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Wang Y, Wang W, Zhang S, Cai W, Song R, Mei T, Wang W, Zhang F, Qi F, Zhang S, Liu Y, Li H, Ji P, Gao M, Song H, Yao H, Meng F, Lu Z, Wang J, Liu L. Diagnostic value of carbohydrate antigen 50 in biliary tract cancer: A large-scale multicenter study. Cancer Med 2024; 13:e7388. [PMID: 38924330 PMCID: PMC11200271 DOI: 10.1002/cam4.7388] [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: 04/01/2024] [Revised: 05/27/2024] [Accepted: 06/02/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND To date, carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) have been widely used for the screening, diagnosis and prediction of biliary tract cancer (BTC) patients. However, few studies with large sample sizes of carbohydrate antigen 50 (CA50) were reported in BTC patients. METHODS A total of 1121 patients from the Liver Cancer Clin-Bio Databank of Anhui Hepatobiliary Surgery Union between January 2017 and December 2022 were included in this study (673 in the training cohort and 448 in the validation cohort): among them, 458 with BTC, 178 with hepatocellular carcinoma (HCC), 23 with combined hepatocellular-cholangiocarcinoma, and 462 with nontumor patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the diagnostic efficacy and clinical usefulness. RESULTS ROC curves obtained by combining CA50, CA19-9, and AFP showed that the AUC value of the diagnostic MODEL 1 was 0.885 (95% CI 0.856-0.885, specificity 70.3%, and sensitivity 84.0%) in the training cohort and 0.879 (0.841-0.917, 76.7%, and 84.3%) in the validation cohort. In addition, comparing iCCA and HCC (235 in the training cohort, 157 in the validation cohort), the AUC values of the diagnostic MODEL 2 were 0.893 (95% CI 0.853-0.933, specificity 96%, and sensitivity 68.6%) in the training cohort and 0.872 (95% CI 0.818-0.927, 94.2%, and 64.6%) in the validation cohort. CONCLUSION The model combining CA50, CA19-9, and AFP not only has good diagnostic value for BTC but also has good diagnostic value for distinguishing iCCA and HCC.
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Affiliation(s)
- Yong‐Shuai Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Wei Wang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Shen‐Yu Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Wei Cai
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Rui‐Peng Song
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Tao Mei
- Department of Physical Examination Center, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Wei Wang
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Feng Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Fei‐Yu Qi
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Bengbu Medical UniversityBengbuAnhuiChina
| | - Sai Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Yan Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Hao‐Ran Li
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Peng Ji
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Miao Gao
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Hua‐Chuan Song
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Huan‐Zhang Yao
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Fan‐Zheng Meng
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Zheng Lu
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Bengbu Medical UniversityBengbuAnhuiChina
| | - Ji‐Zhou Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefeiAnhuiChina
- Anhui Provincial Clinical Research Center for Hepatobiliary DiseasesHefeiAnhuiChina
| | - Lian‐Xin Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefeiAnhuiChina
- Anhui Provincial Clinical Research Center for Hepatobiliary DiseasesHefeiAnhuiChina
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Moffat GT, Hu ZI, Meric-Bernstam F, Kong EK, Pavlick D, Ross JS, Murugesan K, Kwong L, De Armas AD, Korkut A, Javle M, Knox JJ. KRAS Allelic Variants in Biliary Tract Cancers. JAMA Netw Open 2024; 7:e249840. [PMID: 38709532 PMCID: PMC11074811 DOI: 10.1001/jamanetworkopen.2024.9840] [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: 09/27/2023] [Accepted: 03/06/2024] [Indexed: 05/07/2024] Open
Abstract
Importance Biliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation. Objectives To describe the genomic landscape, co-sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants. Design, Setting, and Participants This retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess Margaret Cancer Centre, MD Anderson Cancer Center, Foundation Medicine, American Association for Cancer Research Project GENIE, and cBioPortal for Cancer Genomics. The cohort comprised patients with BTCs who underwent genomic testing. Main Outcome and Measure The main outcome was mOS, defined as date of diagnosis to date of death, which was measured in months. Results A total of 7457 patients (n = 3773 males [50.6%]; mean [SD] age, 63 [5] years) with BTCs and genomic testing were included. Of these patients, 5813 had clinical outcome data available, in whom 1000 KRAS-mutated BTCs were identified. KRAS allelic variants were highly prevalent in perihilar cholangiocarcinoma (28.6%) and extrahepatic cholangiocarcinoma (36.1%). Thirty-six KRAS allelic variants were identified, and the prevalence rates in descending order were G12D (41%), G12V (23%), and Q61H (8%). The variant G12D had the highest mOS of 25.1 (95% CI, 22.0-33.0) months compared with 22.8 (95% CI, 19.6-31.4) months for Q61H and 17.8 (95% CI, 16.3-23.1) months for G12V variants. The majority of KRAS-mutated BTCs (98.9%) were not microsatellite instability-high and had low tumor mutational burden (ranging from a median [IQR] of 1.2 (1.2-2.5) to a mean [SD] of 3.3 [1.3]). Immune profiling through RNA sequencing of KRAS and NRAS-mutated samples showed a pattern toward a more immune-inflamed microenvironment with higher M1 macrophage activation (0.16 vs 0.12; P = .047) and interferon-γ expression compared with wild-type tumors. The G12D variant remained the most common KRAS allelic variant in all patient ancestries. Patients with admixed American ancestry had the highest proportion of G12D variant (45.0%). Conclusions and Relevance This cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group.
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Affiliation(s)
- Gordon Taylor Moffat
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Zishuo Ian Hu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Funda Meric-Bernstam
- Department of Developmental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston
| | - Elisabeth Kathleen Kong
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston
| | - Dean Pavlick
- Foundation Medicine Inc, Cambridge, Massachusetts
| | - Jeffrey S. Ross
- Foundation Medicine Inc, Cambridge, Massachusetts
- State University of New York Upstate Medical University, Syracuse
| | | | - Lawrence Kwong
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston
| | - Anaemy Danner De Armas
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Anil Korkut
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Jennifer J. Knox
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Huang Y, Du Z, Kan A, He M, Li H, Lai Z, Wen D, Huang L, Li Q, Xu L, Shi M. Clinical and biomarker analyses of hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitor for patients with advanced intrahepatic cholangiocarcinoma. Front Immunol 2024; 15:1260191. [PMID: 38384459 PMCID: PMC10880187 DOI: 10.3389/fimmu.2024.1260191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 01/15/2024] [Indexed: 02/23/2024] Open
Abstract
Background Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Methods Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Results Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumor tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. Conclusion FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Li Xu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Ming Shi
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
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Zhu Y, Zhang D, Shukla P, Jung YH, Malgulwar PB, Chagani S, Colic M, Benjamin S, Copland JA, Tan L, Lorenzi PL, Javle M, Huse JT, Roszik J, Hart T, Kwong LN. CRISPR screening identifies BET and mTOR inhibitor synergy in cholangiocarcinoma through serine glycine one carbon. JCI Insight 2024; 9:e174220. [PMID: 38060314 PMCID: PMC10906219 DOI: 10.1172/jci.insight.174220] [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: 07/25/2023] [Accepted: 12/05/2023] [Indexed: 01/24/2024] Open
Abstract
Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged on H3K27ac-marked epigenetic suppression of the serine glycine one carbon (SGOC) metabolism pathway, including the key enzymes PHGDH and PSAT1. Knockdown of PSAT1 was sufficient to replicate synergy with single-agent inhibition of either BET or mTOR. Our results tie together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.
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Affiliation(s)
- Yan Zhu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dengyong Zhang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of general surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Pooja Shukla
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Young-Ho Jung
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Prit Benny Malgulwar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sharmeen Chagani
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Medina Colic
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sarah Benjamin
- Department of Natural Sciences, Rice University, Houston, Texas, USA
| | - John A. Copland
- Department of Cancer Biology, Mayo Clinic Jacksonville, Florida, USA
| | - Lin Tan
- Metabolomics Core Facility, Department of Bioinformatics & Computational Biology
| | - Philip L. Lorenzi
- Metabolomics Core Facility, Department of Bioinformatics & Computational Biology
| | | | - Jason T. Huse
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jason Roszik
- Department of Melanoma Medical Oncology-Research, Division of Cancer Medicine
- Department of Genomic Medicine, Division of Cancer Medicine, and
| | - Traver Hart
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lawrence N. Kwong
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Genomic Medicine, Division of Cancer Medicine, and
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Liu Q, Zhu J, Huang Z, Zhang X, Yang J. Identification of Novel Cuproptosis-Related Genes Mediating the Prognosis and Immune Microenvironment in Cholangiocarcinoma. Technol Cancer Res Treat 2024; 23:15330338241239139. [PMID: 38613350 PMCID: PMC11015765 DOI: 10.1177/15330338241239139] [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: 12/10/2023] [Revised: 01/30/2024] [Accepted: 02/26/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Cuproptosis is a novel type of mediated cell death strongly associated with the progression of several cancers and has been implicated as a potential therapeutic target. However, the role of cuproptosis in cholangiocarcinoma for prognostic prediction, subgroup classification, and therapeutic strategies remains largely unknown. METHODS A systematic analysis was conducted among 146 cuproptosis-related genes and clinical information based on independent mRNA and protein datasets to elucidate the potential mechanisms and prognostic prediction value of cuproptosis-related genes. A 10-cuproptosis-related gene prediction model was constructed, and its effects on cholangiocarcinoma prognosis were significantly connected to poor patient survival. Additionally, the expression patterns of our model included genes that were validated with several cholangiocarcinoma cancer cell lines and a normal biliary epithelial cell line. RESULTS First, a 10-cuproptosis-related gene signature (ADAM9, ADAM17, ALB, AQP1, CDK1, MT2A, PAM, SOD3, STEAP3, and TMPRSS6) displayed excellent predictive performance for the overall survival of cholangiocarcinoma. The low-cuproptosis group had a significantly better prognosis than the high-cuproptosis group with transcriptome and protein cohorts. Second, compared with the high-risk and low-risk groups, the 2 groups displayed distinct tumor microenvironments, reduced proportions of endothelial cells, and increased levels of cancer-associated fibroblasts based on CIBERSORTx and EPIC analyses. Third, patients' sensitivities to chemotherapeutic drugs and immune checkpoints revealed distinctive differences between the 2 groups. Finally, in replicating the expression patterns of the 10 genes, these results were validated with quantitative real-time polymerase chain reaction results validating the abnormal expression pattern of the target genes in cholangiocarcinoma. CONCLUSIONS Collectively, we established and verified an effective prognostic model that could separate cholangiocarcinoma patients into 2 heterogeneous cuproptosis subtypes based on the molecular or protein characteristics of 10 cuproptosis-related genes. These findings may provide potential benefits for unveiling molecular characteristics and defining subgroups could improve the early diagnosis and individualized treatment of cholangiocarcinoma patients.
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Affiliation(s)
- Qiang Liu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Jianpeng Zhu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhicheng Huang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaofeng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, China
| | - Jianfeng Yang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, China
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Sharma R, Majee C, Mazumder R, Mazumder A, Tyagi PK, Chaitanya MVNL. Insight Into the Role of Alkaloids in the Different Signalling Pathways of Cholangiocarcinoma. JOURNAL OF NATURAL REMEDIES 2024:43-58. [DOI: 10.18311/jnr/2024/34661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 09/19/2023] [Indexed: 01/04/2025]
Abstract
Throughout the biliary tree, a variety of cells give rise to cholangiocarcinomas, a broad group of malignancies. The fact that these tumours are silent and asymptomatic, especially in their early stages, seriously impairs the effectiveness of available therapeutic options and contributes to their poor prognosis. Over the past few years, increased efforts have been made to identify the aetiology and signalling pathways of these tumours and to create more potent therapies. Since alkaloids are more potent and effective against cholangiocarcinoma cell lines, they have gained importance in the treatment of cholangiocarcinoma. In cell lines with cholangiocarcinoma, they promote apoptosis. and restrict the spread of cells, departure, and development. This review highlights the recent developments in the study of CCA, primarily concentrating on the regulation of the signalling pathway and revealing alkaloids demonstrating strong anti-cholangiocarcinoma efficacy, providing researchers with a rapid approach for the future development of powerful and efficient pharmaceutical compounds.
