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Sitthirak S, Wangwiwatsin A, Jusakul A, Namwat N, Klanrit P, Dokduang H, Sa-Ngiamwibool P, Titapun A, Jareanrat A, Thanasukarn V, Khuntikeo N, Teh BT, Boulter L, Murakami Y, Loilome W. Whole exome sequencing of multi-regions reveals tumor heterogeneity in Opisthorchis viverrini-associated cholangiocarcinoma. Sci Rep 2025; 15:10886. [PMID: 40157958 PMCID: PMC11954897 DOI: 10.1038/s41598-025-95142-3] [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: 11/10/2024] [Accepted: 03/19/2025] [Indexed: 04/01/2025] Open
Abstract
The study examines Opisthorchis viverrini (OV)-related cholangiocarcinoma (CCA), a serious malignancy common in Southeast Asia. Through multi-regional whole-exome sequencing of 52 tumor samples and 13 adjacent tissues from 13 patients, significant intratumoral heterogeneity (ITH) and inter-patient heterogeneity are shown. Chronic liver fluke infection induces a distinct mutational landscape, with 48-90% of mutations concentrated in each region of the tumor. The average mutation burden is 95 non-synonymous mutations per area, exceeding previous CCA investigations. Critical driver mutations in TP53, SMAD4, and other genes underscore their significance in pathogenesis. Mutational markers elucidate mechanisms including spontaneous deamination and impaired DNA repair. Unique mutation patterns distinguish OV-associated CCA from other variants. Chromosomal instability in patient K110 signifies aggressive tumor behavior and unfavorable prognosis. Targetable mutations such as ERBB2 underscore the possibility for personalized therapeutics. These findings underscore the necessity for personalized strategies for treatment that target both trunk and branch mutations in endemic areas.
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Affiliation(s)
- Sirinya Sitthirak
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Arporn Wangwiwatsin
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
- Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Nisana Namwat
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Poramate Klanrit
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Hasaya Dokduang
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
- Faculty of Medicine, Mahasarakham University, Kantharawichai District, Mahasarakham, 44000, Thailand
| | - Prakasit Sa-Ngiamwibool
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Attapol Titapun
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Apiwat Jareanrat
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Vasin Thanasukarn
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Natcha Khuntikeo
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Bin Tean Teh
- National Cancer Centre Singapore, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, Scotland, UK
| | - Yoshinori Murakami
- Department of Molecular Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
| | - Watcharin Loilome
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
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Neumeyer V, Chavan P, Steiger K, Ebert O, Altomonte J. Cross-Talk Between Tumor Cells and Stellate Cells Promotes Oncolytic VSV Activity in Intrahepatic Cholangiocarcinoma. Cancers (Basel) 2025; 17:514. [PMID: 39941881 PMCID: PMC11816849 DOI: 10.3390/cancers17030514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/27/2025] [Accepted: 01/31/2025] [Indexed: 02/16/2025] Open
Abstract
As the mechanisms underlying tumorigenesis become better understood, the dynamic roles of cellular components of the tumor microenvironment, and their cross-talk with tumor cells, have come to light as key drivers of disease progression and have emerged as important targets of new cancer therapies. In the field of oncolytic virus (OV) therapy, stromal cells have been considered as potential barriers to viral spread, thus limiting virus replication and therapeutic outcome. However, new evidence indicates that intratumoral fibroblasts could support virus replication. We have demonstrated in a rat model of stromal-rich intrahepatic cholangiocarcinoma (CCA) that vesicular stomatitis virus (VSV) can be localized within intratumoral hepatic stellate cells (HSCs), in addition to tumor cells, when the virus was applied via hepatic arterial infusion. Furthermore, VSV was shown to efficiently kill CCA cells and activated HSCs, and co-culture of CCA and HSCs increased viral titers. Interestingly, this effect is also observed when each cell type is cultured alone in a conditioned medium of the other cell type, indicating that secreted cell factors are at least partially responsible for this phenomenon. Partial reduction in sensitivity to type I interferons was observed in co-culture systems, providing a possible mechanism for the increased viral titers. Together, the results indicate that targeting activated HSCs with VSV could provide an additional mechanism of OV therapy, which, until now has not been considered. Furthermore, these findings suggest that VSV is a potentially powerful therapeutic agent for stromal-rich tumors, such as CCA and pancreatic cancer, both of which are very difficult to treat with conventional therapy and have a very poor prognosis.
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Affiliation(s)
- Victoria Neumeyer
- Department of Internal Medicine 2, University Hospital of the Technical University of Munich, 81675 Munich, Germany
| | - Purva Chavan
- Department of Internal Medicine 2, University Hospital of the Technical University of Munich, 81675 Munich, Germany
| | - Katja Steiger
- Department of Pathology, Technical University of Munich, 81675 Munich, Germany
| | - Oliver Ebert
- Department of Internal Medicine 2, University Hospital of the Technical University of Munich, 81675 Munich, Germany
| | - Jennifer Altomonte
- Department of Internal Medicine 2, University Hospital of the Technical University of Munich, 81675 Munich, Germany
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Hong G, Chang JE. Enhancing Cancer Treatment Through Combined Approaches: Photodynamic Therapy in Concert with Other Modalities. Pharmaceutics 2024; 16:1420. [PMID: 39598543 PMCID: PMC11597730 DOI: 10.3390/pharmaceutics16111420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 10/27/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
This review explores the role of photodynamic therapy (PDT) as an adjunctive treatment for cancers, with a focus on its potential to enhance the effects of established therapies like chemotherapy, surgery, and radiotherapy. Given the limitations of conventional cancer treatments, PDT's ability to improve therapeutic outcomes through combination strategies is examined. In cancers such as lung, breast, cholangiocarcinoma, and cervical, PDT shows promise in enhancing response rates, reducing recurrence, and minimizing adverse effects when used alongside standard modalities. This study highlights current findings on PDT's mechanisms in complementing chemotherapy, augmenting surgical precision, and enhancing radiotherapeutic effects, thus offering a multi-faceted approach to cancer treatment. Additionally, insights into the clinical application of PDT in these cancers emphasize its potential for reducing tumor resistance and supporting more effective, personalized care. By providing an overview of PDT's synergistic applications across diverse cancer types, this review underscores its emerging significance in oncology as a tool to address traditional treatment limitations. Ultimately, this review aims to inform and inspire researchers and clinicians seeking to refine and innovate cancer therapy strategies through PDT integration, contributing to the advancement of more effective, synergistic cancer treatments.
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Affiliation(s)
| | - Ji-Eun Chang
- College of Pharmacy, Dongduk Women’s University, Seoul 02748, Republic of Korea
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Porreca V, Barbagallo C, Corbella E, Peres M, Stella M, Mignogna G, Maras B, Ragusa M, Mancone C. Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches. Cancers (Basel) 2024; 16:2889. [PMID: 39199659 PMCID: PMC11352949 DOI: 10.3390/cancers16162889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/01/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is recognized worldwide as the second leading cause of morbidity and mortality among primary liver cancers, showing a continuously increasing incidence rate in recent years. iCCA aggressiveness is revealed through its rapid and silent intrahepatic expansion and spread through the lymphatic system leading to late diagnosis and poor prognoses. Multi-omics studies have aggregated information derived from single-omics data, providing a more comprehensive understanding of the phenomena being studied. These approaches are gradually becoming powerful tools for investigating the intricate pathobiology of iCCA, facilitating the correlation between molecular signature and phenotypic manifestation. Consequently, preliminary stratifications of iCCA patients have been proposed according to their "omics" features opening the possibility of identifying potential biomarkers for early diagnosis and developing new therapies based on personalized medicine (PM). The focus of this review is to provide new and advanced insight into the molecular pathobiology of the iCCA, starting from single- to the latest multi-omics approaches, paving the way for translating new basic research into therapeutic practices.
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Affiliation(s)
- Veronica Porreca
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Cristina Barbagallo
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Eleonora Corbella
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Marco Peres
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Michele Stella
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Giuseppina Mignogna
- Department of Biochemistry Science, Sapienza University of Rome, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Bruno Maras
- Department of Biochemistry Science, Sapienza University of Rome, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Marco Ragusa
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Carmine Mancone
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
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Chang YJ, Chang YJ, Chen LJ. Prognostic factors in patients with intrahepatic cholangiocarcinoma. Sci Rep 2024; 14:19084. [PMID: 39154139 PMCID: PMC11330494 DOI: 10.1038/s41598-024-70124-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second commonly-seen liver malignancy and one of the most fatal cancers in Taiwan. Survival after diagnosis of ICC remains poor. This study aimed to investigate the survival and prognostic factors in patients with ICC. All patients with newly diagnosed ICC during 2004 to 2018 were identified from a national cancer database and followed until December 2020. Estimates of overall survival (OS) were conducted using the Kaplan-Meier method and Cox proportional hazards model. Hazard ratios with 95% confidence intervals were calculated. Initially, 7940 patients with ICC disease (stage IV: 55.6%, 4418/7940) were eligible for this study. Only 32.3% (2563/7940) patients with ICC underwent liver resection. After Propensity score matching, 969 pairs (N = 1938) of patients were matched and selected (mean age 62.8 ± 11.0 years, 53.1% were male, 29.7% had cirrhosis). The median follow-up time was 80.0 months (range 25-201 months). The 3-, 5-year OS rates were 44.0%, 36.4% in the surgical group and 26.0%, 23.7% in the non-surgical group, respectively. Surgery, young patients (≤ 54 years), small tumor size, no vascular invasion and chemotherapy were associated with better OS in patients with stages I-III disease. Surgery benefit was maximum in stage I disease followed by stage II. In patients with stage IV disease, factors such as surgery, young patients (≤ 64 years), single tumor, and no vascular invasion were associated with better OS. Chemotherapy was insignificantly associated with better OS. Long-term survival in patients with ICC is very poor. Compared to non-surgical patients, surgery conveys approximately 18% and 12% better OS rates at 3-year and 5-year, respectively. Early detection and surgical intervention may improve OS substantially in patients with ICC.
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Affiliation(s)
- Yun-Jau Chang
- Department of General Surgery, Zhong-Xing Branch, Taipei City Hospital, Taipei, Taiwan
- Department of General Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Yao-Jen Chang
- Department of General Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
- School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan
| | - Li-Ju Chen
- Department of General Surgery, National Taiwan University Hospital, Taipei, Taiwan.
- University of Taipei, Taipei, Taiwan.
- Division of Surgery, Heping Branch, Taipei City Hospital, No. 33, Section 2, ZhongWha Rd., ZhongZheng District, Taipei, 10065, Taiwan.
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Esmail A, Badheeb M, Alnahar B, Almiqlash B, Sakr Y, Khasawneh B, Al-Najjar E, Al-Rawi H, Abudayyeh A, Rayyan Y, Abdelrahim M. Cholangiocarcinoma: The Current Status of Surgical Options including Liver Transplantation. Cancers (Basel) 2024; 16:1946. [PMID: 38893067 PMCID: PMC11171350 DOI: 10.3390/cancers16111946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
Cholangiocarcinoma (CCA) poses a substantial threat as it ranks as the second most prevalent primary liver tumor. The documented annual rise in intrahepatic CCA (iCCA) incidence in the United States is concerning, indicating its growing impact. Moreover, the five-year survival rate after tumor resection is only 25%, given that tumor recurrence is the leading cause of death in 53-79% of patients. Pre-operative assessments for iCCA focus on pinpointing tumor location, biliary tract involvement, vascular encasements, and metastasis detection. Numerous studies have revealed that portal vein embolization (PVE) is linked to enhanced survival rates, improved liver synthetic functions, and decreased overall mortality. The challenge in achieving clear resection margins contributes to the notable recurrence rate of iCCA, affecting approximately two-thirds of cases within one year, and results in a median survival of less than 12 months for recurrent cases. Nearly 50% of patients initially considered eligible for surgical resection in iCCA cases are ultimately deemed ineligible during surgical exploration. Therefore, staging laparoscopy has been proposed to reduce unnecessary laparotomy. Eligibility for orthotopic liver transplantation (OLT) requires certain criteria to be granted. OLT offers survival advantages for early-detected unresectable iCCA; it can be combined with other treatments, such as radiofrequency ablation and transarterial chemoembolization, in specific cases. We aim to comprehensively describe the surgical strategies available for treating CCA, including the preoperative measures and interventions, alongside the current options regarding liver resection and OLT.
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Affiliation(s)
- Abdullah Esmail
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Mohamed Badheeb
- Department of Internal Medicine, Yale New Haven Health, Bridgeport Hospital, Bridgeport, CT 06605, USA
| | - Batool Alnahar
- College of Medicine, Almaarefa University, Riyadh 13713, Saudi Arabia
| | - Bushray Almiqlash
- Zuckerman College of Public Health, Arizona State University, Tempe, AZ 85287, USA
| | - Yara Sakr
- Department of GI Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bayan Khasawneh
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Ebtesam Al-Najjar
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Hadeel Al-Rawi
- Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Ala Abudayyeh
- Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yaser Rayyan
- Department of Gastroenterology & Hepatology, Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
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Yang Z, Wang L, Zhai Y, Zhao J, Ye F, Wang S, Jiang L, Song Y, Sun Y, Zhu J, Tang Y, Liu Y, Song Y, Fang H, Li N, Qi S, Lu N, Li YX, Zhao H, Chen B. Nodal recurrence mapping and clinical target volumes after resection of intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma. Clin Transl Radiat Oncol 2024; 45:100749. [PMID: 38425471 PMCID: PMC10904232 DOI: 10.1016/j.ctro.2024.100749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 01/29/2024] [Accepted: 02/15/2024] [Indexed: 03/02/2024] Open
Abstract
Background Scarce evidence exists for clinical target volume (CTV) definitions of regional lymph nodes (LNs) in intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We investigated the mapping pattern of nodal recurrence after surgery for iCCA and cHCC-CCA and provided evidence for the nodal CTV definition. Methods We retrospectively reviewed the medical records of patients with iCCA or cHCC-CCA who underwent surgery between 2010 and 2020. Eligibility criteria included patients pathologically diagnosed with iCCA or cHCC-CCA after surgery and a first recurrent event in regional LNs during follow-up. All recurrent LNs were registered onto reference computed tomography images based on the vascular structures to reconstruct the node mapping. Fifty-three patients were eligible. LN regions were classified into four risk groups. Results Hepatic hilar and portal vein-vena cava were the most common recurrent regions, with recurrence rates of 62.3 % and 39.6 % (high-risk regions), respectively. Recurrence rates in the left gastric, diaphragmatic, common hepatic, superior mesenteric vessels, celiac trunk, and paracardial regions ranged from 15.1 % to 30.2 % (intermediate-risk regions). There were fewer recurrences in the para-aortic (16a1, a2, b1) and splenic artery and hilum regions, with rates <10 % (low-risk regions). No LN recurrence was observed in the para-oesophageal or para-aortic region (16b2) (very low-risk regions). Based on node mapping, the CTV should include high- and intermediate-risk regions for pathologically negative LN patients during postoperative radiotherapy. Low-risk regions should be included for pathologically positive LN patients. Conclusion We provide evidence for CTV delineation in patients with iCCA and cHCC-CCA based on recurrent LN mapping.
