|
1
|
Harada F, Miyake K, Matsuyama R, Furuta K, Kida M, Ohkawa S, Tanaka JI, Asakura T, Sugimori K, Kawaguchi Y, Mine T, Kubota K, Shimada H, Endo I. Therapeutic Outcome of Multidisciplinary Treatment in Unresectable Biliary Tract Cancer: A Multicenter Retrospective Analysis. World J Oncol 2024; 15:405-413. [PMID: 38751699 PMCID: PMC11092409 DOI: 10.14740/wjon1821] [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: 01/17/2024] [Accepted: 04/11/2024] [Indexed: 05/18/2024] Open
Abstract
Background There is little established evidence regarding treatment strategies for unresectable biliary tract cancer (BTC). This study aimed to clarify the situation of multidisciplinary treatment for unresectable BTC in the 2000s when there was no international standard first-line therapy. Methods We retrospectively reviewed 315 consecutive patients with unresectable BTC who had been treated at seven tertiary institutions in Kanagawa Prefecture, Japan between 1999 and 2008. Results The unresectable factors were as follows: locally advanced, 101 cases (32.1%); hematogenous metastases, 80 cases (25.4%); and peritoneal dissemination, 30 cases (9.5%). Chemotherapy or radiation therapy was administered to 218 patients (69.2%). The best supportive care was provided in 97 cases (30.8%). The most common regimen was gemcitabine monotherapy, followed by gemcitabine combination therapy and S-1 monotherapy. The 1- and 2-year survival rates of all patients were 34.6% and 12.2%, respectively. The median survival time (MST) was 8 months in all patients. The 1-year survival rate was 65%, and the MST was 12 months among the locally advanced patients, whereas patients with peritoneal dissemination had the worst outcome; the 1-year survival rate was 7%, and the MST was 5 months. Among treated 90 cases of perihilar cholangiocarcinoma, patients who received chemoradiotherapy (n = 24) had a significantly better outcome than those who received chemotherapy alone (MST: 20 vs. 11 months, P < 0.001). Conclusions Unresectable BTC has heterogeneous treatment outcomes depending on the mode of tumor extension and location. Multidisciplinary treatment seems useful for patients with locally advanced BTC, whereas patients with metastatic disease still have a poor prognosis.
Collapse
Affiliation(s)
- Fumi Harada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- These authors contributed equally to this article
| | - Kentaro Miyake
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- These authors contributed equally to this article
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Kazunori Furuta
- Department of Surgery, Kitasato University Kitasato Institute Hospital, Tokyo 108-8642, Japan
| | - Mitsuhiro Kida
- Department of Surgery, Kitasato University Kitasato Institute Hospital, Tokyo 108-8642, Japan
| | - Shinichi Ohkawa
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Kanagawa 241-8515, Japan
| | - Jun-ichi Tanaka
- Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Kanagawa 224-8503, Japan
| | - Takeshi Asakura
- Department of Gastrointestinal Surgery, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan
| | - Kazuya Sugimori
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan
| | - Yoshiaki Kawaguchi
- Department of Gastroenterology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Tetsuya Mine
- Department of Gastroenterology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Kazumi Kubota
- Department of Healthcare Information Management, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Hiroshi Shimada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| |
Collapse
|
|
2
|
Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma. Cancers (Basel) 2024; 16:1690. [PMID: 38730642 PMCID: PMC11083102 DOI: 10.3390/cancers16091690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/17/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.
Collapse
Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| |
Collapse
|
|
3
|
Romanzi A, Villa E. Angiogenesis: the Yin and Yang in intrahepatic cholangiocarcinoma. HEPATOMA RESEARCH 2023. [DOI: 10.20517/2394-5079.2023.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
The tumor microenvironment (TME) constitutes a complex structure comprising different cell types and soluble factors that surround the tumor and promote its progression. Primarily for its pivotal role in malignant growth, TME has become a potential therapeutic objective for developing new targeted therapy and a marker for assessing therapeutic response. In intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver malignancy, TME has also gained a central role in understanding the mechanisms underlying tumor progression. In this review, we focused on the role of angiogenic factors and their pathway in iCCA and analyzed possible therapeutic and prognostic implications.
Collapse
|
|
4
|
Wang L, Zhang N, Wang Y, Zhang T, Zhu W, Mao A, Zhao Y, Wang L. Safety and efficacy of GEMOX plus donafenib and tislelizumab as first-line therapy for advanced epithelial malignant biliary tract cancer. Cancer Med 2023; 12:12263-12271. [PMID: 37039263 PMCID: PMC10278481 DOI: 10.1002/cam4.5924] [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: 12/15/2022] [Revised: 03/13/2023] [Accepted: 03/31/2023] [Indexed: 04/12/2023] Open
Abstract
AIM This study was aimed to evaluate the safety and the efficacy of gemcitabine and oxaliplatin (GEMOX) combined with donafenib plus tislelizumab as the first-line treatment for patients with unresectable biliary tract cancer (BTC). METHODS This is a prospective single-center exploratory study. Eligible patients (Stage III/IV BTC, at least one measurable disease according to RECIST v1.1, etc.) received gemcitabine 1000 mg/m2 IV Q3W, oxaliplatin 100 mg/m2 IV Q3W, donafenib 200 mg PO BID, and tislelizumab 200 mg IV Q3W until disease progression, unacceptable toxicity, or withdrawal of consent whichever occurred first. The primary endpoint was safety and secondary endpoints included disease control rate (DCR), objective response rate (ORR), conversion rate, and overall survival (OS). RESULTS A total of 13 patients were enrolled. The median follow-up time was 420 days (range 345-487). The median duration of treatment was four cycles (range 1-15). The incidence of ≥Grade 3 treatment-related adverse events (TRAEs) was 53.8% and no Grade 5 TRAE. The most frequent Grade 3-4 TRAEs were rash (4/13, 30.8%), platelet count decreased (2/13, 15.4%), and fatigue (2/13, 15.4%). Tumor response was assessed in eight evaluable patients; ORR was 25.0% (95% CI, 3.2%-65.1%) and DCR 87.5% (95% CI, 47.3%-99.7%). The median PFS was 4.8 months (95% CI, 1.25-NE). Three Stage III patients underwent subsequent surgery with a conversion rate of 23.1%. The median OS was not estimable. CONCLUSIONS GEMOX combined with donafenib plus tislelizumab as the first-line therapy for unresectable BTC showed manageable toxicity and encouraging efficacy especially in terms of promising conversion rate in Stage III patients.
Collapse
Affiliation(s)
- Longrong Wang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Ning Zhang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Yixiu Wang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Ti Zhang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Weiping Zhu
- Department of Hepatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Anrong Mao
- Department of Hepatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Yiming Zhao
- Department of Hepatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Lu Wang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityShanghaiChina
| |
Collapse
|
|
5
|
Zeng W, Mao R, Zhang Z, Chen X. Combination Therapies for Advanced Biliary Tract Cancer. J Clin Transl Hepatol 2023; 11:490-501. [PMID: 36643047 PMCID: PMC9817051 DOI: 10.14218/jcth.2022.00277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 08/09/2022] [Accepted: 08/18/2022] [Indexed: 01/18/2023] Open
Abstract
Biliary tract cancers (BTCs) are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis. Surgery is the only curative therapy. However, most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression. The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy. Nonetheless, many patients develop resistance to this regimen. Over the years, few chemotherapy regimens have managed to improve the overall survival of patients. Accordingly, novel therapies such as targeted therapy have been introduced to treat this patient population. Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways, such as EGFR, VEGF, MEK/ERK, PI3K and mTOR. Moreover, mutational analysis has documented the presence of IDH1, FGFR2, HER2, PRKACA, PRKACB, BRAF, and KRAS gene aberrations. The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies. Cancer vaccines, adoptive cell transfer, and immune checkpoint inhibitors have been extensively investigated in trials of BTC. Therefore, patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes. This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.
Collapse
Affiliation(s)
- Weifeng Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruiqi Mao
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Correspondence to: Zhanguo Zhang and Xiaoping Chen, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. ORCID: https://orcid.org/0000-0002-4527-4975 (ZZ). Tel: +86-27-83663400, Fax: +86-27-83662851, E-mail: (ZZ) and (XC)
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Correspondence to: Zhanguo Zhang and Xiaoping Chen, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. ORCID: https://orcid.org/0000-0002-4527-4975 (ZZ). Tel: +86-27-83663400, Fax: +86-27-83662851, E-mail: (ZZ) and (XC)
| |
Collapse
|
|
6
|
Yan X, Zou H, Lai Y, Ung COL, Hu H. Efficacy and Safety of First-Line Targeted Treatment and Immunotherapy for Patients with Biliary Tract Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 15:39. [PMID: 36612035 PMCID: PMC9817514 DOI: 10.3390/cancers15010039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/06/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Biliary tract cancer is one of the most aggressive and fatal tumours. Gemcitabine with cisplatin chemotherapy has long been the first-line treatment, but the prognosis is poor. In recent years, targeted treatment and immunotherapy have produced encouraging outcomes requiring a thorough review and meta-analysis. METHOD For this systematic review and meta-analysis, we searched four databases, starting from the inception dates of databases to 11 January 2022. This study comprised randomised clinical trials and cohort studies that used immunotherapy or targeted treatment as the first line of treatment for patients with biliary tract cancer. RESULTS From the 888 studies extracted, 33 trials were examined and found to meet the criteria. These included 3087 patients, 16 single-arm trials, 13 RCTs, one nRCT, a prospective single-arm pilot study, and a clinical setting in the real world. From 2010 to 2020, 33 studies were conducted using targeted treatment or immunologic therapies as first-line treatments for BTC patients, and 18 of those studies had positive outcomes. CONCLUSION This study demonstrates that immunotherapy combined with chemotherapy as first-line treatment can provide survival benefits by improving the objective response rate for patients with unresectable biliary tract cancer. The potential for combination therapy to become a new trend in clinical treatment is promising but needs further clinical evaluation.