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Zhang N, Zhu W, Zhang S, Liu T, Gong L, Wang Z, Zhang W, Cui Y, Wu Q, Li J, Yu H, El-Omar EM, Hao J, Lu W. A Novel Bifidobacterium/Klebsiella Ratio in Characterization Analysis of the Gut and Bile Microbiota of CCA Patients. MICROBIAL ECOLOGY 2023; 87:5. [PMID: 38030815 PMCID: PMC10687116 DOI: 10.1007/s00248-023-02318-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 10/06/2023] [Indexed: 12/01/2023]
Abstract
Cholangiocarcinoma (CCA) is a serious health problem worldwide. The gut and bile microbiota have not been clearly characterized in patients with CCA, and better noninvasive diagnostic approaches for CCA need to be established. The aim of this study was to investigate the characteristics of the gut and bile microbiota in CCA patients. Forty-two CCA patients and 16 healthy normal controls (HNCs) were enrolled. DNA was extracted from fecal and bile samples and subjected to 16S rRNA gene analysis. We found that there were significant differences in the species diversity, structure, and composition of the microbial communities between the CCA group and the HNC grouAt the phylum level, compared with that in the HNC group, the relative abundance of Firmicutes and Actinobacteriota was significantly decreased in the CCA group, whereas Proteobacteria and Bacteroidota were significantly enriched. The Firmicutes/Bacteroidota (F/B) ratio significantly decreased in the CCA group compared to the HNC grouThe relative abundance of Klebsiella in the CCA group was significantly higher than that in the HNC group, while the relative abundance of Bifidobacterium was significantly decreased. The Bifidobacterium/Klebsiella (B/K) ratio was established as a novel biomarker and was found to be significantly decreased in the CCA group compared with the HNC grouOur findings provide evidence supporting the use of Klebsiella and Bifidobacterium as noninvasive intestinal microbiomarkers for improving the diagnosis of CCA.
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Affiliation(s)
- Ningning Zhang
- Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute and Hospital, Liver Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Wenwen Zhu
- Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute and Hospital, Liver Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Shuwen Zhang
- Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute and Hospital, Liver Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Tian Liu
- Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute and Hospital, Liver Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Lan Gong
- Department of Medicine, Research and Education Centre Building, University of New South Wales, Level 2, 4-10 South Street, Sydney, Australia
- Microbiome Research Centre (MRC), St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia
| | - Zeyu Wang
- Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute and Hospital, Liver Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Wei Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Yunlong Cui
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Qiang Wu
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Jingtong Li
- Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute and Hospital, Liver Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Hao Yu
- Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute and Hospital, Liver Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China
| | - Emad M El-Omar
- Department of Medicine, Research and Education Centre Building, University of New South Wales, Level 2, 4-10 South Street, Sydney, Australia.
- Microbiome Research Centre (MRC), St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia.
| | - Jihui Hao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China.
| | - Wei Lu
- Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute and Hospital, Liver Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China.
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Hatia RI, Eluri M, Hawk ET, Shalaby A, Karatas E, Shalaby A, Abdelhakeem A, Abdel-Wahab R, Chang P, Rashid A, Jalal PK, Amos CI, Han Y, Armaghany T, Shroff RT, Li D, Javle M, Hassan MM. Independent of Primary Sclerosing Cholangitis and Cirrhosis, Early Adulthood Obesity Is Associated with Cholangiocarcinoma. Cancer Epidemiol Biomarkers Prev 2023; 32:1338-1347. [PMID: 37540502 DOI: 10.1158/1055-9965.epi-23-0388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/14/2023] [Accepted: 08/01/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND It is estimated that 6% to 20% of all cholangiocarcinoma (CCA) diagnoses are explained by primary sclerosing cholangitis (PSC), but the underlying risk factors in the absence of PSC are unclear. We examined associations of different risk factors with intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) in the United States. METHODS We conducted a case-control study of 121 patients with ECC and 308 patients with ICC treated at MD Anderson Cancer Center between May 2014 and March 2020, compared with 1,061 healthy controls. Multivariable logistic regression analysis was applied to estimate the adjusted OR (AOR) and 95% confidence interval (CI) for each risk factor. RESULTS Being Asian, diabetes mellitus, family history of cancer, and gallbladder stones were associated with higher odds of developing ICC and ECC. Each 1-unit increase in body mass index in early adulthood (ages 20-40 years) was associated with a decrease in age at diagnosis of CCA (6.7 months, P < 0.001; 6.1 months for ICC, P = 0.001; 8.2 months for ECC, P = 0.007). A family history of cancer was significantly associated with the risk of ICC and ECC development; the AORs (95% CI) were 1.11 (1.06-1.48) and 1.32 (1.01-2.00) for ICC and ECC, respectively. CONCLUSIONS In this study, early adulthood onset of obesity was significantly associated with CCA and may predict early diagnosis at younger age than normal weight individuals. IMPACT The study highlights the association between obesity and CCA, independent of PSC. There is a need to consider the mechanistic pathways of obesity in the absence of fatty liver and cirrhosis.
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Affiliation(s)
- Rikita I Hatia
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Madhulika Eluri
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ernest T Hawk
- Division of Cancer Prevention & Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Akram Shalaby
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Elif Karatas
- Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Ahmed Shalaby
- Department of Radiation Oncology, Robert Wood Johnson University Hospital, New Brunswick, New Jersey
| | - Ahmed Abdelhakeem
- Department of Internal Medicine, Baptist Hospital of Southeast Texas, Beaumont, Texas
| | - Reham Abdel-Wahab
- Department of Melanoma Medicine Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Clinical Oncology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ping Chang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Prasun K Jalal
- Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
| | - Christopher I Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas
| | - Younghun Han
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas
| | - Tannaz Armaghany
- Division of Hematology & Oncology, Baylor College of Medicine, Houston, Texas
| | - Rachna T Shroff
- Division of Hematology/Oncology, University of Arizona Cancer Center, Tucson, Arizona
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Manal M Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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9
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Jiang H, Wang Z. Prognostic role of the controlling nutritional status (CONUT) score in patients with biliary tract cancer: a meta-analysis. Ann Med 2023; 55:2261461. [PMID: 37751485 PMCID: PMC10524794 DOI: 10.1080/07853890.2023.2261461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/15/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Previous reports have not reached consistent results regarding the prognostic significance of the controlling nutritional status (CONUT) score in biliary tract cancer (BTC). Therefore, the present meta-analysis was conducted to investigate the precise role of the CONUT score in predicting the prognosis of BTC. METHODS Electronic platforms including Web of Science, PubMed, Cochrane Library, and Embase were comprehensively searched up to May 2, 2023. We also determined combined hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate the role of the CONUT score in predicting the prognosis of patients with BTC. RESULTS Ten studies involving 1,441 patients were included in the present study. Nine studies treated patients with surgical resection, and one study used percutaneous transhepatic biliary stenting (PTBS) plus 125I seed intracavitary irradiation. Based on the combined data, a higher CONUT score significantly predicted dismal overall survival (OS) (HR = 1.94, 95%CI = 1.41-2.66, p < 0.001), inferior recurrence-free survival (RFS) (HR = 1.79, 95%CI = 1.48-2.17, p < 0.001) in BTC, and low differentiation (OR = 1.57, 95%CI = 1.15-2.14, p = 0.004). Nonetheless, the CONUT score was not related to sex, lymph node metastasis, microvascular invasion, perineural invasion, distant metastasis, TNM stage, or tumor number in patients with BTC. CONCLUSION Higher CONUT scores significantly predicted worse OS and RFS in patients with BTC. Moreover, BTC patients with high CONUT scores tended to have poor tumor differentiation. The CONUT score could help clinicians stratify high-risk patients with BTC and devise individualized treatment plans.
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Affiliation(s)
- Huijun Jiang
- Clinical Laboratory, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Zhibing Wang
- Department of General Surgery, Traditional Chinese Medical Hospital of Huzhou Affiliated to Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
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10
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Asombang AW, Chishinga N, Mohamed MF, Nkhoma A, Chipaila J, Nsokolo B, Manda-Mapalo M, Montiero JFG, Banda L, Dua KS. Systematic review of cholangiocarcinoma in Africa: epidemiology, management, and clinical outcomes. BMC Gastroenterol 2023; 23:66. [PMID: 36906562 PMCID: PMC10007746 DOI: 10.1186/s12876-023-02687-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 02/20/2023] [Indexed: 03/13/2023] Open
Abstract
BACKGROUND The prevalence, management, and clinical outcomes of cholangiocarcinoma in Africa are unknown. The aim is to conduct a comprehensive systematic review on the epidemiology, management, and outcomes of cholangiocarcinoma in Africa. METHODS We searched PubMed, EMBASE, Web of Science and CINHAL from inception up to November 2019 for studies on cholangiocarcinoma in Africa. The results reported follow PRISMA guidelines. Quality of studies and risk of bias were adapted from a standard quality assessment tool. Descriptive data were expressed as numbers with proportions and Chi-squared test was used to compare proportions. P values < 0.05 were considered significant. RESULTS A total of 201 citations were identified from the four databases. After excluding duplicates, 133 full texts were reviewed for eligibility, and 11 studies were included. The 11 studies are reported from 4 countries only: 8 are from North Africa (Egypt 6 and Tunisia 2), and 3 in Sub-Saharan Africa (2 in South Africa, 1 in Nigeria). Ten studies reported management and outcomes, while one study reported epidemiology and risk factors. Median age for cholangiocarcinoma ranged between 52 and 61 years. Despite the proportion with cholangiocarcinoma being higher among males than females in Egypt, this gender disparity could not be demonstrated in other African countries. Chemotherapy is mainly used for palliative care. Surgical interventions are curative and prevent cancer progression. Statistical analyses were performed with Stata 15.1. CONCLUSION The known global major risk factors such as primary sclerosing cholangitis, Clonorchis sinensis and Opisthorchis viverrini infestation are rare. Chemotherapy treatment was mainly used for palliative treatment and was reported in three studies. Surgical intervention was described in at least 6 studies as a curative modality of treatment. Diagnostic capabilities such as radiographic imaging and endoscopic are lacking across the continent which most likely plays a role in accurate diagnosis.
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Affiliation(s)
- Akwi W Asombang
- Division of Gastroenterology/Hepatology, Massachusetts General Hospital, 15 Parkman Street, Wang 5, Boston, MA, 02114, USA.
| | - Nathaniel Chishinga
- Department of Internal Medicine, Piedmont Athens Regional Hospital, 1270 Prince Avenue, Suite 102, Athens, GA, 30606, USA
| | - Mouhand F Mohamed
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | - Alick Nkhoma
- Department of Gastroenterology, Royal Stoke University Hospital, University Hospitals of North Midlands NHS Trust, Staffordshire, ST4 6QG, UK
| | - Jackson Chipaila
- Department of Surgery, University Teaching Hospital-Adult Hospital, Lusaka, 10101, Zambia
| | - Bright Nsokolo
- Department of Internal Medicine, Levy Mwanawasa Medical University, Levy Mwanawasa University Teaching Hospital, Lusaka, 10101, Zambia
| | - Martha Manda-Mapalo
- Division of Hematology/Oncology, Department of Internal Medicine, The University of New Mexico, Albuquerque, NM, 87106, USA
| | | | - Lewis Banda
- Hematology/Oncology, Cancer Disease Hospital, Lusaka, 10101, Zambia
| | - Kulwinder S Dua
- Department of Medicine and Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
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11
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Toyoda J, Sahara K, Maithel SK, Abbott DE, Poultsides GA, Wolfgang C, Fields RC, He J, Scoggins C, Idrees K, Shen P, Endo I, Pawlik TM. Prognostic Utility of Systemic Immune-Inflammation Index After Resection of Extrahepatic Cholangiocarcinoma: Results from the U.S. Extrahepatic Biliary Malignancy Consortium. Ann Surg Oncol 2022; 29:7605-7614. [PMID: 35768667 DOI: 10.1245/s10434-022-12058-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/05/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND We sought to define the association of the systemic immune inflammation index (SII) with prognosis and adjuvant therapy benefit among patients undergoing resection of extrahepatic cholangiocarcinoma (eCCA). METHODS The impact of SII on overall (OS) and recurrence-free survival (RFS) following resection of eCCA was assessed and compared with other inflammatory markers and traditional prognostic factors. Propensity score matching (PSM) was used to determine the impact of adjuvant therapy (AT) on OS and RFS relative to low versus high SII. RESULTS Patients with high versus low SII had worse 5-year OS (15.9% vs. 27.9%) and RFS (12.4% vs. 20.9%) (both p < 0.01). On multivariate analysis, high SII remained associated with worse OS (HR = 1.50, 95% CI 1.20-1.87) and RFS (HR = 1.46, 95% CI 1.18-1.81). Patients with T1/2 disease and a high-SII had worse 5-year OS versus individuals with T3/4 disease and low-SII (5-year OS: T1/2 & low-SII 35.6%, T1/2 & high-SII 16.4%, T3/4 & low-SII 22.1%, T3/4 & high-SII 15.6%, p < 0.01). Similarly, 5-year OS was comparable among individuals with N0 and high-SII versus N1 and low-SII (5-year OS: N0 & high-SII 23.2%, N1 and low-SII 19.8%, p = 0.95). On PSM, AT improved OS and RFS among patients with high SII (5-year OS: 22.5% vs. 12.3%, p < 0.01, 5-year RFS: 19.0% vs. 12.5%; p = 0.01) but not individuals with low SII (5-year OS: 22.9% vs. 26.9%; p = 0.98, 5-year RFS: 18.5% vs. 19.9%; p = 0.94). CONCLUSIONS SII was independently associated with postoperative OS and RFS following curative-intent resection of eCCA. High SII up-staged patients relative T- and N-categories and identified patients with high SII as the most likely to benefit from AT.
