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/10/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND We determined the minimum threshold (Tmin) of annual facility case volume to optimize outcomes for patients with resected perihilar cholangiocarcinoma. METHODS We identified patients with localized perihilar cholangiocarcinoma who underwent resection within the National Cancer Database (2010-2017). We used marginal structural logistic regression models to estimate the average treatment effect of receiving care in facilities meeting/exceeding Tmin on 90-day mortality and other postoperative outcomes. RESULTS A total of 2471 patients underwent resection for perihilar cholangiocarcinoma at 471 facilities. There was no effect of total hepatopancreatobiliary, surgical hepatopancreatobiliary, total hepatobiliary, surgical hepatobiliary, or total perihilar cholangiocarcinoma case volume on 90-day mortality. A Tmin of seven perihilar cholangiocarcinoma resections/year resulted in lower odds of 90-day mortality (IP-weighted OR = 0.49, 95% CI: 0.66-0.87). A total of two facilities met the Tmin. Patients receiving treatment at Tmin facilities had lower odds of length of stay ≥ 7 days (IP-weighted OR = 0.85, 95% CI: 0.75-0.97) and positive surgical resection margins (IP-weighted OR = 0.40, 95% CI: 0.47-0.55). Additionally, undergoing surgery at Tmin facilities resulted in higher (≥ 4 nodes) lymph node yields (IP-weighted OR = 1.94, 95% CI: 1.21-3.11) but no change in the odds of nodal positivity. There was no effect of undergoing surgery at Tmin facilities on 30-day mortality or re-admission. CONCLUSIONS Resection of perihilar cholangiocarcinoma is infrequently performed at a high number of facilities. A Tmin of ≥ 7 resections/year resulted in lower 90-day mortality and improved postoperative outcomes. Our data suggest that regionalization of care for patients with perihilar cholangiocarcinoma could potentially improve outcomes in the USA.
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Affiliation(s)
- Mohamedraed Elshami
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Jonathan J Hue
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Fasih Ali Ahmed
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Hanna Kakish
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Richard S Hoehn
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Luke D Rothermel
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Jeffrey M Hardacre
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - John B Ammori
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Jordan M Winter
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Lee M Ocuin
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA.
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36
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You L, Lin J, Yu Z, Qian Y, Bi Y, Wang F, Zhang L, Zheng C, Zhang J, Li W, Cai Y, Gao Y, Kong X, Sun X. Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β. Int J Biol Sci 2022; 18:5698-5712. [PMID: 36263164 PMCID: PMC9576508 DOI: 10.7150/ijbs.78345] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 09/01/2022] [Indexed: 01/12/2023] Open
Abstract
Background: Cholangiocarcinoma (CCA) is a type of hepatobiliary cancer characterized by uncontrolled cell proliferation, with a poor prognosis and high mortality. Nobiletin (NBT) is a promising anti-tumor compound derived from the peels of oranges and other citrus plants, citrus plant. But the effect of NBT on CCA remains unknown. Results: Our data showed that NBT suppressed CCA cell proliferation in vitro and in vivo. Colony formation and Edu assay indicated that NBT inhibited cell proliferation. Cell cycle analysis showed that NBT arrested the cell cycle in G0/G1 phase. Target prediction showed that GSK3β was a direct target. Western blot and immunofluorescence confirmed that NBT reduced the phosphorylation of GSK3β. The antiproliferative effect of NBT was intercepted in GSK3β knockdown CCA cells. The cellular thermal shift assay (CETSA) showed NBT directly bound to GSK3β. Finally, NBT showed an anti-proliferative effect in tumor-bearing mice with no hepatotoxicity. Conclusion: NBT could inhibit CCA proliferation, and the pharmacological activity of NBT in CCA was attributed to its direct binding to GSK3β. We suggested that NBT might be a potential natural medicine in CCA treatment.