Collapse
Affiliation(s)
- Xin Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Huimin Zou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yunfeng Lai
- School of Public Health and Management, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Carolina Oi Lam Ung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Hao Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
| |
Collapse
|
|
7
|
El Dika I, Shia J, Chen CL, Paroder V, Carver A, Shamseddine A, Mukherji D, Sirohi B, Makondi PT, Asseily C, Matar CF, Elias R, Slater E, Rosenbaum MS, Paramesawaran R, Breitbart W, Abou-Alfa GK. Congenital cardiac liver cirrhosis with combined hepatocellular-cholangiocarcinoma-a case report. J Gastrointest Oncol 2022; 13:3321-3328. [PMID: 36636063 PMCID: PMC9830364 DOI: 10.21037/jgo-21-878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 10/14/2022] [Indexed: 11/23/2022] Open
Abstract
Background Cardiac liver cirrhosis secondary to Fontan procedure has been associated with hepatocellular carcinoma at a younger age. However, Fontan associated liver disease and combined hepatocellular-cholangiocarcinoma has not been previously reported. Combined hepatocellular-cholangiocarcinoma is a rare cancer that accounts for 2-5% of primary liver tumors and poses significant diagnostic and treatment challenges. This case highlights these needs and potential screening and treatment considerations. Herein we describe a case of combined hepatocellular-cholangiocarcinoma in a patient with autism, congenital heart disease, and Fontan procedure. Case Description The patient is a 27-year-old male who presented with a liver mass detected on MRI performed in the context of a rising alpha-fetoprotein during a screening visit. Biopsy of the mass revealed a combined hepatocellular-cholangiocarcinoma which was staged as localized. Due to the COVID-19 pandemic and subsequent halt of all elective surgeries, the patient received local therapy with chemoembolization followed by pembrolizumab. The disease progressed though, and therapy was changed to gemcitabine plus cisplatin. Patient received 2 cycles of therapy, after which he and his family decided to transfer medical care to Memorial Sloan Kettering. Next generation sequencing of the tumor revealed TP53 and FGFR2 mutations. By then patient was also found to have lung metastasis. To help address the hepatocellular carcinoma, lenvatinib was added. Patient had sustainable disease control for about a year, yet eventually developed thrombocytopenia complicated by an episode of gastrointestinal bleeding. With a worsening performance status, adverse events of the treatment, and recurrent hospitalizations, a goals of care discussion with his family led to the discontinuation of active cancer therapy and patient was started on best supportive care. Patient remained in active follow-up until the time of this report and passed away less than a year from initiating best supportive care alone. Conclusions This challenging case raises awareness towards screening and monitoring all patients with Fontan procedure for Fontan associated liver disease and liver cancers, including combined hepatocellular-cholangiocarcinoma. To the best of our knowledge, this is the first description of combined hepatocellular-cholangiocarcinoma occurring in the context of cardiac cirrhosis. The management difficulties that led to altering the goals of care, is another reminder of the dynamic nature of the care oncologists would provide.
Collapse
Affiliation(s)
- Imane El Dika
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell College of Medicine, New York, NY, USA
| | - Jinru Shia
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell College of Medicine, New York, NY, USA
| | - Carol L Chen
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell College of Medicine, New York, NY, USA
| | - Viktoriya Paroder
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell College of Medicine, New York, NY, USA
| | - Alan Carver
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell College of Medicine, New York, NY, USA
| | | | | | | | | | - Clara Asseily
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Rawad Elias
- Hartford Healthcare Cancer Institute, Hartford, CT, USA
| | | | | | - Rekha Paramesawaran
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell College of Medicine, New York, NY, USA
| | - William Breitbart
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell College of Medicine, New York, NY, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell College of Medicine, New York, NY, USA
| |
Collapse
|
|
8
|
Gundlach JP, Kerber J, Hendricks A, Bernsmeier A, Halske C, Röder C, Becker T, Röcken C, Braun F, Sebens S, Heits N. Paracrine Interaction of Cholangiocellular Carcinoma with Cancer-Associated Fibroblasts and Schwann Cells Impact Cell Migration. J Clin Med 2022; 11:jcm11102785. [PMID: 35628911 PMCID: PMC9145811 DOI: 10.3390/jcm11102785] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 11/16/2022] Open
Abstract
Although the Mitogen-activated protein kinase (MAPK) pathway is enriched in cholangiocarcinoma (CCA), treatment with the multityrosine kinase-inhibitor Sorafenib is disappointing. While cancer-associated fibroblasts (CAF) are known to contribute to treatment resistance in CCA, knowledge is lacking for Schwann cells (SC). We investigated the impact of stromal cells on CCA cells and whether this is affected by Sorafenib. Immunohistochemistry revealed elevated expression of CAF and SC markers significantly correlating with reduced tumor-free survival. In co-culture with CAF, CCA cells mostly migrated, which could be diminished by Sorafenib, while in SC co-cultures, SC predominantly migrated towards CCA cells, unaffected by Sorafenib. Moreover, increased secretion of pro-inflammatory cytokines MCP-1, CXCL-1, IL-6 and IL-8 was determined in CAF mono- and co-cultures, which could be reduced by Sorafenib. Corresponding to migration results, an increased expression of phospho-AKT was measured in CAF co-cultured HuCCT-1 cells, although was unaffected by Sorafenib. Intriguingly, CAF co-cultured TFK-1 cells showed increased activation of STAT3, JNK, ERK and AKT pathways, which was partly reduced by Sorafenib. This study indicates that CAF and SC differentially impact CCA cells and Sorafenib partially reverts these stroma-mediated effects. These findings contribute to a better understanding of the paracrine interplay of CAF and SC with CCA cells.
Collapse
Affiliation(s)
- Jan-Paul Gundlach
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (J.K.); (A.B.); (T.B.); (F.B.); (N.H.)
- Institute for Experimental Cancer Research, Kiel University and University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building U30, 24105 Kiel, Germany; (C.R.); (S.S.)
- Correspondence:
| | - Jannik Kerber
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (J.K.); (A.B.); (T.B.); (F.B.); (N.H.)
- Institute for Experimental Cancer Research, Kiel University and University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building U30, 24105 Kiel, Germany; (C.R.); (S.S.)
| | - Alexander Hendricks
- Department of General, Visceral-, Vascular-, and Transplantation Surgery, Medical University Rostock, Schillingallee 35, 18057 Rostock, Germany;
| | - Alexander Bernsmeier
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (J.K.); (A.B.); (T.B.); (F.B.); (N.H.)
| | - Christine Halske
- Institute of Pathology, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany; (C.H.); (C.R.)
| | - Christian Röder
- Institute for Experimental Cancer Research, Kiel University and University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building U30, 24105 Kiel, Germany; (C.R.); (S.S.)
| | - Thomas Becker
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (J.K.); (A.B.); (T.B.); (F.B.); (N.H.)
| | - Christoph Röcken
- Institute of Pathology, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany; (C.H.); (C.R.)
| | - Felix Braun
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (J.K.); (A.B.); (T.B.); (F.B.); (N.H.)
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Kiel University and University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building U30, 24105 Kiel, Germany; (C.R.); (S.S.)
| | - Nils Heits
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (J.K.); (A.B.); (T.B.); (F.B.); (N.H.)
- Gesundheitszentrum Kiel-Mitte, Prüner Gang 15, 24103 Kiel, Germany
| |
Collapse
|
|
9
|
Gray S, Lamarca A, Edeline J, Klümpen HJ, Hubner RA, McNamara MG, Valle JW. Targeted Therapies for Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:1789. [PMID: 35406560 PMCID: PMC8997784 DOI: 10.3390/cancers14071789] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient's cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.
Collapse
Affiliation(s)
- Simon Gray
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Julien Edeline
- Centre Eugène Marquis, Av. de la Bataille Flandres Dunkerque-CS 44229, CEDEX, 35042 Rennes, France;
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Center, P.O. Box 7057, 1081 HV Amsterdam, The Netherlands;
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| |
Collapse
|
|
10
|
Thol F, Gairing SJ, Czauderna C, Thomaidis T, Gamstätter T, Huber Y, Vollmar J, Lorenz J, Michel M, Bartsch F, Müller L, Kloeckner R, Galle PR, Wörns MA, Marquardt JU, Moehler M, Weinmann A, Foerster F. Outcomes in patients receiving palliative chemotherapy for advanced biliary tract cancer. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100417. [PMID: 35141511 PMCID: PMC8792293 DOI: 10.1016/j.jhepr.2021.100417] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/24/2021] [Accepted: 11/30/2021] [Indexed: 11/04/2022]
Abstract
Background & Aims Advanced biliary tract cancer (ABTC) is associated with a poor prognosis. Real-world data on the outcome of patients with ABTC undergoing sequential chemotherapies remain scarce, and little is known about treatment options beyond the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX. This study aimed to evaluate the outcome of patients with regard to different oncological therapies and to identify prognostic factors. Methods From January 2010 until December 2019, 142 patients started palliative chemotherapy at our tertiary care liver center. Overall survival (OS) was calculated using Kaplan-Meier plots. Prognostic factors were evaluated using cox proportional-hazards. Results Patients received a median number of 2 lines of chemotherapy. Median OS was 6.7, 15.2 and 18.2 months for patients who received 1, 2 and 3 lines of chemotherapy, respectively. Patients treated with FOLFIRINOX had a significantly extended OS of 23.8 months (log-rank test: p = 0.018). The univariate cox regression analysis identified several clinical parameters associated with survival (e.g. albumin, bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9 levels). Conclusions Our study provides real-world data on the prognosis of ABTC including survival times for patients receiving third and later lines of chemotherapy. Lay summary Real-world data depicting the outcome of patients with advanced biliary tract cancer outside the framework of controlled trials remain rare despite being extremely important for clinical decision-making. This study therefore provides important real-world data on the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX, as well as on other chemotherapy regimens or later lines of chemotherapy. It further demonstrates that the use of FOLFIRINOX is associated with promising survival and that there is an association between various clinical parameters such as pre-therapeutic albumin, bilirubin or carbohydrate antigen 19-9 levels and survival.