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Affiliation(s)
- Zhuanbo Yang
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yirui Zhai
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Feng Ye
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Shulian Wang
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Liming Jiang
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yan Song
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yongkun Sun
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Ji Zhu
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yuan Tang
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yueping Liu
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Yongwen Song
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Hui Fang
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Ning Li
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Shunan Qi
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Ningning Lu
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Ye-Xiong Li
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
| | - Bo Chen
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No. 17 Panjiayan Nanli, Chaoyang District, Beijing, China
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Yamamoto H, Nakanishi Y, Mitsuhashi T, Hatanaka Y, Hatanaka K, Nange A, Yoshida Y, Ino N, Go M, Okamura K, Tsuchikawa T, Nakamura T, Noji T, Asano T, Matsui A, Tanaka K, Murakami S, Ebihara Y, Kurashima Y, Shichinohe T, Hirano S. Impact of Neutrophil Extracellular Traps Identified by Citrullinated Histone H3 Immunohistochemistry for Postoperative Prognosis in Patients with Extrahepatic Cholangiocarcinomas. Ann Surg Oncol 2024; 31:2090-2100. [PMID: 38052736 DOI: 10.1245/s10434-023-14638-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 11/07/2023] [Indexed: 12/07/2023]
Abstract
BACKGROUND Neutrophil extracellular traps (NETs) are extracellular chromatin structures composed of cytoplasmic, granular, and nuclear components of neutrophils. Recently, NETs have received much attention for their role in tumor biology; however, their impact on the postoperative prognosis of patients with extrahepatic cholangiocarcinomas (EHCCs) remains unclear. The purpose of this study was to clarify the impact of NETs identified by immunohistochemical citrullinated histone H3 (Cit-H3) staining on postoperative overall survival (OS) in patients with perihilar cholangiocarcinoma (PHCC) and distal cholangiocarcinoma (DCC). METHODS This study included 318 patients with EHCC (PHCC, n = 192; DCC, n = 126) who underwent surgical resection with curative intent. Neutrophils and NETs were identified by immunohistochemistry using antibodies against CD15 and Cit-H3, respectively. Based on the distribution of CD15 and Cit-H3 expression in the tumor bed, the patients were classified into four groups: one negative group and three subgroups of the positive group (diffuse, intermediate, and focal subgroups). RESULTS No significant difference was found in the postoperative OS rate depending on the distribution of CD15 expression in patients with PHCC or DCC. However, the three subgroups with positive Cit-H3 expression had significantly poorer OS than the negative group for both PHCC and DCC. Moreover, positive Cit-H3 was an independent OS factor in the multivariable analyses of PHCC (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.11-2.59, P = 0.0115) and DCC (HR 2.03; 95% CI 1.21-3.42, P = 0.0057). CONCLUSIONS The presence of NETs in the tumor microenvironment may have adverse prognostic effects in patients with EHCCs.
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Affiliation(s)
- Hiroyuki Yamamoto
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Yoshitsugu Nakanishi
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan.
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Yutaka Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Kanako Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Ayae Nange
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Yusuke Yoshida
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Norito Ino
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Masaru Go
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Keisuke Okamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Takehiro Noji
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Toshimichi Asano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Aya Matsui
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Kimitaka Tanaka
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Soichi Murakami
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Yuma Ebihara
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Yo Kurashima
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Toshiaki Shichinohe
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
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9
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Myint KZ, Balasubramanian B, Venkatraman S, Phimsen S, Sripramote S, Jantra J, Choeiphuk C, Mingphruedhi S, Muangkaew P, Rungsakulkij N, Tangtawee P, Suragul W, Farquharson WV, Wongprasert K, Chutipongtanate S, Sanvarinda P, Ponpuak M, Poungvarin N, Janvilisri T, Suthiphongchai T, Yacqub-Usman K, Grabowska AM, Bates DO, Tohtong R. Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation. Pharmaceuticals (Basel) 2024; 17:197. [PMID: 38399413 PMCID: PMC10892566 DOI: 10.3390/ph17020197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/25/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib's cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.
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Affiliation(s)
- Kyaw Zwar Myint
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (K.Z.M.); (B.B.); (S.V.); (T.J.)
| | - Brinda Balasubramanian
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (K.Z.M.); (B.B.); (S.V.); (T.J.)
- Translational Medical Sciences Unit, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
| | - Simran Venkatraman
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (K.Z.M.); (B.B.); (S.V.); (T.J.)
| | - Suchada Phimsen
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand; (S.P.); (C.C.)
| | - Supisara Sripramote
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (S.S.); (J.J.); (T.S.)
| | - Jeranan Jantra
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (S.S.); (J.J.); (T.S.)
| | - Chaiwat Choeiphuk
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand; (S.P.); (C.C.)
| | - Somkit Mingphruedhi
- Hepato-Pancreatic-Biliary Surgery Unit, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (S.M.); (P.M.); (N.R.); (P.T.); (W.S.); (W.V.F.)
| | - Paramin Muangkaew
- Hepato-Pancreatic-Biliary Surgery Unit, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (S.M.); (P.M.); (N.R.); (P.T.); (W.S.); (W.V.F.)
| | - Narongsak Rungsakulkij
- Hepato-Pancreatic-Biliary Surgery Unit, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (S.M.); (P.M.); (N.R.); (P.T.); (W.S.); (W.V.F.)
| | - Pongsatorn Tangtawee
- Hepato-Pancreatic-Biliary Surgery Unit, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (S.M.); (P.M.); (N.R.); (P.T.); (W.S.); (W.V.F.)
| | - Wikran Suragul
- Hepato-Pancreatic-Biliary Surgery Unit, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (S.M.); (P.M.); (N.R.); (P.T.); (W.S.); (W.V.F.)
| | - Watoo Vassanasiri Farquharson
- Hepato-Pancreatic-Biliary Surgery Unit, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (S.M.); (P.M.); (N.R.); (P.T.); (W.S.); (W.V.F.)
| | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Somchai Chutipongtanate
- Division of Epidemiology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Pimtip Sanvarinda
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Marisa Ponpuak
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Naravat Poungvarin
- Department of Clinical Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand;
| | - Tavan Janvilisri
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (K.Z.M.); (B.B.); (S.V.); (T.J.)
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (S.S.); (J.J.); (T.S.)
| | - Tuangporn Suthiphongchai
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (S.S.); (J.J.); (T.S.)
| | - Kiren Yacqub-Usman
- Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK; (K.Y.-U.); (A.M.G.); (D.O.B.)
| | - Anna M. Grabowska
- Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK; (K.Y.-U.); (A.M.G.); (D.O.B.)
| | - David O. Bates
- Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK; (K.Y.-U.); (A.M.G.); (D.O.B.)
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (S.S.); (J.J.); (T.S.)
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10
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Consensus statements on endoscopic radiofrequency ablation for malignant biliary strictures. J Dig Dis 2024; 25:2-13. [PMID: 38126618 DOI: 10.1111/1751-2980.13248] [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: 11/30/2023] [Accepted: 12/19/2023] [Indexed: 12/23/2023]
Abstract
Endoscopy-guided endobiliary radiofrequency ablation has emerged as a novel treatment for malignant biliary strictures in recent years. When combined with biliary stenting and systemic chemotherapy, it can effectively postpone local tumor progression, improve patient's quality of life, and prolong their survival, which is mainly indicated for patients with inoperable extrahepatic cholangiocarcinoma and ampullary cancer. Based on the existing clinical evidence, the Digestive Endoscopology Branch of Chinese Medical Association, the Digestive Endoscopy Professional Committee, Endoscopic Physicians Branch of Chinese Medical Doctor Association, and the National Clinical Research Center for Digestive Diseases (Shanghai) organized relevant experts to discuss the indications, contraindications, technical operation specifications, and prevention and treatment of the complications during endoscopy-guided endobiliary radiofrequency ablation. Consensus statements were established, trying to provide references for standard treatment of malignant biliary tumors in clinical practice.
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11
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Giovinazzo F, Pascale MM, Cardella F, Picarelli M, Molica S, Zotta F, Martullo A, Clarke G, Frongillo F, Grieco A, Agnes S. Current Perspectives in Liver Transplantation for Perihilar Cholangiocarcinoma. Curr Oncol 2023; 30:2942-2953. [PMID: 36975438 PMCID: PMC10047046 DOI: 10.3390/curroncol30030225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/17/2023] [Accepted: 01/30/2023] [Indexed: 03/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) encompasses all malignant neoplasms arising from the epithelial cells of the biliary tree. About 40% of CCAs are perihilar, involving the bile ducts distal to the second-order biliary branches and proximal to the cystic duct implant. About two-thirds of pCCAs are considered unresectable at the time of diagnosis or exploration. When resective surgery is deemed unfeasible, liver transplantation (LT) could be an effective alternative. The overall survival rates after LT at 1 and 3 years are 91% and 81%, respectively. The overall five-year survival rate after transplantation is 73% (79% for patients with underlying PSC and 63% for de novo pCCA). Multicenter case series reported a 5-year disease-free survival rate of ~65%. However, different protocols, including neoadjuvant therapy, have been proposed. The scarcity of organ availability represents a crucial limiting factor in recommending LT preferentially in treating pCCA. Living donor transplantations and marginal cadaveric allografts have proven to be exciting options to overcome organ shortage. Management of jaundice and cholangitis is still challenging for these patients and could impact LT listing. Whether to adopt surgical resection or LT as standard-of-care in pCCA is still a matter of debate, and more prospective studies are needed.
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Affiliation(s)
- Francesco Giovinazzo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Correspondence:
| | - Marco Maria Pascale
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesca Cardella
- Surgical Oncology of Gastrointestinal Tract Unit, Vanvitelli University, 80138 Naples, Italy
| | - Matteo Picarelli
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Serena Molica
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesca Zotta
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Annamaria Martullo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - George Clarke
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, UK
| | - Francesco Frongillo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Grieco
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medicine and Translational Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Salvatore Agnes
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medicine and Translational Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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12
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Chung HH, Seo SH, Kim H, Kim Y, Kim DW, Lee KH, Lee KT, Heo JS, Han IW, Park SM, Jang KT, Lee JK, Park JK. Postoperative Prognostic Predictors of Bile Duct Cancers: Clinical Analysis and Immunoassays of Tissue Microarrays. Gut Liver 2023; 17:159-169. [PMID: 36317517 PMCID: PMC9840923 DOI: 10.5009/gnl220044] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/02/2022] [Accepted: 04/14/2022] [Indexed: 01/14/2023] Open
Abstract
Background/Aims Cholangiocarcinoma frequently recurs even after curative resection. Expression levels of proteins such as epidermal growth factor receptor (EGFR), Snail, epithelial cadherin (E-cadherin), and interleukin-6 (IL-6) examined by immunohistochemistry have been studied as potential prognostic factors for cholangiocarcinoma. The aim of this study was to investigate significant factors affecting the prognosis of resectable cholangiocarcinoma. Methods Ninety-one patients who underwent surgical resection at Samsung Medical Center for cholangiocarcinoma from 1995 to 2013 were included in this study. Expression levels of E-cadherin, Snail, IL-6, membranous EGFR, and cytoplasmic EGFR were analyzed by immunohistochemistry using tissue microarray blocks made from surgical specimens. Results Patients with high levels of membranous EGFR in tissue microarrays had significantly shorter overall survival (OS) and disease-free survival (DFS): high membranous EGFR (score 0-2) 38.0 months versus low membranous EGFR (score 3) 14.4 months (p=0.008) and high membranous EGFR (score 0-2) 23.2 months versus low membranous EGFR (score 3) 6.1 months (p=0.004), respectively. On the other hand, E-cadherin, Snail, cytoplasmic EGFR, and IL-6 did not show significant association with OS or DFS. Patients with distant metastasis had significantly higher IL-6 levels than those with locoregional recurrence (p=0.01). Conclusions This study showed that overexpression of membranous EGFR was significantly associated with shorter OS and DFS in surgically resected bile duct cancer patients. In addition, higher IL-6 expression was a predictive marker for recurrence in cholangiocarcinoma patients with distant organ metastasis after surgical resection.