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Affiliation(s)
- Liping You
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.,Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Jiacheng Lin
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Zhuo Yu
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yihan Qian
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yuting Bi
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.,Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Fang Wang
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Lei Zhang
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Chao Zheng
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Jinghao Zhang
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Wenxuan Li
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.,Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yaxuan Cai
- Shanghai experimental school, Shanghai, China
| | - Yueqiu Gao
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.,✉ Corresponding authors: Xiaoni Kong, PhD, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, 528 Zhangheng Road, Shanghai, China, 201203. Telephone: +86 21 20256838. E-mail: ; or Xuehua Sun, MD,; Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine,528 Zhangheng Road, Shanghai, China, 201203; or Yueqiu Gao, MD, E-mail:
| | - Xiaoni Kong
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.,✉ Corresponding authors: Xiaoni Kong, PhD, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, 528 Zhangheng Road, Shanghai, China, 201203. Telephone: +86 21 20256838. E-mail: ; or Xuehua Sun, MD,; Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine,528 Zhangheng Road, Shanghai, China, 201203; or Yueqiu Gao, MD, E-mail:
| | - Xuehua Sun
- Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.,✉ Corresponding authors: Xiaoni Kong, PhD, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, 528 Zhangheng Road, Shanghai, China, 201203. Telephone: +86 21 20256838. E-mail: ; or Xuehua Sun, MD,; Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine,528 Zhangheng Road, Shanghai, China, 201203; or Yueqiu Gao, MD, E-mail:
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Watcharatanyatip K, Chutipongtanate S, Chokchaichamnankit D, Weeraphan C, Mingkwan K, Luevisadpibul V, Newburg DS, Morrow AL, Svasti J, Srisomsap C. Translational Proteomic Approach for Cholangiocarcinoma Biomarker Discovery, Validation, and Multiplex Assay Development: A Pilot Study. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27185904. [PMID: 36144640 PMCID: PMC9501115 DOI: 10.3390/molecules27185904] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 11/23/2022]
Abstract
Cholangiocarcinoma (CCA) is a highly lethal disease because most patients are asymptomatic until they progress to advanced stages. Current CCA diagnosis relies on clinical imaging tests and tissue biopsy, while specific CCA biomarkers are still lacking. This study employed a translational proteomic approach for the discovery, validation, and development of a multiplex CCA biomarker assay. In the discovery phase, label-free proteomic quantitation was performed on nine pooled plasma specimens derived from nine CCA patients, nine disease controls (DC), and nine normal individuals. Seven proteins (S100A9, AACT, AFM, and TAOK3 from proteomic analysis, and NGAL, PSMA3, and AMBP from previous literature) were selected as the biomarker candidates. In the validation phase, enzyme-linked immunosorbent assays (ELISAs) were applied to measure the plasma levels of the seven candidate proteins from 63 participants: 26 CCA patients, 17 DC, and 20 normal individuals. Four proteins, S100A9, AACT, NGAL, and PSMA3, were significantly increased in the CCA group. To generate the multiplex biomarker assays, nine machine learning models were trained on the plasma dynamics of all seven candidates (All-7 panel) or the four significant markers (Sig-4 panel) from 45 of the 63 participants (70%). The best-performing models were tested on the unseen values from the remaining 18 (30%) of the 63 participants. Very strong predictive performances for CCA diagnosis were obtained from the All-7 panel using a support vector machine with linear classification (AUC = 0.96; 95% CI 0.88–1.00) and the Sig-4 panel using partial least square analysis (AUC = 0.94; 95% CI 0.82–1.00). This study supports the use of the composite plasma biomarkers measured by clinically compatible ELISAs coupled with machine learning models to identify individuals at risk of CCA. The All-7 and Sig-4 assays for CCA diagnosis should be further validated in an independent prospective blinded clinical study.
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Affiliation(s)
| | - Somchai Chutipongtanate
- Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
- Center for Population Health Science and Analytics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
- Correspondence: or (S.C.); (C.S.)
| | | | - Churat Weeraphan
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand
- Department of Molecular Biotechnology and Bioinformatics, Faculty of Science, Prince of Songkla University, Songkla 90110, Thailand
| | - Kanokwan Mingkwan
- Division of Surgery, Sapphasitthiprasong Hospital, Ubon Ratchathani 34000, Thailand
| | - Virat Luevisadpibul
- Division of Information and Technology, Ubonrak Thonburi Hospital, Ubon Ratchathani 34000, Thailand
| | - David S. Newburg
- Center for Population Health Science and Analytics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Ardythe L. Morrow
- Center for Population Health Science and Analytics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
- Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Jisnuson Svasti
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand
- Applied Biological Sciences Program, Chulabhorn Graduate Institute, Bangkok 10210, Thailand
| | - Chantragan Srisomsap
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand
- Correspondence: or (S.C.); (C.S.)