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Affiliation(s)
- Junya Toyoda
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Kota Sahara
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan.,Department of Surgery, The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH, USA
| | - Shishir K Maithel
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Daniel E Abbott
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - George A Poultsides
- Department of Surgery, Stanford University Medical Center, Stanford, CA, USA
| | | | - Ryan C Fields
- Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
| | - Jin He
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Charles Scoggins
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, KY, USA
| | - Kamran Idrees
- Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Perry Shen
- Department of Surgery, Wake Forest University, Winston-Salem, NC, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH, USA.
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12
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Uson Junior PLS, Majeed U, Yin J, Botrus G, Sonbol MB, Ahn DH, Starr JS, Jones JC, Babiker H, Inabinett SR, Wylie N, Boyle AW, Bekaii-Saab TS, Gores GJ, Smoot R, Barrett M, Nagalo B, Meurice N, Elliott N, Petit J, Zhou Y, Arora M, Dumbauld C, Barro O, Baker A, Bogenberger J, Buetow K, Mansfield A, Mody K, Borad MJ. Cell-Free Tumor DNA Dominant Clone Allele Frequency Is Associated With Poor Outcomes in Advanced Biliary Cancers Treated With Platinum-Based Chemotherapy. JCO Precis Oncol 2022; 6:e2100274. [PMID: 35666960 PMCID: PMC9200394 DOI: 10.1200/po.21.00274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 10/06/2021] [Accepted: 04/12/2022] [Indexed: 12/14/2022] Open
Abstract
PURPOSE This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. MATERIALS AND METHODS We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). RESULTS The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. CONCLUSION DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.
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Affiliation(s)
- Pedro Luiz Serrano Uson Junior
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
- Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Umair Majeed
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Jun Yin
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN
| | - Gehan Botrus
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Mohamad Bassam Sonbol
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Daniel H. Ahn
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Jason S. Starr
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Jeremy C. Jones
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Hani Babiker
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Samantha R. Inabinett
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Natasha Wylie
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Ashton W.R. Boyle
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Tanios S. Bekaii-Saab
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Rochester, MN
| | - Rory Smoot
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Michael Barrett
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | - Bolni Nagalo
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Nathalie Meurice
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | - Natalie Elliott
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Joachim Petit
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Yumei Zhou
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Mansi Arora
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Chelsae Dumbauld
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Oumar Barro
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - Alexander Baker
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | - James Bogenberger
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
| | | | | | - Kabir Mody
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Mitesh J. Borad
- Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN
- Department of Molecular Medicine, Rochester, MN
- Mayo Clinic Cancer Center, Phoenix, AZ
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13
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Mody K, Jain P, El-Refai SM, Azad NS, Zabransky DJ, Baretti M, Shroff RT, Kelley RK, El-Khouiery AB, Hockenberry AJ, Lau D, Lesinski GB, Yarchoan M. Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures. JCO Precis Oncol 2022; 6:e2100510. [PMID: 35675577 PMCID: PMC9200391 DOI: 10.1200/po.21.00510] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/14/2022] [Accepted: 04/15/2022] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Biliary tract cancers (BTCs) are aggressive cancers that carry a poor prognosis. An enhanced understanding of the immune landscape of anatomically and molecularly defined subsets of BTC may improve patient selection for immunotherapy and inform immune-based combination treatment strategies. METHODS We analyzed deidentified clinical, genomic, and transcriptomic data from the Tempus database to determine the mutational frequency and mutational clustering across the three major BTC subtypes (intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer). We subsequently determined the relationship between specific molecular alterations and anatomical subsets and features of the BTC immune microenvironment. RESULTS We analyzed 454 samples of BTC, of which the most commonly detected alterations were TP53 (42.5%), CDKN2A (23.4%), ARID1A (19.6%), BAP1 (15.5%), KRAS (15%), CDKN2B (14.2%), PBRM1 (11.7%), IDH1 (11.7%), TERT (8.4%), KMT2C (10.4%) and LRP1B (8.4%), and FGFR2 fusions (8.7%). Potentially actionable molecular alterations were identified in 30.5% of BTCs including 39.1% of IHC. Integrative cluster analysis revealed four distinct molecular clusters, with cluster 4 predominately associated with FGFR2 rearrangements and BAP1 mutations in IHC. Immune-related biomarkers indicative of an inflamed tumor-immune microenvironment were elevated in gallbladder cancers and in cluster 1, which was enriched for TP53, KRAS, and ATM mutations. Multiple common driver genes, including TP53, FGFR2, IDH1, TERT, BRAF, and BAP1, were individually associated with unique BTC immune microenvironments. CONCLUSION BTC subtypes exhibit diverse DNA alterations, RNA inflammatory signatures, and immune biomarkers. The association between specific BTC anatomical subsets, molecular alterations, and immunophenotypes highlights new opportunities for therapeutic development.
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Affiliation(s)
| | | | | | | | | | | | - Rachna T. Shroff
- Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ
| | - R. Katie Kelley
- The University of California, San Francisco Medical Center, San Francisco, CA
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14
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Mohamed FEZ, Jalan R, Minogue S, Andreola F, Habtesion A, Hall A, Winstanley A, Damink SO, Malagó M, Davies N, Luong TV, Dhillon A, Mookerjee R, Dhar D, Al-Jehani RM. Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development. Dig Dis Sci 2022; 67:1806-1821. [PMID: 33939146 DOI: 10.1007/s10620-021-06973-9] [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: 05/13/2019] [Accepted: 03/25/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Toll-like receptors (TLRs) are key players in innate immunity and modulation of TLR signaling has been demonstrated to profoundly affect proliferation and growth in different types of cancer. However, the role of TLRs in human intrahepatic cholangiocarcinoma (ICC) pathogenesis remains largely unexplored. AIMS We set out to determine if TLRs play any role in ICCs which could potentially make them useful treatment targets. METHODS Tissue microarrays containing samples from 9 human ICCs and normal livers were examined immunohistochemically for TLR4, TLR7, and TLR9 expression. Proliferation of human ICC cell line HuCCT1 was measured by MTS assay following treatment with CpG-ODN (TLR9 agonist), imiquimod (TLR7 agonist), chloroquine (TLR7 and TLR9 inhibitor) and IRS-954 (TLR7 and TLR9 antagonist). The in vivo effects of CQ and IRS-954 on tumor development were also examined in a NOD-SCID mouse xenograft model of human ICC. RESULTS TLR4 was expressed in all normal human bile duct epithelium but absent in the majority (60%) of ICCs. TLR7 and TLR9 were expressed in 80% of human ICCs. However, TLR7 was absent in all cases of normal human bile duct epithelium and only one was TLR9 positive. HuCCT1 cell proliferation in vitro significantly increased following IMQ or CpG-ODN treatment (P < 0.03 and P < 0.002, respectively) but decreased with CQ (P < 0.02). In the mouse xenograft model there was significant reduction in size of tumors from CQ and IRS-954 treated mice compared to untreated controls. CONCLUSION TLR7 and TLR9 should be further explored for their potential as actionable targets in the treatment of ICC.
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Affiliation(s)
- Fatma El Zahraa Mohamed
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.,Pathology Department, Minia University, El-Minia, Egypt
| | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Shane Minogue
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Fausto Andreola
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Abeba Habtesion
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Andrew Hall
- UCL Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK
| | - Alison Winstanley
- Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Steven Olde Damink
- Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK
| | - Massimo Malagó
- Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK
| | - Nathan Davies
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Amar Dhillon
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Rajeshwar Mookerjee
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Dipok Dhar
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Rajai Munir Al-Jehani
- UCL Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK.
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15
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Yang H, Jiang J, Hu Z, Zhang B, Cai W, Xu L, Lu K. Clinical Experience of Diagnosis and Surgical Treatment of 6 Cases of Acute Subhepatic Appendicitis. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:4969774. [PMID: 35469233 PMCID: PMC9034925 DOI: 10.1155/2022/4969774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/19/2022] [Indexed: 11/30/2022]
Abstract
To summarize the experience of diagnosis and surgical treatment of 6 cases of acute subhepatic appendicitis. The clinical data of 6 patients with subacute appendicitis in Zhejiang Provincial People's Hospital from July 2018 to December 2019 were analyzed retrospectively. Results. There were 5 males and 1 female. All 6 cases were diagnosed as appendicitis by abdominal CT before operation. All patients underwent laparoscopic appendectomy without conversion to laparotomy. One case of ectopic appendix was located under the liver with absence of ascending colon, one case of ectopic appendix was located under the liver with ectopic ascending colon of transverse colon, one case of appendix head was located in the liver cyst, and the resection of liver cyst was performed at the same time, and three cases of retrocolonic appendix head were located under the liver. Postoperative pathology confirmed appendicitis. For patients with right upper abdominal pain and tenderness, the possibility of subhepatic appendicitis should be considered before operation. Emergency abdominal CT has more advantages than ultrasound. Laparoscopy can not only make a definite diagnosis but also perform appendectomy at the same time.
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Affiliation(s)
- Hongguo Yang
- Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Junjie Jiang
- Zhejiang Chinese Medical University, Hangzhou 31001, China
| | - Zhiming Hu
- Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Bing Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Wenwei Cai
- Department of Emergency, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Liming Xu
- Department of Emergency, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Kefeng Lu
- Department of Ultrasonography, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
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16
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Prognostic value of Dickkopf-1 and ß-catenin expression according to the antitumor immunity of CD8-positive tumor-infiltrating lymphocytes in biliary tract cancer. Sci Rep 2022; 12:1931. [PMID: 35121803 PMCID: PMC8816896 DOI: 10.1038/s41598-022-05914-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 01/20/2022] [Indexed: 12/02/2022] Open
Abstract
The role of β-catenin and Dickkopf-1 (DKK1) is dependent on the specific immunobiology of T cell inflammation in biliary tract cancer (BTC). We aimed to analyze the role of DKK1 or β-catenin as a prognostic factor in BTC, and determine the clinical associations of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocytes (TIL). We used data from The Cancer Genome Atlas Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. CD8+ TIL expression was a significant predictor of favorable overall survival (OS) and relapse-free survival (RFS) (median OS, 34.9 months in high-TIL, 16.7 months in low-TIL, P < 0.0001 respectively; median RFS, 27.1 months in high-TIL, 10.0 months in low-TIL, P < 0.0001 respectively). In the high-CD8+ TIL BTC group, the tumor expression of β-catenin and DKK1 had a significant negative impact on either OS or RFS. In the low-TIL BTC group, there were no differences according to ß-catenin and DKK1 expression. Cox regression multivariate analysis demonstrated that CD8+ TIL and β-catenin retained significant association with OS. Among patients with resected BTC, the β-catenin and DKK1 protein and high CD8+ TIL levels were associated with poor and good clinical outcomes, respectively.
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17
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Systemic Treatment for Metastatic Biliary Tract Cancer: State of the Art and a Glimpse to the Future. Curr Oncol 2022; 29:551-564. [PMID: 35200550 PMCID: PMC8871084 DOI: 10.3390/curroncol29020050] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 12/30/2022] Open
Abstract
Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarcinoma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy.
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Matsumoto K, Ohara T, Fujisawa M, Takaki A, Takahara M, Kato H, Yoshida R, Umeda Y, Yagi T, Matsukawa A, Okada H. Diagnostic Utility of the PD-L1 Immunostaining in Biopsy Specimens of Patients with Biliary Tract Neoplasms. J Gastrointest Surg 2022; 26:1213-1223. [PMID: 35137343 PMCID: PMC9184404 DOI: 10.1007/s11605-021-05197-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/30/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND Anti-programmed death 1/programmed death ligand 1 (PD1/PD-L1) antibodies have been successfully used as treatment agents for several solid tumors; however, it is difficult to predict their effectiveness. We evaluated whether biopsy specimens could predict the positive status of PD-L1 in surgically resected tissue. METHODS Among 91 patients who underwent tissue sampling with endoscopic or liver biopsy before surgery for biliary tract neoplasms in an academic center, 45 (49%) patients were selected for retrospective analysis because the quality and quantity of their biopsy specimens were adequate for histologic evaluation. We performed immunohistochemical staining to investigate the PD-L1 expression in both resected and biopsy specimens. The percentage of the positively stained cells was calculated for subsequent use in the correlation investigation. RESULTS The biopsy methods were endoscopic retrograde cholangiopancreatography (ERCP) in 28 cases, percutaneous liver biopsy in 10 cases, and endoscopic ultrasound fine-needle aspiration in 7 cases. Among the 45 patients, when patients with > 10% positive tumor cells in surgically resected tissues were regarded as truly positive PD-L1, the positive and negative concordance rates between surgically resected tissues and biopsy samples were 56% (5/9) and 100% (36/36), respectively. With regard to the use of preoperative biopsy as a diagnostic tool, all (5/5) PD-L1-positive patients had a positive resected specimen. The accuracy of each biopsy method was as follows: ERCP, 89% (25/28); fine-needle aspiration, 86% (6/7); and liver biopsy, 100% (10/10). CONCLUSIONS Biopsy samples could be a surrogate material for the assessment of the PD-L1 expression with substantial positive and high negative concordance rates.
