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Bousou TE, Sarantis P, Anastasiou IA, Trifylli EM, Liapopoulos D, Korakaki D, Koustas E, Katsimpoulas M, Karamouzis MV. Biomarkers for the Evaluation of Immunotherapy in Patients with Cholangiocarcinoma. Cancers (Basel) 2025; 17:555. [PMID: 39941920 PMCID: PMC11817672 DOI: 10.3390/cancers17030555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/27/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
Cholangiocarcinoma is a rare primary liver cancer with poor prognosis, due to the advanced stage at the time of diagnosis and limited therapeutic options, with poor response. Chemotherapy remains the standard first-line treatment, but the advent of immunotherapy has recently induced promising results. Given the fact that diagnosis frequency is increasing nowadays and the survival rate remains very low, it is crucial to recognize patients who are suitable for immunotherapy and will have the best response. Different types of biomarkers, such as interleukins, exosomes, mi-RNA, ctDNA, and gene mutations, have been studied for their feasibility, not only for the early diagnosis of biliary tract cancer but also for the determination of responsiveness in treatment. Less frequently, these studies focus on finding and observing biomarkers in patients who receive immunotherapy. This review aims to summarize current knowledge of existing/promising biomarkers in patients with unresectable or metastatic cholangiocarcinoma, treated with immunotherapy as monotherapy, or combined with chemotherapy.
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Affiliation(s)
- Thaleia-Eleftheria Bousou
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
| | - Panagiotis Sarantis
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Ioanna A. Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Agiou Thoma 17, 115 27 Athens, Greece;
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Agiou Thoma 17, 115 27 Athens, Greece
| | - Eleni-Myrto Trifylli
- GI-Liver Unit, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio”, 114 Vas Sofias, 115 27 Athens, Greece;
| | - Dimitris Liapopoulos
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
| | - Dimitra Korakaki
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Evangelos Koustas
- Oncology Department, General Hospital Evangelismos, Ipsilantou 45-47, 106 76 Athens, Greece;
| | - Michalis Katsimpoulas
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Michalis V. Karamouzis
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
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Groß S, Bitzer M, Albert J, Blödt S, Boda-Heggemann J, Borucki K, Brunner T, Caspari R, Dombrowski F, Evert M, Follmann M, Freudenberger P, Gani C, Gebert J, Geier A, Gkika E, Götz M, Helmberger T, Hoffmann RT, Huppert P, Krug D, Fougère CL, Lang H, Langer T, Lenz P, Lüdde T, Mahnken A, Nadalin S, Nguyen HHP, Nothacker M, Ockenga J, Oldhafer K, Ott J, Paprottka P, Pereira P, Persigehl T, Plentz R, Pohl J, Recken H, Reimer P, Riemer J, Ringe K, Roeb E, Rüssel J, Schellhaas B, Schirmacher P, Schlitt HJ, Schmid I, Schütte K, Schuler A, Seehofer D, Sinn M, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Trojan J, van Thiel I, Utzig M, Vogel A, Vogl T, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wenzel G, Wildner D, Wörns MA, Galle P, Malek N. S3-Leitlinie Diagnostik und Therapie biliärer Karzinome – Langversion. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:e82-e158. [PMID: 39919781 DOI: 10.1055/a-2460-6347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Affiliation(s)
- Sabrina Groß
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Michael Bitzer
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Jörg Albert
- Katharinenhospital, Klinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie, Infektiologie und Pneumologie, Stuttgart
| | - Susanne Blödt
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | | | - Katrin Borucki
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Klinische Chemie und Pathobiochemie
| | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz
| | - Reiner Caspari
- Klinik Niederrhein Erkrankungen des Stoffwechsels der Verdauungsorgane und Tumorerkrankungen, Bad Neuenahr-Ahrweiler
| | | | | | - Markus Follmann
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | | | - Cihan Gani
- Klinik für Radioonkologie, Universitätsklinikum Tübingen
| | - Jamila Gebert
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Andreas Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - Eleni Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | - Martin Götz
- Medizinische Klinik IV - Gastroenterologie/Onkologie, Klinikverbund Südwest, Böblingen
| | - Thomas Helmberger
- Institut für Radiologie, Neuroradiologie und minimal invasive Therapie, München Klinik Bogenhausen
| | - Ralf-Thorsten Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Dresden
| | - Peter Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühlerhöhe
| | - David Krug
- Strahlentherapie Campus Kiel, Universitätsklinikum Schleswig-Holstein
| | - Christian La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Eberhard-Karls Universität, Tübingen
| | - Hauke Lang
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Johannes Gutenberg-Universität, Mainz
| | - Thomas Langer
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | - Philipp Lenz
- Zentrale Einrichtung Palliativmedizin, Universitätsklinikum Münster
| | - Tom Lüdde
- Medizinische Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf
| | - Andreas Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Marburg
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Eberhard-Karls Universität, Tübingen
| | | | - Monika Nothacker
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | - Johann Ockenga
- Medizinische Klinik II, Gesundheit Nord, Klinikverbund Bremen
| | - Karl Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Asklepios Klinik Barmbek
| | - Julia Ott
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Philipp Paprottka
- Sektion für Interventionelle Radiologie, Klinikum rechts der Isar, Technische Universität München
| | - Philippe Pereira
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, SLK-Klinken Heilbronn
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | - Ruben Plentz
- Digestive Diseases and Nutrition, Gastroenterology, University of Kentucky
| | - Jürgen Pohl
- Abteilung für Gastroenterologie, Asklepios Klinik Altona
| | | | - Peter Reimer
- Institut für Diagnostische und Interventionelle Radiologie, Städtisches Klinikum Karlsruhe
| | | | - Kristina Ringe
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | - Elke Roeb
- Medizinische Klinik II Pneumologie, Nephrologie und Gastroenterologie, Universitätsklinikum Gießen
| | - Jörn Rüssel
- Medizinische Klinik IV Hämatologie und Onkologie, Universitätsklinikum Halle (Saale)
| | - Barbara Schellhaas
- Medizinische Klinik I Gastroenterologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität, Erlangen
| | - Peter Schirmacher
- Allgemeine Pathologie und pathologische Anatomie, Universitätsklinikum Heidelberg
| | | | - Irene Schmid
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU München
| | - Kerstin Schütte
- Klinik für Innere Medizin und Gastroenterologie, Niels-Stensen-Kliniken, Marienhospital Osnabrück
| | - Andreas Schuler
- Medizinische Klinik, Gastroenterologie, Alb-Fils-Kliniken, Geislingen an der Steige
| | - Daniel Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - Marianne Sinn
- II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, Knochenmarktransplantation mit Abteilung für Pneumologie), Universitätsklinikum Hamburg-Eppendorf
| | - Andreas Stengel
- Innere Medizin VI - Psychosomatische Medizin und Psychotherapie, Eberhard-Karls Universität, Tübingen
| | | | | | | | - Anne Taubert
- Klinische Sozialarbeit, Universitätsklinikum Heidelberg
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Goethe-Universität, Frankfurt
| | | | - Martin Utzig
- Abteilung Zertifizierung, Deutsche Krebsgesellschaft e.V., Berlin
| | - Arndt Vogel
- Institute of Medical Science, University of Toronto
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Goethe-Universität, Frankfurt
| | - Frank Wacker
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Henning Wege
- Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen
| | - Gregor Wenzel
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | - Dane Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Standort Lauf
| | - Marcus-Alexander Wörns
- Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund
| | - Peter Galle
- 1. Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie, Nephrologie, Rheumatologie, Infektiologie, Johannes Gutenberg-Universität, Mainz
| | - Nisar Malek
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
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Kehmann L, Jördens M, Loosen SH, Luedde T, Roderburg C, Leyh C. Evolving therapeutic landscape of advanced biliary tract cancer: from chemotherapy to molecular targets. ESMO Open 2024; 9:103706. [PMID: 39366294 PMCID: PMC11489061 DOI: 10.1016/j.esmoop.2024.103706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/07/2024] [Accepted: 08/12/2024] [Indexed: 10/06/2024] Open
Abstract
Biliary tract cancer, the second most common type of liver cancer, remains a therapeutic challenge due to its late diagnosis and poor prognosis. In recent years, it has become evident that classical chemotherapy might not be the optimal treatment for patients with biliary tract cancer, especially after failure of first-line therapy. Finding new treatment options and strategies to improve the survival of these patients is therefore crucial. With the rise and increasing availability of genetic testing in patients with tumor, novel treatment approaches targeting specific genetic alterations have recently been proposed and have demonstrated their safety and efficacy in numerous clinical trials. In this review, we will first consider chemotherapy options and the new possibility of combining chemotherapy with immune checkpoint inhibitors in first-line treatment. We will then provide an overview of genomic alterations and their potential for targeted therapy especially in second-line therapy. In addition to the most common alterations such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, fibroblast growth factor receptor 2 (FGFR2) fusions, and alterations, we will also discuss less frequently encountered alterations such as BRAF V600E mutation and neurotrophic tyrosine kinase receptor gene (NTRK) fusion. We highlight the importance of molecular profiling in guiding therapeutic decisions and emphasize the need for continued research to optimize and expand targeted treatment strategies for this aggressive malignancy.
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Affiliation(s)
- L Kehmann
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité University Medicine Berlin, Berlin, Germany; Servier Deutschland GmbH, München, Germany
| | - M Jördens
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - S H Loosen
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - T Luedde
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - C Roderburg
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - C Leyh
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany.
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4
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Niu S, Zhang Y, Li Z, Wang T. Prognostic value of FGFR2 alterations in patients with iCCA undergoing surgery or systemic treatments: A meta-analysis. Liver Int 2024; 44:2208-2219. [PMID: 38829010 DOI: 10.1111/liv.15984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 04/25/2024] [Accepted: 05/13/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND Over recent years, there has been a notable rise in the incidence of intrahepatic cholangiocarcinoma (iCCA), which presents a significant challenge in treatment due to its complex disease characteristics and prognosis. Notably, the identification of fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement, a potential oncogenic driver primarily observed in iCCA, raises questions about its impact on the prognostic outcomes of patients undergoing surgical intervention or other therapeutic approaches. METHODS A comprehensive search from inception to July 2023 was conducted across PubMed, Embase, Web of Science, and the Cochrane Library databases. The objective was to identify relevant publications comparing the prognosis of FGFR2 alterations and no FGFR2 alterations groups among patients with iCCA undergoing surgical resection or other systemic therapies. The primary outcome indicators, specifically Overall Survival (OS) and Disease-Free Survival (DFS), were estimated using Hazard Ratios (HRs) with 95% confidence intervals (CIs), and statistical significance was defined as p < .05. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Statistical analyses were performed using Review Manager 5.4 software and Stata, version 12.0. RESULTS Six studies, involving 1314 patients (FGFR2 alterations group n = 173 and no FGFR2 alterations group n = 1141), were included in the meta-analysis. The analysis revealed that the FGFR2 alterations group exhibited a significantly better OS prognosis compared to the no FGFR2 alterations group, with a fixed-effects combined effect size HR = 1.31, 95%CI = 1.001-1.715, p = .049. Furthermore, meta-regression and subgroup analysis showed that the length of the follow-up period did not introduce heterogeneity into the results. This finding indicates the stability and reliability of the study outcomes. CONCLUSION The current study provides compelling evidence that FGFR2 alterations are frequently associated with improved survival outcomes for patients with iCCA undergoing surgical resection or other systemic treatments. Additionally, the study suggests that FGFR2 holds promise as a safe and dependable therapeutic target for managing metastatic, locally advanced or unresectable iCCA. This study offers a novel perspective in the realm of targeted therapy for iCCA, presenting a new and innovative approach to its treatment.
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Affiliation(s)
- Sen Niu
- Department of General Surgery, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Ye Zhang
- Department of General Surgery, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Zengyao Li
- Department of General Surgery, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Tong Wang
- Department of General Surgery, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
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Zhang Z, Ma S, Li S, Chen Z, Song R, Wang Z. MSH6 germline mutations leading to Lynch syndrome-associated cholangiocarcinoma: a case report. Front Oncol 2024; 14:1414665. [PMID: 39161380 PMCID: PMC11330888 DOI: 10.3389/fonc.2024.1414665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/22/2024] [Indexed: 08/21/2024] Open
Abstract
Lynch syndrome, a hereditary cancer susceptibility syndrome, arises from pathogenic mutations in mismatch repair genes. This syndrome is strongly linked to colorectal and endometrial cancers, as well as an elevated risk for other cancers such as gastric, ovarian, renal pelvis/ureter, and prostate. Notably, Lynch syndrome is rarely associated with cholangiocarcinoma (CCA). In this case study, we present a unique instance of Lynch syndrome-related CCA resulting from a singular MSH6 mutation. Notably, our findings reveal discrepancies between immunohistochemistry (IHC) and microsatellite stability results compared to genetic testing outcomes. This discrepancy underscores the limitations of solely relying on IHC analysis and microsatellite stability testing for the detection of hereditary tumors, emphasizing the crucial role of genetic testing in such cases. This insight enhances our comprehension of the mechanisms involved in cancer development and underscores the significance of thorough analysis integrating immunohistochemistry and genetic testing for diagnosing Lynch syndrome-related cancers.