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Affiliation(s)
- Hwe Hoon Chung
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Hee Seo
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyemin Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yuil Kim
- Department of Clinical Pathology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Dong Wuk Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Hyuck Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyu Taek Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Seok Heo
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - In Woong Han
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seon Mee Park
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Kee-Taek Jang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Kee-Taek Jang, ORCIDhttps://orcid.org/0000-0001-7987-4437, E-mail
| | - Jong Kyun Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Jong Kyun Lee, ORCIDhttps://orcid.org/0000-0002-9384-3079, E-mail
| | - Joo Kyung Park
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea,Corresponding AuthorJoo Kyung Park, ORCIDhttps://orcid.org/0000-0002-9652-5287, E-mail
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13
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Elias C, Zeidan YH, Bouferraa Y, Mukherji D, Temraz S, Charafeddine M, Al Darazi M, Shamseddine A. A phase II single arm study of Nivolumab with stereotactic Ablative radiation Therapy after induction chemotherapy in CHOlangiocarcinoma (NATCHO). BMC Cancer 2022; 22:1296. [PMID: 36503610 PMCID: PMC9743639 DOI: 10.1186/s12885-022-10373-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (CCA) is amongst the most common primary liver tumors worldwide. CCA carries a bad prognosis prompting research to establish new treatment modalities other than surgery and the current chemotherapeutic regimens adopted. Hence, this trial explores a new therapeutic approach, to combine stereotactic body radiation therapy (SBRT) and immunotherapy (Nivolumab), and asses its clinical benefit and safety profile after induction chemotherapy in CCA. METHODOLOGY This is a Phase II open-label, single-arm, multicenter study that investigates Nivolumab (PD-1 inhibitor) treatment at Day 1 followed by SBRT (30 Gy in 3 to 5 fractions) at Day 8, then monthly Nivolumab in 40 patients with non-resectable locally advanced, metastatic or recurrent intrahepatic or extrahepatic CCA. Eligible patients were those above 18 years of age with a pathologically and radiologically confirmed diagnosis of non-resectable locally advanced or metastatic or recurrent intrahepatic or extrahepatic CCA, following 4 cycles of cisplatin-based chemotherapy with an estimated life expectancy of more than 3 months, among other criteria. The primary endpoint is the progression free survival (PFS) rate at 8 months and disease control rate (DCR). The secondary endpoints are overall survival (OS), tumor response rate (TRR), duration of response, evaluation of biomarkers: CD3 + , CD4 + and CD8 + T cell infiltration, as well as any change in the PD-L1 expression through percutaneous core biopsy when compared with the baseline biopsy following 1 cycle of Nivolumab and SBRT. DISCUSSION SRBT alone showed promising results in the literature by both inducing the immune system locally and having abscopal effects on distant metastases. Moreover, given the prevalence of PD-L1 in solid tumors, targeting it or its receptor has become the mainstay of novel immunotherapeutic drugs use. A combination of both has never been explored in the scope of CCA and that is the aim of this study. TRIAL REGISTRATION ClinicalTrials.gov NCT04648319 , April 20, 2018.
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Affiliation(s)
- Charbel Elias
- grid.411654.30000 0004 0581 3406Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Youssef H. Zeidan
- grid.411654.30000 0004 0581 3406Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Youssef Bouferraa
- grid.411654.30000 0004 0581 3406Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Deborah Mukherji
- grid.411654.30000 0004 0581 3406Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sally Temraz
- grid.411654.30000 0004 0581 3406Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Maya Charafeddine
- grid.411654.30000 0004 0581 3406Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Monita Al Darazi
- grid.411654.30000 0004 0581 3406Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali Shamseddine
- grid.411654.30000 0004 0581 3406Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
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14
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Keulen AMV, Gaspersz MP, van Vugt JLA, Roos E, Olthof PB, Coelen RJS, Bruno MJ, van Driel LMJW, Voermans RP, van Eijck CHJ, van Hooft JE, van Lienden KP, de Jonge J, Polak WG, Poley JW, Pek CJ, Moelker A, Willemssen FEJA, van Gulik TM, Erdmann JI, Hol L, IJzermans JNM, Büttner S, Koerkamp BG. Success, complication, and mortality rates of initial biliary drainage in patients with unresectable perihilar cholangiocarcinoma. Surgery 2022; 172:1606-1613. [PMID: 35989132 DOI: 10.1016/j.surg.2022.06.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 06/09/2022] [Accepted: 06/20/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND The patients with unresectable perihilar cholangiocarcinoma require biliary drainage to relieve symptoms and allow for palliative systemic chemotherapy. The aim of this study was to establish the success, complication, and mortality rates of the initial biliary drainage in patients with unresectable perihilar cholangiocarcinoma at presentation. METHODS In this retrospective multicenter study, patients with unresectable perihilar cholangiocarcinoma who underwent initial endoscopic or percutaneous transhepatic biliary drainage between 2002 and 2014 were included. The success of drainage was defined as a successful biliary stent or drain placement, no unscheduled reintervention within 14 days, and serum bilirubin levels <50 μmol/L (ie, 2.9 mg/dL) or a >50% decrease in serum bilirubin after 14 days. Severe complications, and 90-day mortality were recorded. RESULTS Included were 186 patients: 161 (87%) underwent initial endoscopic biliary drainage and 25 (13%) underwent initial percutaneous transhepatic biliary drainage. The success of initial drainage was observed in 73 patients (45%) after endoscopic biliary drainage and 6 (24%) after percutaneous transhepatic biliary drainage. The reasons for an unsuccessful initial drainage were: the failure to place a drain or stent in 39 patients (21%), an unplanned reintervention within 14 days in 52 patients (28%), and the bilirubin level >50 μmol/L (or not halved) after 14 days of initial drainage in 16 patients (9%). Severe drainage-related complications occurred in 19 patients (12%) after endoscopic biliary drainage and in 3 (12%) after percutaneous transhepatic biliary drainage. Overall, 66 patients (36%) died within 90 days after initial biliary drainage. CONCLUSION Initial biliary drainage in patients with unresectable perihilar cholangiocarcinoma had a success rate of 45% and a 90-day mortality rate of 36%. Future studies for patients with perihilar cholangiocarcinoma should focus on improving biliary drainage.
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Affiliation(s)
| | - Marcia P Gaspersz
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Jeroen L A van Vugt
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Eva Roos
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, the Netherlands
| | - Pim B Olthof
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Robert J S Coelen
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, the Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Lydi M J W van Driel
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Rogier P Voermans
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam Gastroenterology and Metabolism Institute, the Netherlands
| | | | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, the Netherlands
| | - Krijn P van Lienden
- Department of Radiology, Amsterdam University Medical Center, the Netherlands
| | - Jeroen de Jonge
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Wojciech G Polak
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Jan-Werner Poley
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Chulja J Pek
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Adriaan Moelker
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - François E J A Willemssen
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Thomas M van Gulik
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, the Netherlands
| | - Joris I Erdmann
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, the Netherlands
| | - L Hol
- Department of Gastroenterology and Hepatology, Maasstad Ziekenhuis, Rotterdam, the Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Stefan Büttner
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
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15
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Caputo F, Gelsomino F, Spallanzani A, Pettorelli E, Benatti S, Ghidini M, Grizzi G, Ratti M, Merz V, Messina C, Tonelli R, Luppi G, Melisi D, Dominici M, Salati M. Multicentre match-paired analysis of advanced biliary cancer long-term survivors: The BILONG study. Clin Res Hepatol Gastroenterol 2022; 46:101955. [PMID: 35609824 DOI: 10.1016/j.clinre.2022.101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 03/23/2022] [Accepted: 05/11/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Advanced biliary cancers (ABC) are aggressive malignancies with a median overall survival (mOS) <12 months when treated with first-line chemotherapy. Nevertheless, a subset of patients experiencing longer survival has been described in the updated analysis of ABC-02 trial. We aimed to provide a real-world description of ABC long-term survivors (LS), identifying which factors impact on survival. METHODS Patients diagnosed with ABC at three Institutions between 2002 and 2019, and who survived ≥18 months, were retrospectively identified. We compared them with a control cohort (C) with a mOS <18 months, matched on age, gender, ECOG PS, disease status, primary tumor site, prior surgery, and treatment modality. Their clinical features, treatments, and outcome were analyzed. RESULTS A total of 78 patients was included, 39 in each group. Both LS and C cohorts had superimposable baseline characteristics, without significant differences. mOS was 29 (95%CI 24.6-33.5) and 9 months (95%CI 6.6-12.9) in the two groups, respectively. After performing a logistic regression analysis, three factors were significantly associated with long-term outcome: low neutrophil-to-lymphocyte ratio (NLR < 3) (Odds Ratio [OR] 0.38), achievement of objective response to treatment (OR 0.16), and the number of lines received (OR 0.29). CONCLUSIONS We described a considerable subset of ABC experiencing long-term survival with conventional chemotherapy in a real-world scenario. Beyond clinical factors, we identified low NLR as a prognostic determinant that may allow for a more accurate selection of long survivors. While waiting for a deeper molecular characterization of this subgroup, we propose NLR as a stratification factor for daily practice and clinical trials.
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Affiliation(s)
- Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrea Spallanzani
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Elisa Pettorelli
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Stefania Benatti
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Michele Ghidini
- Division of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giulia Grizzi
- Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy
| | - Margherita Ratti
- Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy
| | - Valeria Merz
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Carlo Messina
- Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy
| | - Roberto Tonelli
- Department of Medical and Surgical Sciences, Respiratory Diseases Unit and Centre for Rare Lung Diseases, University Hospital of Modena, Modena, Italy; Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, Modena, Italy
| | - Gabriele Luppi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena Cancer Center, Via del Pozzo 71, Modena 41125, Italy.
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16
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Liver Transplant for Non-Hepatocellular Malignancies: A Review for Radiologists. AJR Am J Roentgenol 2022; 219:590-603. [PMID: 35544376 DOI: 10.2214/ajr.22.27783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Although traditionally only performed for hepatocellular carcinoma (HCC), the last decade has seen a resurgence in the use of liver transplant (LT) for non-HCC malignancies, likely due to improvements in neoadjuvant treatment regimens as well as the establishment of well-defined eligibility criteria. Given promising survival results, patients with perihilar cholangiocarcinoma, neuroendocrine liver metastases, and hepatic hemangioendothelioma are eligible to receive Model for End Stage Liver Disease (MELD) exception for tumors that meet well-defined criteria. Additional tumors such as colorectal cancer liver metastases, intrahepatic cholangiocarcinoma, and hepatocholangiocarcinoma may undergo transplant at specialized centers with well-defined protocols, although are not yet eligible for MELD exception. Transplant eligibility criteria commonly incorporate imaging findings, yet due to the relatively novel and evolving nature of LT for non-HCC malignancies, radiologists may be unaware of relevant criteria or of the implications of their imaging interpretations. Knowledge of the allocation process, background, and liver transplant selection criteria facilitates the radiologist' active participation in multidisciplinary discussion, leading to better and more equitable care for transplant candidates with non-HCC malignancy. This review provides an overview of transplant allocation and selection criteria in patients with non-HCC malignancy, with an emphasis on imaging features and the role of the radiologist.
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Chen Y, Zhang B, Liu C, Cao Y, Lyu C, Qiu M. Clinical efficacy of adjuvant treatments for patients with resected biliary tract cancer: a systematic review and network meta-analysis. BMJ Open 2022; 12:e051421. [PMID: 35440445 PMCID: PMC9020290 DOI: 10.1136/bmjopen-2021-051421] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE This study aimed to determine the benefits of adjuvant therapy in patients with resected biliary tract cancer (BTC) and identify the optimal adjuvant treatment scheme. DESIGN Systematic review and network meta-analysis. DATA SOURCES Studies comparing different adjuvant therapies in patients with BTC were searched in PubMed, Embase, CINAHL, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov databases from inception to December 2021. Additionally, the references were manually searched for the related literature. MATERIALS AND METHODS Eligible studies were identified, and data were extracted independently by two authors. A random-effects network meta-analysis was performed using R software. The pooled outcomes of overall survival (OS) and disease-free survival (DFS) were measured using the combined HRs with 95% CIs. RESULTS Nineteen eligible studies reporting three types of adjuvant therapies were included in our network meta-analysis. Adjuvant radiotherapy (ART, HR 0.62; 95% CI 0.42 to 0.93), adjuvant chemoradiotherapy (ACRT; HR 0.71; 95% CI 0.54 to 0.83) and adjuvant chemotherapy (ACT; HR 0.84; 95% CI 0.68 to 0.98) were more effective in prolonging OS than that of observation, with no significant difference between the three adjuvant therapies. Moreover, the improvement in DFS was also found in ACRT and ACT compared with that of observation (HR 0.60; 95% CI 0.45 to 0.75; HR 0.82; 95% CI 0.68 to 0.97, respectively). Furthermore, ACRT obtained a slightly better DFS benefit compared with that of ACT (HR 0.73; 95% CI 0.53 to 0.95). CONCLUSIONS Our primary results demonstrated that, compared with that of observation, ACRT and ACT after radical resection could provide better OS and DFS benefits in patients with BTC. However, ART only showed improvement in OS, but not in DFS. Due to the lack of head-to-head studies of ACT, ACRT and ART, the above results need to be further verified by prospective randomised controlled trials.
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Affiliation(s)
- Ye Chen
- Department of Medical Oncology, Cancer Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Baoxia Zhang
- Department of Medicine, CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, Shijiazhuang, China
| | - Chang Liu
- Department of Medicine, CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, Shijiazhuang, China
| | - Ye Cao
- Department of Medicine, Ascentage Pharma (Suzhou) Co. Ltd, Suzhou, China
| | - Cheng Lyu
- Department of Medicine, CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, Shijiazhuang, China
| | - Meng Qiu
- Department of Medical Oncology, Cancer Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
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18
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Butsri S, Kukongviriyapan V, Senggunprai L, Kongpetch S, Prawan A. All‑ trans‑retinoic acid induces RARB‑dependent apoptosis via ROS induction and enhances cisplatin sensitivity by NRF2 downregulation in cholangiocarcinoma cells. Oncol Lett 2022; 23:179. [PMID: 35464301 PMCID: PMC9025595 DOI: 10.3892/ol.2022.13299] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 03/03/2022] [Indexed: 11/27/2022] Open
Abstract
All-trans-retinoic acid (ATRA) has been clinically used to treat acute promyelocytic leukemia and is being studied to treat other types of cancer; however, the therapeutic role and mechanism of ATRA against cholangiocarcinoma (CCA) remain unclear. The present study investigated the cytotoxic effect and underlying mechanisms of ATRA on CCA cell lines. Cell viability was evaluated by sulforhodamine B assay. Intracellular reactive oxygen species (ROS) levels were assessed by dihydroethidium assay. Apoptosis analysis was performed by flow cytometry. The pathways of apoptotic cell death induction were examined using enzymatic caspase activity assay. Proteins associated with apoptosis were evaluated by western blotting. The effects on gene expression were analyzed by reverse transcription-quantitative PCR analysis. ATRA induced a concentration- and time-dependent toxicity in CCA cells. Furthermore, when the cytotoxicity of ATRA against retinoic acid receptor (RAR)-deficient cells was assessed, it was revealed that ATRA cytotoxicity was RARB-dependent. Following ATRA treatment, there was a significant accumulation of cellular ROS and ATRA-induced ROS generation led to an increase in the expression levels of apoptosis-inducing proteins and intrinsic apoptosis. Pre-treatment with ROS scavengers could diminish the apoptotic effect of ATRA, suggesting that ROS and mitochondria may have an essential role in the induction of apoptosis. Furthermore, following ATRA treatment, an increase in cellular ROS content was associated with suppressing nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2) and NRF2-downstream active genes. ATRA also suppressed cisplatin-induced NRF2 expression, suggesting that the enhancement of cisplatin cytotoxicity by ATRA may be associated with the downregulation of NRF2 signaling. In conclusion, the results of the present study demonstrated that ATRA could be repurposed as an alternative drug for CCA therapy.