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Sonsomnuek P, Tarasuk M, Plengsuriyakarn T, Boonprasert K, Na-Bangchang K. Apoptotic and Anti-metastatic Effects of Atractylodes lancea (Thunb.) DC. in a Hamster Model of Cholangiocarcinoma. Asian Pac J Cancer Prev 2022; 23:3093-3101. [PMID: 36172672 PMCID: PMC9810284 DOI: 10.31557/apjcp.2022.23.9.3093] [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: 04/27/2022] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVES Cholangiocarcinoma (CCA) is a highly aggressive tumor with a greater risk of distant metastasis. The promising anti-CCA activity and safety profile of Atractylodes lancea (AL) have previously been reported in a series of in vitro, in vivo and clinical studies. The present study investigated the effect of AL extract on apoptosis and metastasis signaling pathways in the Opisthorchis viverrini/dimethylnitrosamine (OV/DMN)-induced CCA hamster model. MATERIALS AND METHODS Hamster liver tissues were obtained from the four groups (n = 5 per group), i.e., (i) 5-FU treated CCA (40 µg/mL); (ii) CCA; (iii) AL-treated CCA (5,000 mg/kg), and (iv) normal hamsters. Total RNA was isolated, and the expression levels of apoptosis-related and metastasis-related genes were determined by qRT-PCR analysis. RESULTS The expression levels of p16, caspase-3, caspase-8, caspase-9, Apaf-1, p53 and Eef1a1 were downregulated, while that of the remaining genes were upregulated in CCA hamsters compared with normal hamsters. AL treatment increased the expression of p16, caspase-9, caspase-3, Apaf-1, p53 and E-cadherin and decreased the expression of cyclin D1, cdk4, Bax, Akt/PKB, Bcl-2, Mfge-8, Lass4, S100A6, TGF-β, Smad-2, Smad-3, Smad-4, MMP-9, and N-cadherin. The expression of Eef1a1 was unchanged. CONCLUSION The anti-CCA activity of AL in OV/DMN-induced CCA hamsters could be due to the induction of cell cycle arrest at the G1 phase and activation of the apoptosis pathway, resulting in cancer cell death. The activation of the apoptosis pathway mainly involved the intrinsic pathway (activation of caspase-3 and caspase-9 through p53 and Mfge-8 modulation and downregulation of anti-apoptotic genes Akt and Bcl-2). In addition, AL could also inhibit the canonical TGF-β signaling pathway, MMP-9 and N-cadherin to suppress tumor metastasis.
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Affiliation(s)
- Paradon Sonsomnuek
- Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand., Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.
| | - Mayuri Tarasuk
- Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.
| | - Tullayakorn Plengsuriyakarn
- Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.
| | - Kanyarat Boonprasert
- Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.
| | - Kesara Na-Bangchang
- Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.,Director, Drug discovery, and Development Center, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand. ,For Correspondence:
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39
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Sonsuz A, Bakkaloglu OK. Biomarkers in Liver Disease. Biomark Med 2022. [DOI: 10.2174/9789815040463122010020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Symptoms and signs of liver diseases are highly variable depending on the
etiology, disease stage, and type of liver involvement. There are different types of liver
diseases; causes of liver diseases may be viral, toxic, metabolic, or autoimmune.
However, in some cases, liver disease can develop as a result of diseases of other
organs or systems. It is almost impossible to differentiate all of these solely on the basis
of clinical symptoms and findings. Furthermore, the early stages of liver disease may
be completely asymptomatic, or in some cases, the disease may progress with only
subtle and non-specific symptoms. Therefore, biomarkers have a critical role in
screening, diagnosis, staging, and evaluation of therapeutic response to treatment in
liver diseases.