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Affiliation(s)
- Kazuyuki Matsumoto
- grid.261356.50000 0001 1302 4472Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Toshiaki Ohara
- grid.261356.50000 0001 1302 4472Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Masayoshi Fujisawa
- grid.261356.50000 0001 1302 4472Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Akinobu Takaki
- grid.261356.50000 0001 1302 4472Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Masahiro Takahara
- grid.261356.50000 0001 1302 4472Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Hironari Kato
- grid.261356.50000 0001 1302 4472Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Ryuichi Yoshida
- grid.261356.50000 0001 1302 4472Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Yuzo Umeda
- grid.261356.50000 0001 1302 4472Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Takahito Yagi
- grid.261356.50000 0001 1302 4472Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Akihiro Matsukawa
- grid.261356.50000 0001 1302 4472Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroyuki Okada
- grid.261356.50000 0001 1302 4472Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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19
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Zhang Q, Liu X, Wei S, Zhang L, Tian Y, Gao Z, Jin M, Yan S. Lenvatinib Plus PD-1 Inhibitors as First-Line Treatment in Patients With Unresectable Biliary Tract Cancer: A Single-Arm, Open-Label, Phase II Study. Front Oncol 2021; 11:751391. [PMID: 34900698 PMCID: PMC8651538 DOI: 10.3389/fonc.2021.751391] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
Objective We investigated lenvatinib plus programmed cell death-1 (PD-1) inhibitors as a first-line treatment for initially unresectable biliary tract cancer (BTC). Methods In this Phase II study, adults with initially unresectable BTC received lenvatinib (body weight ≥60 kg, 12 mg; <60 kg, 8 mg) daily and PD-1 inhibitors (pembrolizumab/tislelizumab/sintilimab/camrelizumab 200 mg or toripalimab 240 mg) every 3 weeks. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included surgical conversion rate, disease control rate (DCR), event-free survival (EFS), overall survival (OS) and tumor biomarkers. Results Among 38 enrolled patients, the ORR was 42.1% and the DCR was 76.3%. Thirteen (34.2%) patients achieved downstaging and underwent surgery, six of whom (46.2%) achieved a major pathologic response (n=2) or partial pathologic response (n=4) in the primary tumor. In total, 84.2% of patients experienced ≥1 treatment-related adverse event (TRAE), 34.2% experienced a Grade ≥3 TRAE and no treatment-related deaths occurred. After a median follow-up of 13.7 months the median EFS was 8.0 months (95% CI: 4.6–11.4) and the median OS was 17.7 months (95% CI: not estimable). Conclusions Lenvatinib plus PD-1 inhibitors showed promising anti-tumor efficacy in patients with initially unresectable BTC and was generally well tolerated. Clinical Trial Registration www.chictr.org.cn, ChiCTR2100044476.
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Affiliation(s)
- Qiyi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
| | - Xingyu Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
| | - Shumei Wei
- Department of Pathology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Lufei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
| | - Yang Tian
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
| | - Zhenzhen Gao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
| | - Ming Jin
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
| | - Sheng Yan
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
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20
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Damrauer JS, Smith MA, Walter V, Thennavan A, Mose LE, Selitsky SR, Hoadley KA. Genomic characterization of rare molecular subclasses of hepatocellular carcinoma. Commun Biol 2021; 4:1150. [PMID: 34608257 PMCID: PMC8490450 DOI: 10.1038/s42003-021-02674-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022] Open
Abstract
Primary liver cancer, consisting of both cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC), is the second leading cause of cancer deaths worldwide. Our goal is to genomically characterize rare HCC subclasses to provide insight into disease biology. Leveraging The Cancer Genome Atlas (TCGA) to perform a combined analysis of CCA (n = 36) and HCC (n = 275), we integrated multiple genomic platforms, to assess transcriptional profiles, mutational signatures, and copy number patterns to uncover underlying etiology and linage specific patterns. We identified two molecular classes distinct from prototypical HCC tumors. The first, CCA-Like, although histologically indistinguishable from HCC, had enrichment of CCA mutations (IDH1, BAP1), mutational signatures, and transcriptional patterns (SOX9, KRT19). CCA-Like, however, retained a copy number landscape similar to HCC, suggesting a hepatocellular linage. The second, Blast-Like, is enriched in TP53 mutations, HBV infection, exposure related mutational signatures and transcriptionally similar to hepatoblasts. Although these subclasses are molecularly distinct, they both have a worse progression-free survival compared to classical HCC tumors, yet are clinically treated the same. The identification of and characterization of CCA-Like and Blast-Like subclasses advance our knowledge of HCC as well as represents an urgent need for the identification of class specific biomarkers and targeted therapy.
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Affiliation(s)
- Jeffrey S Damrauer
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Markia A Smith
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Vonn Walter
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Aatish Thennavan
- Oral and Craniofacial Biomedicine Program, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA
| | - Lisle E Mose
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sara R Selitsky
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
- Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Katherine A Hoadley
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
- Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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21
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Sobhrakhshankhah E, Sohrabi M, Norouzi HR, Zamani F, Ajdarkosh H, Nikkhah M, Khoonsari MR, Faraji AH. Tissue Sampling through Endoscopic Ultrasound-Guided Fine Needle Aspiration versus Endoscopic Retrograde Cholangiopancreatographic Brushing Cytology Technique in Suspicious Malignant Biliary Stricture. Middle East J Dig Dis 2021; 13:294-301. [PMID: 36606017 PMCID: PMC9489447 DOI: 10.34172/mejdd.2021.238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 06/09/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Differentiation of benign and malignant biliary strictures plays a pivotal role in managing biliary strictures. Brush cytology via endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are two diagnostic methods. In the present study, we aimed to compare the accuracy of the results of EUS-FNA and ERCP-based sampling of biliary strictures. METHODS In a prospective study, between January 2019 and March 2020, patients with indeterminate biliary strictures who had no history of hepatobiliary surgery, opium usage, cancer of pancratobiliary system, and acute liver disease were selected. They underwent EUS and ERCP in the same session. They were followed up for 6 months, and the sensitivity, specificity, positive and negative predictive values, and accuracy of these imaging modalities were compared. RESULTS A total of 60 patients were enrolled. 28 lesions were located in the distal and 32 lesions in the proximal parts of the biliary tree. 55 malignant and 5 benign lesions were diagnosed. The sensitivity and accuracy of EUS-FNA and ERCP tissue sampling were 78.2% and 80.0% versus 50.9% and 55.0%, respectively (p = 0.024). The combination of both methods improved the sensitivity and accuracy to 85.5% and 86.7%, respectively. Regarding the location, EUS-FNA is superior to ERCP-brush cytology in diagnosing proximal lesions with sensitivity and specificity of 73.3% and 75.0% vs. 50.0% and 53.1%, respectively (p = 0.04). CONCLUSION EUS-FNA is superior to ERCP brushing in the diagnosis of indeterminate biliary strictures, particularly in distal lesions. Combining ERCP brushing and EUS-FNA improves the diagnosis accuracy.
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Affiliation(s)
- Elham Sobhrakhshankhah
- Gastrointestinal and Liver Disease Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Masoudreza Sohrabi
- Gastrointestinal and Liver Disease Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Hamid Reza Norouzi
- Gastrointestinal and Liver Disease Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mehdi Nikkhah
- Gastrointestinal and Liver Disease Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mahmood Reza Khoonsari
- Gastrointestinal and Liver Disease Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Amir Hossein Faraji
- Gastrointestinal and Liver Disease Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
,Corresponding Author: Amirhossein Faraji, MD Gastrointestinal and Liver Disease Research Center (GILDRC), Firoozgar Hospital,ValiasrSq. Tehran,Iran Telefax: + 98 21 88941831
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22
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Spizzo G, Puccini A, Xiu J, Goldberg RM, Grothey A, Shields AF, Arora SP, Khushman M, Salem ME, Battaglin F, Baca Y, El-Deiry WS, Philip PA, Nassem M, Hall M, Marshall JL, Kocher F, Amann A, Wolf D, Korn WM, Lenz HJ, Seeber A. Molecular profile of BRCA-mutated biliary tract cancers. ESMO Open 2021; 5:e000682. [PMID: 32576609 PMCID: PMC7312328 DOI: 10.1136/esmoopen-2020-000682] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/04/2020] [Accepted: 03/13/2020] [Indexed: 12/21/2022] Open
Abstract
Introduction Prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. BRCA mutations are known to occur in BTC but their frequency and the molecular landscape in which they are observed in distinct sites of BTC remain unknown. Material and methods Tumour samples from 1292 patients with BTC, comprising intrahepatic cholangiocarcinoma (IHC, n=746), extrahepatic cholangiocarcinoma (EHC, n=189) and gallbladder cancer (GBC, n=353), were analysed using next-generation sequencing (NGS). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations. Determination of tumour mismatch repair (MMR) or microsatellite instability (MSI) status was done by fragment analysis, immunohistochemistry and the evaluation of known microsatellite loci by NGS. Programmed death ligand 1 expression was analysed using immunohistochemistry. Results Overall, BRCA mutations were detected in 3.6% (n=46) of samples (BRCA1: 0.6%, BRCA2: 3%) with no significant difference in frequency observed based on tumour site. In GBC and IHC, BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4%, p<0.05) while in EHC, similar frequency was observed (2.6% for BRCA2 vs 2.1% for BRCA1). BRCA mutations were associated with a higher rate in subjects with MSI-H/deficient mismatch repair (19.5% vs 1.7%, p<0.0001) and tumours with higher TMB, regardless of the MMR or MSI status (p<0.05). Conclusions BRCA mutations are found in a subgroup of patients with BTC and are characterised by a distinct molecular profile. These data provide a rationale testing poly(ADP-ribose)polymeraseinhibitors and other targeted therapies in patients with BRCA-mutant BTC.
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Affiliation(s)
- Gilbert Spizzo
- Department of Internal Medicine, Oncologic Day Hospital, Hospital of Bressanone (SABES-ASDAA), Bressanone-Brixen, Italy
| | - Alberto Puccini
- Oncologia Medica 1, Ospedale Policlinico San Martino-IRCCS, Genoa, Italy
| | - Joanne Xiu
- Caris Life Sciences, Phoenix, Arizona, USA
| | - Richard M Goldberg
- West Virginia University Cancer Institute, Morgantown, West Virginia, USA
| | | | - Anthony F Shields
- epartment of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA
| | | | | | | | - Francesca Battaglin
- University of Southern California-Norris Comprehensive Cancer Center and Hospital, Los Angeles, California, USA
| | | | | | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Madiha Nassem
- University of Southern California-Norris Comprehensive Cancer Center and Hospital, Los Angeles, California, USA
| | - Michael Hall
- Fox Chase Cancer Institute, Philadelphia, Pennsylvania, USA
| | - John L Marshall
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Washington, DC, USA
| | - Florian Kocher
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | - Arno Amann
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | - Dominik Wolf
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Heinz-Josef Lenz
- University of Southern California-Norris Comprehensive Cancer Center and Hospital, Los Angeles, California, USA
| | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
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23
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Boilève A, Hilmi M, Delaye M, Tijeras-Raballand A, Neuzillet C. Biomarkers in Hepatobiliary Cancers: What is Useful in Clinical Practice? Cancers (Basel) 2021; 13:2708. [PMID: 34070929 PMCID: PMC8198554 DOI: 10.3390/cancers13112708] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) exhibit a poor prognosis with 5-year overall survival rates around 15%, all stages combined. Most of these primary liver malignancies are metastatic at diagnostic, with only limited therapeutic options, relying mainly on systemic therapies. Treatment modalities are different yet partially overlapping between HCC and BTC. The complex molecular profile of BTC yields to several actionable therapeutic targets, contrary to HCC that remains the field of antiangiogenic drugs in non-molecularly selected patients. Immunotherapy is now validated in the first line in HCC in combination with bevacizumab, while clinical activity of single agent immunotherapy appears limited to a subset of patients in BTC, still poorly characterized, and combinations are currently under investigation. In this review, we provide a critical evaluation and grading of clinical relevance on (i) the main prognostic biomarkers in HCC and BTC, (ii) the main theragnostic biomarkers in both tumors, and lastly (iii) what is recommended in clinical practice.