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Affiliation(s)
- Siriwoot Butsri
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Laddawan Senggunprai
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sarinya Kongpetch
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Auemduan Prawan
- Department of Pharmacology, Faculty of Medicine, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
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Liu D, Heij LR, Czigany Z, Dahl E, Lang SA, Ulmer TF, Luedde T, Neumann UP, Bednarsch J. The role of tumor-infiltrating lymphocytes in cholangiocarcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:127. [PMID: 35392957 PMCID: PMC8988317 DOI: 10.1186/s13046-022-02340-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 03/23/2022] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and associated with a dismal prognosis due to the lack of an efficient systemic therapy. In contrast to other cancers, new immunotherapies have demonstrated unsatisfactory results in clinical trials, underlining the importance of a deeper understanding of the special tumor microenvironment of CCA and the role of immune cells interacting with the tumor. Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy. Therefore, the aim of this systemic review is to summarize the current literature focusing on the proportions and distribution, molecular pathogenesis, prognostic significance of TILs and their role in immunotherapy for CCA patients. In CCA, CD8+ and CD4+ T lymphocytes represent the majority of TILs and are mostly sequestered around the cancer cells. CD20+ B lymphocytes and Natural Killer (NK) cells are less frequent. In contrast, Foxp3+ cells (regulatory T cells, Tregs) are observed to infiltrate into the tumor. In the immune microenvironment of CCA, cancer cells and stromal cells such as TAMs, TANs, MSDCs and CAFs inhibit the immune protection function of TILs by secreting factors like IL-10 and TGF-β. With respect to molecular pathogenesis, the Wnt/-catenin, TGF-signaling routes, aPKC-i/P-Sp1/Snail Signaling, B7-H1/PD-1Pathway and Fas/FasL signaling pathways are connected to the malignant potential and contributed to tumor immune evasion by increasing TIL apoptosis. Distinct subtypes of TILs show different prognostic implications for the long-term outcome in CCA. Although there are occasionally conflicting results, CD8+ and CD4+ T cells, and CD20+ B cells are positively correlated with the oncological prognosis of CCA, while a high number of Tregs is very likely associated with worse overall survival. TILs also play a major role in immunotherapy for CCA. In summary, the presence of TILs may represent an important marker for the prognosis and a potential target for novel therapy, but more clinical and translational data is needed to fully unravel the importance of TILs in the treatment of CCA.
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Affiliation(s)
- Dong Liu
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Lara Rosaline Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Edgar Dahl
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Heinrich Heine University Duesseldorf, Duesseldorf, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. .,Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
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20
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Han SY, Kim DU, Nam HS, Kang DH, Jang SI, Lee DK, Shin DW, Cho KB, Yang MJ, Hwang JC, Kim JH, So H, Bang SJ, Sung MJ, Kwon CI, Lee DW, Cho CM, Cho JH. Comparison of the Malignant Predictors in Intrahepatic and Extrahepatic Intraductal Papillary Neoplasm of the Bile Duct. J Clin Med 2022; 11:jcm11071985. [PMID: 35407592 PMCID: PMC8999974 DOI: 10.3390/jcm11071985] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/28/2022] [Accepted: 03/31/2022] [Indexed: 02/01/2023] Open
Abstract
Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a precancerous lesion of cholangiocarcinoma, for which surgical resection is the most effective treatment. We evaluated the predictors of malignancy in IPNB according to anatomical location and the prognosis without surgery. Methods: A total of 196 IPNB patients who underwent pathologic confirmation by surgical resection or endoscopic retrograde cholangiography or percutaneous transhepatic cholangioscopic biopsy were included. Clinicopathological findings of IPNB with invasive carcinoma or mucosal dysplasia were analyzed according to anatomical location. Results: Of the 116 patients with intrahepatic IPNB (I-IPNB) and 80 patients with extrahepatic IPNB (E-IPNB), 62 (53.4%) and 61 (76.3%) were diagnosed with invasive carcinoma, respectively. Multivariate analysis revealed that mural nodule > 12 mm (p = 0.043) in I-IPNB and enhancement of mural nodule (p = 0.044) in E-IPNB were predictive factors for malignancy. For pathologic discrepancy before and after surgery, IPNB has a 71.2% sensitivity and 82.3% specificity. In the non-surgical IPNB group, composed of nine I-IPNB and seven E-IPNB patients, 43.7% progressed to IPNB with invasive carcinoma within 876 days. Conclusions: E-IPNB has a higher rate of malignancy than I-IPNB. The predictive factor for malignancy is mural nodule > 12 mm in I-IPNB and mural nodule enhancement in E-IPNB.
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Affiliation(s)
- Sung Yong Han
- Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan 49241, Korea;
| | - Dong Uk Kim
- Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan 49241, Korea;
- Correspondence: (D.U.K.); (J.H.C.)
| | - Hyeong Seok Nam
- Department of Internal Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Korea; (H.S.N.); (D.H.K.)
| | - Dae Hwan Kang
- Department of Internal Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Korea; (H.S.N.); (D.H.K.)
| | - Sung Ill Jang
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06230, Korea; (S.I.J.); (D.K.L.)
| | - Dong Ki Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06230, Korea; (S.I.J.); (D.K.L.)
| | - Dong Woo Shin
- Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu 42601, Korea; (D.W.S.); (K.B.C.)
| | - Kwang Bum Cho
- Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu 42601, Korea; (D.W.S.); (K.B.C.)
| | - Min Jae Yang
- Department of Gastroenterology, Ajou University School of Medicine, Suwon 16499, Korea; (M.J.Y.); (J.C.H.); (J.H.K.)
| | - Jae Chul Hwang
- Department of Gastroenterology, Ajou University School of Medicine, Suwon 16499, Korea; (M.J.Y.); (J.C.H.); (J.H.K.)
| | - Jin Hong Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon 16499, Korea; (M.J.Y.); (J.C.H.); (J.H.K.)
| | - Hoonsub So
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (H.S.); (S.J.B.)
| | - Sung Jo Bang
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (H.S.); (S.J.B.)
| | - Min Je Sung
- Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13497, Korea; (M.J.S.); (C.-I.K.)
| | - Chang-Il Kwon
- Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13497, Korea; (M.J.S.); (C.-I.K.)
| | - Dong Wook Lee
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 42601, Korea; (D.W.L.); (C.-M.C.)
| | - Chang-Min Cho
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 42601, Korea; (D.W.L.); (C.-M.C.)
| | - Jae Hee Cho
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06230, Korea; (S.I.J.); (D.K.L.)
- Correspondence: (D.U.K.); (J.H.C.)
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21
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Perihilar cholangiocarcinoma: What the radiologist needs to know. Diagn Interv Imaging 2022; 103:288-301. [DOI: 10.1016/j.diii.2022.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/02/2022] [Indexed: 11/17/2022]
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22
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Chueakwon P, Jatooratthawichot P, Talabnin K, Ketudat Cairns JR, Talabnin C. Inhibition of Ceramide Glycosylation Enhances Cisplatin Sensitivity in Cholangiocarcinoma by Limiting the Activation of the ERK Signaling Pathway. Life (Basel) 2022; 12:life12030351. [PMID: 35330102 PMCID: PMC8949529 DOI: 10.3390/life12030351] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 11/20/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive tumor of the biliary epithelium with poor survival that shows limited response to conventional chemotherapy. Increased expression of glucosylceramide synthase (GCS) contributes to drug resistance and the progression of various cancers; the expression profiles of GCS (UGCG) and the genes for glucocerebrosidases 1, 2, and 3 (GBA1, GBA2, and GBA3) were therefore studied in CCA. The biological functions of GCS for cell proliferation and cisplatin sensitivity in CCA were explored. GCS expression was higher in CCA tumor tissues than that of GBA1, GBA2, and GBA3. Verification of GCS expression in 29 paired frozen CCA tissues showed that 8 of 29 cases (27.6%) had high GCS expression. The expression of GCS and GBA2 was induced in CCA cell lines following low-dose cisplatin treatment. Suppression of GCS by either palmitoylamino-3-morpholino-1-propanol (PPMP), GCS knockdown or a combination of the two resulted in reduced cell proliferation. These treatments enhanced the effect of cisplatin-induced CCA cell death, increased the expression of apoptotic proteins and reduced phosphorylation of ERK upon cisplatin treatment. Taken together, inhibition of the GCS increased cisplatin-induced CCA apoptosis via the inhibition of the ERK signaling pathway. Thus, targeting GCS might be a strategy for CCA treatment.
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Affiliation(s)
- Piyasiri Chueakwon
- School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (P.C.); (P.J.); (J.R.K.C.)
| | - Peeranat Jatooratthawichot
- School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (P.C.); (P.J.); (J.R.K.C.)
| | - Krajang Talabnin
- School of Pathology, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand;
| | - James R. Ketudat Cairns
- School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (P.C.); (P.J.); (J.R.K.C.)
| | - Chutima Talabnin
- School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand; (P.C.); (P.J.); (J.R.K.C.)
- Correspondence:
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Chiang KY, Li YW, Li YH, Huang SJ, Wu CL, Gong HY, Wu JL. Progranulin A Promotes Compensatory Hepatocyte Proliferation via HGF/c-Met Signaling after Partial Hepatectomy in Zebrafish. Int J Mol Sci 2021; 22:ijms222011217. [PMID: 34681875 PMCID: PMC8538350 DOI: 10.3390/ijms222011217] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/14/2021] [Accepted: 10/16/2021] [Indexed: 01/11/2023] Open
Abstract
Compensatory hepatocyte proliferation and other liver regenerative processes are activated to sustain normal physiological function after liver injury. A major mitogen for liver regeneration is hepatocyte growth factor (HGF), and a previous study indicated that progranulin could modulate c-met, the receptor for HGF, to initiate hepatic outgrowth from hepatoblasts during embryonic development. However, a role for progranulin in compensatory hepatocyte proliferation has not been shown previously. Therefore, this study was undertaken to clarify whether progranulin plays a regulatory role during liver regeneration. To this end, we established a partial hepatectomy regeneration model in adult zebrafish that express a liver-specific fluorescent reporter. Using this model, we found that loss of progranulin A (GrnA) function by intraperitoneal-injection of a Vivo-Morpholino impaired and delayed liver regeneration after partial hepatectomy. Furthermore, transcriptome analysis and confirmatory quantitative real-time PCR suggested that cell cycle progression and cell proliferation was not as active in the morphants as controls, which may have been the result of comparative downregulation of the HGF/c-met axis by 36 h after partial hepatectomy. Finally, liver-specific overexpression of GrnA in transgenic zebrafish caused more abundant cell proliferation after partial hepatectomy compared to wild types. Thus, we conclude that GrnA positively regulates HGF/c-met signaling to promote hepatocyte proliferation during liver regeneration.
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Affiliation(s)
- Keng-Yu Chiang
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan;
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
| | - Ya-Wen Li
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
| | - Yen-Hsing Li
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
| | - Shin-Jie Huang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
| | - Chih-Lu Wu
- Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 62145, Taiwan;
| | - Hong-Yi Gong
- Department of Aquaculture, National Taiwan Ocean University, Keelung 20224, Taiwan;
- Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 20224, Taiwan
| | - Jen-Leih Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
- College of Life Sciences, National Taiwan Ocean University, Keelung 20224, Taiwan
- Correspondence: ; Tel.: +886-2-27899568
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Choi SH, Rim CH, Shin IS, Yoon WS, Koom WS, Seong J. Adjuvant Radiotherapy for Extrahepatic Cholangiocarcinoma: A Quality Assessment-Based Meta-Analysis. Liver Cancer 2021; 10:419-432. [PMID: 34721505 PMCID: PMC8527906 DOI: 10.1159/000518298] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/05/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION The benefits of adjuvant radiotherapy (ART) for extrahepatic cholangiocarcinoma are uncertain largely because existing publications lack clear comparisons between ART and non-ART arms. METHODS PubMed, Medline, Embase, and the Cochrane library were systematically searched until December 2020. The primary endpoint was overall survival (OS). Sensitivity analysis was performed for studies with reliable comparability (i.e., no favorable prognosticators in the ART arm that could skew the data). RESULTS Twenty-three studies involving 1,731 patients with extrahepatic cholangiocarcinoma were reviewed. The overall median of all median prescribed doses was 50.4 Gy; brachytherapy or an intraoperative boost of 10-21 Gy was applied in 5 studies. The pooled 1-, 3-, and 5-year OS rates in the non-ART and ART arms were 69.2% versus 81.0%, p = 0.035; 34.3% versus 44.7%, p = 0.025; 25.6% versus 31.7%, p = 0.115, respectively. The corresponding pooled locoregional recurrence rates were 52.1% versus 34.9% (p = 0.014). The pooled rate of grade ≥3 gastrointestinal complications was 9.8%. Sensitivity analysis performed on 14 eligible studies showed that the ART arms had a lower pooled R0 rate (36.8% vs. 63.2%, p = 0.02) and a higher rate of positive lymph nodes (47.4% vs. 34.9%, p = 0.08). The pooled 1-, 3-, and 5-year OS rates in the non-ART versus ART arms of the selected studies were 78.2% versus 84.9%, p = 0.143; 38.5% versus 49.2%, p = 0.026; and 27.8% versus 34.5%, p = 0.11, respectively. CONCLUSIONS ART was shown to improve OS in all studies and in those selected for their reliable comparability.