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Affiliation(s)
| | | | | | | | | | - Zhanpeng Wang
- Department of hepatobiliary and pancreatic surgery, China-Japan Union Hospital, Jilin University, Changchun, China
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6
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Hua S, Gu X, Jin H, Zhang X, Liu Q, Yang J. Tumor-infiltrating T lymphocytes: A promising immunotherapeutic target for preventing immune escape in cholangiocarcinoma. Biomed Pharmacother 2024; 177:117080. [PMID: 38972151 DOI: 10.1016/j.biopha.2024.117080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/22/2024] [Accepted: 06/29/2024] [Indexed: 07/09/2024] Open
Abstract
Cholangiocarcinoma (CCA) is becoming more common and deadly worldwide. Tumor-infiltrating T cell subtypes make distinct contributions to the immune system; collectively, they constitute a significant portion of the tumor microenvironment (TME) in CCA. By secreting cytokines and other chemicals, regulatory T cells (Tregs) decrease activated T cell responses, acting as immunosuppressors. Reduced CD8+ T cell activation results in stimulating programmed death-1 (PD-1), which undermines the immunological homeostasis of T lymphocytes. On the other hand, cancer cells are eliminated by activated cytotoxic T lymphocyte (CTL) through the perforin-granzyme or Fas-FasL pathways. Th1 and CTL immune cell infiltration into the malignant tumor is also facilitated by γδ T cells. A higher prognosis is typically implied by CD8+ T cell infiltration, and survival is inversely associated with Treg cell density. Immune checkpoint inhibitors, either singly or in combination, provide novel therapeutic strategies for CCA immunotherapy. Furthermore, it is anticipated that immunotherapeutic strategies-such as the identification of new immune targets, combination treatments involving several immune checkpoint inhibitors, and chimeric antigen receptor-T therapies (CAR-T)-will optimize the effectiveness of anti-CCA treatments while reducing adverse effects.
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Affiliation(s)
- Sijia Hua
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, China.
| | - Xinyi Gu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, China.
| | - Hangbin Jin
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital. School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaofeng Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital. School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research, Hangzhou, Zhejiang 310003, China.
| | - Qiang Liu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital. School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Jianfeng Yang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital. School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research, Hangzhou, Zhejiang 310003, China.
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Yue S, Zhang Y, Zhang W. Recent Advances in Immunotherapy for Advanced Biliary Tract Cancer. Curr Treat Options Oncol 2024; 25:1089-1111. [PMID: 39066855 PMCID: PMC11329538 DOI: 10.1007/s11864-024-01243-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2024] [Indexed: 07/30/2024]
Abstract
OPINION STATEMENT Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies that arise from the epithelium of the biliary tract. Most patients present with locally advanced or metastatic disease at the time of diagnosis. For patients with unresectable BTC, the survival advantage provided by systemic chemotherapy was limited. Over the last decade, immunotherapy has significantly improved the therapeutic landscape of solid tumors. There is an increasing number of studies evaluating the application of immunotherapy in BTC, including immune checkpoint inhibitors (ICIs), cancer vaccines and adoptive cell therapy. The limited response to ICIs monotherapy in unselected patients prompted investigators to explore different combination therapy strategies. Early clinical trials of therapeutic cancer vaccination and adoptive cell therapy have shown encouraging clinical results. However, there still has been a long way to go via validation of therapeutic efficacy and exploration of strategies to increase the efficacy. Identifying biomarkers that predict the response to immunotherapy will allow a more accurate selection of candidates. This review will provide an up-to-date overview of the current clinical data on the role of immunotherapy, summarize the promising biomarkers predictive of the response to ICIs and discuss the perspective for future research direction of immunotherapy in advanced BTC.
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Affiliation(s)
- Shiwei Yue
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China
| | - Yunpu Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China.
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Choi JW, Lee JO, Lee S. Detecting microsatellite instability by length comparison of microsatellites in the 3' untranslated region with RNA-seq. Brief Bioinform 2024; 25:bbae423. [PMID: 39210504 PMCID: PMC11361843 DOI: 10.1093/bib/bbae423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/30/2024] [Accepted: 08/09/2024] [Indexed: 09/04/2024] Open
Abstract
Microsatellite instability (MSI), a phenomenon caused by deoxyribonucleic acid (DNA) mismatch repair system deficiencies, is an important biomarker in cancer research and clinical diagnostics. MSI detection often involves next-generation sequencing data, with many studies focusing on DNA. Here, we introduce a novel approach by measuring microsatellite lengths directly from ribonucleic acid sequencing (RNA-seq) data and comparing its distribution to detect MSI. Our findings reveal distinct instability patterns between MSI-high (MSI-H) and microsatellite stable samples, indicating the efficacy of RNA-based MSI detection. Additionally, microsatellites in the 3'-untranslated regions showed the greatest predictive value for MSI detection. Notably, this efficacy extends to detecting MSI-H samples even in tumors not commonly associated with MSI. Our approach highlights the utility of RNA-seq data in MSI detection, facilitating more precise diagnostics through the integration of various biological data.
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Affiliation(s)
- Jin-Wook Choi
- Department of Health Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, 08826 Seoul, Republic of Korea
| | - Jin-Ok Lee
- Department of Health Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, 08826 Seoul, Republic of Korea
| | - Sejoon Lee
- Department of Health Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, 08826 Seoul, Republic of Korea
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, 13620 Seongnam, Republic of Korea
- Precision Medicine Center, Seoul National University Bundang Hospital, 82 Gumi-ro, Bundang-gu, 13620 Seongnam, Republic of Korea
- Department of Genomic Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, Bundang-gu, 13620 Seongnam, Republic of Korea
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9
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Grimsrud MM, Forster M, Goeppert B, Hemmrich-Stanisak G, Sax I, Grzyb K, Braadland PR, Charbel A, Metzger C, Albrecht T, Steiert TA, Schlesner M, Manns MP, Vogel A, Yaqub S, Karlsen TH, Schirmacher P, Boberg KM, Franke A, Roessler S, Folseraas T. Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis. Hepatol Commun 2024; 8:e0461. [PMID: 38967597 PMCID: PMC11227357 DOI: 10.1097/hc9.0000000000000461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 03/13/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC. METHODS We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies. RESULTS We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival. CONCLUSIONS In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.
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Affiliation(s)
- Marit M. Grimsrud
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Michael Forster
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
- Institute of Pathology, Hospital RKH Kliniken Ludwigsburg, Ludwigsburg, Germany
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | | | - Irmi Sax
- Biomedical Informatics, Data Mining and Data Analytics, University of Augsburg, Augsburg, Germany
| | - Krzysztof Grzyb
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Peder R. Braadland
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Alphonse Charbel
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Carmen Metzger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Thomas Albrecht
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Tim Alexander Steiert
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Matthias Schlesner
- Biomedical Informatics, Data Mining and Data Analytics, University of Augsburg, Augsburg, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Sheraz Yaqub
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Hepatobiliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Tom H. Karlsen
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Kirsten M. Boberg
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Trine Folseraas
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
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10
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Gkekas I, Jan N, Kaprio T, Beilmann-Lehtonen I, Fabian P, Tavelin B, Böckelman C, Edin S, Strigård K, Svoboda T, Hagström J, Barsova L, Jirasek T, Haglund C, Palmqvist R, Gunnarsson U. Sporadic deficient mismatch repair in colorectal cancer increases the risk for non-colorectal malignancy: A European multicenter cohort study. J Surg Oncol 2024; 129:1295-1304. [PMID: 38470492 DOI: 10.1002/jso.27619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 02/11/2024] [Accepted: 02/27/2024] [Indexed: 03/13/2024]
Abstract
BACKGROUND AND OBJECTIVES Disparities between tumors arising via different sporadic carcinogenetic pathways have not been studied systematically. This retrospective multicenter cohort study evaluated the differences in the risk for non-colorectal malignancy between sporadic colorectal cancer (CRC) patients from different DNA mismatch repair status. METHODS A retrospective European multicenter cohort study including in total of 1706 CRC patients treated between 1996 and 2019 in three different countries. The proficiency (pMMR) or deficiency (dMMR) of mismatch repair was determined by immunohistochemistry. Cases were analyzed for tumor BRAFV600E mutation, and BRAF mutated tumors were further analyzed for hypermethylation status in the promoter region of MLH1 to distinguish between sporadic and hereditary cases. Swedish and Finish patients were matched with their respective National Cancer Registries. For the Czech cohort, thorough scrutiny of medical files was performed to identify any non-colorectal malignancy within 20 years before or after the diagnosis of CRC. Poisson regression analysis was performed to identify the incidence rates of non-colorectal malignancies. For validation purposes, standardized incidence ratios were calculated for the Swedish cases adjusted for age, year, and sex. RESULTS Of the 1706 CRC patients included in the analysis, 819 were female [48%], median age at surgery was 67 years [interquartile range: 60-75], and sporadic dMMR was found in 188 patients (11%). Patients with sporadic dMMR CRC had a higher incidence rate ratio (IRR) for non-colorectal malignancy before and after diagnosis compared to patients with a pMMR tumor, in both uni- (IRR = 2.49, 95% confidence interval [CI] = 1.89-3.31, p = 0.003) and multivariable analysis (IRR = 2.24, 95% CI = 1.67-3.01, p = 0.004). This association applied whether or not the non-colorectal tumor developed before or after the diagnosis of CRC in both uni- (IRR = 1.91, 95% CI = 1.28-2.98, p = 0.004), (IRR = 2.45, 95% CI = 1.72-3.49, p = 0.004) and multivariable analysis (IRR = 1.67,95% CI = 1.05-2.65, p = 0.029), (IRR = 2.35, 95% CI = 1.63-3.42, p = 0.005), respectively. CONCLUSION In this retrospective European multicenter cohort study, patients with sporadic dMMR CRC had a higher risk for non-colorectal malignancy than those with pMMR CRC. These findings indicate the need for further studies to establish the need for and design of surveillance strategies for patients with dMMR CRC.
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Affiliation(s)
- Ioannis Gkekas
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - Novotny Jan
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - Tuomas Kaprio
- Department of Gastrointestinal Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ines Beilmann-Lehtonen
- Department of Transplantation and Liver Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Pavel Fabian
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Björn Tavelin
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Camilla Böckelman
- Department of Gastrointestinal Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Sofia Edin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Karin Strigård
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - Tomas Svoboda
- Department of Oncology and Radiotherapy, Faculty Hospital Pilsen, Charles University, Prague, Czech Republic
| | - Jaana Hagström
- Department of Pathology, University of Helsinki, Helsinki, Finland
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Lucie Barsova
- Department of Clinical Oncology, Comprehensive Oncology Center, Liberec, Czech Republic
| | - Tomas Jirasek
- Department of Pathology, Regional Hospital of Liberec, Liberec, Czech Republic
| | - Caj Haglund
- Department of Gastrointestinal Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Richard Palmqvist
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Ulf Gunnarsson
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
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11
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Li Y, Kang J, Zhang X. How to incorporate new agents into precise medicine for cholangiocarcinoma? Am J Cancer Res 2024; 14:2570-2583. [PMID: 38859865 PMCID: PMC11162663 DOI: 10.62347/nfdl2398] [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: 02/06/2024] [Accepted: 05/15/2024] [Indexed: 06/12/2024] Open
Abstract
Cholangiocarcinoma, a rare and aggressive form of cancer originating from the bile ducts in the liver, poses a significant challenge for treatment. However, the emergence of precision medicine has brought newfound hope for more effective therapies. Several precision medicine approaches have demonstrated promise in the treatment of cholangiocarcinoma. One such approach is targeted therapy, which involves utilizing drugs that specifically target the genetic mutations or alterations present in the tumor cells. In the case of cholangiocarcinoma, mutations in the IDH1 and IDH2 genes are frequently observed. Immunotherapy is another precision medicine approach being explored for the treatment of cholangiocarcinoma. Immune checkpoint inhibitors like pembrolizumab and nivolumab can be used to bolster the body's immune response against cancer cells. While the response to immunotherapy can vary among individuals, studies have shown promising results, particularly in patients with high levels of tumor-infiltrating lymphocytes or microsatellite instability. Moreover, molecular profiling of cholangiocarcinoma tumors can play a crucial role in identifying potential targets for precision medicine. Through advanced next-generation sequencing techniques, specific gene alterations or dysregulations in pathways can be identified, potentially guiding treatment decisions. This personalized approach enables tailored treatment plans based on the unique genetic characteristics of each patient's tumor. In conclusion, the advent of precision medicine has opened up new avenues for the treatment of cholangiocarcinoma. Targeted therapy and immunotherapy have exhibited promising results, and further molecular profiling is expected to uncover additional therapeutic options. Such advancements represent a significant step forward in the quest to enhance outcomes for individuals affected by cholangiocarcinoma.