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Affiliation(s)
- Alice Boilève
- Gustave Roussy, Département de Médecine Oncologique, 94805 Villejuif, France;
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
| | - Marc Hilmi
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
| | - Matthieu Delaye
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
| | - Annemilaï Tijeras-Raballand
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- OncoMEGA, 75010 Paris, France
| | - Cindy Neuzillet
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
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Rizzo A. Targeted Therapies in Advanced Cholangiocarcinoma: A Focus on FGFR Inhibitors. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:458. [PMID: 34066684 PMCID: PMC8151905 DOI: 10.3390/medicina57050458] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 12/11/2022]
Abstract
Despite advanced diseases continuing to be associated with grim prognoses, the past decade has witnessed the advent of several novel treatment options for cholangiocarcinoma (CCA) patients. In fact, CCA has emerged as a heterogeneous group of malignancies harboring potentially druggable mutations in approximately 50% of cases, and thus, molecularly targeted therapies have been actively explored in this setting. Among these, fibroblast growth factor receptor (FGFR) inhibitors have reported important results, as witnessed by the FDA approval of pemigatinib in previously treated metastatic CCA patients harboring FGFR2 fusion or other rearrangements. Herein, we provide an overview of available evidence on FGFR inhibitors in CCA, especially focusing on the development, pitfalls and challenges of emerging treatments in this setting.
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Affiliation(s)
- Alessandro Rizzo
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, 40138 Bologna, Italy
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25
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Boilève A, Verlingue L, Hollebecque A, Boige V, Ducreux M, Malka D. Rare cancer, rare alteration: the case of NTRK fusions in biliary tract cancers. Expert Opin Investig Drugs 2021; 30:401-409. [PMID: 33641556 DOI: 10.1080/13543784.2021.1896703] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: For patients with advanced/unresectable biliary tract cancers, cisplatin-gemcitabine combination is the standard first-line treatment. Beyond the first line, the therapeutic arsenal is limited with minimal benefit. Biliary tract cancers exhibit one of the highest frequencies of targetable molecular alterations across cancer types, and several targeted therapies are emerging as treatment options.Areas covered:We discuss neurotrophic tyrosine kinase receptor gene (NTRK) fusions in biliary tract cancers and the use of NTRK inhibitors (now approved in a 'cancer-agnostic' way), mechanisms of resistance, and emerging second-generation NTRK inhibitors.Expert opinion: Despite their rarity in biliary tract cancers, NTRK fusions are promising molecular targets because i) NTRK inhibitors have proven highly effective in NTRK-rearranged cancers and are now approved in a 'cancer-agnostic' way; ii) emerging second-generation NTRK inhibitors may overcome secondary resistance; iii) NTRK rearrangements will be readily detectable with the generalization of next-generation-sequencing in biliary tract cancers, including the detection of other frequent gene rearrangements, such as those involving the fibroblast growth factor receptor 2 gene (FGFR2). However, more data are necessary regarding the prevalence and characteristics of NTRK fusions in biliary tract cancers and the efficacy of NTRK inhibitors in these patients.
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Affiliation(s)
- Alice Boilève
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France
| | - Loïc Verlingue
- Université Paris-Saclay, France.,Département D'innovations Thérapeutiques Et D'essais Précoces, Gustave Roussy, Villejuif, France
| | - Antoine Hollebecque
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France.,Département D'innovations Thérapeutiques Et D'essais Précoces, Gustave Roussy, Villejuif, France
| | - Valérie Boige
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France
| | - Michel Ducreux
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France
| | - David Malka
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France
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Yang W, Sun Y. Promising Molecular Targets for the Targeted Therapy of Biliary Tract Cancers: An Overview. Onco Targets Ther 2021; 14:1341-1366. [PMID: 33658799 PMCID: PMC7920611 DOI: 10.2147/ott.s297643] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancer (BTC) is a leading cause of cancer-related death, due to the limited benefits of current systematic therapies and the heterogeneity of the tumor itself. High heterogeneity means that the clinical and molecular features vary between different subtypes of BTC, while the underlying molecular mechanisms remain unclear. Targeted therapy, where inhibitors are developed to selectively combine with targeted molecules in order to block abnormal signaling pathways in BTC, has shown promise as an emerging form of treatment for various types of cancer. In this article, a comprehensive review is conducted to examine potential molecular targets for BTC targeted therapy and their mechanisms. Furthermore, preliminary data published from clinical trials is utilized to analyze the main drugs used to combat BTC. The collective information presented in this article has provided useful insights into the current understanding of BTC.
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Affiliation(s)
- Wenwei Yang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Yongkun Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
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Chen Z, Lin T, Liao X, Li Z, Lin R, Qi X, Chen G, Sun L, Lin L. Network pharmacology based research into the effect and mechanism of Yinchenhao Decoction against Cholangiocarcinoma. Chin Med 2021; 16:13. [PMID: 33478536 PMCID: PMC7818939 DOI: 10.1186/s13020-021-00423-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 01/01/2021] [Accepted: 01/04/2021] [Indexed: 12/14/2022] Open
Abstract
Background Cholangiocarcinoma refers to an epithelial cell malignancy with poor prognosis. Yinchenhao decoction (YCHD) showed positive effects on cancers, and associations between YCHD and cholangiocarcinoma remain unclear. This study aimed to screen out the effective active components of Yinchenhao decoction (YCHD) using network pharmacology, estimate their potential targets, screen out the pathways, as well as delve into the potential mechanisms on treating cholangiocarcinoma. Methods By the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) as well as literature review, the major active components and their corresponding targets were estimated and screened out. Using the software Cytoscape 3.6.0, a visual network was established using the active components of YCHD and the targets of cholangiocarcinoma. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways of the targets enrichment were performed. The AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The PyMOL software was utilized to visualize the docking results of active compounds and protein targets. In vivo experiment, the IC50 values and apoptosis rate in PI-A cells were detected using CCK-8 kit and Cell Cycle Detection Kit. The predicted targets were verified by the real-time PCR and western blot methods. Results 32 effective active components with anti-tumor effects of YCHD were sifted in total, covering 209 targets, 96 of which were associated with cancer. Quercetin, kaempferol, beta-sitosterol, isorhamnetin, and stigmasterol were identified as the vital active compounds, and AKT1, IL6, MAPK1, TP53 as well as VEGFA were considered as the major targets. The molecular docking revealed that these active compounds and targets showed good binding interactions. These 96 putative targets exerted therapeutic effects on cancer by regulating signaling pathways (e.g., hepatitis B, the MAPK signaling pathway, the PI3K-Akt signaling pathway, and MicroRNAs in cancer). Our in vivo experimental results confirmed that YCHD showed therapeutic effects on cholangiocarcinoma by decreasing IC50 values, down-regulating apoptosis rate of cholangiocarcinoma cells, and lowering protein expressions. Conclusions As predicted by network pharmacology strategy and validated by the experimental results, YCHD exerts anti-tumor effectsthrough multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of cholangiocarcinoma.
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Affiliation(s)
- Zhiqiang Chen
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Tong Lin
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Xiaozhong Liao
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Zeyun Li
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Ruiting Lin
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Xiangjun Qi
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Guoming Chen
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Lingling Sun
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Jichang Road, Baiyun District, 510405, Guangzhou, China
| | - Lizhu Lin
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Jichang Road, Baiyun District, 510405, Guangzhou, China.
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Sun D, Ma J, Wang J, Wang L, Zhang S, Chen G, Li X, Cui P, Zheng X, Hu Y. A real-world study of the efficacy and safety of anti-programmed cell death-1 therapy combined with chemotherapy or targeted therapy in patients with advanced biliary tract cancer. J Gastrointest Oncol 2021; 11:1421-1430. [PMID: 33457011 DOI: 10.21037/jgo-20-562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) represent a breakthrough in cancer treatment. However, they have rarely been used to treat biliary tract cancer (BTC). In the current study, we aimed to evaluate and compare the efficacy and safety of anti-programmed cell death-1 (PD-1) therapy used alone or in combination with chemotherapy or targeted therapy in the treatment of advanced BTC. Methods Patients with advanced BTC who were treated either with anti-PD-1 therapy alone or anti-PD-1 therapy plus chemotherapy or targeted therapy between December, 2015 and October, 2017 were retrospectively screened for eligibility. Patients who had previously received treatment with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated. Results A total of 37 patients were included in this study (15 cases in the monotherapy group and 22 cases in the combination group). Patients in the combination group had significantly longer OS [median, 8.2 vs. 3.6 months, HR 0.47 (0.20-1.10), P=0.011] and PFS (median, 3.9 vs. 2.0 months, HR 0.58 (0.28-1.19), P=0.034) than patients in the monotherapy group. The ORR was 18.2% (4/22) and 0% in the combination group and monotherapy group, respectively, and the difference was not significant (P=0.131). Furthermore, no significant difference was found between the two groups with respect to the incidence of grade 3-4 treatment-related adverse events (P=0.388). Conclusions Anti-PD-1 therapy plus chemotherapy or targeted therapy is an effective and tolerable treatment for patients with advanced BTC and is promising as a first-line treatment or beyond.
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Affiliation(s)
- Danyang Sun
- Intensive Care Unit, West Ward, China-Japan Friendship Hospital, Beijing, China
| | - Junxun Ma
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Jinliang Wang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Lijie Wang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Sujie Zhang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Guangying Chen
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Xiaoyan Li
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Pengfei Cui
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Xuan Zheng
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Yi Hu
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
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Shen T, Zheng S, Geng L, Liu Z, Xu J, Lin B, Qian J, Zheng S. Experience With Anti-PD-1 Antibody, Camrelizumab, Monotherapy for Biliary Tract Cancer Patients and Literature Review. Technol Cancer Res Treat 2020; 19:1533033820979703. [PMID: 33308041 PMCID: PMC7739105 DOI: 10.1177/1533033820979703] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Novel immunotherapy is one of the options for advanced biliary tract cancer (BTC) patients who are traditionally intolerant to chemotherapy. However, clinical evidence for single immunotherapy with pembrolizumab or nivolumab is limited. The present study assessed the safety and efficiency of the anti-PD-1 antibody, camrelizumab, as monotherapy in patients with unresectable or recurrent BTC. METHODS A retrospective evaluation was conducted among 4 patients with BTC, including 2 with intrahepatic cholangiocellular carcinoma (ICC), one with extrahepatic bile duct cancer, and one with gallbladder cancer. The patients with unresectable or recurrent BTC were refractory or intolerant to gemcitabine plus cisplatin treatment regimens and received at least one intravenous dose (3 mg/kg) of camrelizumab monotherapy every 3 weeks. Gene sequencing analysis was also performed for biomarker screening. Patient reaction was evaluated according to modified response evaluation criteria in solid tumor (RECIST) version 1.1, progression-free survival (PFS), and toxicity. RESULTS In this cohort, 1 patient with recurrent ICC had a positive response to treatment, with a substantial tumor size reduction in liver and lung metastases verified using a radiological test after receiving 3 cycles of camrelizumab. The PFS was 4.9 months. The remaining 3 patients showed no response to treatment and experienced disease progression. RNA sequence analysis didn't found high expression on genes that related to PD-L1, microsatellite instability, tumor mutation burden, and DNA mismatch repair in these patients. Grade 3 treatment-related adverse event was observed in 1 patient. CONCLUSIONS Anti-PD-1 antibody camrelizumab had a manageable safety profile in patients with advanced BTC. This initial assessment of camrelizumab monotherapy provides effective evidence for patients with refractory BTC in biomarker-unselected patients.
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Affiliation(s)
- Tian Shen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shanhua Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lei Geng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bingyi Lin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Rizzo A, Tavolari S, Ricci AD, Frega G, Palloni A, Relli V, Salati M, Fenocchio E, Massa A, Aglietta M, Brandi G. Molecular Features and Targeted Therapies in Extrahepatic Cholangiocarcinoma: Promises and Failures. Cancers (Basel) 2020; 12:E3256. [PMID: 33158162 PMCID: PMC7694193 DOI: 10.3390/cancers12113256] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 10/28/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
Biliary tract cancers (BTCs) include a heterogenous group of aggressive malignancies with limited therapeutic options. According to their anatomical location, these hepatobiliary tumors are usually classified into intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer (GBC). Unfortunately, BTCs are often diagnosed when already metastatic, and although the advent of genomic sequencing has led to a deeper understanding of iCCA pathogenesis, very little data are currently available about the molecular landscape of eCCA. Moreover, despite novel systemic treatments emerging in BTC, the grim prognosis of eCCA patients has not changed in the past decade, and no targeted therapies have been approved so far. The aim of the current review is to provide an overview regarding molecular features and potential targeted therapies in eCCA, together with novel therapeutic approaches and future directions of translational and clinical research on this highly aggressive disease that poses many unanswered questions.