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Affiliation(s)
- Abdullah Sonsuz
- Department of Internal Medicine-Gastroenterology, Cerrahpasa Medical Faculty, Istanbul
University – Cerrahpasa, Istanbul, Turkey
| | - Oguz Kagan Bakkaloglu
- Department of Internal Medicine-Gastroenterology, Cerrahpasa Medical Faculty, Istanbul
University – Cerrahpasa, Istanbul, Turkey
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40
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Wang Y, Yuan Y, Gu D. Hepatitis B and C virus infections and the risk of biliary tract cancers: a meta-analysis of observational studies. Infect Agent Cancer 2022; 17:45. [PMID: 36030232 PMCID: PMC9420284 DOI: 10.1186/s13027-022-00457-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
Background Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important risk factors for hepatocellular carcinoma. However, their effect on other hepatobiliary cancers, such as biliary tract cancers (BTCs), is not well established. We aimed to investigate associations between HBV or HCV infection and BTCs risk by conducting a systematic review and meta-analysis. Methods We searched PubMed to identify all relevant articles published before June 9, 2021. Meta-analysis was performed to calculate pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The meta-analysis was evaluated by heterogeneity testing, sensitivity analyses, and publication bias assessment. Results In total, 48 articles involving 69,723 cases and 4,047,574 controls were obtained to calculate the associations between HBV or HCV infection and the risk of BTCs. We found that both HBV and HCV infections were associated with the risk of BTCs, with pooled ORs of 2.16 (95% CI 1.73–2.69) and 2.12 (95% CI 1.62–2.77), respectively. Subgroup analyses by ethnicity suggested that HBV infection could increase the risk of BTCs in both Asian (OR = 2.29, 95% CI 1.76–2.97) and Caucasian (OR = 1.80, 95% CI 1.18–2.75) populations. In addition, HCV infection resulted in a higher increased risk of BTCs in Caucasian populations than in Asian populations (OR = 3.93 vs. 1.51, P = 0.014). In particular, significantly increased risks of intrahepatic cholangiocarcinoma (ICC) were identified in individuals with HBV (OR = 3.96, 95% CI 3.05–5.15) or HCV infection (OR = 2.90, 95% CI 2.07–4.08). Conclusions This study suggests that both HBV and HCV infections are risk factors for BTCs, particularly ICC, highlighting the necessity of cancer screening for BTCs in patients with either HBV or HCV infection. Supplementary Information The online version contains supplementary material available at 10.1186/s13027-022-00457-9.
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Affiliation(s)
- Yizhou Wang
- Department of Pathology, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, 621000, China
| | - Ye Yuan
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
| | - Dongqing Gu
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.
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41
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Borakati A, Froghi F, Bhogal RH, Mavroeidis VK. Stereotactic radiotherapy for intrahepatic cholangiocarcinoma. World J Gastrointest Oncol 2022; 14:1478-1489. [PMID: 36160742 PMCID: PMC9412934 DOI: 10.4251/wjgo.v14.i8.1478] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/07/2022] [Accepted: 07/06/2022] [Indexed: 02/05/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy with an increasing incidence worldwide and poor prognosis, despite several advances and continuous efforts to develop effective treatments. Complete surgical resection is the mainstay of treatment and offers a potentially curative option, but is only possible in less than a third of patients, owing to advanced disease. Chemotherapy is a well-established treatment in the adjuvant and palliative setting, however, confers limited benefit. Conventional radiotherapy is challenging due to local toxicity. With recent advances in stereotactic ablative radiotherapy (SABR), it is now possible to focus ablative beams of radiotherapy precisely aimed at tumours to minimise damage to surrounding viscera. This review details the history, technical background and application of SABR to iCCA, with directions for future research suggested.
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Affiliation(s)
- Aditya Borakati
- Department of Surgery, The Royal London Hospital, Barts Health NHS Trust, London E1 1FR, United Kingdom
| | - Farid Froghi
- Department of HPB and Liver Transplantation Surgery, Royal Free Hospital NHS Foundation Trust, London NW3 2QG, United Kingdom
| | - Ricky H Bhogal
- Department of Academic Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
| | - Vasileios K Mavroeidis
- Department of Academic Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
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Lertpanprom M, Silsirivanit A, Tippayawat P, Proungvitaya T, Roytrakul S, Proungvitaya S. High expression of protein tyrosine phosphatase receptor S (PTPRS) is an independent prognostic marker for cholangiocarcinoma. Front Public Health 2022; 10:835914. [PMID: 35991009 PMCID: PMC9387352 DOI: 10.3389/fpubh.2022.835914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive tumor of the bile duct with a high rate of mortality. Lymph node metastasis is an important factor facilitating the progression of CCA. A reliable biomarker for diagnosis, progression status, or prognosis of CCA is still lacking. To identify a novel and reliable biomarker for diagnosis/prognosis of CCA, liquid chromatography-mass spectrometry and tandem mass spectrometry (LC-MS/MS) in combination with bioinformatics analysis were applied for the representative serum samples of patients with CCA. The proteome results showed that protein tyrosine phosphatase receptor S (PTPRS) had the highest potential candidate. Then, a dot blot assay was used to measure the level of serum PTPRS in patients with CCA (n = 80), benign biliary disease patients (BBD; n = 39), and healthy controls (HC; n = 55). PTPRS level of CCA sera (14.38 ± 9.42 ng/ml) was significantly higher than that of BBD (10.7 ± 5.05 ng/ml) or HC (6 ± 3.73 ng/ml) (P < 0.0001). PTPRS was associated with serum albumin (P = 0.028), lymph node metastasis (P = 0.038), and the survival time of patients (P = 0.011). Using a log-rank test, higher serum PTPRS level was significantly (P = 0.031) correlated with a longer overall survival time of patients with CCA, and PTPRS was an independent prognostic marker for CCA superior to carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) or alkaline phosphatase (ALP). High expression of PTPRS could be a good independent prognostic marker for CCA.