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Affiliation(s)
- Yifan Li
- Department of Hepatobiliary, Pancreatic and Gastrointestinal Surgery, Shanxi Province Carcinoma Hospital, Shanxi Hospital Affiliated to Carcinoma Hospital, Chinese Academy of Medical Sciences, Carcinoma Hospital Affiliated to Shanxi Medical UniversityTaiyuan 030013, Shanxi, PR China
| | - Juying Kang
- Department of Information, Shanxi Province Carcinoma Hospital, Shanxi Hospital Affiliated to Carcinoma Hospital, Chinese Academy of Medical Sciences, Carcinoma Hospital Affiliated to Shanxi Medical UniversityTaiyuan 030013, Shanxi, PR China
| | - Xiaojuan Zhang
- Department of Radiology, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuan 030013, Shanxi, PR China
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12
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Makino K, Ishii T, Takeda H, Saito Y, Fujiwara Y, Fujimoto M, Ito T, Wakama S, Kumagai K, Munekage F, Horie H, Tomofuji K, Oshima Y, Uebayashi EY, Kawai T, Ogiso S, Fukumitsu K, Takai A, Seno H, Hatano E. Integrated analyses of the genetic and clinicopathological features of cholangiolocarcinoma: cholangiolocarcinoma may be characterized by mismatch-repair deficiency. J Pathol 2024; 263:32-46. [PMID: 38362598 DOI: 10.1002/path.6257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 10/25/2023] [Accepted: 12/21/2023] [Indexed: 02/17/2024]
Abstract
Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole-exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch-repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Kenta Makino
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takamichi Ishii
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoichi Saito
- Laboratory of Bioengineering, Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan
| | - Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Masakazu Fujimoto
- Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Ito
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Wakama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Kumagai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Fumiaki Munekage
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Horie
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Katsuhiro Tomofuji
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yu Oshima
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Takayuki Kawai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Surgery, Medical Research Institute Kitano Hospital, Osaka, Japan
| | - Satoshi Ogiso
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Fukumitsu
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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13
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Wirta EV, Szeto S, Koppatz H, Nordin A, Mäkisalo H, Arola J, Sirén J, Ahtiainen M, Böhm J, Mecklin JP, Sallinen V, Seppälä TT. High immune cell infiltration predicts improved survival in cholangiocarcinoma. Front Oncol 2024; 14:1333926. [PMID: 38751812 PMCID: PMC11094285 DOI: 10.3389/fonc.2024.1333926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 04/19/2024] [Indexed: 05/18/2024] Open
Abstract
Background Antitumoral immune response has a crucial role in constraining cancer. However, previous studies on cholangiocarcinoma (CCA), a rare and aggressive cancer, have reported contradictory findings on the prognostic impact of tumor-infiltrating T-lymphocytes. We aimed to clarify the effect of tumor-infiltrating CD3+ and CD8+ lymphocytes and PD-1/PD-L1 expression on CCA prognosis. Methods CD3+, CD8+, and PD-1+ lymphocyte densities, as well as PD-L1 expression rate were analyzed from stained tissue microarray samples from the tumor center and invasive margin of 47 cholangiocarcinomas. The association of CD3+ and CD8+ based Immune cell score (ICS) and its components with overall survival was evaluated, adjusting for age, sex, TNM stage, radicality of surgery, tumor location, and PD-L1 expression on immune cells. Results Low ICS was a strong independent prognostic factor for worse overall survival (Hazard ratio 9.27, 95% confidence interval 2.72-31.64, P<0.001). Among the ICS components, high CD8+ lymphocyte infiltration at the tumor center had the most evident impact on patient outcome. PD-1 and PD-L1 expression on immune cells did not have a significant impact on overall survival alone; however, PD-L1 positivity seemed to impair survival for ICSlow subgroup. Conclusion Identifying patient subgroups that could benefit from immunotherapy with PD-1/PD-L1 pathway blockade may help improve treatment strategies for this aggressive cancer. Our findings highlight the importance of evaluating the immune contexture in cholangiocarcinoma, as ICS serves as a strong independent prognostic and selective factor for patients who might benefit from immunotherapy.
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Affiliation(s)
- Erkki-Ville Wirta
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland
| | - Säde Szeto
- Applied Tumor Genomics Research Program, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hanna Koppatz
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Arno Nordin
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Heikki Mäkisalo
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Jukka Sirén
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Maarit Ahtiainen
- Department of Molecular Pathology, Central Finland Hospital Nova, Well Being Services County of Central Finland, Jyväskylä, Finland
| | - Jan Böhm
- Department of Molecular Pathology, Central Finland Hospital Nova, Well Being Services County of Central Finland, Jyväskylä, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Science, Central Finland Hospital Nova, Well Being Services County of Central Finland, Jyväskylä, Finland
- Faculty of Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Ville Sallinen
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Toni T. Seppälä
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland
- Applied Tumor Genomics Research Program, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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14
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Yoon SB, Woo SM, Chun JW, Kim DU, Kim J, Park JK, So H, Chung MJ, Cho IR, Heo J. The predictive value of PD-L1 expression in response to anti-PD-1/PD-L1 therapy for biliary tract cancer: a systematic review and meta-analysis. Front Immunol 2024; 15:1321813. [PMID: 38605964 PMCID: PMC11007040 DOI: 10.3389/fimmu.2024.1321813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 03/18/2024] [Indexed: 04/13/2024] Open
Abstract
Background Recently, anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy offers promising results for advanced biliary tract cancer (BTC). However, patients show highly heterogeneous responses to treatment, and predictive biomarkers are lacking. We performed a systematic review and meta-analysis to assess the potential of PD-L1 expression as a biomarker for treatment response and survival in patients with BTC undergoing anti-PD-1/PD-L1 therapy. Methods We conducted a comprehensive systematic literature search through June 2023, utilizing the PubMed, EMBASE, and Cochrane Library databases. The outcomes of interest included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) according to PD-L1 expression. Subgroup analyses and meta-regression were performed to identify possible sources of heterogeneity. Results A total of 30 studies was included in the final analysis. Pooled analysis showed no significant differences in ORR (odds ratio [OR], 1.56; 95% confidence intervals [CIs], 0.94-2.56) and DCR (OR, 1.84; 95% CIs, 0.88-3.82) between PD-L1 (+) and PD-L1 (-) patients. In contrast, survival analysis showed improved PFS (hazard ratio [HR], 0.54, 95% CIs, 0.41-0.71) and OS (HR, 0.58; 95% CI, 0.47-0.72) among PD-L1 (+) patients compared to PD-L1 (-) patients. Sensitivity analysis excluding retrospective studies showed no significant differences with the primary results. Furthermore, meta-regression demonstrated that drug target (PD-1 vs. PD-L1), presence of additional intervention (monotherapy vs. combination therapy), and PD-L1 cut-off level (1% vs. ≥5%) significantly affected the predictive value of PD-L1 expression. Conclusion PD-L1 expression might be a helpful biomarker for predicting PFS and OS in patients with BTC undergoing anti-PD-1/PD-L1 therapy. The predictive value of PD-L1 expression can be significantly influenced by diagnostic or treatment variables. Systematic review registration https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023434114.
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Affiliation(s)
- Seung Bae Yoon
- Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Myung Woo
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Jung Won Chun
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Dong Uk Kim
- Department of Internal Medicine, CHA University School of Medicine, Pocheon, Republic of Korea
| | - Jaihwan Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Joo Kyung Park
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hoonsub So
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Moon Jae Chung
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - In Rae Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jun Heo
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea
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15
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Olkus A, Tomczak A, Berger AK, Rauber C, Puchas P, Wehling C, Longerich T, Mehrabi A, Chang DH, Liermann J, Schäfer S, Pfeiffenberger J, Jäger D, Michl P, Springfeld C, Dill MT. Durvalumab Plus Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer: An Exploratory Analysis of Real-World Data. Target Oncol 2024; 19:213-221. [PMID: 38416377 DOI: 10.1007/s11523-024-01044-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2024] [Indexed: 02/29/2024]
Abstract
BACKGROUND The combination of gemcitabine and cisplatin (gem/cis) with the anti-PD-L1-antibody durvalumab was recently approved as first line therapy for biliary tract cancer (BTC) based on the results of the TOPAZ-1 trial. OBJECTIVE We aim to analyse the feasibility and efficacy of the triple combination therapy in patients with BTC in a real-world setting and in correspondence with the genetic alterations of the cancer. METHODS In this single-centre retrospective analysis, all patients with BTC and treated with durvalumab plus gem/cis from April 2022 to September 2023 were included. Survival and treatment response were investigated, within the context of the inclusion and exclusion criteria of TOPAZ-1 and in correspondence with genetic alterations of the cancer. RESULTS In total, 35 patients, of which 51% met the inclusion criteria of the TOPAZ-1 trial, were analysed. Patients treated within TOPAZ-1 criteria did not have a significantly different median overall survival and progression free survival than the rest of the patients (10.3 versus 9.7 months and 5.3 versus 5 months, respectively). The disease control rate of patients within the TOPAZ-1 criteria was 61.1%, in comparison to 58.8% in the rest of patients. A total of 51 grade 3 and 4 adverse events were observed without significant differences in the subgroups. No specific correlating patterns of genetic alterations with survival and response were observed. CONCLUSIONS The treatment of advanced patients with BTC with durvalumab and gem/cis, even beyond the inclusion criteria of the TOPAZ-1 trial, shows promising safety.
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Affiliation(s)
- Alexander Olkus
- Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Aurelie Tomczak
- Liver Cancer Center Heidelberg, Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Anne Katrin Berger
- Department of Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany
- National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Conrad Rauber
- Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Philip Puchas
- Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Cyrill Wehling
- Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Thomas Longerich
- Liver Cancer Center Heidelberg, Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Arianeb Mehrabi
- Liver Cancer Center Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - De-Hua Chang
- Liver Cancer Center Heidelberg, Heidelberg, Germany
- Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Jakob Liermann
- Liver Cancer Center Heidelberg, Heidelberg, Germany
- Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Sophia Schäfer
- Liver Cancer Center Heidelberg, Heidelberg, Germany
- Department of Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany
- National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
- Clinical Cancer Registry, Heidelberg University Hospital, Heidelberg, Germany
| | - Jan Pfeiffenberger
- Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Dirk Jäger
- Liver Cancer Center Heidelberg, Heidelberg, Germany
- Department of Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany
- National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Patrick Michl
- Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Christoph Springfeld
- Liver Cancer Center Heidelberg, Heidelberg, Germany
- Department of Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany
- National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Michael T Dill
- Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
- Liver Cancer Center Heidelberg, Heidelberg, Germany.
- National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
- German Cancer Research Center (DKFZ) Heidelberg, Research Group Experimental Hepatology, Inflammation and Cancer, Heidelberg, Germany.
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16
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Warren EAK, Maithel SK. Molecular pathology for cholangiocarcinoma: a review of actionable genetic targets and their relevance to adjuvant & neoadjuvant therapy, staging, follow-up, and determination of minimal residual disease. Hepatobiliary Surg Nutr 2024; 13:29-38. [PMID: 38322206 PMCID: PMC10839719 DOI: 10.21037/hbsn-22-563] [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: 11/18/2022] [Accepted: 02/28/2023] [Indexed: 02/08/2024]
Abstract
Cholangiocarcinoma (CCA) represents a group of epithelial cell tumors classified based on their anatomic location along the biliary tree. This rare malignancy is often diagnosed at an advanced stage and deemed unresectable. Even for those patients who are surgical candidates, recurrence rates are high and survival rates low. The mainstay of therapy for advanced CCA remains cisplatin plus gemcitabine, with a median overall survival (mOS) under 12 months, although the TOPAZ-1 trial showed a survival benefit with the addition of programmed cell death ligand 1 (PD-L1) blockade. In recent years, molecular profiling has revealed a wealth of potentially targetable genetic alterations, including fibroblast growth factor receptor (FGFR) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, human epidermal growth factor receptor 2 (HER2) amplification and overexpression, and microsatellite instability (MSI). These discoveries have prompted numerous clinical trials employing drugs against these specific genetic changes. The foundation laid by early clinical studies and the landscape of ongoing trials are both summarized here. While the role of adjuvant therapy has yet to be defined in this disease, we emphasize the importance of employing targeted therapies in trials in the adjuvant and neoadjuvant spaces and discuss ways to overcome challenges due to low incidence of targetable mutations. Personalized medicine for this disease promises significant clinical benefit to patients, but further investigation is needed.
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Affiliation(s)
- Emilie A K Warren
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Shishir K Maithel
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
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17
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Groß S, Bitzer M, Albert J, Blödt S, Boda-Heggemann J, Brunner T, Caspari R, De Toni E, Dombrowski F, Evert M, Follmann M, Freudenberger P, Gani C, Geier A, Gkika E, Götz M, Helmberger T, Hoffmann RT, Huppert P, Krug D, La Fougère C, Lang H, Langer T, Lenz P, Lüdde T, Mahnken A, Nadalin S, Nguyen HHP, Nothacker M, Ockenga J, Oldhafer K, Paprottka P, Pereira P, Persigehl T, Plentz R, Pohl J, Recken H, Reimer P, Riemer J, Ritterbusch U, Roeb E, Rüssel J, Schellhaas B, Schirmacher P, Schlitt HJ, Schmid I, Schuler A, Seehofer D, Sinn M, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Tholen R, Trojan J, van Thiel I, Vogel A, Vogl T, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wildner D, Wörns MA, Galle P, Malek N. S3-Leitlinie „Diagnostik und Therapie biliärer Karzinome“ – Langversion 4.0. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:e213-e282. [PMID: 38364849 DOI: 10.1055/a-2189-8567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2024]
Affiliation(s)
- Sabrina Groß
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Michael Bitzer
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Jörg Albert
- Katharinenhospital, Klinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie, Infektiologie und Pneumologie, Stuttgart
| | - Susanne Blödt
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | | | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz
| | - Reiner Caspari
- Klinik Niederrhein, Erkrankungen des Stoffwechsels der Verdauungsorgane und Tumorerkrankungen, Bad Neuenahr-Ahrweiler
| | | | | | | | - Markus Follmann
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e. V., Berlin
| | | | - Cihan Gani
- Klinik für Radioonkologie, Universitätsklinikum Tübingen
| | - Andreas Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - Eleni Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | - Martin Götz
- Medizinische Klinik IV - Gastroenterologie/Onkologie, Klinikverbund Südwest, Böblingen
| | - Thomas Helmberger
- Institut für Radiologie, Neuroradiologie und minimal invasive Therapie, München Klinik Bogenhausen
| | - Ralf-Thorsten Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Dresden
| | - Peter Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühlerhöhe
| | - David Krug
- Strahlentherapie Campus Kiel, Universitätsklinikum Schleswig-Holstein
| | - Christian La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Eberhard-Karls Universität, Tübingen
| | - Hauke Lang
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Johannes Gutenberg-Universität, Mainz
| | - Thomas Langer
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e. V., Berlin
| | - Philipp Lenz
- Zentrale Einrichtung Palliativmedizin, Universitätsklinikum Münster
| | - Tom Lüdde
- Medizinische Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf
| | - Andreas Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Marburg
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Eberhard-Karls Universität, Tübingen
| | | | - Monika Nothacker
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | - Johann Ockenga
- Medizinische Klinik II, Gesundheit Nord, Klinikverbund Bremen
| | - Karl Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Asklepios Klinik Barmbek
| | - Philipp Paprottka
- Sektion für Interventionelle Radiologie, Klinikum rechts der Isar, Technische Universität München
| | - Philippe Pereira
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, SLK-Klinken Heilbronn
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | - Ruben Plentz
- Klinik für Innere Medizin, Gesundheit Nord, Klinikverbund Bremen
| | - Jürgen Pohl
- Abteilung für Gastroenterologie, Asklepios Klinik Altona
| | | | - Peter Reimer
- Institut für Diagnostische und Interventionelle Radiologie, Städtisches Klinikum Karlsruhe
| | | | | | - Elke Roeb
- Medizinische Klinik II Pneumologie, Nephrologie und Gastroenterologie, Universitätsklinikum Gießen
| | - Jörn Rüssel
- Medizinische Klinik IV Hämatologie und Onkologie, Universitätsklinikum Halle (Saale)
| | - Barbara Schellhaas
- Medizinische Klinik I Gastroenterologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität, Erlangen
| | - Peter Schirmacher
- Allgemeine Pathologie und pathologische Anatomie, Universitätsklinikum Heidelberg
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg
| | - Irene Schmid
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU München
| | - Andreas Schuler
- Medizinische Klinik, Gastroenterologie, Alb-Fils-Kliniken, Geislingen an der Steige
| | - Daniel Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - Marianne Sinn
- II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, Knochenmarktransplantation mit Abteilung für Pneumologie), Universitätsklinikum Hamburg-Eppendorf
| | - Andreas Stengel
- Innere Medizin VI - Psychosomatische Medizin und Psychotherapie, Eberhard-Karls Universität, Tübingen
| | | | | | | | - Anne Taubert
- Klinische Sozialarbeit, Universitätsklinikum Heidelberg
| | - Reina Tholen
- Deutscher Bundesverband für Physiotherapie (ZVK) e. V
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Goethe-Universität, Frankfurt
| | | | - Arndt Vogel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Goethe-Universität, Frankfurt
| | - Frank Wacker
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Henning Wege
- Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen
| | - Dane Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Standort Lauf
| | - Marcus-Alexander Wörns
- Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund
| | - Peter Galle
- 1. Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie, Nephrologie, Rheumatologie, Infektiologie, Johannes Gutenberg-Universität, Mainz
| | - Nisar Malek
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
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18
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Yang X, Lian B, Zhang N, Long J, Li Y, Xue J, Chen X, Wang Y, Wang Y, Xun Z, Piao M, Zhu C, Wang S, Sun H, Song Z, Lu L, Dong X, Wang A, Liu W, Pan J, Hou X, Guan M, Huo L, Shi J, Zhang H, Zhou J, Lu Z, Mao Y, Sang X, Wu L, Yang X, Wang K, Zhao H. Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma. BMC Med 2024; 22:42. [PMID: 38281914 PMCID: PMC10823746 DOI: 10.1186/s12916-024-03257-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 01/15/2024] [Indexed: 01/30/2024] Open
Abstract
BACKGROUND Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).