This study provides important real-world data on the clinical outcomes of patients with ABTC. Patients may benefit from later lines of chemotherapy beyond second line. The use of FOLFIRINOX was associated with a promising overall survival of 23.8 months in our study. Many prognostically relevant factors, such as pre-therapeutic albumin, bilirubin or CA19-9 levels, were identified. Targeted therapies will become an integral part of the standard of care for patients with ABTC.
Collapse
|
|
11
|
Pavicevic S, Reichelt S, Uluk D, Lurje I, Engelmann C, Modest DP, Pelzer U, Krenzien F, Raschzok N, Benzing C, Sauer IM, Stintzing S, Tacke F, Schöning W, Schmelzle M, Pratschke J, Lurje G. Prognostic and Predictive Molecular Markers in Cholangiocarcinoma. Cancers (Basel) 2022; 14:1026. [PMID: 35205774 PMCID: PMC8870611 DOI: 10.3390/cancers14041026] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA.
Collapse
Affiliation(s)
- Sandra Pavicevic
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sophie Reichelt
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Deniz Uluk
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Isabella Lurje
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Cornelius Engelmann
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Dominik P. Modest
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Uwe Pelzer
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Christian Benzing
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Frank Tacke
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| |
Collapse
|
|
12
|
Rimini M, Puzzoni M, Pedica F, Silvestris N, Fornaro L, Aprile G, Loi E, Brunetti O, Vivaldi C, Simionato F, Zavattari P, Scartozzi M, Burgio V, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021; 15:1367-1383. [PMID: 34669536 DOI: 10.1080/17474124.2021.1991313] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.
Collapse
Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Puzzoni
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Silvestris
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Lorenzo Fornaro
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy
| | - Caterina Vivaldi
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | | |
Collapse
|
|
13
|
Lee TY, Bates SE, Abou-Alfa GK. Equipoise, drug development, and biliary cancer. Cancer 2021; 128:944-949. [PMID: 34817855 DOI: 10.1002/cncr.34020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 01/07/2023]
Affiliation(s)
- Tristan Y Lee
- Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
| | - Susan E Bates
- Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Medical College, Cornell University, New York, New York
| |
Collapse
|
|
14
|
Aimar G, Paratore C, Zichi C, Marino D, Sperti E, Caglio A, Gamba T, De Vita F, Di Maio M. A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step? EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:448-464. [PMID: 36045702 PMCID: PMC9400771 DOI: 10.37349/etat.2021.00056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022] Open
Abstract
Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.
Collapse
Affiliation(s)
- Giacomo Aimar
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Chiara Paratore
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Clizia Zichi
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Donatella Marino
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Elisa Sperti
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Andrea Caglio
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Teresa Gamba
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Francesca De Vita
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| |
Collapse
|
|
15
|
Wang Y, Chen T, Li K, Mu W, Liu Z, Shi A, Liu J, Zhao W, Lian S, Huang S, Pan C, Zhang Z. Recent Advances in the Mechanism Research and Clinical Treatment of Anti-Angiogenesis in Biliary Tract Cancer. Front Oncol 2021; 11:777617. [PMID: 34778094 PMCID: PMC8581488 DOI: 10.3389/fonc.2021.777617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/11/2021] [Indexed: 12/25/2022] Open
Abstract
Biliary tract cancers (BTCs), including cholangiocarcinoma (CCA) and gallbladder cancer (GC), are malignancies originating from the biliary tract with poor prognosis. In the early stage of BTCs, surgery is the only choice for cure. Unfortunately, most patients with BTC are diagnosed at an advanced stage and lose the opportunity for surgery. For many advanced solid tumors, antiangiogenic therapy has achieved encouraging results. While most clinical studies on antiangiogenic therapy in advanced BTCs have shown an excellent disease control rate (DCR), the improvement in overall survival (OS) is controversial. Understanding how the relevant signaling molecules influence the angiogenic response and the functional interaction is necessary for the formulation of new treatment regimens and the selection of enrolled patients. In this review, we aim to summarize and discuss the latest advances in antiangeogenesis for BTCs, mainly focusing on the molecular mechanism of angiogenesis in BTCs and the therapeutic effects from clinical trials. Furthermore, the horizon of antiangiogenesis for BTCs is highlighted.
Collapse
Affiliation(s)
- Yue Wang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tianli Chen
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Kangshuai Li
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wentao Mu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zengli Liu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Anda Shi
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jialiang Liu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Zhao
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shuo Lian
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shaohui Huang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chang Pan
- Department of Emergency, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| |
Collapse
|
|
16
|
Ioffe D, Phull P, Dotan E. Optimal Management of Patients with Advanced or Metastatic Cholangiocarcinoma: An Evidence-Based Review. Cancer Manag Res 2021; 13:8085-8098. [PMID: 34737637 PMCID: PMC8558827 DOI: 10.2147/cmar.s276104] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 09/18/2021] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinomas are rare tumors originating at any point along the biliary tree. These tumors often pose significant challenges for diagnosis and treatment, and often carry a poor prognosis. However, in recent years, studies have identified significant molecular heterogeneity with up to 50% of tumors having detectable mutations, leading to the guideline recommendations for molecular testing as part of the diagnostic workup for these tumors. In addition, better classification of these tumors and understanding of their biology has led to new drugs being approved for treatment of this resistant tumor. This manuscript will provide a comprehensive review of the epidemiology, risk factors, diagnostic approach, molecular classification, and treatment options for patients with advanced cholangiocarcinomas.
Collapse
Affiliation(s)
- Dina Ioffe
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Pooja Phull
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Efrat Dotan
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| |
Collapse
|
|
17
|
Vignone A, Biancaniello F, Casadio M, Pesci L, Cardinale V, Ridola L, Alvaro D. Emerging Therapies for Advanced Cholangiocarcinoma: An Updated Literature Review. J Clin Med 2021; 10:4901. [PMID: 34768421 PMCID: PMC8584870 DOI: 10.3390/jcm10214901] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/19/2021] [Accepted: 10/22/2021] [Indexed: 12/14/2022] Open
Abstract
Cholangiocarcinoma is a group of malignancies with poor prognosis. Treatments for the management of advanced-stage cholangiocarcinoma are limited, and the 5-year survival rate is estimated to be approximately 5-15%, considering all tumor stages. There is a significant unmet need for effective new treatment approaches. The present review is provided with the aim of summarizing the current evidence and future perspectives concerning new therapeutic strategies for cholangiocarcinoma. The role of targeted therapies and immunotherapies is currently investigational in cholangiocarcinoma. These therapeutic options might improve survival outcomes, as shown by the promising results of several clinical trials illustrated in the present review. The co-presence of driver mutations and markers of susceptibility to immunotherapy may lead to rational combination strategies and clinical trial development. A better understanding of immunologically based therapeutic weapons is needed, which will lead to a form of a precision medicine strategy capable of alleviating the clinical aggressiveness and to improve the prognosis of cholangiocarcinoma.
Collapse
Affiliation(s)
- Anthony Vignone
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Francesca Biancaniello
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Marco Casadio
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Ludovica Pesci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Vincenzo Cardinale
- Department of Medical-Surgical and Biotechnologies Sciences, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, 04100 Latina, Italy;
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| |
Collapse
|
|
18
|
Kam AE, Masood A, Shroff RT. Current and emerging therapies for advanced biliary tract cancers. Lancet Gastroenterol Hepatol 2021; 6:956-969. [PMID: 34626563 DOI: 10.1016/s2468-1253(21)00171-0] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/30/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (cholangiocarcinomas and gallbladder cancers) are increasing in incidence and have a poor prognosis. Most patients present with advanced disease, for which the treatment is palliative chemotherapy. Over the past few years, the genomic landscape of biliary tract cancers has been examined and several targeted therapies have been developed. Molecular targets with clinically meaningful activity include fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), RAS-RAF-MEK (MAP2K1)-ERK (MAPK3), HER2 (also known as ERBB2), DNA mismatch repair, and NTRK. Pemigatinib, a FGFR1-3 inhibitor, showed encouraging response rates and survival data as second-line treatment and received US Food and Drug Administration (FDA) approval in April, 2020, for previously treated advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion or rearrangements. Ivosidenib, an IDH1 inhibitor, showed improved progression-free survival versus placebo in second-line treatment in the phase 3 ClarIDHy trial. Early phase trials of dabrafenib plus trametinib (BRAF and MEK inhibition) and zanidatamab (a bispecific HER2-antibody) have yielded encouraging response rates. Immunotherapy has mainly produced responses in tumours with deficient mismatch repair or high microsatellite instability (also known as dMMR or MSI-H) or higher PD-L1 score, or both. However, early phase trials of immunotherapy plus chemotherapy in unselected patient populations appear promising. NTRK inhibitors have also shown promise in early phase trials of NTRK-fusion positive solid tumours, including cholangiocarcinoma. In this Review, we discuss current and emerging therapies for advanced biliary tract cancers, with a focus on molecularly targeted therapy.