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Affiliation(s)
- Alessandro Rizzo
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy; (A.D.R.); (G.F.); (A.P.); (G.B.)
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40128 Bologna, Italy; (S.T.); (V.R.)
| | - Simona Tavolari
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40128 Bologna, Italy; (S.T.); (V.R.)
- Center of Applied Biomedical Research, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy
| | - Angela Dalia Ricci
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy; (A.D.R.); (G.F.); (A.P.); (G.B.)
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40128 Bologna, Italy; (S.T.); (V.R.)
| | - Giorgio Frega
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy; (A.D.R.); (G.F.); (A.P.); (G.B.)
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40128 Bologna, Italy; (S.T.); (V.R.)
| | - Andrea Palloni
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy; (A.D.R.); (G.F.); (A.P.); (G.B.)
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40128 Bologna, Italy; (S.T.); (V.R.)
| | - Valeria Relli
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40128 Bologna, Italy; (S.T.); (V.R.)
- Center of Applied Biomedical Research, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy
| | - Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, 41100 Modena, Italy;
- PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41100 Modena, Italy
| | - Elisabetta Fenocchio
- Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy;
| | - Annamaria Massa
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 142 km 3.95, 10060 Candiolo (TO), Italy; (A.M.); (M.A.)
| | - Massimo Aglietta
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 142 km 3.95, 10060 Candiolo (TO), Italy; (A.M.); (M.A.)
- Department of Oncology, University of Torino, 10124 Torino, Italy
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy; (A.D.R.); (G.F.); (A.P.); (G.B.)
- Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40128 Bologna, Italy; (S.T.); (V.R.)
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Ricci AD, Rizzo A, Bonucci C, Tober N, Palloni A, Mollica V, Maggio I, Deserti M, Tavolari S, Brandi G. PARP Inhibitors in Biliary Tract Cancer: A New Kid on the Block? MEDICINES 2020; 7:medicines7090054. [PMID: 32878011 PMCID: PMC7555445 DOI: 10.3390/medicines7090054] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/25/2020] [Accepted: 08/29/2020] [Indexed: 12/14/2022]
Abstract
Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent an effective therapeutic strategy for cancer patients harboring germline and somatic aberrations in DNA damage repair (DDR) genes. BRCA1/2 mutations occur at 1–7% across biliary tract cancers (BTCs), but a broader spectrum of DDR gene alterations is reported in 28.9–63.5% of newly diagnosed BTC patients. The open question is whether alterations in genes that are well established to have a role in DDR could be considered as emerging predictive biomarkers of response to platinum compounds and PARPi. Currently, data regarding PARPi in BTC patients harboring BRCA and DDR mutations are sparse and anecdotal; nevertheless, a variety of clinical trials are testing PARPi as monotherapy or in combination with other anticancer agents. In this review, we provide a comprehensive overview regarding the genetic landscape of DDR pathway deficiency, state of the art and future therapeutic implications of PARPi in BTC, looking at combination strategies with immune-checkpoint inhibitors and other anticancer agents in order to improve survival and quality of life in BTC patients.
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Affiliation(s)
- Angela Dalia Ricci
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy; (A.D.R.); (C.B.); (N.T.); (A.P.); (V.M.); (I.M.); (G.B.)
| | - Alessandro Rizzo
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy; (A.D.R.); (C.B.); (N.T.); (A.P.); (V.M.); (I.M.); (G.B.)
- Correspondence:
| | - Chiara Bonucci
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy; (A.D.R.); (C.B.); (N.T.); (A.P.); (V.M.); (I.M.); (G.B.)
| | - Nastassja Tober
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy; (A.D.R.); (C.B.); (N.T.); (A.P.); (V.M.); (I.M.); (G.B.)
| | - Andrea Palloni
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy; (A.D.R.); (C.B.); (N.T.); (A.P.); (V.M.); (I.M.); (G.B.)
| | - Veronica Mollica
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy; (A.D.R.); (C.B.); (N.T.); (A.P.); (V.M.); (I.M.); (G.B.)
| | - Ilaria Maggio
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy; (A.D.R.); (C.B.); (N.T.); (A.P.); (V.M.); (I.M.); (G.B.)
| | - Marzia Deserti
- Center of Applied Biomedical Research, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy; (M.D.); (S.T.)
| | - Simona Tavolari
- Center of Applied Biomedical Research, S. Orsola-Malpighi University Hospital, 40128 Bologna, Italy; (M.D.); (S.T.)
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy; (A.D.R.); (C.B.); (N.T.); (A.P.); (V.M.); (I.M.); (G.B.)
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Chakrabarti S, Kamgar M, Mahipal A. Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm. Cancers (Basel) 2020; 12:E2039. [PMID: 32722188 PMCID: PMC7465131 DOI: 10.3390/cancers12082039] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 12/18/2022] Open
Abstract
Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.
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Affiliation(s)
- Sakti Chakrabarti
- Department of Hematology-Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; (S.C.); (M.K.)
| | - Mandana Kamgar
- Department of Hematology-Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; (S.C.); (M.K.)
| | - Amit Mahipal
- Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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Wakai T, Nagahashi M, Shimada Y, Prasoon P, Sakata J. Genetic analysis in the clinical management of biliary tract cancer. Ann Gastroenterol Surg 2020; 4:316-323. [PMID: 32724874 PMCID: PMC7382432 DOI: 10.1002/ags3.12334] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/24/2020] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
Biliary tract cancer (BTC) is clinically and pathologically heterogeneous and responds inadequately to treatment. A small section of patients develop resectable disease, although the relapse rates are high; the benefits of adjuvant capecitabine chemotherapy for BTC are now understood, and gemcitabine-based combination chemotherapy is the first line of therapeutic strategy for BTC; however, alternative therapy for BTC is not known. Genomic profiling can provide detailed information regarding the carcinogenesis, identification, and therapy for BTC. Currently, confirmed restorative targets for BTC are lacking. In this review, we aimed to analyze the preclinical and clinical implications of a spectrum of genomic alterations associated with new potentially remedial targets. We focused on eight draggable genes for BTC, which were described as having evidence of therapeutic impact (evidence level 2A-3B) based on the clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment; these include ERBB2, NTRK1, RNF43, CDK6, CDKN2B, FGFR2, IDH1, and IDH2. Moreover, some of the BTC present microsatellite instability, hypermutation, and germline variants, which we also reviewed. Finally, we discussed the therapeutic options based on the next-generation sequencing findings in BTC. Studies have demonstrated that BTC includes subgroups with individually distinct driver mutations, most of which will be targeted with new treatment plans.
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Affiliation(s)
- Toshifumi Wakai
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Masayuki Nagahashi
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Yoshifumi Shimada
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Pankaj Prasoon
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Jun Sakata
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
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Zhu Y, Kwong LN. Insights Into the Origin of Intrahepatic Cholangiocarcinoma From Mouse Models. Hepatology 2020; 72:305-314. [PMID: 32096245 DOI: 10.1002/hep.31200] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/17/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Yan Zhu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Lawrence N Kwong
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Zheng Y, Zhang J, Ye B. miR-138 mediates sorafenib-induced cell survival and is associated with poor prognosis in cholangiocarcinoma cells. Clin Exp Pharmacol Physiol 2019; 47:459-465. [PMID: 31663629 DOI: 10.1111/1440-1681.13205] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 10/22/2019] [Accepted: 10/28/2019] [Indexed: 12/22/2022]
Abstract
Cholangiocarcinoma is an aggressive malignancy with rapid invasion, metastasis and poor prognosis, however, the mechanism mediating its cholangiocarcinoma development needs further investigation. Here, we demonstrate that decreased miR-138 in tumor tissues is related to the poor prognosis in patients, and that miR-138 mediates sorafenib-induced cell survival in cholangiocarcinoma cells. Moreover, miR-138 negatively regulates SOX4 expression by specifically targeting its 3' untranslated region (3' UTR). As per our results, overexpression of SOX4 reversed sorafenib-induced changes in cell viability and apoptosis. Furthermore, the elevated levels of SOX4 in the tumor tissues that correlated with poor prognosis. Overall, the present study reveals that miR-138/SOX4 is involved in sorafinib-mediated cell survival in cholangiocarcinoma cells, and is associated with poor prognosis.
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Affiliation(s)
- Yingjie Zheng
- Department of Gastroenterology, Lianshui County People's Hospital, Huai'an, China
| | - Jingyu Zhang
- Department of Gastroenterology, Lianshui County People's Hospital, Huai'an, China
| | - Bin Ye
- Department of Gastroenterology, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
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Lau DK, Mouradov D, Wasenang W, Luk IY, Scott CM, Williams DS, Yeung YH, Limpaiboon T, Iatropoulos GF, Jenkins LJ, Reehorst CM, Chionh F, Nikfarjam M, Croagh D, Dhillon AS, Weickhardt AJ, Muramatsu T, Saito Y, Tebbutt NC, Sieber OM, Mariadason JM. Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets. iScience 2019; 21:624-637. [PMID: 31731200 PMCID: PMC6889747 DOI: 10.1016/j.isci.2019.10.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/21/2019] [Accepted: 10/22/2019] [Indexed: 01/07/2023] Open
Abstract
Biliary tract cancers (BTCs) currently have no approved targeted therapies. Although genomic profiling of primary BTCs has identified multiple potential drug targets, accurate models are needed for their evaluation. Genomic profiling of 22 BTC cell lines revealed they harbor similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumors. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumors. Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression. Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro. These findings establish BTC cell lines as robust models of primary disease, reveal specific molecular disease subsets, and highlight specific molecular vulnerabilities in these cancers.
BTC cell lines harbor similar genomic alterations to primary tumors Transcriptomic profiling of BTC cell lines identified two molecular subtypes MAPK signaling is activated in BTC via multiple mechanisms BTC lines with deregulated ERBB2 or FGFRs respond to specific targeted therapies
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Affiliation(s)
- David K Lau
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Dmitri Mouradov
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Wiphawan Wasenang
- School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia; Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Ian Y Luk
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Cameron M Scott
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
| | - David S Williams
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Yvonne H Yeung
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
| | - Temduang Limpaiboon
- Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand
| | - George F Iatropoulos
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Laura J Jenkins
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Camilla M Reehorst
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Fiona Chionh
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia
| | - Daniel Croagh
- Department of Surgery, Monash Medical Centre, Monash University, Melbourne, VIC 3168, Australia
| | - Amardeep S Dhillon
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Medicine, Deakin University, Geelong, VIC 3216, Australia
| | - Andrew J Weickhardt
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Toshihide Muramatsu
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan
| | - Yoshimasa Saito
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan
| | - Niall C Tebbutt
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Oliver M Sieber
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia; Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia; Department of Biochemistry & Molecular Biology, Monash University, Melbourne, VIC 3800, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - John M Mariadason
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia.
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Bayesian spatial analysis of cholangiocarcinoma in Northeast Thailand. Sci Rep 2019; 9:14263. [PMID: 31582774 PMCID: PMC6776517 DOI: 10.1038/s41598-019-50476-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 09/02/2019] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant neoplasm of the biliary tract. Thailand reports the highest incidence of CCA in the world. The aim of this study was to map the distribution of CCA and identify spatial disease clusters in Northeast Thailand. Individual-level data of patients with histopathologically confirmed CCA, aggregated at the sub-district level, were obtained from the Cholangiocarcinoma Screening and Care Program (CASCAP) between February 2013 and December 2017. For analysis a multivariate Zero-inflated, Poisson (ZIP) regression model was developed. This model incorporated a conditional autoregressive (CAR) prior structure, with posterior parameters estimated using Bayesian Markov chain Monte Carlo (MCMC) simulation with Gibbs sampling. Covariates included in the models were age, sex, normalized vegetation index (NDVI), and distance to water body. There was a total of 1,299 cases out of 358,981 participants. CCA incidence increased 2.94 fold (95% credible interval [CrI] 2.62–3.31) in patients >60 years as compared to ≤60 years. Males were 2.53 fold (95% CrI: 2.24–2.85) more likely to have CCA when compared to females. CCA decreased with a 1 unit increase of NDVI (Relative Risk =0.06; 95% CrI: 0.01–0.63). When posterior means were mapped spatial clustering was evident after accounting for the model covariates. Age, sex and environmental variables were associated with an increase in the incidence of CCA. When these covariates were included in models the maps of the posterior means of the spatially structured random effects demonstrated evidence of spatial clustering.
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Sun D, Ma J, Wang J, Han C, Qian Y, Chen G, Li X, Zhang J, Cui P, Du W, Wu Z, Chen S, Zheng X, Yue Z, Song J, Gao C, Zhao X, Cai S, Hu Y. Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer. Cancer Immunol Immunother 2019; 68:1527-1535. [PMID: 31535160 PMCID: PMC6768892 DOI: 10.1007/s00262-019-02386-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 08/26/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. METHODS Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. RESULTS The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17-0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42-0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31-1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45-0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). CONCLUSIONS Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.