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Affiliation(s)
- Muntinee Lertpanprom
- Centre of Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Atit Silsirivanit
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Patcharaporn Tippayawat
- Centre of Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Tanakorn Proungvitaya
- Centre of Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Sittiruk Roytrakul
- Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand
| | - Siriporn Proungvitaya
- Centre of 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
- *Correspondence: Siriporn Proungvitaya
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Tang M, Zhao Y, Zhao J, Wei S, Liu M, Zheng N, Geng D, Han S, Zhang Y, Zhong G, Li S, Zhang X, Wang C, Yan H, Cao X, Li L, Bai X, Ji J, Feng XH, Qin J, Liang T, Zhao B. Liver cancer heterogeneity modeled by in situ genome editing of hepatocytes. SCIENCE ADVANCES 2022; 8:eabn5683. [PMID: 35731873 PMCID: PMC9216519 DOI: 10.1126/sciadv.abn5683] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Mechanistic study and precision treatment of primary liver cancer (PLC) are hindered by marked heterogeneity, which is challenging to recapitulate in any given liver cancer mouse model. Here, we report the generation of 25 mouse models of PLC by in situ genome editing of hepatocytes recapitulating 25 single or combinations of human cancer driver genes. These mouse tumors represent major histopathological types of human PLCs and could be divided into three human-matched molecular subtypes based on transcriptomic and proteomic profiles. Phenotypical characterization identified subtype- or genotype-specific alterations in immune microenvironment, metabolic reprogramming, cell proliferation, and expression of drug targets. Furthermore, single-cell analysis and expression tracing revealed spatial and temporal dynamics in expression of pyruvate kinase M2 (Pkm2). Tumor-specific knockdown of Pkm2 by multiplexed genome editing reversed the Warburg effect and suppressed tumorigenesis in a genotype-specific manner. Our study provides mouse PLC models with defined genetic drivers and characterized phenotypical heterogeneity suitable for mechanistic investigation and preclinical testing.
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Affiliation(s)
- Mei Tang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
| | - Yang Zhao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
| | - Jianhui Zhao
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Shumei Wei
- Department of Pathology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Mingwei Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Nairen Zheng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Didi Geng
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Shixun Han
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yuchao Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Guoxuan Zhong
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Shuaifeng Li
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xiuming Zhang
- Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Chenliang Wang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Huan Yan
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xiaolei Cao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Li Li
- School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
| | - Xueli Bai
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Junfang Ji
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
| | - Xin-Hua Feng
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
| | - Jun Qin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Tingbo Liang
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
- Corresponding author. (T.L.); (B.Z.)
| | - Bin Zhao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
- Shaoxing Institute, Zhejiang University, Shaoxing 321000, China
- Corresponding author. (T.L.); (B.Z.)
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Kosai‑Fujimoto Y, Itoh S, Yugawa K, Fukuhara T, Okuzaki D, Toshima T, Harada N, Oda Y, Yoshizumi T, Mori M. Impact of JMJD6 on intrahepatic cholangiocarcinoma. Mol Clin Oncol 2022; 17:131. [PMID: 35911665 PMCID: PMC9326512 DOI: 10.3892/mco.2022.2564] [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: 01/07/2022] [Accepted: 04/06/2022] [Indexed: 11/30/2022] Open
Abstract
The association of Jumonji domain-containing 6 (JMJD6) with the prognosis of various types of cancer has been demonstrated, except in intrahepatic cholangiocarcinoma (ICC). The present study aimed to clarify the impact of JMJD6 on ICC. The liver specimens of 51 patients who underwent surgery for ICC were analyzed for JMJD6 expression using immunohistochemistry staining. The relationship between clinicopathological factors and JMJD6 expression was investigated. The cellular activity was also evaluated in JMJD6 knocked down cells with Transwell migration assay and viability assay. In the immunohistochemistry staining of clinical samples, high expression of JMJD6 was seen in 32 of 51 samples. High expression was also associated with improved overall survival (OS) and recurrence-free survival (RFS) (P=0.0033 and 0.048, respectively). Further analyses revealed that higher JMJD6 expression was one of the improved independent prognostic factors of OS and RFS. Expression of JMJD6 was knocked down in commercial culture cell lines of ICC, and RNA and protein were extracted to analyze the downstream gene expression using RNA-sequencing and western blotting. JMJD6 knockdown was associated with higher programmed death-ligand 1 (PD-L1) expression in RNA-sequencing and western blotting. In addition, PD-L1 expression was higher in JMJD6 low expression clinical samples when measured using immunohistochemistry staining. In conclusion, high expression of JMJD6 was an independent favorable prognostic factor of ICC. JMJD6 may influence the prognosis of ICC through the regulation of PD-L1 expression.