Collapse
Affiliation(s)
- Audrey E Kam
- Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL, USA.
| | - Ashiq Masood
- Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL, USA
| | - Rachna T Shroff
- Division of Hematology and Oncology, University of Arizona Cancer Center, Tucson, AZ, USA
| |
Collapse
|
|
19
|
Oh MY, Kim H, Choi YJ, Byun Y, Han Y, Kang JS, Sohn H, Lee JM, Kwon W, Jang JY. Conversion surgery for initially unresectable extrahepatic biliary tract cancer. Ann Hepatobiliary Pancreat Surg 2021; 25:349-357. [PMID: 34402435 PMCID: PMC8382869 DOI: 10.14701/ahbps.2021.25.3.349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/24/2021] [Accepted: 06/20/2021] [Indexed: 12/12/2022] Open
Abstract
Backgrounds/Aims Surgical resection is the only curative treatment for biliary tract cancers; however, most patients undergo palliative chemotherapy because they are contraindicated for surgery. Conversion surgery, a treatment strategy for downsizing chemotherapy and subsequent surgical resection, is feasible for initially unresectable biliary tract cancers following the introduction of effective chemotherapeutic agents. Methods Patients initially diagnosed with unresectable biliary tract cancers, and treated with conversion surgery after palliative chemotherapy between 2013 and 2019, were reviewed retrospectively. Results Twelve patients underwent conversion surgery after palliative chemotherapy for initially unresectable biliary tract cancers. The final pathological diagnosis included six perihilar cholangiocarcinomas, four distal common bile duct cancers, and two gallbladder cancers. Different chemotherapy regimens were used, but all the patients were treated with gemcitabine at some point during their treatment. The median overall survival was 28 months, which was longer than that of patients treated with isolated palliative chemotherapy in previous studies. Conclusions Conversion surgery represents a therapeutic alternative for specific cases of unresectable biliary tract cancers. Palliative chemotherapy for initially unresectable biliary tract cancers is recommended for downsizing the tumor and expanding the indications for surgery. Further studies and clinical trials are required to develop new and effective chemotherapeutic regimens.
Collapse
Affiliation(s)
- Moon Young Oh
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hongbeom Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Yoo Jin Choi
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Yoonhyeong Byun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Youngmin Han
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Seung Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Heeju Sohn
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Min Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Wooil Kwon
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jin-Young Jang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| |
Collapse
|
|
20
|
Casadio M, Biancaniello F, Overi D, Venere R, Carpino G, Gaudio E, Alvaro D, Cardinale V. Molecular Landscape and Therapeutic Strategies in Cholangiocarcinoma: An Integrated Translational Approach towards Precision Medicine. Int J Mol Sci 2021; 22:5613. [PMID: 34070643 PMCID: PMC8199244 DOI: 10.3390/ijms22115613] [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: 04/30/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/15/2022] Open
Abstract
Cholangiocarcinomas (CCAs) are heterogeneous biliary tract malignancies with dismal prognosis, mainly due to tumor aggressiveness, late diagnosis, and poor response to current therapeutic options. High-throughput technologies have been used as a fundamental tool in unveiling CCA molecular landscape, and several molecular classifications have been proposed, leading to various targeted therapy trials. In this review, we aim to analyze the critical issues concerning the status of precision medicine in CCA, discussing molecular signatures and clusters, related to both anatomical classification and different etiopathogenesis, and the latest therapeutic strategies. Furthermore, we propose an integrated approach comprising the CCA molecular mechanism, pathobiology, clinical and histological findings, and treatment perspectives for the ultimate purpose of improving the methods of patient allocations in clinical trials and the response to personalized therapies.
Collapse
Affiliation(s)
- Marco Casadio
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (R.V.); (D.A.)
| | - Francesca Biancaniello
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (R.V.); (D.A.)
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy; (D.O.); (E.G.)
| | - Rosanna Venere
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (R.V.); (D.A.)
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome “Foro Italico”, Piazza Lauro de Bosis 6, 00135 Rome, Italy;
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy; (D.O.); (E.G.)
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (R.V.); (D.A.)
| | - Vincenzo Cardinale
- Medical-Surgical and Biotechnologies Sciences, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, 04100 Latina, Italy;
| |
Collapse
|
|
21
|
Rimini M, Casadei-Gardini A. Angiogenesis in biliary tract cancer: targeting and therapeutic potential. Expert Opin Investig Drugs 2021; 30:411-418. [PMID: 33491502 DOI: 10.1080/13543784.2021.1881479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.
Collapse
Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.,Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
22
|
Sutherland M, Ahmed O, Zaidi A, Ahmed S. Current progress in systemic therapy for biliary tract cancers. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 29:1094-1107. [PMID: 33735541 DOI: 10.1002/jhbp.939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 12/30/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Biliary tract cancers (BTCs) are heterogeneous cancers that include cancers of the bile duct and gallbladder. Although they are relatively uncommon, most patients with BTC are diagnosed at advanced-stage disease with high mortality rates. Recently, systemic therapy options for patients with BTC have evolved. This paper reviews recent advancements in systemic therapy and the results of key clinical trials in BTC. METHODS A literature search in PubMed and Google Scholar was performed using keywords related to BTC and systemic therapy. Studies that were presented in major international cancer research conferences were also included. RESULTS The evidence shows that adjuvant capecitabine has been associated with a lower relapse rate in early-stage BTC. In unselected patients with advanced BTC, combination chemotherapy is a standard treatment option. However, with a better understanding of the molecular profile of BTC, there has been a shift toward targeted agents in BTC that have shown promising responses. The evolving data also support the evolving role of immunotherapy in patients with deficient DNA mismatch repair or PD-L1-positive BTC. DISCUSSION Systemic treatment options for BTC have improved. The future identification of new targets, novel compounds, and predictive markers is a key step toward the use of personalized medicine in BTC.
Collapse
Affiliation(s)
| | - Osama Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
| | - Adnan Zaidi
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
| | - Shahid Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
| |
Collapse
|
|
23
|
Rahnemai-Azar AA, Pawlik TM. Cholangiocarcinoma: shedding light on the most promising drugs in clinical development. Expert Opin Investig Drugs 2021; 30:419-427. [PMID: 33645382 DOI: 10.1080/13543784.2021.1897103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a diverse group of fatal malignancies arising from the biliary tract. Surgical resection with negative margin offers the only potentially curative option. The majority of patients present at locally advanced or metastatic stages, when surgical resection is not feasible, highlighting the significance of systemic therapy. Given the limited effectiveness of traditional chemotherapy regimens in CCA, many investigators have focused on developing novel molecular therapies targeting key aberrant signaling pathways.Areas covered: We present the main genomic aberrations known to play a key role in cholangiocarcinogenesis and discuss promising targeted therapies in clinical development.In October of 2020, a review of the English literature was performed utilizing PubMed and Web of Science databases for the keywords of 'cholangiocarcinoma', 'biliary tract cancer', and 'targeted therapy'.Expert opinion: Unfortunately, despite encouraging results in preclinical studies, the outcome of clinical trials with established targeted therapies like anti-EGFR medications have been discouraging. Currently, agents targeting FGFR2 fusion and IDH1/2 mutations hold great promise for improving the management of CCA. Future studies focused on enhancing our understanding of key aberrant signaling pathways of cholangiocarcinogenesis and the design of homogeneous and biomarker-driven cohorts are key elements of establishing precision medicine in CCA.
Collapse
Affiliation(s)
- Amir A Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, The James Comprehensive Cancer Center, Columbus, OH, USA
| |
Collapse
|
|
24
|
Yang W, Sun Y. Promising Molecular Targets for the Targeted Therapy of Biliary Tract Cancers: An Overview. Onco Targets Ther 2021; 14:1341-1366. [PMID: 33658799 PMCID: PMC7920611 DOI: 10.2147/ott.s297643] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancer (BTC) is a leading cause of cancer-related death, due to the limited benefits of current systematic therapies and the heterogeneity of the tumor itself. High heterogeneity means that the clinical and molecular features vary between different subtypes of BTC, while the underlying molecular mechanisms remain unclear. Targeted therapy, where inhibitors are developed to selectively combine with targeted molecules in order to block abnormal signaling pathways in BTC, has shown promise as an emerging form of treatment for various types of cancer. In this article, a comprehensive review is conducted to examine potential molecular targets for BTC targeted therapy and their mechanisms. Furthermore, preliminary data published from clinical trials is utilized to analyze the main drugs used to combat BTC. The collective information presented in this article has provided useful insights into the current understanding of BTC.
Collapse
Affiliation(s)
- Wenwei Yang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Yongkun Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| |
Collapse
|
|
25
|
Rizzo A, Brandi G. First-line Chemotherapy in Advanced Biliary Tract Cancer Ten Years After the ABC-02 Trial: "And Yet It Moves!". Cancer Treat Res Commun 2021; 27:100335. [PMID: 33592561 DOI: 10.1016/j.ctarc.2021.100335] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/07/2021] [Accepted: 02/09/2021] [Indexed: 12/12/2022]
Abstract
Biliary tract cancers (BTCs) include a heterogeneous group of highly aggressive hepatobiliary malignancies, representing the 3% of all gastrointestinal cancers and the second most frequent type of primary liver cancer after hepatocellular carcinoma. Ten years after the publication of the phase III, randomized, ABC-02 trial, the combination of cisplatin plus gemcitabine remains the standard first-line treatment for patients with advanced BTC. In the last decade, a large number of attempts has been made to improve the efficacy of the reference doublet by using novel drugs or adding a third agent to cisplatin-gemcitabine. Unfortunately, despite the addition of different cytotoxic drugs failed to improve clinical outcomes in several studies, recently published clinical trials have provided interesting results, and other first-line chemotherapy options are currently under investigation in randomized phase III studies. Moreover, recent years have witnessed the parallel emergence of molecularly targeted therapies and immune checkpoint inhibitors, with these novel agents having the potential to revolutionize the therapeutic algorithm of advanced BTC. In this review, we will provide an overview on first-line therapeutic opportunities currently available in the management of advanced BTCs, especially focusing on recently published data and ongoing clinical trials in this setting.