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Affiliation(s)
- Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Breast Surgery, Peking, Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | | | - Nan Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junyu Long
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiran Li
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingnan Xue
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangqi Chen
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunchao Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanyu Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ziyu Xun
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingjian Piao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenpei Zhu
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shanshan Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huishan Sun
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | | | | | | | | | - Jie Pan
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaorong Hou
- Department of Radiotherapy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Mei Guan
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Li Huo
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jie Shi
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Haohai Zhang
- Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jinxue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Zhenhui Lu
- Hepatobiliary and Pancreatic Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China
| | - Yilei Mao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liqun Wu
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaobo Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Kai Wang
- OrigiMed Co., Ltd, Shanghai, China.
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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19
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Bitzer M, Groß S, Albert J, Blödt S, Boda-Heggemann J, Brunner T, Caspari R, De Toni E, Dombrowski F, Evert M, Follmann M, Freudenberger P, Gani C, Geier A, Gkika E, Götz M, Helmberger T, Hoffmann RT, Huppert P, Krug D, Fougère CL, Lang H, Langer T, Lenz P, Lüdde T, Mahnken A, Nadalin S, Nguyen HHP, Nothacker M, Ockenga J, Oldhafer K, Paprottka P, Pereira P, Persigehl T, Plentz R, Pohl J, Recken H, Reimer P, Riemer J, Ritterbusch U, Roeb E, Rüssel J, Schellhaas B, Schirmacher P, Schlitt HJ, Schmid I, Schuler A, Seehofer D, Sinn M, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Tholen R, Trojan J, van Thiel I, Vogel A, Vogl T, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wildner D, Wörns MA, Galle P, Malek N. S3-Leitlinie „Diagnostik und Therapie des Hepatozellulären Karzinoms“ – Langversion 4.0. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:e67-e161. [PMID: 38195102 DOI: 10.1055/a-2189-6353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Affiliation(s)
- Michael Bitzer
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Sabrina Groß
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Jörg Albert
- Katharinenhospital, Klinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie, Infektiologie und Pneumologie, Stuttgart
| | - Susanne Blödt
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V.(AWMF), Berlin
| | | | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz
| | - Reiner Caspari
- Klinik Niederrhein Erkrankungen des Stoffwechsels der Verdauungsorgane und Tumorerkrankungen, Bad Neuenahr-Ahrweiler
| | | | | | | | - Markus Follmann
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e. V., Berlin
| | | | - Cihan Gani
- Klinik für Radioonkologie, Universitätsklinikum Tübingen
| | - Andreas Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - Eleni Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | - Martin Götz
- Medizinische Klinik IV - Gastroenterologie/Onkologie, Klinikverbund Südwest, Böblingen
| | - Thomas Helmberger
- Institut für Radiologie, Neuroradiologie und minimal invasive Therapie, München Klinik Bogenhausen
| | - Ralf-Thorsten Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Dresden
| | - Peter Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühlerhöhe
| | - David Krug
- Strahlentherapie Campus Kiel, Universitätsklinikum Schleswig-Holstein
| | - Christian La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Eberhard-Karls Universität, Tübingen
| | - Hauke Lang
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Johannes Gutenberg-Universität, Mainz
| | - Thomas Langer
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e. V., Berlin
| | - Philipp Lenz
- Zentrale Einrichtung Palliativmedizin, Universitätsklinikum Münster
| | - Tom Lüdde
- Medizinische Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf
| | - Andreas Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Marburg
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Eberhard-Karls Universität, Tübingen
| | | | - Monika Nothacker
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V.(AWMF), Berlin
| | - Johann Ockenga
- Medizinische Klinik II, Gesundheit Nord, Klinikverbund Bremen
| | - Karl Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Asklepios Klinik Barmbek
| | - Philipp Paprottka
- Sektion für Interventionelle Radiologie, Klinikum rechts der Isar, Technische Universität München
| | - Philippe Pereira
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, SLK-Klinken Heilbronn
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | - Ruben Plentz
- Klinik für Innere Medizin, Gesundheit Nord, Klinikverbund Bremen
| | - Jürgen Pohl
- Abteilung für Gastroenterologie, Asklepios Klinik Altona
| | | | - Peter Reimer
- Institut für Diagnostische und Interventionelle Radiologie, Städtisches Klinikum Karlsruhe
| | | | | | - Elke Roeb
- Medizinische Klinik II Pneumologie, Nephrologie und Gastroenterologie, Universitätsklinikum Gießen
| | - Jörn Rüssel
- Medizinische Klinik IV Hämatologie und Onkologie, Universitätsklinikum Halle (Saale)
| | - Barbara Schellhaas
- Medizinische Klinik I Gastroenterologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität, Erlangen
| | - Peter Schirmacher
- Allgemeine Pathologie und pathologische Anatomie, Universitätsklinikum Heidelberg
| | | | - Irene Schmid
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU München
| | - Andreas Schuler
- Medizinische Klinik, Gastroenterologie, Alb-Fils-Kliniken, Geislingen an der Steige
| | - Daniel Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - Marianne Sinn
- II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, Knochenmarktransplantation mit Abteilung für Pneumologie), Universitätsklinikum Hamburg-Eppendorf
| | - Andreas Stengel
- Innere Medizin VI - Psychosomatische Medizin und Psychotherapie, Eberhard-Karls Universität, Tübingen
| | | | | | | | - Anne Taubert
- Klinische Sozialarbeit, Universitätsklinikum Heidelberg
| | - Reina Tholen
- Deutscher Bundesverband für Physiotherapie (ZVK) e. V
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Goethe-Universität, Frankfurt
| | | | - Arndt Vogel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Goethe-Universität, Frankfurt
| | - Frank Wacker
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Henning Wege
- Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen
| | - Dane Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Standort Lauf
| | - Marcus-Alexander Wörns
- Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund
| | - Peter Galle
- 1. Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie, Nephrologie, Rheumatologie, Infektiologie, Johannes Gutenberg-Universität, Mainz
| | - Nisar Malek
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
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20
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Rushbrook SM, Kendall TJ, Zen Y, Albazaz R, Manoharan P, Pereira SP, Sturgess R, Davidson BR, Malik HZ, Manas D, Heaton N, Prasad KR, Bridgewater J, Valle JW, Goody R, Hawkins M, Prentice W, Morement H, Walmsley M, Khan SA. British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma. Gut 2023; 73:16-46. [PMID: 37770126 PMCID: PMC10715509 DOI: 10.1136/gutjnl-2023-330029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 09/05/2023] [Indexed: 10/03/2023]
Abstract
These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.
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Affiliation(s)
- Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | - Timothy James Kendall
- Division of Pathology, University of Edinburgh, Edinburgh, UK
- University of Edinburgh MRC Centre for Inflammation Research, Edinburgh, UK
| | - Yoh Zen
- Department of Pathology, King's College London, London, UK
| | - Raneem Albazaz
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | | | | | - Richard Sturgess
- Digestive Diseases Unit, Aintree University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Brian R Davidson
- Department of Surgery, Royal Free Campus, UCL Medical School, London, UK
| | - Hassan Z Malik
- Department of Surgery, University Hospital Aintree, Liverpool, UK
| | - Derek Manas
- Department of Surgery, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Nigel Heaton
- Department of Hepatobiliary and Pancreatic Surgery, King's College London, London, UK
| | - K Raj Prasad
- John Goligher Colorectal Unit, St. James University Hospital, Leeds, UK
| | - John Bridgewater
- Department of Oncology, UCL Cancer Institute, University College London, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK
| | - Rebecca Goody
- Department of Oncology, St James's University Hospital, Leeds, UK
| | - Maria Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | - Wendy Prentice
- King's College Hospital NHS Foundation Trust, London, UK
| | | | | | - Shahid A Khan
- Hepatology and Gastroenterology Section, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Imperial College Healthcare NHS Trust, London, UK
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21
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Yang S, Zou R, Dai Y, Hu Y, Li F, Hu H. Tumor immune microenvironment and the current immunotherapy of cholangiocarcinoma (Review). Int J Oncol 2023; 63:137. [PMID: 37888583 PMCID: PMC10631767 DOI: 10.3892/ijo.2023.5585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 10/12/2023] [Indexed: 10/28/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy originating from the epithelial system of the bile ducts, and its incidence in recent years is steadily increasing. The immune microenvironment of CCA is characterized by diversity and complexity, with a substantial presence of cancer‑associated fibroblasts and immune cell infiltration, which plays a key role in regulating the distinctive biological behavior of cholangiocarcinoma, including tumor growth, angiogenesis, lymphangiogenesis, invasion and metastasis. Despite the notable success of immunotherapy in the treatment of solid tumors in recent years, patients with CCA have responded poorly to immune checkpoint inhibitor therapy. The interaction of tumor cells with cellular components of the immune microenvironment can regulate the activity and function of immune cells and form an immunosuppressive microenvironment, which may cause ineffective immunotherapy. Therefore, the components of the tumor immune microenvironment appear to be novel targets for immune therapies. Combination therapy focusing on immune checkpoint inhibitors is a promising and valuable first‑line or translational treatment approach for intractable biliary tract malignancies. The present review discusses the compositional characteristics and regulatory factors of the CCA immune microenvironment and the possible immune escape mechanisms. In addition, a summary of the advances in immunotherapy for CCA is also provided. It is hoped that the present review may function as a valuable reference for the development of novel immunotherapeutic strategies for CCA.
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Affiliation(s)
- Siqi Yang
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ruiqi Zou
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yushi Dai
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yafei Hu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fuyu Li
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Haijie Hu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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22
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Gehl V, O'Rourke CJ, Andersen JB. Immunogenomics of cholangiocarcinoma. Hepatology 2023:01515467-990000000-00649. [PMID: 37972940 DOI: 10.1097/hep.0000000000000688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/16/2023] [Indexed: 11/19/2023]
Abstract
The development of cholangiocarcinoma spans years, if not decades, during which the immune system becomes corrupted and permissive to primary tumor development and metastasis. This involves subversion of local immunity at tumor sites, as well as systemic immunity and the wider host response. While immune dysfunction is a hallmark of all cholangiocarcinoma, the specific steps of the cancer-immunity cycle that are perturbed differ between patients. Heterogeneous immune functionality impacts the evolutionary development, pathobiological behavior, and therapeutic response of these tumors. Integrative genomic analyses of thousands of primary tumors have supported a biological rationale for immune-based stratification of patients, encompassing immune cell composition and functionality. However, discerning immune alterations responsible for promoting tumor initiation, maintenance, and progression from those present as bystander events remains challenging. Functionally uncoupling the tumor-promoting or tumor-suppressing roles of immune profiles will be critical for identifying new immunomodulatory treatment strategies and associated biomarkers for patient stratification. This review will discuss the immunogenomics of cholangiocarcinoma, including the impact of genomic alterations on immune functionality, subversion of the cancer-immunity cycle, as well as clinical implications for existing and novel treatment strategies.