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Affiliation(s)
- Yukiko Kosai‑Fujimoto
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Shinji Itoh
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kyohei Yugawa
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Takasuke Fukuhara
- Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060‑8638, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Takeo Toshima
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Noboru Harada
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Masaki Mori
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
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KHAMKO RICUPHAN, WASENANG WIPHAWAN, DADUANG JUREERUT, SETTASATIAN CHATRI, LIMPAIBOON TEMDUANG. Combined OPCML and AXL Expression as a Prognostic Marker and OPCML Enhances AXL Inhibitor in Cholangiocarcinoma. In Vivo 2022; 36:1168-1177. [PMID: 35478117 PMCID: PMC9087092 DOI: 10.21873/invivo.12816] [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: 01/25/2022] [Revised: 03/02/2022] [Accepted: 03/10/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIM Cholangiocarcinoma (CCA) is a type of liver cancer originating from bile duct epithelium which has an unfavorable prognosis. Therefore, novel prognostic markers and effective therapeutic regimens are required. Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor-suppressor protein that suppresses CCA cell proliferation via AXL receptor tyrosine kinase/signal transducer and activator of transcription 3 (AXL/STAT3) inactivation. However, this association in clinical samples remains unknown. We aimed to determine OPCML and AXL expression and investigate their association with clinicopathological features in patients with CCA. In addition, we also addressed whether OPCML enhanced the sensitivity of CCA cells to AXL inhibitor R428 in vitro. MATERIALS AND METHODS The expression of OPCML and AXL was determined by immunohistochemistry in 90 CCA tissue samples. The study of CCA cell line sensitivity to R428 was performed by cell viability assay. RESULTS The expression of OPCML was significantly lower while AXL expression was substantially higher in CCA than in adjacent normal tissue (p<0.001). Furthermore, high AXL expression was significantly associated with lymph node metastasis (p=0.035). Interestingly, patients with combined low OPCML/high AXL expression had significantly shorter overall survival (p=0.007). OPCML enhanced the effect of AXL inhibitor R428 in AXL-expressing CCA cell lines. CONCLUSION Combined expression of OPCML and AXL shows potential value as a prognostic marker and OPCML as an agent enhancing the effect of R428 may contribute to better prognosis for patients with CCA.
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Affiliation(s)
- RICUPHAN KHAMKO
- Biomedical Science Program, Graduate School, 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
| | - WIPHAWAN WASENANG
- Faculty of Medical Technology, Nakhon Ratchasima College, Nakhon Ratchasima, Thailand
| | - JUREERUT DADUANG
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - CHATRI SETTASATIAN
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - TEMDUANG LIMPAIBOON
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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Izquierdo-Sanchez L, Lamarca A, La Casta A, Buettner S, Utpatel K, Klümpen HJ, Adeva J, Vogel A, Lleo A, Fabris L, Ponz-Sarvise M, Brustia R, Cardinale V, Braconi C, Vidili G, Jamieson NB, Macias RI, Jonas JP, Marzioni M, Hołówko W, Folseraas T, Kupčinskas J, Sparchez Z, Krawczyk M, Krupa Ł, Scripcariu V, Grazi GL, Landa-Magdalena A, Ijzermans JN, Evert K, Erdmann JI, López-López F, Saborowski A, Scheiter A, Santos-Laso A, Carpino G, Andersen JB, Marin JJ, Alvaro D, Bujanda L, Forner A, Valle JW, Koerkamp BG, Banales JM. Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry. J Hepatol 2022; 76:1109-1121. [PMID: 35167909 DOI: 10.1016/j.jhep.2021.12.010] [Citation(s) in RCA: 169] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 11/17/2021] [Accepted: 12/06/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. METHODS The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. RESULTS Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. CONCLUSION CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. LAY SUMMARY This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.