Collapse
Affiliation(s)
- Alessandro Rizzo
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni, 15 Bologna, Italy.
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni, 15 Bologna, Italy
| |
Collapse
|
|
26
|
Sarkis Y, Al Soueidy A, Kourie HR. Will advanced cholangiocarcinoma become a targetable malignancy? Crit Rev Oncol Hematol 2021; 159:103233. [PMID: 33482346 DOI: 10.1016/j.critrevonc.2021.103233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/15/2020] [Accepted: 01/16/2021] [Indexed: 02/08/2023] Open
Abstract
Cholangiocarcinoma and biliary tract cancers are rare but aggressive tumors that are characterized by an heterogenous molecular and genetic footprint. Genetic aberrations such as FGFR2 fusion and ErBb2 amplification are common in those cancers. Recent studies aimed at exploring the efficacy and benefit of targeted therapy in the treatment of advanced cholangiocarcinoma. Many promising drugs exist and warrant additional investigations. This review will summarize available results and highlight therapeutic strategies incorporated in clinical trials.
Collapse
Affiliation(s)
- Yara Sarkis
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon.
| | - Amine Al Soueidy
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
| | - Hampig Raphael Kourie
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
| |
Collapse
|
|
27
|
Houron C, Danielou M, Mir O, Fromenty B, Perlemuter G, Voican CS. Multikinase inhibitor-induced liver injury in patients with cancer: A review for clinicians. Crit Rev Oncol Hematol 2020; 157:103127. [PMID: 33161366 DOI: 10.1016/j.critrevonc.2020.103127] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 09/29/2020] [Accepted: 10/05/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Multikinase inhibitors (MKI) are targeted molecular agents that have revolutionized cancer management. However, there is a paucity of data concerning MKI-related liver injury risk and clinical guidelines for the management of liver toxicity in patients receiving MKI for cancer are scarce. DESIGN We conducted a PubMed search of articles in English published from January 2000 to December 2018 related to hepatotoxicity of the 29 FDA-approved MKIs at doses used in clinical practice. The search terms were the international non-proprietary name of each agent cross-referenced with «hepatotoxicity», «hepatitis», «hepatic adverse event», or «liver failure», and «phase II clinical trial», «phase III clinical trial», or «case report». RESULTS Following this search, 140 relevant studies and 99 case reports were considered. Although asymptomatic elevation of aminotransferase levels has been frequently observed in MKI clinical trials, clinically significant hepatotoxicity is a rare event. In most cases, the interval between treatment initiation and the onset of liver injury is between one week and two months. Liver toxicity is often hepatocellular and less frequently mixed. Life-threatening MKI-induced hepatic injury has been described, involving fulminant liver failure or death. Starting from existing data, a description of MKI-related liver events, grading of hepatotoxicity risk, and recommendations for management are also given for various MKI molecules. CONCLUSION All MKIs can potentially cause liver injury, which is sometimes irreversible. As there is still no strategy available to prevent MKI-related hepatotoxicity, early detection remains crucial. The surveillance of liver function during treatment may help in the early detection of hepatotoxicity. Furthermore, the exclusion of potential causes of hepatic injury is essential to avoid unnecessary MKI withdrawal.
Collapse
Affiliation(s)
- Camille Houron
- Faculté de Médecine Paris-Saclay, Université Paris-Saclay, F-94276, Le Kremlin-Bicêtre, France; INSERM U996, DHU Hepatinov, Labex LERMIT, F-92140, Clamart, France
| | - Marie Danielou
- Faculté de Médecine Paris-Saclay, Université Paris-Saclay, F-94276, Le Kremlin-Bicêtre, France; Service d'Hépato-Gastroentérologie et Nutrition, Hôpital Antoine-Béclère, AP-HP, Université Paris-Saclay, F-92140, Clamart, France
| | - Olivier Mir
- Gustave Roussy Cancer Campus, Department of Ambulatory Care, F-94805, Villejuif, France
| | - Bernard Fromenty
- INSERM, INRAE, Univ Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), UMR_A 1341, UMR_S 1241, F-35000, Rennes, France
| | - Gabriel Perlemuter
- Faculté de Médecine Paris-Saclay, Université Paris-Saclay, F-94276, Le Kremlin-Bicêtre, France; INSERM U996, DHU Hepatinov, Labex LERMIT, F-92140, Clamart, France; Service d'Hépato-Gastroentérologie et Nutrition, Hôpital Antoine-Béclère, AP-HP, Université Paris-Saclay, F-92140, Clamart, France.
| | - Cosmin Sebastian Voican
- Faculté de Médecine Paris-Saclay, Université Paris-Saclay, F-94276, Le Kremlin-Bicêtre, France; INSERM U996, DHU Hepatinov, Labex LERMIT, F-92140, Clamart, France; Service d'Hépato-Gastroentérologie et Nutrition, Hôpital Antoine-Béclère, AP-HP, Université Paris-Saclay, F-92140, Clamart, France
| |
Collapse
|
|
28
|
Continuum of care for advanced biliary tract cancers. Clin Res Hepatol Gastroenterol 2020; 44:810-824. [PMID: 32586782 DOI: 10.1016/j.clinre.2020.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 05/24/2020] [Accepted: 05/27/2020] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. Advanced BTC remains a challenging, non-curable disease. In this review, we provide an overview of the medical treatment options in advanced BTC and new strategies under development. Gemcitabine plus platinum chemotherapy is the standard first-line therapy in this setting. Recently, 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX) regimen became the only second-line therapy to be prospectively validated beyond failure of gemcitabine plus cisplatin combination in a phase III study, even though chemotherapy yielded modest survival improvement over best supportive care. Anti-epidermal growth factor receptor and antiangiogenic antibodies have not demonstrated any survival benefit in unselected patient populations. In recent years, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyses, opening up new perspectives for so-called personalised targeted therapies. Patients with BTC may be particularly good candidates for biomarker-driven strategies in clinical practice. Among current developments, the targeting of fibroblast growth factor receptor and isocitrate dehydrogenase gene alterations are the most promising avenues, and combination immunotherapies are under investigation.
Collapse
|
|
29
|
Xie C, McGrath NA, Monge Bonilla C, Fu J. Systemic treatment options for advanced biliary tract carcinoma. J Gastroenterol 2020; 55:944-957. [PMID: 32748173 PMCID: PMC7519922 DOI: 10.1007/s00535-020-01712-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/25/2020] [Indexed: 02/04/2023]
Abstract
Advanced biliary tract cancers (BTC) include a diverse collection of rare and heterogenous tumors with poor prognosis. The combination of gemcitabine and cisplatin is the established first-line therapy for advanced BTC. There are no accepted standard treatments in the second line setting, though there are several ongoing clinical trials that implement chemotherapy as a therapeutic strategy. The understanding of the molecular landscape of BTC has offered hope of targeted therapies to the identified actionable genomic aberrations, such as FGFR2 gene fusions, mutations of IDH1/2, HER2, BRAC1/2 and BRAF. Pembigatinib has become the first approved targeted therapy for BTC with FGFR2 fusion or other rearrangements. Recent immunotherapy has opened new therapy avenues in BTC with pembrolizumab approved for either microsatellite instability high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors, including BTC. The combination of immunotherapy with other modalities is currently being evaluated in different clinical trials, since single agent immunotherapy appears to provide modest benefits in advanced BTC. In this review, we summarize the current status of treatment options, including systemic chemotherapy, targeted therapy, immunotherapy, and various combinations in advanced BTC.
Collapse
Affiliation(s)
- Changqing Xie
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Nicole A McGrath
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Cecilia Monge Bonilla
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jianyang Fu
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
30
|
Emerging pathways for precision medicine in management of cholangiocarcinoma. Surg Oncol 2020; 35:47-55. [PMID: 32827952 DOI: 10.1016/j.suronc.2020.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 08/06/2020] [Indexed: 12/27/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common biliary tract malignancy with a dismal prognosis. Surgical resection with a negative microscopic margin offers the only hope for long-term survival. However, the majority of patients present with advanced disease not amenable to curative resection, mainly due to late presentation and aggressive nature of the disease. Unfortunately, due to the heterogeneous nature of CCA as well as limitations of available chemotherapy medications, traditional chemotherapy regimens offer limited survival benefit. Recent advances in genomic studies and next-generation sequencing techniques have assisted in better understanding of cholangiocarcinogenesis and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in management of CCA with encouraging results in preclinical studies and early clinical trials. In this review, we present emerging therapies for precision medicine in CCA.
Collapse
|
|
31
|
Athauda A, Fong C, Lau DK, Javle M, Abou-Alfa GK, Morizane C, Steward K, Chau I. Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation. Cancer Treat Rev 2020; 86:101998. [PMID: 32203843 PMCID: PMC8222858 DOI: 10.1016/j.ctrv.2020.101998] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/06/2020] [Accepted: 03/08/2020] [Indexed: 02/06/2023]
Abstract
Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.