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Affiliation(s)
- Virag Gehl
- Department of Health and Medical Sciences, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
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23
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Khuntikeo N, Padthaisong S, Loilome W, Klanrit P, Ratchatapusit S, Techasen A, Jareanrat A, Thanasukarn V, Srisuk T, Luvira V, Chindaprasirt J, Sa-ngiamwibool P, Aphivatanasiri C, Intarawichian P, Koonmee S, Prajumwongs P, Titapun A. Mismatch Repair Deficiency Is a Prognostic Factor Predicting Good Survival of Opisthorchis viverrini-Associated Cholangiocarcinoma at Early Cancer Stage. Cancers (Basel) 2023; 15:4831. [PMID: 37835526 PMCID: PMC10572072 DOI: 10.3390/cancers15194831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/13/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND The mismatch repair (MMR) system prevents DNA mutation; therefore, deficient MMR protein (dMMR) expression causes genetic alterations and microsatellite instability (MSI). dMMR is correlated with a good outcome and treatment response in various cancers; however, the situation remains ambiguous in cholangiocarcinoma (CCA). This study aims to evaluate the prevalence of dMMR and investigate the correlation with clinicopathological features and the survival of CCA patients after resection. MATERIALS AND METHODS Serum and tissues were collected from CCA patients who underwent resection from January 2005 to December 2017. Serum OV IgG was examined using ELISA. The expression of MMR proteins MLH1, MSH2, MSH6 and PMS2 was investigated by immunohistochemistry; subsequently, MMR assessment was evaluated as either proficient or as deficient by pathologists. The clinicopathological features and MMR status were compared using the Chi-square test. Univariate and multivariate analyses were conducted to identify prognostic factors. RESULTS Among the 102 CCA patients, dMMR was detected in 22.5%. Survival analysis revealed that dMMR patients had better survival than pMMR (HR = 0.50, p = 0.008). In multivariate analysis, dMMR was an independent factor for a good prognosis in CCA patients (HR = 0.58, p = 0.041), especially at an early stage (HR = 0.18, p = 0.027). Moreover, subgroup analysis showed dMMR patients who received adjuvant chemotherapy had better survival than surgery alone (HR = 0.28, p = 0.012). CONCLUSION This study showed a high prevalence of dMMR in cholangiocarcinoma with dMMR being the independent prognostic factor for good survival, especially in early-stage CCA and for patients who received adjuvant chemotherapy. dMMR should be the marker for selecting patients to receive a specific adjuvant treatment after resection for CCA.
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Affiliation(s)
- Natcha Khuntikeo
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Sureerat Padthaisong
- Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand;
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Poramate Klanrit
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Soontaree Ratchatapusit
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Apiwat Jareanrat
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Vasin Thanasukarn
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Tharatip Srisuk
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Vor Luvira
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Jarin Chindaprasirt
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Medical Oncology Program, Department of Medicine Srinagarind Hospital, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Prakasit Sa-ngiamwibool
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chaiwat Aphivatanasiri
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Piyapharom Intarawichian
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Supinda Koonmee
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Piya Prajumwongs
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
| | - Attapol Titapun
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (N.K.); (A.J.); (V.T.); (T.S.); (V.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (W.L.); (P.K.); (S.R.); (A.T.); (J.C.); (P.S.-n.); (C.A.); (P.I.); (S.K.); (P.P.)
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24
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Jin B, Wang Y, Zhang B, Xu H, Lu X, Sang X, Wang W, Mao Y, Chen P, Wang S, Qian Z, Wang Y, Du S. Immune checkpoint inhibitor-related molecular markers predict prognosis in extrahepatic cholangiocarcinoma. Cancer Med 2023; 12:20470-20481. [PMID: 37814942 PMCID: PMC10652350 DOI: 10.1002/cam4.6441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications. METHODS Whole-exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS Mutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056-0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36. CONCLUSIONS TMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.
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Affiliation(s)
- Bao Jin
- Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences& Peking Union Medical CollegeBeijingChina
| | - Yuxin Wang
- Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences& Peking Union Medical CollegeBeijingChina
| | - Baoluhe Zhang
- Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences& Peking Union Medical CollegeBeijingChina
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences& Peking Union Medical CollegeBeijingChina
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences& Peking Union Medical CollegeBeijingChina
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences& Peking Union Medical CollegeBeijingChina
| | - Wenze Wang
- Department of Pathology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences& Peking Union Medical CollegeBeijingChina
| | | | - Shun Wang
- Beidou Precision Medicine InstituteGuangzhouChina
| | - Zhirong Qian
- Beidou Precision Medicine InstituteGuangzhouChina
| | - Yingyi Wang
- Department of Medical Oncology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences& Peking Union Medical CollegeBeijingChina
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25
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Mishima S, Naito Y, Akagi K, Hayashi N, Hirasawa A, Hishiki T, Igarashi A, Ikeda M, Kadowaki S, Kajiyama H, Kato M, Kenmotsu H, Kodera Y, Komine K, Koyama T, Maeda O, Miyachi M, Nishihara H, Nishiyama H, Ohga S, Okamoto W, Oki E, Ono S, Sanada M, Sekine I, Takano T, Tao K, Terashima K, Tsuchihara K, Yatabe Y, Yoshino T, Baba E. Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with DNA mismatch repair deficient (dMMR) tumors, third edition. Int J Clin Oncol 2023; 28:1237-1258. [PMID: 37599324 PMCID: PMC10542286 DOI: 10.1007/s10147-023-02397-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 07/28/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition". METHODS Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done. RESULTS The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested. CONCLUSION In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.
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Affiliation(s)
- Saori Mishima
- National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoichi Naito
- National Cancer Center Hospital East, Kashiwa, Japan
| | | | - Naomi Hayashi
- The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | | | - Ataru Igarashi
- Yokohama City University School of Medicine, Yokohama, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Eiji Oki
- Kyushu University, Fukuoka, Japan
| | | | - Masashi Sanada
- National Hospital Organization Nagoya Medical Center, Aichi, Japan
| | | | | | - Kayoko Tao
- National Cancer Center Hospital, Tokyo, Japan
| | - Keita Terashima
- National Center for Child Health and Development, Tokyo, Japan
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Vivaldi C, Genovesi V, Ugolini C, Bernardini L, Casadei-Gardini A, Formica V, Salani F, Orsi G, Massa V, Cacciato-Insilla A, Caccese M, Cesario S, Andrikou K, Graziani J, Campani D, Vasile E, Fontanini G, Fornaro L, Masi G. Mismatch Repair Deficiency in Biliary Tract Cancer: Prognostic Implications and Correlation with Histology. Oncology 2023; 102:157-167. [PMID: 37699372 DOI: 10.1159/000533406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 07/25/2023] [Indexed: 09/14/2023]
Abstract
INTRODUCTION Mismatch repair (MMR) deficiency represents a biomarker and therapeutic target in various neoplasms, but its role in biliary tract cancers (BTCs) remains misunderstood. METHODS MMR status was retrospectively assessed using immunohistochemistry in 163-BTCs patients. We identified MMR proficiency (pMMR)/deficiency (dMMR) according to the loss of MMR proteins (MLH1, PMS2, MSH2, MSH6). The primary objective of the study was to assess the incidence of dMMR in BTCs; the secondary purpose was to explore its association with prognosis and clinical features. RESULTS dMMR was recorded in 9 patients, and it was strongly associated with mucinous histology (p < 0.01). Regarding the prognostic effect, in 122-radically resected patients, disease-free survival (DFS) resulted significantly shorter in dMMR patients compared to pMMR patients (10.7 vs. 31.3 months, p = 0.025) and so did nodal status (48.2 vs. 15.3 months in N0 vs. N+) (p < 0.01). Moreover, dMMR confirmed its prognostic role in terms of DFS at multivariate analysis (p = 0.03), together with nodal status (p = 0.01), and resection margin (p = 0.03). In 103 M+ patients (encompassing 41 metastatic de novo and 62 recurred after surgery patients) there were not differences between dMMR and pMMR regarding survival analyses. CONCLUSIONS dMMR status is strongly correlated with mucinous histology and represents an independent prognostic factor in terms of disease relapse in patients with resected BTC. IMPLICATIONS FOR PRACTICE MMR may play an independent role in promoting an aggressive behaviour in patients with radically resected BTC. These results could be useful in improving the selection of patients after resection and, above all, should justify the evaluation of MMR status as a therapeutic target in BTC, especially in patients with atypical histology.
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Affiliation(s)
- Caterina Vivaldi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Virginia Genovesi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Clara Ugolini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, Division of Pathology, University of Pisa, Pisa, Italy
| | - Laura Bernardini
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Vincenzo Formica
- Medical Oncology Unit, Tor Vergata University Hospital, Rome, Italy
| | - Francesca Salani
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy
| | - Giulia Orsi
- Department of Medical Oncology, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - Valentina Massa
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Miriam Caccese
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Silvia Cesario
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Kalliopi Andrikou
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Jessica Graziani
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Daniela Campani
- Department of Surgical, Medical, Molecular Pathology and Critical Area, Division of Pathology, University of Pisa, Pisa, Italy
| | - Enrico Vasile
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Gabriella Fontanini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, Division of Pathology, University of Pisa, Pisa, Italy
| | - Lorenzo Fornaro
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Gianluca Masi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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27
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Koay EJ, Javle M, Belknap M, Derasari S, Roach M, Ludmir EB. What Role Does Radiotherapy Play in the Molecular Era for Intrahepatic Cholangiocarcinoma? Cancer J 2023; 29:272-278. [PMID: 37796645 DOI: 10.1097/ppo.0000000000000685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
ABSTRACT Intrahepatic cholangiocarcinoma is a rare disease, yet with rising incidence globally. Most patients are not eligible for potentially curative surgical resection, and many patients with unresectable disease die within 12 months of diagnosis, primarily due to liver failure from the primary tumor. Recent prospective and retrospective studies indicate that local control of the primary tumor can be achieved with hypofractionated radiotherapy in patients with unresectable disease, translating into prolonged survival of these patients. During the time that these encouraging reports for radiotherapy have been published, numerous concurrent studies have also shown that intrahepatic cholangiocarcinoma is a molecularly diverse disease with multiple targetable genetic alterations and a complex tumor microenvironment. These biological insights have translated into new drug approvals for subsets of patients. We review the current knowledge about the biology and targeted treatment of intrahepatic cholangiocarcinoma and describe these developments in the context of modern radiotherapy.
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Affiliation(s)
- Eugene J Koay
- From the University of Texas MD Anderson Cancer Center, Houston, TX
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28
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Frega G, Cossio FP, Banales JM, Cardinale V, Macias RIR, Braconi C, Lamarca A. Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis. Cells 2023; 12:2098. [PMID: 37626908 PMCID: PMC10453268 DOI: 10.3390/cells12162098] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/06/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC. METHODS Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible. RESULTS A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs-15 studies), perihilar-distal CCAs (p/dCCAs-7 studies), and gallbladder cancer (GBC-5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively. CONCLUSION From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies.
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Affiliation(s)
- Giorgio Frega
- Osteoncology, Soft Tissue and Bone Sarcomas, Innovative Therapy Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Fernando P. Cossio
- Department of Organic Chemistry I, Center of Innovation in Advanced Chemistry (ORFEO-CINQA), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Donostia International Physics Center (DIPC), 48940 Donostia-San Sebastian, Spain;
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute—Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, 48940 San Sebastian, Spain;
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31009 Pamplona, Spain
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00185 Rome, Italy;
| | - Rocio I. R. Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, 37007 Salamanca, Spain
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK;
- Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
| | - Angela Lamarca
- Department of Oncology—OncoHealth Institute, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
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Greten TF, Schwabe R, Bardeesy N, Ma L, Goyal L, Kelley RK, Wang XW. Immunology and immunotherapy of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2023; 20:349-365. [PMID: 36697706 DOI: 10.1038/s41575-022-00741-4] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/23/2022] [Indexed: 01/27/2023]
Abstract
Cholangiocarcinoma is the second most common primary liver cancer. Its incidence is low in the Western world but is rising globally. Surgery, chemotherapy and radiation therapy have been the only treatment options for decades. Progress in our molecular understanding of the disease and the identification of druggable targets, such as IDH1 mutations and FGFR2 fusions, has provided new treatment options. Immunotherapy has emerged as a potent strategy for many different types of cancer and has shown efficacy in combination with chemotherapy for cholangiocarcinoma. In this Review, we discuss findings related to key immunological aspects of cholangiocarcinoma, including the heterogeneous landscape of immune cells within the tumour microenvironment, the immunomodulatory effect of the microbiota and IDH1 mutations, and the association of immune-related signatures and patient outcomes. We introduce findings from preclinical immunotherapy studies, discuss future immune-mediated treatment options, and provide a summary of results from clinical trials testing immune-based approaches in patients with cholangiocarcinoma. This Review provides a thorough survey of our knowledge on immune signatures and immunotherapy in cholangiocarcinoma.