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Affiliation(s)
- Danyang Sun
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Junxun Ma
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Jinliang Wang
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Chun Han
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Yuanyu Qian
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Guangying Chen
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Xiaoyan Li
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Juan Zhang
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Pengfei Cui
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Wushuang Du
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Zhaozhen Wu
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Shixue Chen
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Xuan Zheng
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Zhichao Yue
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China
| | - Jia Song
- The Medical Department, 3D Medicines Inc., 158 Xinjunhuan Road, Minhang, Shanghai, 201114, People's Republic of China
| | - Chan Gao
- The Medical Department, 3D Medicines Inc., 158 Xinjunhuan Road, Minhang, Shanghai, 201114, People's Republic of China
| | - Xiaochen Zhao
- The Medical Department, 3D Medicines Inc., 158 Xinjunhuan Road, Minhang, Shanghai, 201114, People's Republic of China
| | - Shangli Cai
- The Medical Department, 3D Medicines Inc., 158 Xinjunhuan Road, Minhang, Shanghai, 201114, People's Republic of China.
| | - Yi Hu
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China.
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Haznadar M, Diehl CM, Parker AL, Krausz KW, Bowman ED, Rabibhadana S, Forgues M, Bhudhisawasdi V, Gonzalez FJ, Mahidol C, Budhu A, Wang XW, Ruchirawat M, Harris CC. Urinary Metabolites Diagnostic and Prognostic of Intrahepatic Cholangiocarcinoma. Cancer Epidemiol Biomarkers Prev 2019; 28:1704-1711. [PMID: 31358519 DOI: 10.1158/1055-9965.epi-19-0453] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 06/06/2019] [Accepted: 07/23/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Liver cancer is the second leading cause of cancer-related deaths worldwide. With a predicted 2.4-fold rise in liver cancer incidence by 2020, there is an urgent need for early, inexpensive diagnostic biomarkers to deploy in the clinic. METHODS We employed ultraperformance liquid chromatography tandem mass-spectrometry (UPLC/MS-MS) for the quantitation of four metabolites, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and a lipid molecule designated as 561+, in urine samples from the NCI-MD cohort comprising 98 hepatocellular carcinoma (HCC) cases, 101 high-risk subjects, and 95 controls. Validation was carried out in the TIGER-LC cohort [n = 370 HCC and intrahepatic cholangiocarcinoma (ICC) cases, 471 high-risk subjects, 251 controls], where ICC, the second most common primary hepatic malignancy, is highly prevalent. Metabolite quantitation was also conducted in TIGER-LC tissue samples (n = 48 ICC; n = 51 HCC). RESULTS All profiled metabolites were significantly increased in liver cancer when compared with high-risk subjects and controls in the NCI-MD study. In the TIGER-LC cohort, the four-metabolite profile was superior at classifying ICC than a clinically utilized marker, CA19-9, and their combination led to a significantly improved model (AUC = 0.88, P = 4E-8). Metabolites CR and NANA were significantly elevated in ICC when compared with HCC cases in both urine and tissue samples. High levels of CR were associated with poorer prognosis in ICC. CONCLUSIONS Four metabolites are significantly increased in HCC and ICC and are robust at classifying ICC in combination with the clinically utilized marker CA19-9. IMPACT Noninvasive urinary metabolite biomarkers hold promise for diagnostic and prognostic evaluation of ICC.
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Affiliation(s)
- Majda Haznadar
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Christopher M Diehl
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Amelia L Parker
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Elise D Bowman
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Siritida Rabibhadana
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, Thailand
| | - Marshonna Forgues
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | | | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Chulabhorn Mahidol
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, Thailand.,Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, Thailand
| | - Anuradha Budhu
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Xin W Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Mathuros Ruchirawat
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, Thailand.,Center of Excellence on Environmental Health and Toxicology, Office of Higher Education Commission, Ministry of Education, Bangkok, Thailand
| | - Curtis C Harris
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
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Malik MN, Saleem T, Aslam S, Riaz R, Yousaf MA. Cholangiocarcinoma in a Resected Biliary Cyst: Importance of Follow-up. Cureus 2019; 11:e4532. [PMID: 31263640 PMCID: PMC6592459 DOI: 10.7759/cureus.4532] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Biliary cysts are rare cystic dilatations of the biliary tree. Biliary cysts are positively associated with several significant complications, amongst them, cholangiocarcinoma befalls the most dreadful one. The elevated incidence is 20-30% in the unresected cyst and 0.7% in resected cysts. Magnetic resonance imaging (MRI) scan, magnetic resonance cholangiopancreatography (MRCP) or a contrast-enhanced computed tomography (CECT) is applied for the initial diagnostic study but the ultimate diagnosis ordinarily requires the tissue biopsy. Currently, the sole curative option involves the complete surgical resection of the lesion, with standard chemotherapy and active radiation applied as an alternative for the unresectable tumors. Despite the curative surgery the percentage of eternal recurrence of the tumor indefinitely persists, and effective post-surgical surveillance is reasonably demanded. We report a case of 29-year-old female with local recurrence of cholangiocarcinoma in a previously resected biliary cyst type I. The curative resection of the choledochal cyst only minimizes the considerable risk of the possible development of future cholangiocarcinoma but it does not completely prevent it. The appropriate follow-up for potential patients who have been typically treated for a biliary cyst is unclear. The lethal course of cholangiocarcinoma is believed due to its slow asymptomatic growing phase. Therefore, to adequately screen for malignancy, periodic imaging along with annual liver tests represents a reasonable approach to prevent the possible development of this appalling complication.
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Affiliation(s)
| | - Tabinda Saleem
- Internal Medicine, Shifa International Hospital, Islamabad, PAK
| | - Shehroz Aslam
- Internal Medicine, Maricopa Medical Center, Phoenix, USA
| | - Rida Riaz
- Internal Medicine, Nawaz Sharif Medical College - University of Gujrat, Gujrat, PAK
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Tariq NUA, McNamara MG, Valle JW. Biliary tract cancers: current knowledge, clinical candidates and future challenges. Cancer Manag Res 2019; 11:2623-2642. [PMID: 31015767 PMCID: PMC6446989 DOI: 10.2147/cmar.s157092] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Biliary tract cancers (BTCs) are rare with poor prognosis. Due to the advent of genomic sequencing, new data have emerged regarding the molecular makeup of this disease. To add to the complexity, various subtypes also harbor a varied genetic composition. The commonly mutated genes associated with this cancer are KRAS, EGFR, IDH, FGFR and BAP1. Various clinical studies are looking at targeting these genetic mutations. Another therapeutic area of note is the potential for the use of immunotherapy in patients with BTC. Although BTC may be a result of chronic inflammation, this does not necessarily translate into increased immunogenicity. This literature review discusses the diverse molecular and immune-related pathways in patients with BTC and their potential therapeutic implications.
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Affiliation(s)
- Noor-Ul-Ain Tariq
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| | - Mairéad G McNamara
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| | - Juan W Valle
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
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42
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Chiang KC, Huang ST, Wu RC, Huang SC, Yeh TS, Chen MH, Hsu JT, Chen LW, Kuo SF, Chueh HY, Juang HH, Hung SI, Yeh CN, Pang JHS. Interferon α-inducible protein 27 is an oncogene and highly expressed in cholangiocarcinoma patients with poor survival. Cancer Manag Res 2019; 11:1893-1905. [PMID: 30881116 PMCID: PMC6400119 DOI: 10.2147/cmar.s196485] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Objective Cholangiocarcinoma (CCA) is a devastating disease. Interferon α-inducible protein 27 (IFI27), originally known to involve in innate immunity, is later found to intervene in cell proliferation, leading to inventive studies regarding the role of IFI27 in cancer treatment. We aimed to investigate the role of IFI27 in CCA. Materials and methods Cell proliferation, migration, and invasion assays, Western blot, gene transfection and knockdown, immunofluorescent and immunohistochemical stains, and xenograft animal model were applied. Results IFI27 knockdown in CCA cells induced cell cycle arrest in S phase, resulting in lower cell proliferative rate in vitro and in vivo. IFI27 knockdown attenuated CCA cell migration and invasion through inhibition of epithelial–mesenchymal transition, which was supported by increased E-cadherin and decreased N-cadherin and fibronectin. Filamentous actin level was also reduced. IFI27 knockdown further repressed expression and secretion of vascular endothelial growth factor (VEGF-A), a strong stimulator of angiogenesis, through downregulation of c-jun and c-fos, which was supported in vitro by the finding that human vascular endothelial cells grew more slowly in conditioned medium of IFI27 knockdown on CCA cells and in vivo by the lower erythropoietin concentration found in the xenografted tumors derived from IFI27 knockdown on CCA cells. In addition, anti-VEGF-A antibody treatment was able to repress CCA cell growth. To the contrary, IFI27 overexpression could increase CCA cell proliferation, migration, and invasion. Clinically, higher IFI27 expression was linked to inferior overall survival of CCA patients. Conclusion Our data strongly suggest that IFI27 could be deemed as a potential target for CCA treatment.
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Affiliation(s)
- Kun-Chun Chiang
- General Surgery Department, Chang Gung, Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC
| | - Sheng-Teng Huang
- Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan, ROC
| | - Ren-Chin Wu
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Shih-Chiang Huang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Ta-Sen Yeh
- General Surgery Department, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC,
| | - Ming-Huang Chen
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Jun-Te Hsu
- General Surgery Department, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC,
| | - Li-Wei Chen
- Department of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC
| | - Sheng-Fong Kuo
- Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC
| | - Ho-Yen Chueh
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Horng-Heng Juang
- Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC
| | - Shuen-Iu Hung
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Chun-Nan Yeh
- General Surgery Department, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC,
| | - Jong-Hwei S Pang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC, .,Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Linkow, Taoyuan City, Taiwan, ROC,
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Sabaté-Llobera A, Gràcia-Sánchez L, Reynés-Llompart G, Ramos E, Lladó L, Robles J, Serrano T, Mestres-Martí J, Gámez-Cenzano C. Differences on metabolic behavior between intra and extrahepatic cholangiocarcinomas at 18F-FDG–PET/CT: prognostic implication of metabolic parameters and tumor markers. Clin Transl Oncol 2018; 21:324-333. [DOI: 10.1007/s12094-018-1926-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 07/12/2018] [Indexed: 01/10/2023]
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Chen G, Yu H, Wang Y, Li C, Zhou M, Yu Z, Zheng X, Wu X, Shan Y, Zhang Q, Zeng Q. A novel nomogram for the prediction of intrahepatic cholangiocarcinoma in patients with intrahepatic lithiasis complicated by imagiologically diagnosed mass. Cancer Manag Res 2018; 10:847-856. [PMID: 29720881 PMCID: PMC5918625 DOI: 10.2147/cmar.s157506] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Accurate preoperative diagnosis of intrahepatic cholangiocarcinoma (ICC) among patients with imagiologically intrahepatic lithiasis (IHL) complicated by mass is crucial for timely and effective surgical intervention. The aim of the present study was to develop a nomogram to identify ICC associated with IHL (IHL-ICC). Patients and methods Data were obtained from a total of 252 consecutive patients with IHL complicated by mass. Multivariate logistic regression analysis was conducted to identify the clinicopathologic and imagiological characteristics that were potentially associated with ICC. A nomogram was developed based on the results of the multivariate analysis, and the value for prediction of ICC was assessed. Results The study revealed six potential predictors for IHL-ICC, including comprehensive imagiological diagnosis, biliary tract operation history, fever, ascites, cancer antigen (CA) 19-9, and carcinoembryonic antigen (CEA). The optimal cutoff value was 3.75 μg/L for serum CEA and 143.15 U/mL for serum CA 19-9. The accuracy of the nomogram in predicting ICC was 78.5%. The Youden index provided a value of 0.348, corresponding to a cutoff of 95 points, with an area under the curve of 0.863. Conclusion The nomogram holds promise as a novel and accurate tool in identifying IHL-ICC for hepatectomy, and in the differentiation of benign occupying lesions in IHL patients, resulting in the avoidance of unnecessary surgical resection.