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Affiliation(s)
- Seo Hee Choi
- Department of Radiation Oncology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea
| | - Chai Hong Rim
- Department of Radiation Oncology, Korea University Ansan Hospital, Korea University Medical College, Seoul, Republic of Korea,*Chai Hong Rim,
| | - In-Soo Shin
- Graduate School of Education, AI Convergence Education, Dongguk University, Seoul, Republic of Korea
| | - Won Sup Yoon
- Department of Radiation Oncology, Korea University Ansan Hospital, Korea University Medical College, Seoul, Republic of Korea
| | - Woong Sub Koom
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University Medical College, Seoul, Republic of Korea
| | - Jinsil Seong
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University Medical College, Seoul, Republic of Korea
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Kim H, Kim ST, Yoo KH, Hong JY, Park YS, Lim HY, Park JO. ATM Expression as a Prognostic Marker in Patients With Advanced Biliary Tract Cancer Treated With First-line Gemcitabine and Platinum Chemotherapy. In Vivo 2021; 35:499-505. [PMID: 33402502 DOI: 10.21873/invivo.12284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM Biliary tract cancer (BTC) has a poor prognosis due to its highly invasive and metastatic potential. Ataxia-telangiectasia mutated (ATM) is a key regulator of DNA damage response and an emerging therapeutic target; however, the association between the expression of ATM and the prognosis in advanced BTC is unknown. We aimed to identify the relationship between ATM expression, clinicopathological characteristics, and survival outcomes in patients with advanced BTC. PATIENTS AND METHODS We analyzed 113 patients with advanced BTC who received first-line gemcitabine and platinum. RESULTS The tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 43 patients, extrahepatic cholangiocarcinoma (EH-CCC) in 49, and gallbladder (GB) cancer in 21 patients. Fifty-four patients (47.8%) exhibited loss of ATM protein expression. The overall response rate (ORR) of ATM loss and intact ATM was 13.3% and 19.6%, respectively. In a subgroup analysis, EH-CCC patients with ATM loss tended to have improved PFS after platinum-based chemotherapy compared to those with intact ATM (7.9 vs. 6.2 months, respectively; p=0.050). CONCLUSION We demonstrated that ATM loss could be a prognostic marker after platinum-based chemotherapy in patients with advanced EH-CCC.
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Affiliation(s)
- Hyera Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Division of Hematology-Oncology, Department of Internal Medicine, Keimyung University Dongsan Hospital, Daegu, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kwai Han Yoo
- Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Jung Yong Hong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;
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Nagaoka K, Ogawa K, Ji C, Cao KY, Bai X, Mulla J, Cheng Z, Wands JR, Huang CK. Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis. Dig Dis Sci 2021; 66:1080-1089. [PMID: 32445050 DOI: 10.1007/s10620-020-06330-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 05/08/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cholangiocarcinoma is a devastating disease with a 2% 5-year survival if the disease has spread outside the liver. The enzyme aspartate beta-hydroxylase (ASPH) has been demonstrated to be highly expressed in cholangiocarcinoma but not in normal bile ducts and found to stimulate tumor cell migration. In addition, it was found that targeting ASPH inhibits cholangiocarcinoma malignant progression. However, it is not clear whether targeting ASPH with the small molecule inhibitor MO-I-1182 suppresses cholangiocarcinoma metastasis. The current study aims to study the efficacy of MO-I-1182 in suppressing cholangiocarcinoma metastasis. METHODS The analysis was performed in vitro and in vivo with a preclinical animal model by using molecular and biochemical strategies to regulate ASPH expression and function. RESULTS Knockdown of ASPH substantially inhibited cell migration and invasion in two human cholangiocarcinoma cell lines. Targeting ASPH with a small molecule inhibitor suppressed cholangiocarcinoma progression. Molecular mechanism studies demonstrated that knockdown of ASPH subsequently suppressed protein levels of the matrix metalloproteinases. The ASPH knockdown experiments suggest that this enzyme may modulate cholangiocarcinoma metastasis by regulating matrix metalloproteinases expression. Furthermore, using an ASPH inhibitor in a rat cholangiocarcinoma intrahepatic model established with BED-Neu-CL#24 cholangiocarcinoma cells, it was found that targeting ASPH inhibited intrahepatic cholangiocarcinoma metastasis and downstream expression of the matrix metalloproteinases. CONCLUSION ASPH may modulate cholangiocarcinoma metastasis via matrix metalloproteinases expression. Taken together, targeting ASPH function may inhibit intrahepatic cholangiocarcinoma metastasis and improve survival.
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Affiliation(s)
- Katsuya Nagaoka
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA
| | - Kousuke Ogawa
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA
| | - Chengcheng Ji
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA
| | - Kevin Y Cao
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA
| | - Xuewei Bai
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA
| | - Joud Mulla
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA
| | - Zhixiang Cheng
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA
| | - Jack R Wands
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA
| | - Chiung-Kuei Huang
- Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA.
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Kim H, Kim J, Byeon S, Jang KT, Hong JY, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK, Kim ST. Programmed Death Ligand 1 Expression as a Prognostic Marker in Patients with Advanced Biliary Tract Cancer. Oncology 2021; 99:365-372. [PMID: 33730723 DOI: 10.1159/000514404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 01/07/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. PATIENTS AND METHODS We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity. RESULTS Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer. CONCLUSION This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.
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Affiliation(s)
- Hyera Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Division of Hematology-Oncology, Department of Internal Medicine, Keimyung University Dongsan Hospital, Daegu, Republic of Korea
| | - Jinchul Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seonggyu Byeon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Yong Hong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea,
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Huang D, Joo H, Song N, Cho S, Kim W, Shin A. Association between gallstones and the risk of biliary tract cancer: a systematic review and meta-analysis. Epidemiol Health 2021; 43:e2021011. [PMID: 33541011 PMCID: PMC8060519 DOI: 10.4178/epih.e2021011] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 01/29/2021] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Biliary tract cancers (BTCs) are rare but highly fatal. Although the etiology of BTC is poorly understood, gallstones are proposed to be a major risk factor. We conducted a systematic review and meta-analysis to examine the associations between gallstone characteristics and BTC risk. METHODS We searched the MEDLINE, Embase, and Cochrane Central databases and systematically reviewed cohort and case-control studies published before April 9, 2018. All the included studies reported appropriate risk estimates and confidence intervals (CIs) for associations between the presence, size, number, or duration of gallstones and the risk of BTC, including gallbladder cancer (GBC), extrahepatic bile duct cancer (EBDC), and ampulla of Vater cancer (AOVC). Summary odds ratios (ORs) and their 95% CIs were calculated using a random-effects model in the meta-analysis. Subgroup analyses were conducted to inspect sources of potential heterogeneity, and the Egger test was performed to assess publication bias. RESULTS Seven cohort studies and 23 case-control studies in Asian, European, and American populations were included. The presence of gallstones was associated with an increased risk of BTC (OR, 4.38; 95% CI, 3.23 to 5.93; I2=91.2%), GBC (OR, 7.26; 95% CI, 4.33 to 12.18), EBDC (OR, 3.17; 95% CI, 2.24 to 4.50), and AOVC (OR, 3.28; 95% CI, 1.33 to 8.11). Gallstone size (>1 vs. <1 cm; OR, 1.88; 95% CI, 1.10 to 3.22) was significantly associated with the risk of GBC. CONCLUSIONS Gallstone characteristics, such as presence, size, and number, are associated with an increased risk of BTC. However, significantly high heterogeneity in the meta-analyses is a limitation of this study.
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Affiliation(s)
- Dan Huang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Division of Cancer Control and Policy, National Cancer Control Institute, National Cancer Center, Goyang, Korea
| | - Hyundeok Joo
- Seoul National University College of Medicine, Seoul, Korea
| | - Nan Song
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Sooyoung Cho
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Woosung Kim
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Aesun Shin
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
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Ferrucci PF, Cocorocchio E, Bonomo G, Varano GM, Della Vigna P, Orsi F. A New Option for the Treatment of Intrahepatic Cholangiocarcinoma: Percutaneous Hepatic Perfusion with CHEMOSAT Delivery System. Cells 2021; 10:E70. [PMID: 33466278 PMCID: PMC7824743 DOI: 10.3390/cells10010070] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 12/29/2020] [Accepted: 12/31/2020] [Indexed: 12/30/2022] Open
Abstract
Liver metastases are a major management problem; since they occur in tumors of different origin, they are often multiple, difficult to visualize and can lie dormant for many years. Patients with liver metastases usually die of their disease, mostly due to liver failure, since systemic treatments are unable to eradicate micro-metastasis, and interventional loco-regional procedures cannot treat all existing ones. Cholangiocarcinoma (CCA) is the second most common primary liver tumor, showing a poor overall prognosis. When resection is not possible, treatment options include tumor-focused or local ablative therapy, organ-focused or regional therapy and systemic therapy. We reviewed available loco-regional therapeutic options, with particular focus on the CHEMOSAT® Melphalan/Hepatic Delivery System (CS-HDS), which is uniquely positioned to perform a percutaneous hepatic perfusion (PHP), in order to treat the entire liver as a standalone or as complementary therapy. This system isolates the liver circulation, delivers a high concentration of chemotherapy (melphalan), filters most chemotherapy out of the blood and is a repeatable procedure. Most CS-HDS benefits are demonstrated in liver-predominant diseases, like liver metastasis from uveal melanoma (UM), hepatocarcinoma (HCC) and CCA. More than 650 procedures have been performed in Europe to date, mostly to treat liver metastases from UM. In CCA, experience is still limited, but retrospective analyses have been reported, while phase II and III studies are closed, waiting for results or ongoing.
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Affiliation(s)
- Pier Francesco Ferrucci
- Tumor Biotherapy Unit, Department of Experimental Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Emilia Cocorocchio
- Hematoncology Division, European Institute of Oncology, IRCCS, 20141 Milan, Italy;
| | - Guido Bonomo
- Interventional Radiology Division, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (G.B.); (G.M.V.); (P.D.V.); (F.O.)
| | - Gianluca Maria Varano
- Interventional Radiology Division, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (G.B.); (G.M.V.); (P.D.V.); (F.O.)
| | - Paolo Della Vigna
- Interventional Radiology Division, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (G.B.); (G.M.V.); (P.D.V.); (F.O.)
| | - Franco Orsi
- Interventional Radiology Division, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (G.B.); (G.M.V.); (P.D.V.); (F.O.)
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30
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Zhang Y, Zhang L, Lu S, Xiang Y, Zeng C, He T, Ding Y, Wang W. Long Non-coding RNA CASC15 Promotes Intrahepatic Cholangiocarcinoma Possibly through Inducing PRDX2/PI3K/AKT Axis. Cancer Res Treat 2020; 53:184-198. [PMID: 33017884 PMCID: PMC7812017 DOI: 10.4143/crt.2020.192] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022] Open
Abstract
Purpose Intrahepatic cholangiocarcinoma (ICC) is one of the most common liver primary tumors but its treatments are limited. Bioinformatics showed that the expression level of long non-coding RNA cancer-associated susceptibility 15 gene (CASC15) is correlated with ICC progression, but its functional mechanism remains unclear. Materials and Methods Tissues from ICC patients, tumor and adjacent tissue, were used for detection of the expression of CASC15. Clinical data were also collected for clinicopathologic and survival analysis. Short interfering RNA and lentiviral short hairpin RNA were used to knock down CASC15 and PRDX2 expression in ICC cell lines, for the analysis of changes of cell function and xenografts. RNA-pulldown and RNA immunoprecipitation assays were used to detect RNA-binding protein, PRDX2. Male nude mice were used for ICC xenografts, and livers were collected after 4 weeks for immunohistochemistry. Results CASC15 is highly expressed in ICC tissues and is related to higher TNM stage. Knockdown of CASC15 in ICC cells reduced cell proliferation, migration, invasiveness and increased apoptosis, and G1/S block. PRDX2 bound to CASC15. Knockdown of CASC15 decreased PRDX2 expression which was rescued by the inhibition of proteasome formation. Downregulation of PRDX2 resulted in G1/S block, reduced ICC cell invasion. Downregulation of CASC15 inhibited phosphoinositide 3-kinase (PI3K)/AKT/c-Myc pathway through downregulating of PRDX2 and overexpressed PRDX2 rescued the block. CASC15 knockout in ICC xenografts suppressed tumor development in vivo, decreased the expression of PRDX2 and Ki67 and inhibited PI3K/AKT pathway. Conclusion CASC15 promotes ICC possibly by targeting PRDX2 via the PI3K/AKT pathway, indicating poor prognosis and high degree of malignancy of ICC.