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Affiliation(s)
- Laura Izquierdo-Sanchez
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, "Instituto de Salud Carlos III" (ISCIII), Madrid, Spain
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust/Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - Adelaida La Casta
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Stefan Buettner
- Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Kirsten Utpatel
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, the Netherlands
| | - Jorge Adeva
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Humanitas Clinical Research Center IRCSS, Humanitas University, Rozzano, Milan, Italy
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua School of Medicine, Padua, Italy; Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Mariano Ponz-Sarvise
- Clinica Universidad de Navarra and Program in Solid Tumors (CIMA), Universidad de Navarra, IDISNA, Pamplona, Spain
| | - Raffaele Brustia
- Department of Hepatobiliary and Liver Transplantation Surgery, AP-HP, Hôpital Pitié Salpêtrière, CRSA, Sorbonne Université, Paris, France
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino "Sapienza" University of Rome, Latina, Italy
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, UK; The Royal Marsden NHS Trust, London & Surrey, UK
| | - Gianpaolo Vidili
- Department of Medical, Surgical and Experimental Sciences, Clinica Medica Unit, University of Sassari, Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy
| | - Nigel B Jamieson
- Institute of Cancer Sciences, University of Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Rocio Ir Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, "Instituto de Salud Carlos III" (ISCIII), Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Biomedical Research Institute (IBSAL), Salamanca, Spain
| | - Jan Philipp Jonas
- University Hospital Zurich, Department of Visceral- and Transplant Surgery, Zurich, Switzerland; Clinic Favoriten, Department for Surgery, Wien, Austria
| | - Marco Marzioni
- Università Politecnica delle Marche, Department of Gastroenterology, Ancona, Italy
| | - Wacław Hołówko
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Juozas Kupčinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Zeno Sparchez
- 3rd Medical Department, Institute for Gastroenterology and Hepatology, University of Medicine and Pharmacy, Cluj Napoca, Romania
| | - Marcin Krawczyk
- Department of Medicine II Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Łukasz Krupa
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Teaching Hospital No 1 in Rzeszów, Poland; Medical Department, University of Rzeszów, Poland
| | - Viorel Scripcariu
- Department of Morpho-Functional Sciences I, Department of Surgery II, Grigore T. Popa University of Medicine and Pharmacy, Iaşi, Romania
| | | | - Ana Landa-Magdalena
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Jan Nm Ijzermans
- Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Joris I Erdmann
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Flora López-López
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Alvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jose Jg Marin
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, "Instituto de Salud Carlos III" (ISCIII), Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Biomedical Research Institute (IBSAL), Salamanca, Spain
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, "Instituto de Salud Carlos III" (ISCIII), Madrid, Spain
| | - Alejandro Forner
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, "Instituto de Salud Carlos III" (ISCIII), Madrid, Spain; Liver Unit. Barcelona Clinic Liver Cancer (BCLC) group. Hospital Clinic Barcelona. IDIBAPS. University of Barcelona, Spain
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust/Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, "Instituto de Salud Carlos III" (ISCIII), Madrid, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
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Mishra S, Kumari S, Srivastava P, Pandey A, Shukla S, Husain N. Genomic profiling of gallbladder carcinoma: Targetable mutations and pathways involved. Pathol Res Pract 2022; 232:153806. [DOI: 10.1016/j.prp.2022.153806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/27/2022] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
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Chen P, Yang T, Shi P, Shen J, Feng Q, Su J. Benefits and safety of photodynamic therapy in patients with hilar cholangiocarcinoma: A meta-analysis. Photodiagnosis Photodyn Ther 2022; 37:102712. [PMID: 34995788 DOI: 10.1016/j.pdpdt.2022.102712] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/16/2021] [Accepted: 01/03/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Photodynamic therapy (PDT) is a therapy evaluated for the treatment of cancers resistant to standard oncological treatments. PDT might be beneficial for the palliation of hilar cholangiocarcinoma. AIM To evaluate the efficacy and safety of PDT for treating hilar cholangiocarcinoma. METHODS PubMed, Embase, the Cochrane Library, and Web of Science were searched for articles published up to May 2021. The patients were grouped as PDT+stent vs. stent alone. The outcomes were survival, quality of life, and adverse events (AEs). Data were summarized using hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs). RESULTS Six studies were included in this meta-analysis. There were 235 and 211 patients in the PDT+stent and stent groups, respectively. The 1-year survival rate of the PDT+stent group was 0.56, and that of the control group was 0.25. The 2-year survival rate of the PDT+stent group was 0.16, and that of the control group was 0.07. PDT significantly prolonged overall survival compared to the controls (P = 0.002). No differences were detected in the occurrence of cholangitis (P = 0.996) and all other AEs (early complications, stent malfunction, total AEs, acute pancreatitis, liver abscess, and biliary hemorrhage) between the two groups. CONCLUSION PDT in patients with hilar cholangiocarcinoma could improve survival without additional AEs. Large-scale randomized controlled trials are needed to confirm the findings.