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Affiliation(s)
- Tim F Greten
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Liver Cancer Program, Bethesda, MD, USA.
| | - Robert Schwabe
- Institute of Human Nutrition, Columbia University, New York, NY, USA
- Department of Medicine, Columbia University, New York, NY, USA
| | - Nabeel Bardeesy
- Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Lichun Ma
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Lipika Goyal
- Division of Oncology, Stanford School of Medicine, Palo Alto, CA, USA
| | - Robin K Kelley
- Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Xin W Wang
- Liver Cancer Program, Bethesda, MD, USA
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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30
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Conci S, Catalano G, Roman D, Zecchetto C, Lucin E, De Bellis M, Tripepi M, Guglielmi A, Milella M, Ruzzenente A. Current Role and Future Perspectives of Immunotherapy and Circulating Factors in Treatment of Biliary Tract Cancers. Int J Med Sci 2023; 20:858-869. [PMID: 37324191 PMCID: PMC10266048 DOI: 10.7150/ijms.82008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/07/2023] [Indexed: 06/17/2023] Open
Abstract
Biliary tract cancers (BTCs) are a heterogenous group of malignancies arising from the epithelial cells of the biliary tree and the gallbladder. They are often locally advanced or already metastatic at the time of the diagnosis and therefore prognosis remains dismal. Unfortunately, the management of BTCs has been limited by resistance and consequent low response rate to cytotoxic systemic therapy. New therapeutic approaches are needed to improve the survival outcomes for these patients. Immunotherapy, one of the newest therapeutic options, is changing the approach to the oncological treatment. Immune checkpoint inhibitors are by far the most promising group of immunotherapeutic agents: they work by blocking the tumor-induced inhibition of the immune cellular response. Immunotherapy in BTCs is currently approved as second-line treatment for patients whose tumors have a peculiar molecular profile, such as high levels of microsatellites instability, PD-L1 overexpression, or high levels of tumor mutational burden. However, emerging data from ongoing clinical trials seem to suggest that durable responses can be achieved in other subsets of patients. The BTCs are characterized by a highly desmoplastic microenvironment that fuels the growth of cancer tissue, but tissue biopsies are often difficult to obtain or not feasible in BTCs. Recent studies have hence proposed to use liquid biopsy approaches to search the blood circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to use as biomarkers in BTCs. So far studies are insufficient to promote their use in clinical management, however trials are still in progress with promising preliminary results. Analysis of blood samples for ctDNA to research possible tumor-specific genetic or epigenetic alterations that could be linked to treatment response or prognosis was already feasible. Although there are still few data available, ctDNA analysis in BTC is fast, non-invasive, and could also represent a way to diagnose BTC earlier and monitor tumor response to chemotherapy. The prognostic capabilities of soluble factors in BTC are not yet precisely determined and more studies are needed. In this review, we will discuss the different approaches to immunotherapy and tumor circulating factors, the progress that has been made so far, and the possible future developments.
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Affiliation(s)
- Simone Conci
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Giovanni Catalano
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Diletta Roman
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Camilla Zecchetto
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Eleonora Lucin
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Mario De Bellis
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Marzia Tripepi
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Alfredo Guglielmi
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Michele Milella
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, University of Verona, University Hospital G.B. Rossi, Verona, Italy
| | - Andrea Ruzzenente
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy
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31
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Milardi G, Lleo A. Tumor-Infiltrating B Lymphocytes: Promising Immunotherapeutic Targets for Primary Liver Cancer Treatment. Cancers (Basel) 2023; 15:2182. [PMID: 37046842 PMCID: PMC10093314 DOI: 10.3390/cancers15072182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/23/2023] [Accepted: 04/03/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatocellular carcinoma and cholangiocarcinoma are the fourth most lethal primary cancers worldwide. Therefore, there is an urgent need for therapeutic strategies, including immune cell targeting therapies. The heterogeneity of liver cancer is partially explained by the characteristics of the tumor microenvironment (TME), where adaptive and innate immune system cells are the main components. Pioneering studies of primary liver cancers revealed that tumor-infiltrating immune cells and their dynamic interaction with cancer cells significantly impacted carcinogenesis, playing an important role in cancer immune evasion and responses to immunotherapy treatment. In particular, B cells may play a prominent role and have a controversial function in the TME. In this work, we highlight the effect of B lymphocytes as tumor infiltrates in relation to primary liver cancers and their potential prognostic value. We also present the key pathways underlying B-cell interactions within the TME, as well as the way that a comprehensive characterization of B-cell biology can be exploited to develop novel immune-based therapeutic approaches.
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Affiliation(s)
- Giulia Milardi
- Hepatobiliary Immunopathology Labaratory, IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
- Department of Gastroenterology, Division of Internal Medicine and Hepatology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
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32
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Angerilli V, Fornaro L, Pepe F, Rossi SM, Perrone G, Malapelle U, Fassan M. FGFR2 testing in cholangiocarcinoma: translating molecular studies into clinical practice. Pathologica 2023; 115:71-82. [PMID: 37017301 PMCID: PMC10462997 DOI: 10.32074/1591-951x-859] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 04/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms burdened by a dismal prognosis. Several studies have investigated the genomic profile of CCA and identified numerous druggable genetic alterations, including FGFR2 fusions/rearrangements. Approximately 5-7% of CCAs and 10-20% of intrahepatic iCCAs harbor FGFR2 fusions. With the recent advent of FGFR-targeting therapies into clinical practice, a standardization of molecular testing for FGFR2 alterations in CCA will be necessary. In this review, we describe the technical aspects and challenges related to FGFR2 testing in routine practice, focusing on the comparison between Next-Generation Sequencing (NGS) and FISH assays, the best timing to perform the test, and on the role of liquid biopsy.
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Affiliation(s)
- Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua (PD), Italy
| | - Lorenzo Fornaro
- Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa (PI), Italy
| | - Francesco Pepe
- Department of Public Health, University of Naples Federico II, Naples (NA), Italy
| | - Silvia Maria Rossi
- Department of Medicine and Surgery, Research Unit of Anatomical Pathology, Università Campus Bio-Medico di Roma, Roma, Italy
- Anatomical Pathology Operative Research Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy
| | - Giuseppe Perrone
- Department of Medicine and Surgery, Research Unit of Anatomical Pathology, Università Campus Bio-Medico di Roma, Roma, Italy
- Anatomical Pathology Operative Research Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples (NA), Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua (PD), Italy
- Veneto Institute of Oncology, IOV - IRCCS, Padua (PD), Italy
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33
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Bitzer M, Groß S, Albert J, Boda-Heggemann J, Brunner T, Caspari R, De Toni E, Dombrowski F, Evert M, Geier A, Gkika E, Götz M, Helmberger T, Hoffmann RT, Huppert P, Kautz A, Krug D, Fougère CL, Lang H, Lenz P, Lüdde T, Mahnken A, Nadalin S, Nguyen HHP, Ockenga J, Oldhafer K, Paprottka P, Pereira P, Persigehl T, Plentz R, Pohl J, Recken H, Reimer P, Riemer J, Ritterbusch U, Roeb E, Rüssel J, Schellhaas B, Schirmacher P, Schlitt HJ, Schmid I, Schuler A, Seehofer D, Sinn M, Stengel A, Stoll C, Tannapfel A, Taubert A, Tholen R, Trojan J, van Thiel I, Vogel A, Vogl T, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wildner D, Wörns MA, Galle P, Malek N. S3-Leitlinie Diagnostik und Therapie biliärer Karzinome – Langversion. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:e92-e156. [PMID: 37040776 DOI: 10.1055/a-2026-1240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/13/2023]
Affiliation(s)
- Michael Bitzer
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Sabrina Groß
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Jörg Albert
- Katharinenhospital, Klinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie, Infektiologie und Pneumologie, Stuttgart
| | | | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz
| | - Reiner Caspari
- Klinik Niederrhein Erkrankungen des Stoffwechsels der Verdauungsorgane und Tumorerkrankungen, Bad Neuenahr-Ahrweiler
| | | | | | | | - Andreas Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - Eleni Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | - Martin Götz
- Medizinische Klinik IV - Gastroenterologie/Onkologie, Klinikverbund Südwest, Böblingen
| | - Thomas Helmberger
- Institut für Radiologie, Neuroradiologie und minimal invasive Therapie, München Klinik Bogenhausen
| | - Ralf-Thorsten Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Dresden
| | - Peter Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühlerhöhe
| | | | - David Krug
- Strahlentherapie Campus Kiel, Universitätsklinikum Schleswig-Holstein
| | - Christian La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Eberhard-Karls Universität, Tübingen
| | - Hauke Lang
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Johannes Gutenberg-Universität, Mainz
| | - Philipp Lenz
- Zentrale Einrichtung Palliativmedizin, Universitätsklinikum Münster
| | - Tom Lüdde
- Medizinische Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf
| | - Andreas Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Marburg
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschrirugie, Eberhard-Karls Universität, Tübingen
| | | | - Johann Ockenga
- Medizinische Klinik II, Gesundheit Nord, Klinikverbund Bremen
| | - Karl Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Asklepios Klinik Barmbek
| | - Philipp Paprottka
- Sektion für Interventionelle Radiologie, Klinikum rechts der Isar, Technische Universität München
| | - Philippe Pereira
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, SLK-Klinken Heilbronn
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | - Ruben Plentz
- Klinik für Innere Medizin, Gesundheit Nord, Klinikverbund Bremen
| | - Jürgen Pohl
- Abteilung für Gastroenterologie, Asklepios Klinik Altona
| | | | - Peter Reimer
- Institut für Diagnostische und Interventionelle Radiologie, Städtisches Klinikum Karlsruhe
| | | | | | - Elke Roeb
- Medizinische Klinik II Pneumologie, Nephrologie und Gastroenterologie, Universitätsklinikum Gießen
| | - Jörn Rüssel
- Medizinische Klinik IV Hämatologie und Onkologie, Universitätsklinikum Halle (Saale)
| | - Barbara Schellhaas
- Medizinische Klinik I Gastroenterologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität, Erlangen
| | - Peter Schirmacher
- Allgemeine Pathologie und pathologische Anatomie, Universitätsklinikum Heidelberg
| | | | - Irene Schmid
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU München
| | - Andreas Schuler
- Medizinische Klinik, Gastroenterologie, Alb-Fils-Kliniken, Geislingen an der Steige
| | - Daniel Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - Marianne Sinn
- II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, Knochenmarktransplantation mit Abteilung für Pneumologie), Universitätsklinikum Hamburg-Eppendorf
| | - Andreas Stengel
- Innere Medizin VI - Psychosomatische Medizin und Psychotherapie, Eberhard-Karls Universität, Tübingen
| | | | | | - Anne Taubert
- Klinische Sozialarbeit, Universitätsklinikum Heidelberg
| | - Reina Tholen
- Deutscher Bundesverband für Physiotherapie (ZVK) e. V
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Goethe-Universität, Frankfurt
| | | | - Arndt Vogel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Goethe-Universität, Frankfurt
| | - Frank Wacker
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Henning Wege
- Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen
| | - Dane Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Standort Lauf
| | - Marcus-Alexander Wörns
- Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund
| | - Peter Galle
- 1. Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie, Nephrologie, Rheumatologie, Infektiologie, Johannes Gutenberg-Universität, Mainz
| | - Nisar Malek
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
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Patel TH, Marcus L, Horiba MN, Donoghue M, Chatterjee S, Mishra-Kalyani PS, Schuck RN, Li Y, Zhang X, Zirkelbach JF, Charlab R, Liu J, Yang Y, Lemery SJ, Pazdur R, Theoret MR, Fashoyin-Aje LA. FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement. Clin Cancer Res 2023; 29:838-842. [PMID: 36206041 PMCID: PMC9991984 DOI: 10.1158/1078-0432.ccr-22-2036] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/24/2022] [Accepted: 10/06/2022] [Indexed: 11/16/2022]
Abstract
On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose. Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% confidence interval: 27-45). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.
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Affiliation(s)
- Timil H. Patel
- Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Leigh Marcus
- Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - M. Naomi Horiba
- Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Martha Donoghue
- Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Somak Chatterjee
- Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | | | - Robert N. Schuck
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Yangbing Li
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Xinyuan Zhang
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Jeanne Fourie Zirkelbach
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Rosane Charlab
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Jiang Liu
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Yuching Yang
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Steven J. Lemery
- Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
- Oncology Center of Excellence, U.S. Food and Drug Administration
| | - Richard Pazdur
- Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
- Oncology Center of Excellence, U.S. Food and Drug Administration
| | - Marc R. Theoret
- Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
- Oncology Center of Excellence, U.S. Food and Drug Administration
| | - Lola A. Fashoyin-Aje
- Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
- Oncology Center of Excellence, U.S. Food and Drug Administration
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35
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Chan EM, Foster KJ, Bass AJ. WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI). Cancer Treat Res 2023; 186:313-328. [PMID: 37978143 DOI: 10.1007/978-3-031-30065-3_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
Microsatellite instability (MSI), a type of genetic hypermutability arising from impaired DNA mismatch repair (MMR), is observed in approximately 3% of all cancers. Preclinical work has identified the RecQ helicase WRN as a promising synthetic lethal target for patients with MSI cancers. WRN depletion substantially impairs the viability of MSI, but not microsatellite stable (MSS), cells. Experimental evidence suggests that this synthetic lethal phenotype is driven by numerous TA dinucleotide repeats that undergo expansion mutations in the setting of long-standing MMR deficiency. The lengthening of TA repeats increases their propensity to form secondary DNA structures that require WRN to resolve. In the absence of WRN helicase activity, these unresolved DNA secondary structures stall DNA replication forks and induce catastrophic DNA damage.
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Affiliation(s)
- Edmond M Chan
- Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, USA.
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, USA.
- Broad Institute of MIT and Harvard, Cambridge, USA.
- New York Genome Center, New York, USA.
| | | | - Adam J Bass
- Novartis Institutes for BioMedical Research, Cambridge, USA
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Tan S, Yu J, Huang Q, Zhou N, Xiong X, Gou H. Durable response to the combination of pembrolizumab and nab-paclitaxel in a metastatic extrahepatic cholangiocarcinoma: A case report and literature review. Front Pharmacol 2022; 13:1037646. [DOI: 10.3389/fphar.2022.1037646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/14/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor with poor overall survival. Although the first-line standard chemotherapy (gemcitabine plus cisplatin) combined with immunotherapy has yielded positive results with survival prolongation, the efficacy remains unsatisfactory, and new treatment modalities need to be explored.Case presentation: We report the case of a patient with metastatic extrahepatic CCA who achieved a durable response and good tolerance to the combination treatment of pembrolizumab and nab-paclitaxel following progression on gemcitabine plus capecitabine chemotherapy. The tumor samples of the patient revealed low TMB, MSS, negative PD-L1 expression, and negative CD8+ TIL expression. This patient was treated with 3 cycles of pembrolizumab plus nab-paclitaxel and cisplatin, followed by 5 cycles of pembrolizumab plus nab-paclitaxel. Finally, 10 cycles of pembrolizumab monotherapy were administered. The patient survived for over 27 months after the initiation of combined therapy and was still in continuous remission at the last follow-up.Conclusion: As far as we know, this is the first report that pembrolizumab plus nab-paclitaxel successfully treated a patient with advanced CCA. This combination therapy might be a potential treatment option for patients with cholangiocarcinoma, and further clinical trials are needed to explore the outcomes.