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Affiliation(s)
- Yuan 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.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, 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.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Sinan Lu
- 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.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Yucheng Xiang
- 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.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Cheng Zeng
- 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.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Tianyu He
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Yuan Ding
- 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.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Weilin Wang
- 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.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
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31
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Dee EC, Freret ME, Horick N, Raldow AC, Goyal L, Zhu AX, Parikh AR, Ryan DP, Clark JW, Allen JN, Ferrone CR, Fernandez-Del Castillo C, Tanabe KK, Drapek LC, Hong TS, Qadan M, Wo JY. Patterns of Failure and the Need for Biliary Intervention in Resected Biliary Tract Cancers After Chemoradiation. Ann Surg Oncol 2020; 27:5161-5172. [PMID: 32740733 DOI: 10.1245/s10434-020-08967-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 06/10/2020] [Indexed: 01/04/2023]
Abstract
BACKGROUND This study assessed patterns of failure and rates of subsequent biliary intervention among patients with resected biliary tract cancers (BTCs) including gallbladder carcinoma (GBC) and extra- and intrahepatic cholangiocarcinoma (eCCA and iCCA) treated with adjuvant chemoradiation therapy (CRT). METHODS In this single-institution retrospective analysis of 80 patients who had GBC (n = 29), eCCA (n = 43), or iCCA (n = 8) treated with curative-intent resection and adjuvant CRT from 2007 to 2017, the median radiation dose was 50.4 Gy (range 36-65 Gy) with concurrent 5-fluorouracil (5-FU) chemotherapy. All but two of the patients received adjuvant chemotherapy. The 2-year locoregional failure (LRF), 2-year recurrence-free survival (RFS), and 2-year overall survival (OS), and univariate predictors of LRF, RFS, and OS were calculated for the entire cohort and for a subgroup excluding patients with iCCA (n = 72). The predictors of biliary interventions also were assessed. RESULTS Of the 80 patients (median follow-up period, 30.5 months; median OS, 33.9 months), 54.4% had American Joint Committee on Cancer (AJCC) stage 1 or 2 disease, 57.1% were lymph node-positive, and 66.3% underwent margin-negative resection. For the entire cohort, 2-year LRF was 23.8%, 2-year RFS was 43.7%, and 2-year OS was 62.1%. When patients with iCCA were excluded, the 2-year LRF was 22.6%, the 2-year RFS was 43.9%, and the 2-year OS was 59.2%. In the overall and subgroup univariate analyses, lymph node positivity was associated with greater LRF, whereas resection margin was not. Biliary intervention was required for 12 (63.2%) of the 19 patients with LRF versus 11 (18%) of the 61 patients without LRF (P < 0.001). Of the 12 patients with LRF who required biliary intervention, 4 died of biliary complications. CONCLUSIONS The LRF rates remained significant despite adjuvant CRT. Lymph node positivity may be associated with increased risk of LRF. Positive margins were not associated with greater LRF, suggesting that CRT may mitigate LRF risk for this group. An association between LRF and higher rates of subsequent biliary interventions was observed, which may yield significant morbidity. Novel strategies to decrease the rates of LRF should be considered.
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Affiliation(s)
| | - Morgan E Freret
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nora Horick
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | - Ann C Raldow
- Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Lipika Goyal
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andrew X Zhu
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Aparna R Parikh
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David P Ryan
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jeffrey W Clark
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jill N Allen
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Carlos Fernandez-Del Castillo
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Kenneth K Tanabe
- Department of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Lorraine C Drapek
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Motaz Qadan
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Murahashi S, Takeuchi Y, Hayashida S, Ohya Y, Shindo S, Terasaki T, Inomata Y, Hara Y. Trousseau syndrome with intrahepatic cholangiocarcinoma that could be removed radically after endovascular treatment: Report of a case. Brain Behav 2020; 10:e01660. [PMID: 32506690 PMCID: PMC7375083 DOI: 10.1002/brb3.1660] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/15/2020] [Accepted: 04/20/2020] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Trousseau syndrome is a poor prognosis. We report a case of Trousseau syndrome treated by radical resection after endovascular treatment. CASE A 59-year-old woman presented to our department reporting spontaneous dizziness and pain of the upper abdomen. Magnetic resolution imaging (MRI) showed shower embolization of Brain. Contrast-enhanced computer tomography (CT) showed renal infarction and splenic infarction, and a tumor was observed in the retrohepatic area. On day 9, sudden right side joint prejudice, neglect of left half space, and left hemiplegia were observed. MRI revealed obstruction of the right middle cerebral artery (MCA) perfusion zone. On the same day, endovascular treatment was performed and reperfusion was obtained. We decided on a radical surgery policy because there were a primary lesion and a high risk of new embolism, and no metastasis was seen. DISCUSSION Trousseau syndrome generally has a poor prognosis, but active treatment should be considered as an option when we can expect the recovery of function.
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Affiliation(s)
| | | | | | - Yuki Ohya
- Department of Pediatric SurgeryKumamoto Rosai HospitalKumamotoJapan
| | - Seigo Shindo
- Department of NeurologyKumamoto Sekijyuji HospitalKumamotoJapan
| | | | - Yukihiro Inomata
- Department of Pediatric SurgeryKumamoto Rosai HospitalKumamotoJapan
| | - Yasuyuki Hara
- Department of NeurologyKumamoto Rosai HospitalKumamotoJapan
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Adjuvant chemotherapy in biliary tract cancer: state of the art and future perspectives. Curr Opin Oncol 2020; 32:364-369. [DOI: 10.1097/cco.0000000000000643] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Perez-Montoyo H. Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma. Cells 2020; 9:E614. [PMID: 32143356 PMCID: PMC7140412 DOI: 10.3390/cells9030614] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/25/2020] [Accepted: 02/26/2020] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.
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35
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Salati M, Filippi R, Vivaldi C, Caputo F, Leone F, Salani F, Cerma K, Aglietta M, Fornaro L, Sperti E, Di Maio M, Ortega C, Fenocchio E, Lombardi P, Cagnazzo C, Depetris I, Gelsomino F, Spallanzani A, Santini D, Silvestris N, Aprile G, Roviello G, Scartozzi M, Cascinu S, Casadei-Gardini A. The prognostic nutritional index predicts survival and response to first-line chemotherapy in advanced biliary cancer. Liver Int 2020; 40:704-711. [PMID: 31773848 DOI: 10.1111/liv.14314] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/06/2019] [Accepted: 11/23/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND An accurate risk-stratification is key to optimize the benefit-to-risk ratio of palliative treatment in advanced biliary cancer. We aimed at assessing the impact of the prognostic nutritional index (PNI) on survival and treatment response in advanced biliary cancer (ABC) receiving first-line chemotherapy. METHODS Medical records of ABC treated with standard chemotherapy at the Modena Cancer Centre were retrospectively reviewed for variables deemed of potential interest, including the PNI. Univariate and multivariate analyses were performed to investigate the association between the covariates and overall survival (OS). RESULTS 114 ABC fulfilled the inclusion criteria and made up the training cohort. A PNI cut-off value of 36.7 was established using the receiver operating characteristic (ROC) analysis. At both the univariate and the multivariate analysis, low PNI value (<36.7) was associated with shorter OS (P = .0011), together with increased NLR (P = .0046) and ECOG >1 (P < .0001). The median OS was 5.4 vs 12.1 months in the low- vs high PNI-group. Moreover, a PNI value >36.7 resulted in a higher disease control in patients treated with gemcitabine/platinum combination (61.4% vs 34.3%). These results were validated in an independent cohort of 253 ABC. CONCLUSIONS We demonstrated and externally validated a prognostic role for the PNI in ABC treated with first-line chemotherapy. Although the PNI turned out to be predictive in the subset of patients receiving platinum/gemcitabine combination, future prospective confirmation is needed.
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Affiliation(s)
- Massimiliano Salati
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto Filippi
- Department of Oncology, University of Turin, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | | | - Francesco Caputo
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Francesco Leone
- Department of Oncology, University of Turin, Turin, Italy.,SC Oncologia ASL Biella, Biella, Italy
| | | | - Krisida Cerma
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Aglietta
- Department of Oncology, University of Turin, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | | | - Elisa Sperti
- Department of Oncology, University of Turin, Turin, Italy.,Oncologia Medica AO Ordine Mauriziano, Turin, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Turin, Italy.,Oncologia Medica AO Ordine Mauriziano, Turin, Italy
| | | | - Elisabetta Fenocchio
- Department of Oncology, University of Turin, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Pasquale Lombardi
- Department of Oncology, University of Turin, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Celeste Cagnazzo
- Department of Public Health and Pediatrics, University of Turin, Turin, Italy.,City of Health and Science Hospital of Turin, Pediatric Oncoematology, Regina Margherita Children's Hospital, Turin, Italy
| | - Ilaria Depetris
- SC Medical Oncology 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy
| | - Fabio Gelsomino
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Andrea Spallanzani
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Daniele Santini
- Department of Medical Oncology, Università Campus Bio-Medico, Rome, Italy
| | - Nicola Silvestris
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.,Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | | | - Mario Scartozzi
- Medical Oncology Unit, University of Cagliari, Cagliari, Italy
| | - Stefano Cascinu
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
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Gao YH, Li MY, Sajjad F, Wang JH, Meharban F, Gadoora MA, Yan YJ, Nyokong T, Chen ZL. Synthesis and pharmacological evaluation of chlorin derivatives for photodynamic therapy of cholangiocarcinoma. Eur J Med Chem 2020; 189:112049. [DOI: 10.1016/j.ejmech.2020.112049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/17/2019] [Accepted: 01/07/2020] [Indexed: 01/15/2023]
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Kish M, Chan K, Perry K, Ko YJ. A systematic review and network meta-analysis of adjuvant therapy for curatively resected biliary tract cancers. Curr Oncol 2020; 27:e20-e26. [PMID: 32218664 PMCID: PMC7096209 DOI: 10.3747/co.27.5465] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Background Recent randomized controlled trials (rcts) have contributed high-quality data about adjuvant therapy in curatively resected biliary tract cancer (btc); however, a standard approach to treating those patients still has not been developed. Methods We conducted a systematic review of published studies and abstracts up to and including June 2018, choosing rcts involving patients with btc receiving adjuvant chemotherapy after complete surgical resection. Network meta-analysis methods were used for indirect comparisons of overall survival (os) and relapse-free survival (rfs) for various adjuvant therapies. Results Five rcts were included in qualitative synthesis, and three rcts (bilcap, prodige 12-accord 18, and bcat) had data sufficient for inclusion in the meta-analysis. Results from the indirect comparison demonstrated no significant improvement in os for capecitabine compared with gemcitabine or with gemcitabine-oxaliplatin (gemox), the hazard ratios (hrs) being 0.82 [95% confidence interval (ci): 0.53 to 1.27] and 0.86 (95% ci: 0.56 to 1.34) respectively. Similarly, no significant improvement in rfs was observed for capecitabine compared with gemcitabine or gemox. Conclusions Although in the present analysis, we found no statistically significant improvements in os or rfs for capecitabine compared with gemox or gemcitabine, capecitabine can-until further prospective trials are completed-be considered the standard of care in the adjuvant setting based on a single randomized phase iii study.
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Affiliation(s)
- M Kish
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON
- Department of Medicine, Queen's University, Kingston, ON
| | - K Chan
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON
| | - K Perry
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON
| | - Y J Ko
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON
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38
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Kim H, Heo MH, Kim JY. Comparison of the effects of adjuvant concurrent chemoradiotherapy and chemotherapy for resected biliary tract cancer. BMC Gastroenterol 2020; 20:20. [PMID: 31992208 PMCID: PMC6986049 DOI: 10.1186/s12876-020-1171-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 01/15/2020] [Indexed: 12/01/2022] Open
Abstract
Background Biliary tract cancers (BTC) have a poor prognosis even after curative resection because of frequent local and distant recurrences. Therefore, the importance of adjuvant therapy in BTC has been advocated to improve outcomes. However, the choice of adjuvant therapy is still controversial. The aim of this study was to compare the effects of adjuvant concurrent chemoradiotherapy (CCRT) and chemotherapy on resected BTC. Methods We analyzed 92 patients who had curatively resected BTC and had received adjuvant CCRT or chemotherapy from January 2000 to December 2017 at Keimyung University Dongsan Medical Center. Results Of the patients, 46 received adjuvant CCRT and 46 received adjuvant chemotherapy. The median recurrence-free survival (RFS) for the adjuvant CCRT and chemotherapy groups were 13.8 and 11.2 months (p = 0.014), respectively. The median overall survival (OS) for the adjuvant CCRT and chemotherapy groups were 30.1 and 26.0 months (p = 0.222), respectively. Adjuvant CCRT had significantly better RFS and numerically higher OS than did chemotherapy. For subgroups with no lymph node (LN) involvement (RFS p = 0.006, OS p = 0.420) or negative resection margins (RFS p = 0.042, OS p = 0.098), adjuvant CCRT led to significantly longer RFS and numerically higher OS than did chemotherapy. For multivariate analysis, the pattern of adjuvant treatment (chemotherapy vs. CCRT, p = 0.004, HR 2.351), histologic grade (poor vs. well, p = 0.023, HR 4.793), and LN involvement (p = 0.028, HR 1.912) were the significant prognostic factors for RFS. Conclusions Our study demonstrated the superiority of adjuvant CCRT over chemotherapy for improving RFS in curatively resected BTC.
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Affiliation(s)
- Hyera Kim
- Division of Hematology and Oncology, Department of Internal Medicine, Keimyung University, Dongsan Medical Center, 56 Dalseong-ro, Jung-gu, Daegu, 41931, South Korea.
| | - Mi Hwa Heo
- Division of Hematology and Oncology, Department of Internal Medicine, Keimyung University, Dongsan Medical Center, 56 Dalseong-ro, Jung-gu, Daegu, 41931, South Korea
| | - Jin Young Kim
- Division of Hematology and Oncology, Department of Internal Medicine, Keimyung University, Dongsan Medical Center, 56 Dalseong-ro, Jung-gu, Daegu, 41931, South Korea
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Abstract
Abdominal pain is a common cause for emergency department visits in the United States, and biliary tract disease is the fifth most common cause of hospital admission. Common causes of acute hepatobiliary include gallstones and its associated complications and multiple other hepatobiliary etiologies, including infectious, inflammatory, vascular, and neoplastic causes. Postoperative complications of the biliary tract can result in an acute abdomen. Imaging of the hepatobiliary tree is integral in the diagnostic evaluation of acute hepatobiliary dysfunction, and imaging of the biliary tree requires a multimodality approach utilizing ultrasound, computed tomography, nuclear medicine, and MR imaging.