Collapse
Affiliation(s)
- Avani Athauda
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - Caroline Fong
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - David K Lau
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - Milind Javle
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Weill Medical College at Cornell University, New York, NY, USA.
| | - Chigusa Morizane
- National Cancer Center Hospital, Tsukiji, Tokyo 104-0045, Japan.
| | - Keith Steward
- QED Therapeutics Inc, 75 Federal Street, San Francisco, CA 94107, USA.
| | - Ian Chau
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| |
Collapse
|
|
32
|
D'Andrea MR, Gill CM, Umphlett M, Tsankova NM, Fowkes M, Bederson JB, Brastianos PK, Shrivastava RK. Brain Metastases from Biliary Tract Cancers: A Case Series and Review of the Literature in the Genomic Era. Oncologist 2020; 25:447-453. [PMID: 31694894 PMCID: PMC7216433 DOI: 10.1634/theoncologist.2019-0306] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/12/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Biliary tract cancers (BTCs) are highly fatal malignancies that make up less than 1% of all cancers. BTC is often diagnosed at an unresectable stage; surgical resection remains the only definitive treatment. Brain metastases (BMs) from BTC are extremely rare, and few studies on patients with BMs from BTC exist. The aim of this study was to identify clinical characteristics associated with poor prognosis for patients with BMs from BTC. MATERIALS AND METHODS We performed a retrospective review of electronic medical records for patients with BMs from BTC managed at Mount Sinai Hospital from 2000 to 2017. Data on patient characteristics, magnetic resonance imaging findings, treatment regimens, and clinical outcomes were analyzed. RESULTS We identified 1,910 patients with BTC. Nine patients developed BMs, with an incidence of 0.47%. Of these nine patients, six had intrahepatic cholangiocarcinoma, two had extrahepatic cholangiocarcinoma, and one had gallbladder cancer. Six (66.7%) patients had one BM, one (11.1%) patient had two BMs, and two (22.2%) patients had three or more BMs. Four (44.4%) patients underwent BM resection, and seven (77.8%) received BM radiation. Median overall survival from time of BM diagnosis was 3.8 months (95% confidence interval 0.1-16.9). CONCLUSION Development of BMs from BTC is rare; however, prognosis is less than 4 months. BM diagnosis can occur within 2 years of primary diagnosis. As targeted therapeutics emerge, future studies ought to focus on identifying genomic BM markers associated with BTC subtypes. IMPLICATIONS FOR PRACTICE In the largest retrospective study of biliary tract cancer brain metastases, the clinical presentation and outcomes are reported of nine patients with an extremely rare clinical entity. The genomic literature and potential therapeutic targets for these patients with limited treatment options is comprehensively and exhaustively discussed.
Collapse
Affiliation(s)
- Megan R. D'Andrea
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Corey M. Gill
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Melissa Umphlett
- Department of Pathology, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | | | - Mary Fowkes
- Department of Pathology, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Joshua B. Bederson
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Priscilla K. Brastianos
- Department of Neurology and Cancer Center, Massachusetts General HospitalBostonMassachusettsUSA
| | - Raj K. Shrivastava
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| |
Collapse
|
|
33
|
Palmieri LJ, Lavolé J, Dermine S, Brezault C, Dhooge M, Barré A, Chaussade S, Coriat R. The choice for the optimal therapy in advanced biliary tract cancers: Chemotherapy, targeted therapies or immunotherapy. Pharmacol Ther 2020; 210:107517. [PMID: 32109491 DOI: 10.1016/j.pharmthera.2020.107517] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 02/18/2020] [Indexed: 01/09/2023]
Abstract
Biliary tract cancers (BTCs) represent a heterogeneous group that includes intrahepatic cholangiocarcinomas (CCAs), perihilar-CCAs or Klatskin tumors, extrahepatic-CCAs, and gallbladder adenocarcinoma. These entities have distinct demographics, risk factors, clinical presentation, and molecular characteristics. In advanced BTCs, the recommendations are mainly supporting a doublet chemotherapy regimen using cisplatin/gemcitabine (CisGem) with a 5-year overall survival rate close to 5% and median overall survival (mOS) of less than a year. The lack of overall efficacy stresses the need for personalized therapies. Recently, whole-genome and transcriptome sequencing highlighted the diversity of BTCs' subtypes. Distinct genetic alterations were retrieved according to the localization, with a high rate of potentially actionable alterations. Targeted therapies and immunotherapy have since then been tested for BTCs, trying to propose a more personalized treatment. This review describes the different therapeutic options, validated and in development, for patients with advanced BTCs.
Collapse
Affiliation(s)
- L-J Palmieri
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France.
| | - J Lavolé
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - S Dermine
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - C Brezault
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - M Dhooge
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - A Barré
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - S Chaussade
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - R Coriat
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| |
Collapse
|
|
34
|
Iyer P, Chen MH, Goyal L, Denlinger CS. Targets for therapy in biliary tract cancers: the new horizon of personalized medicine. Chin Clin Oncol 2020; 9:7. [PMID: 32146818 PMCID: PMC8650725 DOI: 10.21037/cco.2019.12.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 12/05/2019] [Indexed: 12/18/2022]
Abstract
Biliary tract cancers (BTCs) are a set of molecularly distinct and heterogeneous diseases. While cytotoxic chemotherapy remains the current standard of care for treatment-naïve and treatment-refractory unresectable disease, recently identified mutations driving oncologic development offer opportunities for targeted therapy. Currently, alterations in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), v-Raf murine sarcoma viral oncogene homolog B (BRAF), DNA damage repair, and HER2 pathways have demonstrated promising new therapeutic avenues, among others, and various studies have demonstrated clinical activity with targeted tyrosine kinase inhibitors and/or antibodies. In this review, we will discuss the currently identified targets for therapy in BTCs and review currently available data regarding clinical development of treatment options in these molecularly distinct subsets.
Collapse
Affiliation(s)
- Pritish Iyer
- Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA
| | - Ming-Huang Chen
- Department of Oncology, Taipei Veteran's General Hospital, Taipei
| | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Crystal S Denlinger
- Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA.
| |
Collapse
|
|
35
|
Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
36
|
Lamarca A, Frizziero M, McNamara MG, Valle JW. Clinical and Translational Research Challenges in Biliary Tract Cancers. Curr Med Chem 2020; 27:4756-4777. [PMID: 31971102 DOI: 10.2174/0929867327666200123090153] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 11/27/2019] [Accepted: 01/13/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research. OBJECTIVE This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies. FINDINGS The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research. CONCLUSION Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.
Collapse
Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| |
Collapse
|
|
37
|
Xue L, Guo C, Zhang K, Jiang H, Pang F, Dou Y, Liu X, Lin H, Dong X, Zhao S, Yao M, Wang K, Feng Y, Gu W. Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice. Hepatobiliary Surg Nutr 2019; 8:615-622. [PMID: 31929988 DOI: 10.21037/hbsn.2019.08.05] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background Cholangiocarcinoma (CCA) is a diverse group of malignancies arising from the intra- or extrahepatic biliary epithelium and characterized by its late diagnosis and fatal outcome. Extrahepatic cholangiocarcinoma (ECC) accounts for 90% of CCA. However, little is known about the comprehensive genomic alterations of ECC in Chinese population for providing clinical managements especially targeted therapy. Methods Comprehensive genomic profiling (CGP) was performed with next generation sequencing panel on paraffin-embedded tumor from a cohort of 80 Chinese ECC patients. Results The most frequently altered genes were TP53 (68%), KRAS (46%), SMAD4 (22%), ARID1A (20%) and CDKN2A (19%). Mutual exclusivity was observed between multiple genes including ARID1A:TP53, KRAS:LRP1B and NF2:TP53. Genetic alterations with potential therapeutic implications were identified in 43% of patients. The top three actionable alterations include CDKN2A (n=11), BRAF (n=5) and ERBB2 (n=4). Potentially actionable alterations were mainly enriched in the G1-S transition, homologous recombination repair, MAPK/ERK pathway. Conclusions This is the largest data set of ECC cases providing a comprehensive view on genetic alterations in Chinese population which differs significantly from a US cohort, and indicates the potential clinical implications for targeted therapies.
Collapse
Affiliation(s)
- Liang Xue
- Department of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chao Guo
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha 410005, China
| | - Kang Zhang
- Department of Cancer, People's Hospital of Wuzhou, Wuzhou 543000, China
| | - Hang Jiang
- Department of Hepato-Biliary-Pancreatic Surgery, The Third People's Hospital of Yunnan Province, Kunming 650011, China
| | - Fei Pang
- OrigiMed Inc., Shanghai 201114, China
| | - Ying Dou
- OrigiMed Inc., Shanghai 201114, China
| | | | | | | | | | - Ming Yao
- OrigiMed Inc., Shanghai 201114, China
| | - Kai Wang
- OrigiMed Inc., Shanghai 201114, China
| | - Yujie Feng
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Weiguang Gu
- Department of Medical Oncology, People's Hospital of Nanhai District, Foshan 528200, China.,Department of Medical Oncology, Southern Medical University Nanfang Hospital, Guangzhou 510515, China
| |
Collapse
|
|
38
|
Song IH, Jeong MS, Hong HJ, Shin JI, Park YS, Woo SK, Moon BS, Kim KI, Lee YJ, Kang JH, Lee TS. Development of a Theranostic Convergence Bioradiopharmaceutical for Immuno-PET Based Radioimmunotherapy of L1CAM in Cholangiocarcinoma Model. Clin Cancer Res 2019; 25:6148-6159. [PMID: 31337646 DOI: 10.1158/1078-0432.ccr-19-1157] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 05/31/2019] [Accepted: 07/18/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE Cholangiocarcinoma is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiotherapy are generally ineffective, and surgical resection is the only curative treatment for cholangiocarcinoma. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for cholangiocarcinoma. This study aimed to evaluate the feasibility of immuno-PET imaging-based radioimmunotherapy using radiolabeled anti-L1CAM antibody in cholangiocarcinoma xenograft model. EXPERIMENTAL DESIGN We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with 64Cu or 177Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with 64Cu-/177Lu-cA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by 177Lu-cA10-A3 and 18F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67. RESULTS Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized cholangiocarcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. 177Lu-cA10-A3 (12.95 MBq/100 μg) showed statistically significant reduction in tumor volumes (P < 0.05) and decreased glucose metabolism (P < 0.01). IHC analysis revealed 177Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or 177Lu-isotype. CONCLUSIONS Anti-L1CAM immuno-PET imaging using 64Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using 177Lu-cA10-A3 may provide survival benefit in L1CAM-expressing cholangiocarcinoma tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as imaging biomarker-based personalized medicine in L1CAM-expressing patients with cholangiocarcinoma.