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37
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Marques AC, Ferraro-Peyret C, Michaud F, Song L, Smith E, Fabre G, Willig A, Wong MML, Xing X, Chong C, Brayer M, Fenouil T, Hervieu V, Bancel B, Devouassoux M, Balme B, Meyronet D, Menu P, Lopez J, Xu Z. Improved NGS-based detection of microsatellite instability using tumor-only data. Front Oncol 2022; 12:969238. [PMID: 36465367 PMCID: PMC9714634 DOI: 10.3389/fonc.2022.969238] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 10/18/2022] [Indexed: 01/09/2024] Open
Abstract
Microsatellite instability (MSI) is a molecular signature of mismatch repair deficiency (dMMR), a predictive marker of immune checkpoint inhibitor therapy response. Despite its recognized pan-cancer value, most methods only support detection of this signature in colorectal cancer. In addition to the tissue-specific differences that impact the sensitivity of MSI detection in other tissues, the performance of most methods is also affected by patient ethnicity, tumor content, and other sample-specific properties. These limitations are particularly important when only tumor samples are available and restrict the performance and adoption of MSI testing. Here we introduce MSIdetect, a novel solution for NGS-based MSI detection. MSIdetect models the impact of indel burden and tumor content on read coverage at a set of homopolymer regions that we found are minimally impacted by sample-specific factors. We validated MSIdetect in 139 Formalin-Fixed Paraffin-Embedded (FFPE) clinical samples from colorectal and endometrial cancer as well as other more challenging tumor types, such as glioma or sebaceous adenoma or carcinoma. Based on analysis of these samples, MSIdetect displays 100% specificity and 96.3% sensitivity. Limit of detection analysis supports that MSIdetect is sensitive even in samples with relatively low tumor content and limited microsatellite instability. Finally, the results obtained using MSIdetect in tumor-only data correlate well (R=0.988) with what is obtained using tumor-normal matched pairs, demonstrating that the solution addresses the challenges posed by MSI detection from tumor-only data. The accuracy of MSI detection by MSIdetect in different cancer types coupled with the flexibility afforded by NGS-based testing will support the adoption of MSI testing in the clinical setting and increase the number of patients identified that are likely to benefit from immune checkpoint inhibitor therapy.
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Affiliation(s)
| | - Carole Ferraro-Peyret
- Cancer Research Centre of Lyon, INSERM 1052, Centre National de la Recherche Scientifique (CNRS) 5286, University of Lyon, Lyon, France
- Hospices Civils de Lyon, Biopathology of Tumours, GH Est (GHE) Hospital, Bron, France
| | | | - Lin Song
- SOPHiA GENETICS, Saint-Sulpice, Switzerland
| | - Ewan Smith
- SOPHiA GENETICS, Saint-Sulpice, Switzerland
| | | | | | | | | | | | | | - Tanguy Fenouil
- Hospices Civils de Lyon, Biopathology of Tumours, GH Est (GHE) Hospital, Bron, France
| | - Valérie Hervieu
- Hospices Civils de Lyon, Biopathology of Tumours, GH Est (GHE) Hospital, Bron, France
| | - Brigitte Bancel
- Hospices Civils de Lyon, Biopathology of Tumours, GH Est (GHE) Hospital, Bron, France
| | - Mojgan Devouassoux
- Hospices Civils de Lyon, Department of Anatomopathology, Lyon-Sud Hospital, Lyon, France
| | - Brigitte Balme
- Hospices Civils de Lyon, Department of Anatomopathology, Lyon-Sud Hospital, Lyon, France
| | - David Meyronet
- Hospices Civils de Lyon, Biopathology of Tumours, GH Est (GHE) Hospital, Bron, France
| | | | - Jonathan Lopez
- Cancer Research Centre of Lyon, INSERM 1052, Centre National de la Recherche Scientifique (CNRS) 5286, University of Lyon, Lyon, France
- Hospices Civils de Lyon, Biochemistry and Molecular Biology Department, Lyon-Sud Hospital, Lyon, France
| | - Zhenyu Xu
- SOPHiA GENETICS, Saint-Sulpice, Switzerland
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Apport de l'immunothérapie dans le traitement des cancers des voies biliaires avancés. Bull Cancer 2022; 109:11S11-11S20. [DOI: 10.1016/s0007-4551(22)00464-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Høgdall D, O'Rourke CJ, Andersen JB. Molecular therapeutic targets for cholangiocarcinoma: Present challenges and future possibilities. Adv Cancer Res 2022; 156:343-366. [PMID: 35961705 DOI: 10.1016/bs.acr.2022.01.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A diagnosis of cholangiocarcinoma (CCA) is implicit with poor prognosis and limited treatment options, underscoring the near equivalence of incidence and mortality rates in this disease. In less than 9years from genomic identification to FDA-approval of the corresponding inhibitors, fibroblast growth factor receptor 2 (FGFR2) rearrangements and isocitrate dehydrogenase 1 (IDH1) mutations became exemplary successes of precision oncology in subsets of patients with CCA. However, clinical trial results from multikinase inhibitors in unselected populations have been less successful, while the impact of immunotherapies are only beginning to impact this setting. Development of future therapeutics is incumbent with new challenges. Many driver alterations occur in tumor suppressor-like genes which are not directly druggable. Therapeutically, this will require identification of ensuant "non-oncogene addiction" involving genes which are not themselves oncogenes but become tumor survival dependencies when a specific driver alteration occurs. The low recurrence frequency of genomic alterations between CCA patients will require careful evaluation of targeted agents in biomarker-enrolled trials, including basket trial settings. Systematic expansion of candidate drug targets must integrate genes affected by non-genetic alterations which incorporates the fundamental contribution of the microenvironment and immune system to treatment response, disease facets which have been traditionally overlooked by DNA-centric analyses. As treatment resistance is an inevitability in advanced disease, resistance mechanisms require characterization to guide the development of combination therapies to increase the duration of clinical benefit. Patient-focused clinical, technological and analytical synergy is needed to deliver future solutions to these present therapeutic challenges.
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Affiliation(s)
- Dan Høgdall
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Oncology, Herlev and Gentofte Hospital, Herlev, Copenhagen University Hospital, Copenhagen, Denmark
| | - Colm J O'Rourke
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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40
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Chen R, Zheng D, Li Q, Xu S, Ye C, Jiang Q, Yan F, Jia Y, Zhang X, Ruan J. Immunotherapy of cholangiocarcinoma: Therapeutic strategies and predictive biomarkers. Cancer Lett 2022; 546:215853. [DOI: 10.1016/j.canlet.2022.215853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/02/2022]
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Ning Z, Zhao Y, Yan X, Hua Y, Meng Z. Flower-like Composite Material Delivery of Co-Packaged Lenvatinib and Bufalin Prevents the Migration and Invasion of Cholangiocarcinoma. NANOMATERIALS 2022; 12:nano12122048. [PMID: 35745387 PMCID: PMC9230555 DOI: 10.3390/nano12122048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 05/20/2022] [Indexed: 02/01/2023]
Abstract
The co-delivery of multiple drugs using nanocarriers has been recognized as a promising strategy for cancer treatment to enhance therapeutic efficacy. In this study, a monodisperse mesoporous silica nanoparticle (mSiO2) is prepared and functionalized into high-efficiency loaded Lenvatinib and Bufalin for targeted delivery to Cholangiocarcinoma (CCA). mSiO2 was synthesized on solid silica nanoparticles by oil–water interface method, and highly monodisperse mSiO2 with uniform morphology was obtained. mSiO2 was then sequentially modified by polyethylene glycol (PEG) and the targeting molecule folic acid (FA). mSiO2-FA was designed as co-delivery system for Lenvatinib (Le) and Bufalin (Bu) to increase drug availability and highly target tumor cells. Compared with unfunctionalized mSiO2, mSiO2-FA can more efficiently enter human CCA cell lines (9810 cells) and enhance intracellular drug delivery. Moreover, drug-loaded mSiO2-FA (Le/Bu@mSiO2-FA) significantly inhibited the viability, migration and invasion of 9810 cells. In vivo, the nanocomplex significantly reduced the tumor load in CCA tumor-bearing mouse models compared to Le or Bu alone. The current work provides a useful strategy for highly targeted and multidrug-resistance reversal therapy for CCA.
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42
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Normanno N, Martinelli E, Melisi D, Pinto C, Rimassa L, Santini D, Scarpa A. Role of molecular genetics in the clinical management of cholangiocarcinoma. ESMO Open 2022; 7:100505. [PMID: 35696744 PMCID: PMC9198375 DOI: 10.1016/j.esmoop.2022.100505] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/05/2022] [Accepted: 05/07/2022] [Indexed: 11/13/2022] Open
Abstract
The incidence of cholangiocarcinoma (CCA) has steadily increased during the past 20 years, and mortality is increasing. The majority of patients with CCA have advanced or metastatic disease at diagnosis, and treatment options for unresectable disease are limited, resulting in poor prognosis. However, recent identification of targetable genomic alterations has expanded treatment options for eligible patients. Given the importance of early and accurate diagnosis in optimizing patient outcomes, this review discusses best practices in CCA diagnosis, with a focus on categorizing molecular genetics and available targeted therapies. Imaging and staging of CCAs are discussed, as well as recommended biopsy collection techniques, and molecular and genomic profiling methodologies, which have become increasingly important as molecular biomarker data accumulate. Approved agents targeting actionable genomic alterations specifically in patients with CCA include ivosidenib for tumors harboring IDH1 mutations, and infigratinib and pemigatinib for those with FGFR2 fusions. Other agents currently under development in this indication have shown promising results, which are presented here.
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Affiliation(s)
- N Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale-IRCCS, Naples, Italy.
| | - E Martinelli
- Medical Oncology, Department of Precision Medicine, Università della Campania 'L. Vanvitelli', Naples, Italy
| | - D Melisi
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Digestive Molecular Clinical Oncology Research Unit, University of Verona, Policlinico B.B. Rossi, Verona, Italy
| | - C Pinto
- Medical Oncology Unit, Comprehensive Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - L Rimassa
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy
| | - D Santini
- Medical Oncology, University Campus Bio-Medico, Rome, Italy
| | - A Scarpa
- ARC-Net Research Centre and Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Policlinico G.B. Rossi, Verona, Italy
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Liddell SS, Chakrabarti S, Wintheiser GA, Zemla TJ, Shi Q, Tella SH, Jin Z, Wookey VB, Hassan H, Tran NH, Borad MJ, Mahipal A. Tumor Mutational Burden Is a Potential Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Patients With Advanced Biliary Tract Cancer. JCO Precis Oncol 2022; 6:e2200003. [PMID: 35772047 DOI: 10.1200/po.22.00003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Patients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC. MATERIALS AND METHODS The prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers. RESULTS The institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed. CONCLUSION ICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.
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Affiliation(s)
| | - Sakti Chakrabarti
- Department of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI
| | | | - Tyler J Zemla
- Department of Biostatistics, Mayo Clinic, Rochester, MN
| | - Qian Shi
- Department of Biostatistics, Mayo Clinic, Rochester, MN
| | | | - Zhaohui Jin
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | | | - Hind Hassan
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Nguyen H Tran
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | | | - Amit Mahipal
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
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Liu D, Heij LR, Czigany Z, Dahl E, Lang SA, Ulmer TF, Luedde T, Neumann UP, Bednarsch J. The role of tumor-infiltrating lymphocytes in cholangiocarcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:127. [PMID: 35392957 PMCID: PMC8988317 DOI: 10.1186/s13046-022-02340-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 03/23/2022] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and associated with a dismal prognosis due to the lack of an efficient systemic therapy. In contrast to other cancers, new immunotherapies have demonstrated unsatisfactory results in clinical trials, underlining the importance of a deeper understanding of the special tumor microenvironment of CCA and the role of immune cells interacting with the tumor. Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy. Therefore, the aim of this systemic review is to summarize the current literature focusing on the proportions and distribution, molecular pathogenesis, prognostic significance of TILs and their role in immunotherapy for CCA patients. In CCA, CD8+ and CD4+ T lymphocytes represent the majority of TILs and are mostly sequestered around the cancer cells. CD20+ B lymphocytes and Natural Killer (NK) cells are less frequent. In contrast, Foxp3+ cells (regulatory T cells, Tregs) are observed to infiltrate into the tumor. In the immune microenvironment of CCA, cancer cells and stromal cells such as TAMs, TANs, MSDCs and CAFs inhibit the immune protection function of TILs by secreting factors like IL-10 and TGF-β. With respect to molecular pathogenesis, the Wnt/-catenin, TGF-signaling routes, aPKC-i/P-Sp1/Snail Signaling, B7-H1/PD-1Pathway and Fas/FasL signaling pathways are connected to the malignant potential and contributed to tumor immune evasion by increasing TIL apoptosis. Distinct subtypes of TILs show different prognostic implications for the long-term outcome in CCA. Although there are occasionally conflicting results, CD8+ and CD4+ T cells, and CD20+ B cells are positively correlated with the oncological prognosis of CCA, while a high number of Tregs is very likely associated with worse overall survival. TILs also play a major role in immunotherapy for CCA. In summary, the presence of TILs may represent an important marker for the prognosis and a potential target for novel therapy, but more clinical and translational data is needed to fully unravel the importance of TILs in the treatment of CCA.