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Affiliation(s)
- HeiShun Yu
- Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Jennifer W Uyeda
- Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
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40
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Rangarajan K, Simmons G, Manas D, Malik H, Hamady ZZ. Systemic adjuvant chemotherapy for cholangiocarcinoma surgery: A systematic review and meta-analysis. Eur J Surg Oncol 2019; 46:684-693. [PMID: 31761507 DOI: 10.1016/j.ejso.2019.11.499] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 11/08/2019] [Accepted: 11/12/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The role of adjuvant therapy for biliary tract cancer is not clearly defined with conflicting results demonstrated across nonrandomized and randomized studies. We report a systematic review and meta-analysis to delineate the effect of AT on overall survival. METHODS Eligible studies were identified from MEDLINE, EMBASE, Cochrane and PubMed. Studies comparing adjuvant chemotherapy or chemoradiotherapy after curative-intent surgery with curative surgery only for biliary tract cancer were included. Data pertaining to tumours of the gallbladder and bile ducts were included. The primary outcome assessed was overall survival. Random-effects meta-analysis was performed, as well as pooling of unadjusted Kaplan-Meier curve data. RESULTS 35 studies involving 42,917 patients were analysed. There was a significant improvement in overall survival with any adjuvant therapy after surgery compared with surgery only (HR 0.74; 95% CI, 0.67 to 0.83; P < 0.001). There was a significant benefit for adjuvant therapy in those with margin positive surgery (RR, 0.83; 95% CI, 0.77 to 0.91; P < 0.001) and node-positive disease (RR 0.82; 95% CI 0.76 to 0.89; P < 0.001) CONCLUSION: Our review advocates the use of adjuvant therapy in bile duct cancer after curative intent resection. Further prospective studies are needed to determine the optimal regime and timing of an adjuvant approach.
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Affiliation(s)
- Karan Rangarajan
- Hepato-pancreto-biliary Unit, University Hospital Southampton NHS FT, Southampton, UK; Department of Surgery, Frimley Park Hospital NHS FT, Camberley, UK
| | - George Simmons
- Hepato-pancreto-biliary Unit, University Hospital Southampton NHS FT, Southampton, UK
| | - Derek Manas
- Hepato-panceato-biliary and Transplant Unit, Newcastle, UK
| | - Hasan Malik
- Hepato-biliary Department, Aintree University Hospital, Liverpool, UK
| | - Zaed Z Hamady
- Hepato-pancreto-biliary Unit, University Hospital Southampton NHS FT, Southampton, UK.
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Yu W, Hu C, Shui Y, Wu K, Zhang L, Chen Y, Li C, Xu J, Wei Q. Failure patterns after curative resection for intrahepatic cholangiocarcinoma: possible implications for postoperative radiotherapy. BMC Cancer 2019; 19:1108. [PMID: 31727017 PMCID: PMC6857295 DOI: 10.1186/s12885-019-6328-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 11/04/2019] [Indexed: 01/06/2023] Open
Abstract
Background To explore the patterns of failures and areas at highest risk of recurrence for postoperative intrahepatic cholangiocarcinoma (IHCC), with the aim to guide IHCC adjuvant radiotherapy. Methods Patients with IHCC who had undergone radical surgery at our institution from July 2010 to August 2017 were retrospectively analyzed. The survival and prognostic factors were analyzed by univariate and multivariate analysis. All sites of recurrence were found out and classified as the surgical margin, regional lymph nodes, liver remnant and distant metastasis. According to the recurring area at highest risk, the target volume of adjuvant radiotherapy was proposed. Results The median follow-up time was 23.5 months (2–85 months). The median recurrence free survival (RFS) and overall survival (OS) were 12.1 months and 24.8 months, respectively. Seventy-three (73/127, 57.5%) IHCC patients developed tumor recurrence. Initial recurrences occurred in the potential postoperative radiotherapy (PORT) volume, remnant liver and distant sits were 46 (46/73, 63.0%), 36 (36/73, 49.3%) and 22 (22/73, 30.1%) cases, respectively. Of the 46 patients whose initial recurrence inside the potential PORT volume, 29 (29/73, 39.7%) developed recurrence only inside the potential PORT volume, including 13 tumor bed recurrences, 7 lymph node metastases, and 9 with both tumor bed recurrences and lymph node metastases. The most common lymph node metastases sites were nodes around the abdominal aorta, followed by lymph nodes along the celiac artery, the common hepatic artery, and in the hepatoduodenal ligament. Conclusions High proportion of the recurrences occurred only inside the potential PORT volume, implying adjuvant radiotherapy might improve the local-regional control. Surgical margins and lymph node stations No.16a2, 9, 8, 12, 13, and 14 are suggested to be included in the radiation volume.
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Affiliation(s)
- Wei Yu
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China.,Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, 310009, People's Republic of China
| | - Chunxiu Hu
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China.,Department of Radiation Oncology, Zhejiang Quhua Hospital, Quzhou, 324000, People's Republic of China
| | - Yongjie Shui
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China
| | - Kui Wu
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China
| | - Lili Zhang
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China
| | - Ying Chen
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People's Republic of China
| | - Chao Li
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China
| | - Jing Xu
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China
| | - Qichun Wei
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China. .,Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, 310009, People's Republic of China.
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Chemoembolization with Degradable Starch Microspheres for Treatment of Patients with Primary or Recurrent Unresectable, Locally Advanced Intrahepatic Cholangiocarcinoma: A Pilot Study. Cardiovasc Intervent Radiol 2019; 42:1709-1717. [PMID: 31578633 DOI: 10.1007/s00270-019-02344-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 09/08/2019] [Accepted: 09/18/2019] [Indexed: 01/04/2023]
Abstract
PURPOSE To evaluate efficacy and complication rates of TACE with degradable starch microspheres (DSM-TACE) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) with or without prior major liver resection (MLR). METHODS This is a retrospective single-center study on 21 patients (age 63 ± 15 years) with either unresectable ICC progressive under systemic chemotherapy or unresectable intrahepatic tumor recurrence after prior MLR. Patients were treated by multi-agent (cisplatin/doxorubicin/mitomycin C) DSM-TACE between August 2012 and July 2016, repeated 3 times at 4-week intervals. Imaging response was evaluated using RECIST 1.1. Overall survival (OS) and complication rates, stratified by history of MLR, were investigated. RESULTS Patients underwent a total 64 DSM-TACE sessions. Two patients (without MLR) were lost to follow-up after one uneventful DSM-TACE session. One patient underwent living-donor-liver transplantation after one DSM-TACE-session yielding partial remission. Of the remaining 18 patients, imaging response according to RECIST 1.1 was: complete remission in 2/18 (11.1%); PR in 9/18 (50%), and stable disease in 7/18 (38.9%), yielding an objective response rate of 61.1% and a disease control rate of 100%. Median OS of patients with objective response was significantly longer (18.0 months) than that of survival of patients with stable disease (4.8 months) (p = 0.001). Median OS of patients with MLR (12.5 months) was similar to that of patients without MLR (13.2 months). Of 21 patients, 2 (9.5%) developed post-interventional hepatobiliary abscesses, and one of these patients died due to subsequent sepsis. CONCLUSION DSM-TACE is an effective treatment for unresectable and otherwise therapy-refractory intrahepatic cholangiocarcinoma, even in those patients with intrahepatic disease recurrence after prior MLR. LEVEL OF EVIDENCE Level II, therapeutic study.
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Intuyod K, Armartmuntree N, Jusakul A, Sakonsinsiri C, Thanan R, Pinlaor S. Current omics-based biomarkers for cholangiocarcinoma. Expert Rev Mol Diagn 2019; 19:997-1005. [PMID: 31566016 DOI: 10.1080/14737159.2019.1673162] [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] [Indexed: 12/28/2022]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a malignancy of the biliary tract. CCA generally has a low incidence worldwide but incidence is typically high in Southeast Asian countries, particularly in northeastern Thailand, where small liver-fluke (Opisthorchis viverrini) infection is endemic. CCA has a poor prognosis as most CCA patients present with advanced stages. Poor prognosis and worse outcomes are due to the lack of specific and early-stage CCA biomarkers. Areas covered: In this review, we discuss the use of CCA tissues, serum and bile samples as sources of diagnostic and prognostic markers by using -omics approaches, including genomics, epigenomics, transcriptomics and proteomics. The current state of the discovery of molecular candidates and their potential to be used as diagnostic and prognostic biomarkers for CCA are summarized and discussed. Expert opinion: Various potential molecules have been discovered, some of which have been verified as diagnostic biomarkers for CCA. However, most identified molecules require much further evaluation to help us find markers with high specificity, low cost and ease-of-use in routine diagnostic laboratories.
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Affiliation(s)
- Kitti Intuyod
- Department of Parasitology, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Napat Armartmuntree
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Faculty of Associated Medical Sciences, Khon Kaen University , Khon Kaen , Thailand
| | - Chadamas Sakonsinsiri
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Raynoo Thanan
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
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44
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Tang Z, Liu WR, Zhou PY, Ding ZB, Jiang XF, Wang H, Tian MX, Tao CY, Fang Y, Qu WF, Dai Z, Qiu SJ, Zhou J, Fan J, Shi YH. Prognostic Value and Predication Model of Microvascular Invasion in Patients with Intrahepatic Cholangiocarcinoma. J Cancer 2019; 10:5575-5584. [PMID: 31632502 PMCID: PMC6775679 DOI: 10.7150/jca.32199] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 08/05/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Whether microvascular invasion (MVI) adversely influences oncological outcomes for intrahepatic cholangiocarcinoma (ICC) patients remains unclear. The purpose of this study was to determine the impact of MVI on postoperative survival and establish a new predictive model for MVI before surgical intervention in patients with ICC. Methods: In this two-center retrospective study, 556 and 31 consecutive patients who underwent curative liver resection for ICC at ZSH and XJFH were analyzed, respectively. Propensity score matching (PSM) and Cox regression analyses were used to explore the prognostic role of MVI on the OS and DFS. Multivariate logistic regression was used to identify the relative risk factors of MVI, which were incorporated into the nomogram. Results: After PSM, 50 MVI cases matched with 172 non-MVI cases, and no bias was observed between the two groups (propensity score, 0.118 (0.099, 0.203) vs. 0.115 (0.059, 0.174), p=0.251). The multivariate Cox analysis showed that MVI was negatively associated with OS (HR 1.635, 95% CI 1.405-1.993, p=0.04) and DFS (HR 1.596, 95% CI 1.077-2.366, p=0.02). The independent factors associated with MVI were ALT, AFP, tumor maximal diameter, and tumor capsule. The nomogram that incorporated these variables achieved good concordance indexes for predicting MVI. Patients with a cutoff score of 168 were considered to have different risks of the presence of MVI preoperatively. Conclusions: The presence of MVI was an adverse prognostic factor for ICC patients. Using the nomogram model, the risk of an individual patient harboring MVI was determined, which led to a rational therapeutic choice.
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Affiliation(s)
- Zheng Tang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Wei-Ren Liu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Pei-Yun Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Zhen-Bin Ding
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Xi-Fei Jiang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Han Wang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Meng-Xin Tian
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Chen-Yang Tao
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Yuan Fang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Wei-Feng Qu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Zhi Dai
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Shuang-Jian Qiu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Ying-Hong Shi
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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45
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Sebastian NT, Tan Y, Miller ED, Williams TM, Noonan AM, Hays JL, Abdel-Misih S, Diaz DA. Association of Liver-Directed Local Therapy With Overall Survival in Adults With Metastatic Intrahepatic Cholangiocarcinoma. JAMA Netw Open 2019; 2:e1911154. [PMID: 31517963 PMCID: PMC6745054 DOI: 10.1001/jamanetworkopen.2019.11154] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
IMPORTANCE Intrahepatic cholangiocarcinoma is an aggressive hepatobiliary malignant neoplasm characterized by local progression and frequent metastasis. Definitive local therapy to the liver in the setting of metastatic intrahepatic cholangiocarcinoma may improve overall survival. OBJECTIVE To compare the overall survival of patients with metastatic intrahepatic cholangiocarcinoma treated with chemotherapy alone vs chemotherapy with definitive liver-directed local therapy. DESIGN, SETTING, AND PARTICIPANTS This cohort study used the National Cancer Database to identify 2201 patients with metastatic intrahepatic cholangiocarcinoma diagnosed between January 2004 and December 2014 who received chemotherapy with or without hepatic surgery or external beam radiation to a dose 45 Gy or higher. Multiple imputation, Cox proportional hazards, propensity score matching, and landmark analysis were used to adjust for confounding variables. Analyses were performed between September 2018 and February 2019. EXPOSURES Chemotherapy alone and chemotherapy with liver-directed surgery or radiation. MAIN OUTCOMES AND MEASURES Overall survival. RESULTS A total of 2201 patients (1131 [51.4%] male; median [interquartile range] age, 63 [55-71] years) who received chemotherapy alone (2097 [95.3%]) or chemotherapy with liver-directed local therapy (total, 104 [4.7%]; surgery, 76 [73.1%]; radiation, 28 [26.9%]) were identified. Patients treated with chemotherapy alone had larger median (interquartile range) primary tumor size (7.0 [4.4-10.0] cm vs 5.6 [4.0-8.3] cm; P = .048) and higher frequency of lung metastases (383 [25.9%] vs 7 [6.7%]; P = .004). Patients treated with liver-directed local therapy had higher frequency of distant lymph node metastases (34 [32.7%] vs 528 [25.2%]; P = .045). Liver-directed local therapy was associated with higher overall survival compared with chemotherapy alone on multivariable analysis (hazard ratio [HR], 0.60; 95% CI, 0.48-0.74; P < .001). A total of 208 patients treated with chemotherapy alone were propensity score matched with 104 patients treated with chemotherapy plus liver-directed local therapy. Liver-directed local therapy continued to be associated with higher overall survival (HR, 0.57; 95% CI, 0.44-0.74; P < .001), which persisted on landmark analysis at 3 months (HR, 0.61; 95% CI, 0.47-0.79; log-rank P < .001), 6 months (HR, 0.68; 95% CI, 0.50-0.92; log-rank P = .01), and 12 months (HR, 0.68; 95% CI, 0.47-0.98; log-rank P = .04). CONCLUSIONS AND RELEVANCE In this study, the addition of hepatic surgery or irradiation to chemotherapy was associated with higher overall survival when compared with chemotherapy alone in patients with metastatic intrahepatic cholangiocarcinoma. These findings may be valuable given the paucity of available data for this disease and should be validated in an independent cohort or prospective study.