Collapse
Affiliation(s)
- In Ho Song
- Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.,Department of Biomedical Laboratory Science, Yonsei University, Wonju, South Korea
| | - Mun Sik Jeong
- Department of Systems Immunology, Kangwon National University, Chuncheon, South Korea
| | - Hyo Jeong Hong
- Department of Systems Immunology, Kangwon National University, Chuncheon, South Korea.,Scripps Korea Antibody Institute, Chuncheon, South Korea
| | - Jong Il Shin
- Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Yong Serk Park
- Department of Biomedical Laboratory Science, Yonsei University, Wonju, South Korea
| | - Sang-Keun Woo
- Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Byung Seok Moon
- Department of Nuclear Medicine, Ewha Womans University Seoul Hospital, Ewha Womans University School of Medicine, Seoul, South Korea
| | - Kwang Il Kim
- Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Yong Jin Lee
- Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Joo Hyun Kang
- Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Tae Sup Lee
- Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
| |
Collapse
|
|
39
|
Saeed A, Park R, Al-Jumayli M, Al-Rajabi R, Sun W. Biologics, Immunotherapy, and Future Directions in the Treatment of Advanced Cholangiocarcinoma. Clin Colorectal Cancer 2019; 18:81-90. [DOI: 10.1016/j.clcc.2019.02.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/15/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023]
|
|
40
|
Fabris L, Perugorria MJ, Mertens J, Björkström NK, Cramer T, Lleo A, Solinas A, Sänger H, Lukacs-Kornek V, Moncsek A, Siebenhüner A, Strazzabosco M. The tumour microenvironment and immune milieu of cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:63-78. [PMID: 30907492 PMCID: PMC10878127 DOI: 10.1111/liv.14098] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 12/11/2022]
Abstract
Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.
Collapse
Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padova, Italy
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - María Jesús Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Niklas K. Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- ESCAM – European Surgery Center Aachen Maastricht, Germany and The Netherlands
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Antonio Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Hanna Sänger
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital, Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Veronika Lukacs-Kornek
- Institute of Experimental Immunology, University Hospital, Friedrich-Wilhelms-Universität Bonn, Germany
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Alexander Siebenhüner
- Department of Hematology and Medical Oncology, University Hospital Zürich, Zürich, Switzerland
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| |
Collapse
|
|
41
|
Adeva J, Sangro B, Salati M, Edeline J, La Casta A, Bittoni A, Berardi R, Bruix J, Valle JW. Medical treatment for cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:123-142. [PMID: 30892822 DOI: 10.1111/liv.14100] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 03/10/2019] [Accepted: 03/12/2019] [Indexed: 02/13/2023]
Abstract
Most of the patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention-to-treat analysis; however, a survival benefit was seen in a preplanned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to the uptake of adjuvant capecitabine by many clinicians. In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first-line treatment of patients with advanced disease; there is no established second-line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor and vascular endothelial growth factor pathways). An increasing number of genomic subtypes are being defined; for some of these on-target therapeutic options are under active investigation. The most developed are studies targeting IDH-1 (isocitrate dehydrogenase) mutations and FGFR-2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed.
Collapse
Affiliation(s)
- Jorge Adeva
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
| | - Maximiliano Salati
- Department of Oncology, University Hospital of Modena and Reggio Emilia, Modena, Italy.,Division of Molecular Pathology, Institute of Cancer Research and Gastrointestinal Unit, Royal Marsden Hospital, London and Sutton, UK
| | - Julien Edeline
- Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
| | - Adelaida La Casta
- Department of Medical Oncology, Hospital Universitario Donostia, Navarra, Spain
| | - Alessandro Bittoni
- Clinica Oncologica, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy
| | - Rosanna Berardi
- Clinica Oncologica, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester, Manchester, UK.,Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| |
Collapse
|
|
42
|
Wang L, Li S, Yu X, Han Y, Wu Y, Wang S, Chen X, Zhang J, Wang S. α2,6-Sialylation promotes immune escape in hepatocarcinoma cells by regulating T cell functions and CD147/MMP signaling. J Physiol Biochem 2019; 75:199-207. [PMID: 30972697 DOI: 10.1007/s13105-019-00674-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 03/07/2019] [Indexed: 10/27/2022]
Abstract
Altered glycosylation is a common feature of cancer cells and plays an important role in tumor progression. β-Galactoside α2-6-sialyltransferase 1 (ST6Gal-I) is the critical sialyltransferase responsible for the addition of α2-6-sialic acid to the terminal N-glycans on the cell surface. However, the functions and mechanism of ST6Gal-I in tumor immune escape remain poorly understood. Here, we found that ST6Gal-I overexpression promoted hepatocarcinoma cell proliferation, migration, and immune escape by increasing the levels of CD147, MMP9, MMP2, and MMP7. When CD8+ T cells were co-cultured with cell lines expressing different levels of ST6Gal-I, we found that ST6Gal-I upregulation inhibited the T cell proliferation and increased the secretion of IL-10 and TGF-β1, while secretion of IFN-γ and TNF-α was diminished. In a syngeneic tumor transplant model, ST6Gal-I upregulated Hca-P. In addition, Hepa1-6 cells formed significantly larger tumors and suppressed intratumoral penetration by CD8+ T cells. In combination, these results suggest that ST6Gal-I promotes the immune escape of hepatocarcinoma cells in the tumor microenvironment and highlight the importance of assessing ST6Gal-I status for immunotherapies.
Collapse
Affiliation(s)
- Liping Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China.,School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, Liaoning, China
| | - Shijun Li
- Department of inspection, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning Province, China
| | - Xiao Yu
- Department of Pathology, Dalian Medical University, Dalian, 116044, Liaoning Province, China
| | - Yang Han
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China
| | - Yinshuang Wu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China
| | - Shidan Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China
| | - Xixi Chen
- School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, Liaoning, China
| | - Jianing Zhang
- School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, Liaoning, China.
| | - Shujing Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China.
| |
Collapse
|
|
43
|
Jie Y, Gong J, Xiao C, Zheng J, Zhang Z, Li X, Gao Z, Hu B, Chong Y. The clinical value of Fibulin-1 for prognosis and its prospective mechanism in intrahepatic cholangiocarcinoma. HPB (Oxford) 2019; 21:499-507. [PMID: 30266493 DOI: 10.1016/j.hpb.2018.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 08/20/2018] [Accepted: 09/02/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy arising from the liver. Fibulin-1 has been demonstrated to be involved in various cancers, however, its role in ICC remains unclear. METHODS To study the clinical value and potential molecular mechanism of Fibulin-1 in ICC, immunohistochemistry and bioinformatic analyses were performed using data in the Gene Expression Omnibus Datasets and The Cancer Genome Atlas database. RESULTS Fibulin-1 expression was overexpressed in ICC tissues compared with adjacent non-cancerous tissues, and was significantly associated with unfavorable overall survival. Moreover, similar genes were identified by Gene Expression Profiling Interactive Analysis and microarray data set. Next, functional and pathway enrichment analysis demonstrated that Fibulin-1 was overrepresented in the pathways of extracellular matrix organization and angiogenesis, which are associated with tumor progression and potential for metastasis. Gene set enrichment analysis indicated that the gene sets of epithelial mesenchymal transition, TGF-beta signaling pathway and angiogenesis were enriched in tissues with high Fibulin-1 level. Furthermore, Fibulin-1 silencing suppressed the ability of ICC tumor cells to form colonies and siFibulin-1 repressed the endogenous protein level of p-AKT. CONCLUSION Collectively, this study suggests that Fibulin-1 overexpression may play key roles in the carcinogenesis and progression of ICC via regulation of tumor-related pathways.
Collapse
Affiliation(s)
- Yusheng Jie
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, PR China
| | - Jiao Gong
- Department of Laboratory Medicine, Third Affiliated Hospital, Sun Yat-sen University, PR China
| | - Cuicui Xiao
- Cell-gene Therapy Translational Medicine Research Center, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, PR China
| | - Jun Zheng
- Department of Hepatic Surgery and Liver Transplantation Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Zhiwei Zhang
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, PR China
| | - Xinhua Li
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, PR China
| | - Zhiliang Gao
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, PR China
| | - Bo Hu
- Department of Laboratory Medicine, Third Affiliated Hospital, Sun Yat-sen University, PR China.
| | - Yutian Chong
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, PR China.
| |
Collapse
|
|
44
|
Vienot A, Neuzillet C. Cholangiocarcinoma: the quest for a second-line systemic treatment. Transl Cancer Res 2019; 8:S275-S288. [PMID: 35117107 PMCID: PMC8797902 DOI: 10.21037/tcr.2018.10.05] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 10/09/2018] [Indexed: 11/13/2022]
Abstract
Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. Advanced BTC remains a challenging, non-curable disease. Gemcitabine plus platinum chemotherapy is the standard of care as first-line (L1) therapy in this setting. Beyond failure of L1, available evidence to guide therapeutic decisions is scarce. Data from phase III studies are lacking and there is no validated strategy to date. In this review, we provide an overview of the systemic therapeutic options that can be proposed and unsolved questions in the management of patients with advanced BTC in the second-line (L2) setting. Criteria to select which patients should receive L2 therapy are ill defined and reliable prognostic tools and models to help estimate individual patient survival at the beginning of L2 are needed. Chemotherapy, mainly fluoropyrimidine-based yields modest survival results. There is insufficient evidence level to recommend a specific L2 chemotherapy regimen, and anti-epidermal growth factor receptor and antiangiogenic agents failed to demonstrate any survival improvement in a non-selected patient population. In recent years, knowledge about BTC molecular heterogeneity has considerably increased with the advent of high-throughput genomic and transcriptomic analyses, opening new avenues for targeted therapies. Patients with BTC may be particularly good candidates for biomarker-driven therapy in clinical practice. Among the ongoing developments, targeting of FGFR and IDH mutations and immune therapies hold many promises for the next future. In future L2 clinical trials, patients should be carefully characterized and stratified according to prognostic factors, disease subtype, and genetic drivers.