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Affiliation(s)
- Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huajun Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yi Wang
- Division of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chenhao Li
- Division of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mengtao Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhengping Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangwu Zheng
- Radiological Department, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiuling Wu
- Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yunfeng Shan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiyu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiqiang Zeng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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De Moura DTH, Moura EGHD, Bernardo WM, De Moura ETH, Baraca FI, Kondo A, Matuguma SE, Almeida Artifon EL. Endoscopic retrograde cholangiopancreatography versus endoscopic ultrasound for tissue diagnosis of malignant biliary stricture: Systematic review and meta-analysis. Endosc Ultrasound 2018; 7:10-19. [PMID: 27824027 PMCID: PMC5838722 DOI: 10.4103/2303-9027.193597] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background and Aims: There are no systematic reviews comparing the use of endoscopic retrograde cholangiopancreatography (ERCP)-based brush cytology and forceps biopsy and endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) for the diagnosis of malignant biliary stricture; so in this revision, we will compare ERCP against EUS-FNA for tissue diagnosis of malignant biliary stricture. Design: A systematic review was conducted of comparative studies (prospective or retrospective) analyzing EUS and ERCP for tissue diagnosis of malignant biliary stricture. Materials and Methods: The databases Medline, EMBASE, Cochrane, LILACS, CINAHL, and Scopus were searched for studies dated previous to November 2014. We identified three prospective studies comparing EUS-FNA and ERCP for the diagnosis of malignant biliary stricture and five prospective studies comparing EUS-FNA with the same diagnosis of the other three studies. All patients were subjected to the same gold standard method. We calculated study variables (sensitivity, specificity, prevalence, positive and negative predictive values, and accuracy) and performed a meta-analysis using the Review Manager (RevMan) 5.3 software. Results: A total of 294 patients were included in the analysis. The pretest probability for malignant biliary stricture was 76.66%. The mean sensitivities of ERCP and EUS-FNA for tissue diagnosis of malignant biliary stricture were 49% and 75%, respectively; the specificities were 96.33% and 100%, respectively. The posttest probabilities positive predictive value (98.33% and 100%, respectively) and negative predictive value (34% and 47%, respectively) were determined. The accuracies were 60.66% and 79%, respectively. Conclusion: We found that EUS-FNA was superior to ERCP with brush cytology and forceps biopsy for diagnosing malignant biliary strictures. However, a negative EUS-FNA or ERCP test may not exclude malignant biliary stricture because both have low negative posttest probabilities.
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Affiliation(s)
| | | | - Wanderlei Marques Bernardo
- Departament of Gastroenteroly, Hospital das Clínicas da Faculdade De Medicina Da Universidade de São Paulo, São Paulo, Brazil
| | | | - Felipe I Baraca
- Departament of Gastroenteroly, Hospital das Clínicas da Faculdade De Medicina Da Universidade de São Paulo, São Paulo, Brazil
| | - André Kondo
- Departament of Gastroenteroly, Hospital das Clínicas da Faculdade De Medicina Da Universidade de São Paulo, São Paulo, Brazil
| | - Sérgio Eijii Matuguma
- Departament of Gastroenteroly, Hospital das Clínicas da Faculdade De Medicina Da Universidade de São Paulo, São Paulo, Brazil
| | - Everson Luis Almeida Artifon
- Departament of Gastroenteroly, Hospital das Clínicas da Faculdade De Medicina Da Universidade de São Paulo, São Paulo, Brazil
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Abstract
Cholangiocarcinomas (CC) are rare tumors which usually present late and are often difficult to diagnose and treat. CCs are categorized as intrahepatic, hilar, or extrahepatic. Epidemiologic studies suggest that the incidence of intrahepatic CCs may be increasing worldwide. In this chapter, we review the risk factors, clinical presentation, and management of cholangiocarcinoma.
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Guo Y, Feng K, Liu Y, Wu Z, Dai H, Yang Q, Wang Y, Jia H, Han W. Phase I Study of Chimeric Antigen Receptor-Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers. Clin Cancer Res 2017; 24:1277-1286. [PMID: 29138340 DOI: 10.1158/1078-0432.ccr-17-0432] [Citation(s) in RCA: 179] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 06/15/2017] [Accepted: 11/09/2017] [Indexed: 11/16/2022]
Abstract
Purpose: This study is an expanded and parallel clinical trial of EGFR-specific chimeric antigen receptor-engineered autologous T (CART) cell immunotherapy (NCT01869166) to assess the safety and activity of CART-EGFR cell therapy in EGFR-positive advanced unresectable, relapsed/metastatic biliary tract cancers (BTC).Experimental Design: Patients with EGFR-positive (>50%) advanced unresectable, relapsed/metastatic BTCs were enrolled. Well-produced CART-EGFR cells were infused in a manner of dose escalation after the conditioning treatment with nab-paclitaxel (100-250 mg/m2) and cyclophosphamide (15-35 mg/kg).Results: A total of 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) received one to three cycles of CART-EGFR cell infusion (median CART cell dose, 2.65 × 106/kg; range, 0.8-4.1 × 106/kg) within 6 months. The CART-EGFR cell infusion was tolerated, but 3 patients suffered grade ≥3 acute fever/chill. Grade 1/2 target-mediated toxicities including mucosal/cutaneous toxicities and acute pulmonary edema and grade ≥3 lymphopenia and thrombocytopenia related to the conditioning treatment were observed. Of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5-22 months) from the first cycle of treatment. Analysis of data indicated that the enrichment of central memory T cells (Tcm) in the infused CART-EGFR cells improved the clinical outcome.Conclusions: The CART-EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced BTCs. The enrichment of Tcm in the infused CART-EGFR cells could predict clinical response. Clin Cancer Res; 24(6); 1277-86. ©2017 AACRSee related commentary by Kalos, p. 1246.
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Affiliation(s)
- Yelei Guo
- Department of Molecular and Immunology, Chinese PLA General Hospital, Beijing, China
| | - Kaichao Feng
- Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China
| | - Yang Liu
- Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, China
| | - Zhiqiang Wu
- Department of Molecular and Immunology, Chinese PLA General Hospital, Beijing, China
| | - Hanren Dai
- Department of Molecular and Immunology, Chinese PLA General Hospital, Beijing, China
| | - Qingming Yang
- Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China
| | - Yao Wang
- Department of Molecular and Immunology, Chinese PLA General Hospital, Beijing, China
| | - Hejin Jia
- Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China
| | - Weidong Han
- Department of Molecular and Immunology, Chinese PLA General Hospital, Beijing, China. .,Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China
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Zhang D, Li H, Jiang X, Cao L, Wen Z, Yang X, Xue P. Role of AP-2α and MAPK7 in the regulation of autocrine TGF-β/miR-200b signals to maintain epithelial-mesenchymal transition in cholangiocarcinoma. J Hematol Oncol 2017; 10:170. [PMID: 29084594 PMCID: PMC5663068 DOI: 10.1186/s13045-017-0528-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 09/21/2017] [Indexed: 12/15/2022] Open
Abstract
Background Cholangiocarcinoma (CCA) is characterized by early lymphatic, metastasis, and low survival rate. Epithelial-mesenchymal transition (EMT) is able to induce tumor metastasis. Although the TGF-β/miR-200 signals promote EMT in various types of cancer, the regulatory mechanism in CCA is still unclear. Methods Expression of miR-200b, TGF-β, and EMT markers were measured in tumor samples and cell lines by qRT-PCR and western blot. CCK8 assay was performed to measure the cell viability. Transwell assay was used to evaluate migration and invasion. The target genes of miR-200b and transcription factor of TGF-β were analyzed using dual-luciferase reporter system. Results We have demonstrated that CCA exhibited remarkable EMT phenotype and miR-200b was reduced in CCA patients (n = 20) and negatively correlated to TGF-β. Moreover, two CCA cells, HCCC, and RBE, with epithelial appearances treated with TGF-β, showed fibroblastic-like cell morphology with downregulated miR-200b expression. Forced expression of miR-200b abrogated TGF-β-induced EMT initiation, with decreased cell proliferation, migration, and invasion in vitro. Also, TFAP2A (encode AP-2α) and MAPK7 were found to be targeted by miR-200b to downregulate EMT and AP-2α inhibited miR-200b by directly promoting transcription of TGFB1. Overexpression of MAPK7 significantly reversed miR-200b-induced inhibition of EMT, migration, and proliferation by increasing the expression of TGF-β, cyclin D1, and Cdk2. Further, the administration of miR-200b induced a remarkably tumor regression in vivo and reduced the effect of TGF-β-related EMT in AP-2α and MAPK7-dependent manner. Conclusions Our study highlights that miR-200b-based gene therapy is effective in the treatment of CCA.
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Affiliation(s)
- Dawei Zhang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, No 250 East Changgang Road, Guangzhou, 510260, China
| | - Haiyan Li
- Department of Breast and Thyroid Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Xiaofeng Jiang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, No 250 East Changgang Road, Guangzhou, 510260, China
| | - Liangqi Cao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, No 250 East Changgang Road, Guangzhou, 510260, China
| | - Zilong Wen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, No 250 East Changgang Road, Guangzhou, 510260, China
| | - Xuewei Yang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, No 250 East Changgang Road, Guangzhou, 510260, China
| | - Ping Xue
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, No 250 East Changgang Road, Guangzhou, 510260, China.
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Sritananuwat P, Sueangoen N, Thummarati P, Islam K, Suthiphongchai T. Blocking ERK1/2 signaling impairs TGF-β1 tumor promoting function but enhances its tumor suppressing role in intrahepatic cholangiocarcinoma cells. Cancer Cell Int 2017; 17:85. [PMID: 28959141 PMCID: PMC5615482 DOI: 10.1186/s12935-017-0454-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 09/19/2017] [Indexed: 12/19/2022] Open
Abstract
Background Transforming growth factor-β (TGF-β) plays a paradoxical role in cancer: it suppresses proliferation at early stages but promotes metastasis at late stages. This cytokine is upregulated in cholangiocarcinoma and is implicated in cholangiocarcinoma invasion and metastasis. Here we investigated the roles of non-Smad pathway (ERK1/2) and Smad in TGF-β tumor promoting and suppressing activities in intrahepatic cholangiocarcinoma (ICC) cells. Methods TGF-β1 effects on proliferation, invasion and migration of ICC cells, KKU-M213 and/or HuCCA-1, were investigated using MTT, colony formation, in vitro Transwell and wound healing assays. Levels of mRNAs and proteins/phospho-proteins were measured by quantitative (q)RT-PCR and Western blotting respectively. E-cadherin localization was examined by immunofluorescence and secreted MMP-9 activity was assayed by gelatin zymography. The role of ERK1/2 signaling was evaluated by treating cells with TGF-β1 in combination with MEK1/2 inhibitor U0126, and that of Smad2/3 and Slug using siSmad2/3- and siSlug-transfected cells. Results h-TGF-β1 enhanced KKU-M213 cell invasion and migration and induced epithelial-mesenchymal transition as shown by an increase in vimentin, Slug and secreted MMP-9 levels and by a change in E-cadherin localization from membrane to cytosol, while retaining the cytokine’s ability to attenuate cell proliferation. h-TGF-β1 stimulated Smad2/3 and ERK1/2 phosphorylation, and the MEK1/2 inhibitor U0126 attenuated TGF-β1-induced KKU-M213 cell invasion and MMP-9 production but moderately enhanced the cytokine growth inhibitory activity. The latter effect was more noticeable in HuCCA-1 cells, which resisted TGF-β-anti-proliferative activity. Smad2/3 knock-down suppressed TGF-β1 ability to induce ERK1/2 phosphorylation, Slug expression and cell invasion, whereas Slug knock-down suppressed cell invasion and vimentin expression but marginally affected ERK1/2 activation and MMP-9 secretion. These results indicate that TGF-β1 activated ERK1/2 through Smad2/3 but not Slug pathway, and that ERK1/2 enhanced TGF-β1 tumor promoting but repressed its tumor suppressing functions. Conclusions Inhibiting ERK1/2 activation attenuates TGF-β1 tumor promoting effect (invasion) but retains its tumor suppressing role, thereby highlighting the importance of ERK1/2 in resolving the TGF-β paradox switch. Electronic supplementary material The online version of this article (doi:10.1186/s12935-017-0454-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Phaijit Sritananuwat
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand.,Present Address: Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand
| | - Natthaporn Sueangoen
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand.,Present Address: Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Parichut Thummarati
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand
| | - Kittiya Islam
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand
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50
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Yeung Y, Lau DK, Chionh F, Tran H, Tse JWT, Weickhardt AJ, Nikfarjam M, Scott AM, Tebbutt NC, Mariadason JM. K-Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines. Mol Oncol 2017; 11:1130-1142. [PMID: 28544747 PMCID: PMC5579335 DOI: 10.1002/1878-0261.12078] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 05/10/2017] [Accepted: 05/14/2017] [Indexed: 02/06/2023] Open
Abstract
Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K-Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback-mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP-competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K-Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.
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Affiliation(s)
- Yvonne Yeung
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia
| | - David K Lau
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Fiona Chionh
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia
| | - Hoanh Tran
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia
| | - Janson W T Tse
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia
| | - Andrew J Weickhardt
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, Austin Health, University of Melbourne, Australia
| | - Andrew M Scott
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Niall C Tebbutt
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - John M Mariadason
- Olivia Newton John Cancer Research Institute, Melbourne, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
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