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Affiliation(s)
- Nikhil T. Sebastian
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus
| | - Yubo Tan
- Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus
| | - Eric D. Miller
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus
| | - Terence M. Williams
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus
| | - Anne M. Noonan
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus
| | - John L. Hays
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus
| | - Sherif Abdel-Misih
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus
| | - Dayssy Alexandra Diaz
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus
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Kasuya G, Terashima K, Shibuya K, Toyama S, Ebner DK, Tsuji H, Okimoto T, Ohno T, Shioyama Y, Nakano T, Kamada T. Carbon-ion radiotherapy for cholangiocarcinoma: a multi-institutional study by and the Japan carbon-ion radiation oncology study group (J-CROS). Oncotarget 2019; 10:4369-4379. [PMID: 31320991 PMCID: PMC6633891 DOI: 10.18632/oncotarget.27028] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 06/05/2019] [Indexed: 12/11/2022] Open
Abstract
To evaluate the safety and efficacy of carbon-ion radiotherapy (CIRT) for cholangiocarcinoma via a multicenter retrospective study. Clinical data were collected from patients with cholangiocarcinoma who had received CIRT at one of four treating institutions in Japan. Of 56 eligible patients, none received surgery for cholangiocarcinoma before or after CIRT. The primary endpoint was overall survival (OS). Based on the tumor site, the 56 cases were categorized as intrahepatic cholangiocarcinoma (IHC) (n=27) or perihilar cholangiocarcinoma (PHC) (n=29). In all patients, the median tumor size was 37 (range, 15‒110) mm, and the most commonly prescribed dose was 76 Gy (relative biological effectiveness) in 20 fractions. The median survival was 14.8 (range, 2.1-129.2) months, and the 1- and 2-year OS rates were 69.7% and 40.9%, respectively. The median survival times of the patients with IHC and those with PHC were 23.8 and 12.6 months, respectively. Both univariate and multivariate analyses revealed that cholangitis pre-CIRT and Child‒Pugh class B were significant prognostic factors for an unfavorable OS. Of four patients who died of liver failure, one with IHC was suspected to have radiation-induced liver disease because of newly developed ascites, and died at 4.3 months post-CIRT. Grade 3 CIRT-related bile duct stenosis was observed in one IHC case. No other CIRT-related severe adverse events, including gastrointestinal events, were observed. These results suggest that CIRT yields relatively favorable treatment outcomes, especially for patients with IHC, and acceptable toxicities were observed in patients with cholangiocarcinoma who did not receive surgery.
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Affiliation(s)
- Goro Kasuya
- QST Hospital (Former Hospital of the National Institute of Radiological Sciences), National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Kazuki Terashima
- Department of Radiology, Hyogo Ion Beam Medical Center, Tatsuno, Japan
| | - Kei Shibuya
- Gunma University Heavy Ion Medical Center, Maebashi, Japan
| | - Shingo Toyama
- Ion Beam Therapy Center, SAGA-HIMAT Foundation, Tosu, Japan
| | - Daniel K Ebner
- QST Hospital (Former Hospital of the National Institute of Radiological Sciences), National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.,Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Hiroshi Tsuji
- QST Hospital (Former Hospital of the National Institute of Radiological Sciences), National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Tomoaki Okimoto
- Department of Radiology, Hyogo Ion Beam Medical Center, Tatsuno, Japan
| | - Tatsuya Ohno
- Gunma University Heavy Ion Medical Center, Maebashi, Japan
| | | | - Takashi Nakano
- QST Hospital (Former Hospital of the National Institute of Radiological Sciences), National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Tadashi Kamada
- QST Hospital (Former Hospital of the National Institute of Radiological Sciences), National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
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Peng C, Sun Z, Li O, Guo C, Yi W, Tan Z, Jiang B. Leptin stimulates the epithelial‑mesenchymal transition and pro‑angiogenic capability of cholangiocarcinoma cells through the miR‑122/PKM2 axis. Int J Oncol 2019; 55:298-308. [PMID: 31115511 DOI: 10.3892/ijo.2019.4807] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 03/23/2019] [Indexed: 11/05/2022] Open
Abstract
Leptin is an adipokine minimally known for its activities or underlying mechanisms in cholangiocarcinoma. The present study explored the effects of leptin on the epithelial‑mesenchymal transition (EMT) and pro‑angiogenic capability of cholangiocarcinoma cells, and investigated the underlying mechanisms. Cholangiocarcinoma cells were treated with leptin, and their migration and invasion rates were investigated using Transwell assays. Furthermore, conditioned medium was collected from cholangiocarcinoma cells following leptin treatment and applied to human umbilical vein endothelial cells to assess tube formation. The expression of EMT and pro‑angiogenic factors was examined by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses. Mechanistically, the function of pyruvate kinase muscle isozyme M2 (PKM2) was assessed in leptin‑induced phenotypes using siRNA targeting PKM2 (si‑PKM2). Bioinformatics screening and luciferase reporter assays were used to reveal microRNA (miR)‑122 as the potential mediator between leptin and PKM2. Finally, the associations between leptin and miR‑122 or PKM2 levels in patients with cholangiocarcinoma were assessed by ELISA and RT‑qPCR. Leptin significantly increased the EMT and pro‑angiogenic capability of cholangiocarcinoma cells, visibly inhibited endogenous miR‑122 expression, and upregulated PKM2. Furthermore, si‑PKM2 inhibited leptin‑induced migration, invasion, EMT‑associated marker expression levels and the pro‑angiogenic capability in cholangiocarcinoma cells. In addition, miR‑122 negatively regulated the expression of PKM2. When applied together with leptin, miR‑122 was sufficient to reverse the multiple malignancy‑promoting effects of leptin. Consistently, the serum leptin level positively correlated with that of PKM2, but negatively with that of miR‑122 in patients with cholangiocarcinoma. Leptin, by downregulating miR‑122 and elevating PKM2 expression, acts as a pleiotropic pro‑malignancy cytokine for cholangiocarcinoma. Therefore, increasing miR‑122 expression and inhibiting PKM2 may be future approaches for cholangiocarcinoma treatment.
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Affiliation(s)
- Chuang Peng
- Department of Hepatobiliary Surgery, The People's Hospital of Hunan Province, The First Teaching Hospital of Hunan Normal University, Changsha, Hunan 410005, P.R. China
| | - Zengpeng Sun
- Department of Hepatobiliary Surgery, The People's Hospital of Hunan Province, The First Teaching Hospital of Hunan Normal University, Changsha, Hunan 410005, P.R. China
| | - Ou Li
- Department of Hepatobiliary Surgery, The People's Hospital of Hunan Province, The First Teaching Hospital of Hunan Normal University, Changsha, Hunan 410005, P.R. China
| | - Chao Guo
- Department of Hepatobiliary Surgery, The People's Hospital of Hunan Province, The First Teaching Hospital of Hunan Normal University, Changsha, Hunan 410005, P.R. China
| | - Weimin Yi
- Department of Hepatobiliary Surgery, The People's Hospital of Hunan Province, The First Teaching Hospital of Hunan Normal University, Changsha, Hunan 410005, P.R. China
| | - Zhaoxia Tan
- Department of Hepatobiliary Surgery, The People's Hospital of Hunan Province, The First Teaching Hospital of Hunan Normal University, Changsha, Hunan 410005, P.R. China
| | - Bo Jiang
- Department of Hepatobiliary Surgery, The People's Hospital of Hunan Province, The First Teaching Hospital of Hunan Normal University, Changsha, Hunan 410005, P.R. China
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48
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Weeraphan C, Phongdara A, Chaiyawat P, Diskul-Na-Ayudthaya P, Chokchaichamnankit D, Verathamjamras C, Netsirisawan P, Yingchutrakul Y, Roytrakul S, Champattanachai V, Svasti J, Srisomsap C. Phosphoproteome Profiling of Isogenic Cancer Cell-Derived Exosome Reveals HSP90 as a Potential Marker for Human Cholangiocarcinoma. Proteomics 2019; 19:e1800159. [PMID: 31054213 DOI: 10.1002/pmic.201800159] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 03/18/2019] [Indexed: 12/19/2022]
Abstract
The northeastern region of Thailand is well known to have a high incidence and mortality of cholangiocarcinoma (CCA). Protein phosphorylation status has been reported to reflect a key determinant of cellular physiology, but identification of phosphoproteins can be a problem due to the presence of phosphatase. Exosomes are stable toward circulating proteases and other enzymes in human blood and can be recognized before the onset of cancer progression. Here an in vitro metastatic model of isogenic CCA cells is used to provide insight into the phosphorylation levels of exosomal proteins derived from highly invasive cells. Gel-based and gel-free proteomics approaches are used to reveal the proteins differentially phosphorylated in relation to tumor cell phenotypes. Forty-three phosphoproteins are identified with a significant change in phosphorylation level. Phos-tag western blotting and immunohistochemistry staining are then employed to validate the candidate phosphoproteins. Heat shock protein 90 is successfully confirmed as being differentially phosphorylated in relation to tumor malignancy. Importantly, the aberrant phosphorylation of exosomal proteins might serve as a promising tool for the development of a biomarker for metastatic CCA.
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Affiliation(s)
- Churat Weeraphan
- Department of Molecular, Biotechnology and Bioinformatics, Faculty of Science, Prince of Songkla University, Songkla, 90112, Thailand
| | - Amornrat Phongdara
- Department of Molecular, Biotechnology and Bioinformatics, Faculty of Science, Prince of Songkla University, Songkla, 90112, Thailand.,Center for Genomics and Bioinformatics Research, Faculty of Science, Prince of Songkla University, Songkla, 90112, Thailand
| | - Parunya Chaiyawat
- Applied Biological Sciences Program, Chulabhorn Graduate Institute, Bangkok, 10210, Thailand
| | - Penchatr Diskul-Na-Ayudthaya
- Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Chungcheongnam-do, 31151, Republic of Korea
| | | | - Chris Verathamjamras
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | | | - Yodying Yingchutrakul
- Proteomics Research Laboratory, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, 12120, Thailand
| | - Sittiruk Roytrakul
- Proteomics Research Laboratory, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, 12120, Thailand
| | | | - Jisnuson Svasti
- Applied Biological Sciences Program, Chulabhorn Graduate Institute, Bangkok, 10210, Thailand.,Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Chantragan Srisomsap
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand
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49
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Promraksa B, Phetcharaburanin J, Namwat N, Techasen A, Boonsiri P, Loilome W. Evaluation of anticancer potential of Thai medicinal herb extracts against cholangiocarcinoma cell lines. PLoS One 2019; 14:e0216721. [PMID: 31120926 PMCID: PMC6532846 DOI: 10.1371/journal.pone.0216721] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 04/26/2019] [Indexed: 01/01/2023] Open
Abstract
Although cholangiocarcinoma (CCA) has a low incidence globally, this is extremely high in Northeast Thailand. The lack of both early detection measures and effective therapeutic drugs is the major problem for the poor prognosis of CCA patients. Based on regional knowledge, it would be advantageous to search for effective natural phyto-products for the treatment of CCA. Cardiospermum halicacabum L., Gomphrena celosioides Mart. and Scoparia dulcis L., very well-known medicinal herbs in Asian countries, were selected for the investigation of inhibitory effects on CCA cells. Of the three different ethanolic extracts, S. dulcis L extract showed most inhibitory effects on cell growth of CCA cell lines KKU-100 and KKU-213, at percentages of 56.06 and 74.76, respectively, compared to the untreated group after treatment with 250 μg/mL of extracts for 72 hrs. At 400 and 500 μg/mL of the extracts, the inhibitory effect of KKU-213 was indicated by a significant increase in the BAX/Bcl-2 ratio and cell membrane permeability. Moreover, metabolic profiling-based screening employed in the current study revealed a significant positive association between the lignin compound and a decrease in CCA cell viability. Our study suggests, for the first time, that ESD has the ability to inhibit CCA cell growth through the induction of apoptosis.
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Affiliation(s)
- Bundit Promraksa
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Jutarop Phetcharaburanin
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Center of Excellence for Innovation in Chemistry, Mahidol University, Bangkok, Thailand
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen, Thailand
| | - Patcharee Boonsiri
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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50
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Saisomboon S, Kariya R, Vaeteewoottacharn K, Wongkham S, Sawanyawisuth K, Okada S. Antitumor effects of flavopiridol, a cyclin-dependent kinase inhibitor, on human cholangiocarcinoma in vitro and in an in vivo xenograft model. Heliyon 2019; 5:e01675. [PMID: 31193061 PMCID: PMC6515137 DOI: 10.1016/j.heliyon.2019.e01675] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 03/08/2019] [Accepted: 05/03/2019] [Indexed: 12/22/2022] Open
Abstract
Flavopiridol, a pan-cyclin-dependent kinase (CDK) inhibitor, was recently identified as an effective antitumor agent for several cancers. We investigated the antitumor effect of flavopiridol on cholangiocarcinoma (CCA), in vitro and in vivo. A methylthiotetrazole assay revealed that the proliferation of certain CCA cells was inhibited by flavopiridol, which induced the caspase-dependent apoptosis of CCA cells. Although increased cell cycle arrest was observed at the G2/M phase, caspase activation occurred earlier than 24 h, indicating that caspase-dependent apoptosis is the major pathway for the suppression of cell proliferation. Flavopiridol potently reduced the CCA tumor growth in a xenograft model without observable adverse effects. These findings indicated that flavopiridol could be a potential antitumor agent for the treatment of CCA.
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Affiliation(s)
- Saowaluk Saisomboon
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Ryusho Kariya
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Corresponding author.
| | - Seiji Okada
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
- Corresponding author.
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