Collapse
Affiliation(s)
- Angélique Vienot
- Department of Medical Oncology, Besançon University Hospital, 3 Boulevard Alexandre Fleming, 25030 Besançon, France
| | - Cindy Neuzillet
- Department of Medical Oncology, Curie Institute, Versailles Saint-Quentin University, 35 Rue Dailly, 92210 Saint-Cloud, France
| |
Collapse
|
|
45
|
Tariq NUA, McNamara MG, Valle JW. Biliary tract cancers: current knowledge, clinical candidates and future challenges. Cancer Manag Res 2019; 11:2623-2642. [PMID: 31015767 PMCID: PMC6446989 DOI: 10.2147/cmar.s157092] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Biliary tract cancers (BTCs) are rare with poor prognosis. Due to the advent of genomic sequencing, new data have emerged regarding the molecular makeup of this disease. To add to the complexity, various subtypes also harbor a varied genetic composition. The commonly mutated genes associated with this cancer are KRAS, EGFR, IDH, FGFR and BAP1. Various clinical studies are looking at targeting these genetic mutations. Another therapeutic area of note is the potential for the use of immunotherapy in patients with BTC. Although BTC may be a result of chronic inflammation, this does not necessarily translate into increased immunogenicity. This literature review discusses the diverse molecular and immune-related pathways in patients with BTC and their potential therapeutic implications.
Collapse
Affiliation(s)
- Noor-Ul-Ain Tariq
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| | - Mairéad G McNamara
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| | - Juan W Valle
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| |
Collapse
|
|
46
|
Simile MM, Bagella P, Vidili G, Spanu A, Manetti R, Seddaiu MA, Babudieri S, Madeddu G, Serra PA, Altana M, Paliogiannis P. Targeted Therapies in Cholangiocarcinoma: Emerging Evidence from Clinical Trials. ACTA ACUST UNITED AC 2019; 55:medicina55020042. [PMID: 30743998 PMCID: PMC6409688 DOI: 10.3390/medicina55020042] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 01/28/2019] [Accepted: 02/01/2019] [Indexed: 12/13/2022]
Abstract
Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs and symptoms in the early stages. This fact, along with the poor results of the local and systemic therapies currently employed, is responsible for the poor outcome of CCA patients and strongly supports the need for novel therapeutic agents and strategies. In recent years, the introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the genetic pathophysiology of CCA and, consequently, for the identification and evaluation of new treatments tailored to the molecular features or alterations progressively elucidated. In this review article, we describe the potential targets under investigation and the current molecular therapies employed in biliary tract cancers. In addition, we summarize the main drugs against CCA under evaluation in ongoing trials and describe the preliminary data coming from these pioneering studies.
Collapse
Affiliation(s)
- Maria Maddalena Simile
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Imai H, Saijo K, Komine K, Otsuki Y, Ohuchi K, Sato Y, Okita A, Takahashi M, Takahashi S, Shirota H, Takahashi M, Ishioka C. Antibiotic therapy augments the efficacy of gemcitabine-containing regimens for advanced cancer: a retrospective study. Cancer Manag Res 2019; 11:7953-7965. [PMID: 31686910 PMCID: PMC6709792 DOI: 10.2147/cmar.s215697] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/16/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The addition of antibiotics reportedly augments the efficacy of gemcitabine (GEM) in tumor-bearing mice. However, whether this phenomenon is also observed in cancer patients remains unclear. In the present study, we aimed to assess whether antibiotics for treatment or prevention of infection augments treatment efficacies of GEM-containing regimens in patients with any type of cancer. METHODS Medical records of patients diagnosed with cancer histopathologically and treated with GEM-containing regimens (n=169) were retrospectively reviewed. Patients were assigned into two groups: antibiotics-untreated group (patients who were treated with GEM-containing regimens but without antibiotics) and antibiotics-treated group (patients who were treated with GEM-containing regimens plus antibiotics). Response rates, progression-free survival (PFS) time, and overall survival (OS) time were analyzed for each group. RESULTS The response rates of the antibiotics-untreated and antibiotics-treated groups with GEM-containing regimens were 15.1% and 27.6%, respectively. The median PFS times of the antibiotics-untreated and antibiotics-treated groups were 2.5 (95% CI: 1.86-3.73) and 4.9 (95% CI: 3.47-6.0) months, respectively. The median OS times of the antibiotics-untreated and antibiotics-treated groups were 7.53 (95% CI: 5.63-9.57) months and 13.83 (95% CI: 10.83-16.43) months, respectively. CONCLUSION The addition of antibiotics augments the treatment efficacies of GEM-containing regimens, and it may be a potential therapeutic option to improve treatment efficacies of GEM-containing regimens in patients with advanced cancer.
Collapse
Affiliation(s)
- Hiroo Imai
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Ken Saijo
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Keigo Komine
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Yasufumi Otsuki
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Kota Ohuchi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Yuko Sato
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Akira Okita
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Masahiro Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Shin Takahashi
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Hidekazu Shirota
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Masanobu Takahashi
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Chikashi Ishioka
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
- Correspondence: Chikashi IshiokaDepartment of Medical Oncology, Tohoku University Hospital, 4-1, Seiryo-machi, Aobaku, Sendai980-8575, JapanTel +81 22 717 8543Fax +81 22 717 8548Email
| |
Collapse
|
|
48
|
Wang LY, Gong S, Gao LP, Hou LX, He W. Apatinib for treating advanced intrahepatic cholangiocarcinoma after failed chemotherapy: A case report and literature review. Medicine (Baltimore) 2018; 97:e13372. [PMID: 30544406 PMCID: PMC6310551 DOI: 10.1097/md.0000000000013372] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
RATIONALE Intrahepatic cholangiocarcinoma (ICC) originates from the secondary branch of the bile duct and the intrahepatic bile duct epithelial cells, and is a rare pathological type of primary liver cancer. Recently, apatinib has been successfully used for a variety of malignancies. PATIENT CONCERNS A 23-year-old female was noted with intermittent right upper abdominal distension, abdominal pain, and vomiting after eating for more than 1 month. The enhanced CT scan revealed multiple intrahepatic lesions, portal vein and right branch tumor emboli were present. DIAGNOSIS Combined with the patient's medical history and pathology and immunohistochemistry, the diagnosis was confirmed as locally advanced unresectable ICC (cT4N1M1, Stage IVB). INTERVENTIONS The disease progressed after six cycles of gemcitabine plus capecitabine chemotherapy. She received oral apatinib treatment since September 30, 2017. Due to related adverse reactions, the patient could not tolerate the treatment, and the subsequent reduction therapy was given. OUTCOMES On April 11, 2018, the review of CT evaluation suggested that the disease was progressed. Hence, in this patient, apatinib as second-line treatment for advanced ICC showed a progression-free survival with 6 months. LESSONS Apatinib as second-line treatment for advanced ICC is effective, and the adverse effects are tolerable. However, the efficacy and safety of apatinib in the treatment of ICC need to be further confirmed by large sample of prospective randomized controlled trials.
Collapse
|
|
49
|
Xi SY, Fang D, Huo JG. Progress in molecular targeted therapy of intrahepatic cholangiocarcinoma. Shijie Huaren Xiaohua Zazhi 2018; 26:1707-1716. [DOI: 10.11569/wcjd.v26.i29.1707] [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] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma is an uncommon malignant tumor with a poor prognosis due to an incomplete understanding of its molecular pathogenesis and a lack of effective treatment. Precision medical planning and cancer genomics can help to understand the molecular pathogenesis of cancer and identify potential therapeutic targets. With the deepening of basic and clinical research, accurate targeted therapy will be able to improve the prognosis and overall survival of patients with intrahepatic cholangiocarcinoma.
Collapse
Affiliation(s)
- Song-Yang Xi
- Department of Oncology, Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang 212000, Jiangsu Province, China
| | - Dong Fang
- Department of Oncology, Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang 212000, Jiangsu Province, China
| | - Jie-Ge Huo
- Department of Oncology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing 210028, Jiangsu Province, China
| |
Collapse
|
|
50
|
Nakagawa S, Okabe H, Ouchi M, Tokunaga R, Umezaki N, Higashi T, Kaida T, Arima K, Kitano Y, Kuroki H, Mima K, Nitta H, Imai K, Hashimoto D, Yamashita YI, Chikamoto A, Baba H. Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma. HPB (Oxford) 2018; 20:939-948. [PMID: 29759640 DOI: 10.1016/j.hpb.2018.03.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 03/10/2018] [Accepted: 03/30/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). METHODS The influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays. The prognostic significance of EZH2 and VASH1 expression by IHC was also examined in the ICC cohort. RESULTS Bioinformatics analysis showed that EZH2 was associated with several angiogenesis gene sets in the public database. EZH2 suppressed VASH1 expression in in vitro assays and IHC studies. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P = 0.019) and poor overall survival (P = 0.0055). CONCLUSION The current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and activation of the EZH2-mediated angiogenesis pathway predicted the prognosis of patients with ICC.
Collapse
Affiliation(s)
- Shigeki Nakagawa
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan.
| | - Hirohisa Okabe
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Mayuko Ouchi
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Ryuma Tokunaga
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Naoki Umezaki
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Takaaki Higashi
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Takatoshi Kaida
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Kota Arima
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Yuki Kitano
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Hideyuki Kuroki
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Kosuke Mima
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Hidetoshi Nitta
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Katsunori Imai
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | | | | | - Akira Chikamoto
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Hideo Baba
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| |
Collapse
|