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Affiliation(s)
- Dong Liu
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Lara Rosaline Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Edgar Dahl
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Heinrich Heine University Duesseldorf, Duesseldorf, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. .,Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
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45
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Cowzer D, Harding JJ. Advanced Bile Duct Cancers: A Focused Review on Current and Emerging Systemic Treatments. Cancers (Basel) 2022; 14:1800. [PMID: 35406572 PMCID: PMC8997852 DOI: 10.3390/cancers14071800] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 12/17/2022] Open
Abstract
Cancers arising in the biliary tract are rare, with varied incidence depending on geographical location. As clinical presentation is typically vague with non-specific symptoms, a large proportion of patients present with unresectable or metastatic disease at diagnosis. When unresectable, the mainstay of treatment is cytotoxic chemotherapy; however, despite this, 5-year overall survival remains incredibly poor. Diagnostic molecular pathology, using next-generation sequencing, has identified a high prevalence of targetable alterations in bile duct cancers, which is transforming care. Substantial genomic heterogeneity has been identified depending on both the anatomical location and etiology of disease, with certain alterations enriched for subtypes. In addition, immune checkpoint inhibitors with anti-PD-1/PD-L1 antibodies in combination with chemotherapy are now poised to become the standard first-line treatment option in this disease. Here, we describe the established role of cytotoxic chemotherapy, targeted precision treatments and immunotherapy in what is a rapidly evolving treatment paradigm for advanced biliary tract cancer.
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Affiliation(s)
| | - James J. Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA;
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Chung T, Park YN. Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front Med (Lausanne) 2022; 9:857140. [PMID: 35433771 PMCID: PMC9008308 DOI: 10.3389/fmed.2022.857140] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/07/2022] [Indexed: 12/26/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver malignancy with an increasing incidence worldwide. Recently, histopathologic classification of small duct type and large duct type iCCA has been introduced. Both these types of tumors exhibit differences in clinicopathological features, mutational profiles, and prognosis. Small duct type iCCA is composed of non-mucin-producing cuboidal cells, whereas large duct type iCCA is composed of mucin-producing columnar cells, reflecting different cells of origin. Large duct type iCCA shows more invasive growth and poorer prognosis than small duct type iCCA. The background liver of small duct type iCCA often shows chronic liver disease related to hepatitis B or C viral infection, or alcoholic or non-alcoholic fatty liver disease/steatohepatitis, in contrast to large duct type iCCA that is often related to hepatolithiasis and liver fluke infection. Cholangiolocarcinoma is a variant of small duct type iCCA composed of naïve-looking cuboidal cells forming cords or ductule-like structures, and shows better prognosis than the conventional small duct type. Fibrous tumor stroma, one of the characteristic features of iCCA, contains activated fibroblasts intermixed with innate and adaptive immune cells. The types of stroma (mature versus immature) are related to tumor behavior and prognosis. Low tumor-infiltrating lymphocyte density, KRAS alteration, and chromosomal instability are related to immune-suppressive tumor microenvironments with resistance to programmed death 1/ programmed death ligand 1 blockade. Data from recent large-scale exome analyses have revealed the heterogeneity in the molecular profiles of iCCA, showing that small duct type iCCA exhibit frequent BAP1, IDH1/2 hotspot mutations and FGFR2 fusion, in contrast to frequent mutations in KRAS, TP53, and SMAD4 observed in large duct type iCCA. Multi-omics analyses have proposed several molecular classifications of iCCA, including inflammation class and proliferation class. The inflammation class is enriched in inflammatory signaling pathways and expression of cytokines, while the proliferation class has activated oncogenic growth signaling pathways. Diverse pathologic features of iCCA and its associated multi-omics characteristics are currently under active investigation, thereby providing insights into precision therapeutics for patients with iCCA. This review provides the latest knowledge on the histopathologic classification of iCCA and its associated molecular features, ranging from tumor microenvironment to genomic and transcriptomic research.
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Affiliation(s)
- Taek Chung
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea
| | - Young Nyun Park
- Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Young Nyun Park,
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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.
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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
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Vij M, Puri Y, Rammohan A, G G, Rajalingam R, Kaliamoorthy I, Rela M. Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review. World J Gastrointest Oncol 2022; 14:607-627. [PMID: 35321284 PMCID: PMC8919011 DOI: 10.4251/wjgo.v14.i3.607] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/13/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Yogesh Puri
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Gowripriya G
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Rajesh Rajalingam
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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STAT1 and STAT3 Exhibit a Crosstalk and Are Associated with Increased Inflammation in Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14051154. [PMID: 35267462 PMCID: PMC8909292 DOI: 10.3390/cancers14051154] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Liver cancer is the fourth-leading cause of cancer-related mortality worldwide and lacks effective therapies. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of liver cancer and both are associated with underlying inflammatory diseases. Thereby, interleukin-6 (IL-6)-mediated STAT3 signaling is critically involved in early carcinogenesis and disease progression. Here, we assessed the interplay between STAT1 and STAT3 in IL-6 signaling in vitro and studied the activation of STAT1 and STAT3 in a cohort of 124 HCC and a cohort of 138 CCA patients by immunohistochemistry. We found that IL-6 induced STAT1 transcriptional activity upon STAT3 depletion, suggesting that HCC tumor cells may activate both STAT1 and STAT3 signaling under pro-inflammatory conditions. Furthermore, HCC patient tissues showed a strong positive correlation of STAT1 and STAT3 activation in distinct patient groups. These patients also exhibited a high degree of immune cell infiltration, suggesting that these tumors are immune “hot”. Abstract Liver cancers, which are mostly hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are very aggressive tumors with poor prognosis. Therapeutic options with curative intent are largely limited to surgery and available systemic therapies show limited benefit. Signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) are key transcription factors activated by pro-inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6 (IL-6). In this study, we combined in vitro cell culture experiments and immunohistochemical analyses of human HCC (N = 124) and CCA (N = 138) specimens. We observed that in the absence of STAT3, IL-6 induced the activation of STAT1 and its target genes suggesting that IL-6 derived from the tumor microenvironment may activate both STAT1 and STAT3 target genes in HCC tumor cells. In addition, STAT1 and STAT3 were highly activated in a subset of HCC, which exhibited a high degree of infiltrating CD8- and FOXP3-positive immune cells and PD-L1 expression. Our results demonstrate that STAT1 and STAT3 are expressed and activated in HCC and tumor infiltrating immune cells. In addition, HCC cases with high STAT1 and STAT3 expression also exhibited a high degree of immune cell infiltration, suggesting increased immunological tolerance.
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Bitzer M, Voesch S, Albert J, Bartenstein P, Bechstein W, Blödt S, Brunner T, Dombrowski F, Evert M, Follmann M, La Fougère C, Freudenberger P, Geier A, Gkika E, Götz M, Hammes E, Helmberger T, Hoffmann RT, Hofmann WP, Huppert P, Kautz A, Knötgen G, Körber J, Krug D, Lammert F, Lang H, Langer T, Lenz P, Mahnken A, Meining A, Micke O, Nadalin S, Nguyen HP, Ockenga J, Oldhafer K, Paprottka P, Paradies K, Pereira P, Persigehl T, Plauth M, Plentz R, Pohl J, Riemer J, Reimer P, Ringwald J, Ritterbusch U, Roeb E, Schellhaas B, Schirmacher P, Schmid I, Schuler A, von Schweinitz D, Seehofer D, Sinn M, Stein A, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Trojan J, van Thiel I, Tholen R, Vogel A, Vogl T, Vorwerk H, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wildner D, Wittekind C, Wörns MA, Galle P, Malek N. S3-Leitlinie – Diagnostik und Therapie biliärer Karzinome. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:e186-e227. [PMID: 35148560 DOI: 10.1055/a-1589-7854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- M Bitzer
- Medizinische Klinik I, Universitätsklinikum Tübingen
| | - S Voesch
- Medizinische Klinik I, Universitätsklinikum Tübingen
| | - J Albert
- Abteilung für Gastroenterologie, Hepatologie und Endokrinologie, Robert-Bosch-Krankenhaus, Stuttgart
| | - P Bartenstein
- Klinik und Poliklinik für Nuklearmedizin, LMU Klinikum, München
| | - W Bechstein
- Klinik für Allgemein-, Viszeral-, Transplantations- und Thoraxchirurgie, Universitätsklinikum Frankfurt
| | - S Blödt
- AWMF-Geschäftsstelle, Berlin
| | - T Brunner
- Klinik für Strahlentherapie, Universitätsklinikum Magdeburg
| | - F Dombrowski
- Institut für Pathologie, Universitätsmedizin Greifswald
| | - M Evert
- Institut für Pathologie, Regensburg
| | - M Follmann
- Office des Leitlinienprogrammes Onkologie, c/o Deutsche Krebsgesellschaft e.V., Berlin
| | - C La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Tübingen
| | | | - A Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - E Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | | | - E Hammes
- Lebertransplantierte Deutschland e. V., Ansbach
| | - T Helmberger
- Institut für Radiologie, Neuroradiologie und minimal-invasive Therapie, München Klinik Bogenhausen, München
| | - R T Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Dresden
| | - W P Hofmann
- Gastroenterologie am Bayerischen Platz, medizinisches Versorgungszentrum, Berlin
| | - P Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühl
| | - A Kautz
- Deutsche Leberhilfe e.V., Köln
| | - G Knötgen
- Konferenz onkologischer Kranken- und Kinderkrankenpflege, Hamburg
| | - J Körber
- Klinik Nahetal, Fachklinik für onkologische Rehabilitation und Anschlussrehabilitation, Bad Kreuznach
| | - D Krug
- Klinik für Strahlentherapie, Universitätsklinikum Schleswig-Holstein, Kiel
| | | | - H Lang
- Klinik für Allgemein-, Viszeral und Transplantationschirurgie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz
| | - T Langer
- Office des Leitlinienprogrammes Onkologie, c/o Deutsche Krebsgesellschaft e.V., Berlin
| | - P Lenz
- Universitätsklinikum Münster, Zentrale Einrichtung Palliativmedizin, Münster
| | - A Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Gießen und Marburg GmbH, Marburg
| | - A Meining
- Medizinische Klinik und Poliklinik II des Universitätsklinikums Würzburg
| | - O Micke
- Klinik für Strahlentherapie und Radioonkologie, Franziskus Hospital Bielefeld
| | - S Nadalin
- Universitätsklinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Tübingen
| | | | - J Ockenga
- Medizinische Klinik II, Klinikum Bremen-Mitte, Bremen
| | - K Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Semmelweis Universität, Asklepios Campus Hamburg
| | - P Paprottka
- Abteilung für interventionelle Radiologie, Klinikum rechts der Isar der Technischen Universität München
| | - K Paradies
- Konferenz onkologischer Kranken- und Kinderkrankenpflege, Hamburg
| | - P Pereira
- Abteilung für interventionelle Radiologie, Klinikum rechts der Isar der Technischen Universität München
| | - T Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | | | - R Plentz
- Klinikum Bremen-Nord, Innere Medizin, Bremen
| | - J Pohl
- Interventionelles Endoskopiezentrum und Schwerpunkt Gastrointestinale Onkologie, Asklepios Klinik Altona, Hamburg
| | - J Riemer
- Lebertransplantierte Deutschland e. V., Bretzfeld
| | - P Reimer
- Institut für diagnostische und interventionelle Radiologie, Städtisches Klinikum Karlsruhe gGmbH, Karlsruhe
| | - J Ringwald
- Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Tübingen
| | | | - E Roeb
- Medizinische Klinik II, Universitätsklinikum Gießen und Marburg GmbH, Gießen
| | - B Schellhaas
- Medizinische Klinik I, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen
| | - P Schirmacher
- Pathologisches Institut, Universitätsklinikum Heidelberg
| | - I Schmid
- Zentrum Pädiatrische Hämatologie und Onkologie, Dr. von Haunersches Kinderspital, Klinikum der Universität München
| | - A Schuler
- Medizinische Klinik, Alb Fils Kliniken GmbH, Göppingen
| | | | - D Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - M Sinn
- Medizinische Klinik II, Universitätsklinikum Hamburg-Eppendorf
| | - A Stein
- Hämatologisch-Onkologischen Praxis Eppendorf, Hamburg
| | - A Stengel
- Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Tübingen
| | | | - C Stoll
- Klinik Herzoghöhe Bayreuth, Bayreuth
| | - A Tannapfel
- Institut für Pathologie der Ruhr-Universität Bochum am Berufsgenossenschaftlichen Universitätsklinikum Bergmannsheil, Bochum
| | - A Taubert
- Kliniksozialdienst, Universitätsklinikum Heidelberg, Bochum
| | - J Trojan
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Frankfurt am Main
| | | | - R Tholen
- Deutscher Verband für Physiotherapie e. V., Köln
| | - A Vogel
- Klinik für Gastroenterologie, Hepatologie, Endokrinologie der Medizinischen Hochschule Hannover, Hannover
| | - T Vogl
- Universitätsklinikum Frankfurt, Institut für Diagnostische und Interventionelle Radiologie, Frankfurt
| | - H Vorwerk
- Klinik für Strahlentherapie, Universitätsklinikum Gießen und Marburg GmbH, Marburg
| | - F Wacker
- Institut für Diagnostische und Interventionelle Radiologie der Medizinischen Hochschule Hannover, Hannover
| | - O Waidmann
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Frankfurt am Main
| | - H Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie Medizinische Hochschule Hannover, Hannover
| | - H Wege
- Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg
| | - D Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Lauf an der Pegnitz
| | - C Wittekind
- Institut für Pathologie, Universitätsklinikum Leipzig, Leipzig
| | - M A Wörns
- Medizinische Klinik und Poliklinik, Universitätsklinikum Mainz, Mainz
| | - P Galle
- Medizinische Klinik und Poliklinik, Universitätsklinikum Mainz, Mainz
| | - N Malek
- Medizinische Klinik I, Universitätsklinikum Tübingen, Tübingen
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