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Affiliation(s)
- Pengcheng Chen
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Ting Yang
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Peidong Shi
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Jiangbo Shen
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Qingchun Feng
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Jingen Su
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China.
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Jifcovici A, Caraty J, Vincken G, Bongartz A. End‐to‐end anastomosis of the common bile duct and cholecystoduodenostomy for the treatment of extrahepatic cholangiocarcinoma in an 11‐year‐old cat. VETERINARY RECORD CASE REPORTS 2021. [DOI: 10.1002/vrc2.161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Alexandra Jifcovici
- Department of Surgery Vet Team Liège Belgium
- Department of Surgery Benjamin Franklin/VetRef Breton France
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50
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Zhao F, Pang G, Li X, Yang S, Zhong H. Value of perfusion parameters histogram analysis of triphasic CT in differentiating intrahepatic mass forming cholangiocarcinoma from hepatocellular carcinoma. Sci Rep 2021; 11:23163. [PMID: 34848818 PMCID: PMC8633216 DOI: 10.1038/s41598-021-02667-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/22/2021] [Indexed: 02/08/2023] Open
Abstract
We aim to gain further insight into identifying differential perfusion parameters and corresponding histogram parameters of intrahepatic mass-forming cholangiocarcinoma (IMCC) from hepatocellular carcinomas (HCCs) on triphasic computed tomography (CT) scans. 90 patients with pathologically confirmed HCCs (n = 54) and IMCCs (n = 36) who underwent triple-phase enhanced CT imaging were included. Quantitative analysis of CT images derived from triphasic CT scans were evaluated to generate liver perfusion and histogram parameters. The differential performances, including the area under the receiver operating characteristic curve (AUC), specificity, and sensitivity were assessed. The mean value, and all thepercentiles of the arterial enhancement fraction (AEF) were significantly higher in HCCs than in IMCCs. The difference in hepatic arterial blood supply perfusion (HAP) and AEF (ΔHAP = HAPtumor − HAPliver, ΔAEF = AEFtumor − AEFliver) for the mean perfusion parameters and all percentile parameters between tumor and peripheral normal liver were significantly higher in HCCs than in IMCCs. The relative AEF (rAEF = ΔAEF/AEFliver), including the mean value and all corresponding percentile parameters were statistically significant between HCCs and IMCCs. The 10th percentiles of the ΔAEF and rAEF had the highest AUC of 0.788 for differentiating IMCC from HCC, with sensitivities and specificities of 87.0%, 83.3%, and 61.8%, 64.7%, respectively. Among all parameters, the mean value of ∆AEF, the 75th percentiles of ∆AEF and rAEF, and the 25th percentile of HFtumor exhibited the highest sensitivities of 94.4%, while the 50th percentile of rAEF had the highest specificity of 82.4%. AEF (including ΔAEF and rAEF) and the corresponding histogram parameters derived from triphasic CT scans provided useful value and facilitated the accurate discrimination between IMCCs and HCCs.
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Affiliation(s)
- Fang Zhao
- Department of Radiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Guodong Pang
- Department of Radiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, No.247, Beiyuan Road, Tianqiao District, Jinan, 250033, Shandong, China
| | - Xuejing Li
- Jinan Blood Center, Jinan, 250001, Shandong, China
| | - Shuo Yang
- Department of Radiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, No.247, Beiyuan Road, Tianqiao District, Jinan, 250033, Shandong, China
| | - Hai Zhong
- Department of Radiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, No.247, Beiyuan Road, Tianqiao District, Jinan, 250033, Shandong, China.
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