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Maccio U, Wicki A, Ruschitzka F, Beuschlein F, Wolleb S, Varga Z, Moch H. Frequency and Consequences of Immune Checkpoint Inhibitor-Associated Inflammatory Changes in Different Organs: An Autopsy Study Over 13 -Years. Mod Pathol 2025; 38:100683. [PMID: 39675428 DOI: 10.1016/j.modpat.2024.100683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024]
Abstract
Although immune checkpoint inhibitors (ICIs) have revolutionized modern oncology, they are also associated with immune-related adverse events (irAEs). Previous histopathologic descriptions of organ-related inflammatory changes do not consider systemic effects of ICIs, because of the absence of comprehensive autopsy studies. We performed a retrospective study on 42 whole-body autopsies of patients treated with ICIs from January 2011 to March 2024 to determine the frequency, organ distribution, and morphology of ICI-associated inflammatory changes as well as their clinical relevance. Twenty-three of 42 (54.8%) patients presented irAEs with inflammatory changes in at least one organ. Most frequent irAEs were ICI-related hypophysitis (N = 12; 28.6%), myocarditis (N = 8; 19.0%), pneumonitis (N = 5; 11.9%), hepatitis (N = 6; 14.3%), and adrenalitis (N = 5; 11.9%). ICI-related inflammation was mainly characterized by lymphohistiocytic and macrophage-rich tissue infiltrates, whereas a granulomatous "sarcoid-like" reaction was observed in 1 patient. Cause of death was attributable to ICI therapy in 7 (16.7%) patients, with ICI-associated myocarditis as the most common cause of death (N = 5; 71.4%). Clinically, irAEs were unsuspected in 5 of 7 ICI-related deaths (71.4%). Among irAEs, myocarditis has been clinically undiagnosed in 5 out of 8 cases (62.5%). Encephalitis was identified only at autopsy in all cases (N = 2). Hypophysitis was clinically unsuspected in 8 of 12 (66.7%) cases. Patients who died from irAEs developed more frequently a complete tumor regression than patients who died from other causes (P = .018). Of note, ICI-related myocarditis and pneumonitis were both associated with a systemic occurrence irAEs. Our study demonstrates that some irAEs, especially myocarditis, hypophysitis, and encephalitis, are clinically underdiagnosed. Autopsy remains a valuable tool to monitor diagnostic accuracy and therapeutic side effects in patients who died under ICI therapy.
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Affiliation(s)
- Umberto Maccio
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland.
| | - Andreas Wicki
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland
| | - Frank Ruschitzka
- University of Zurich, Zurich, Switzerland; Department of Cardiology, University Heart Center, University Hospital of Zurich and University of Zurich, Zurich, Switzerland; Department of Cardiology, Center for Translational and Experimental Cardiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Felix Beuschlein
- University of Zurich, Zurich, Switzerland; Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland; The LOOP Zurich-Medical Research Center, Zurich, Switzerland
| | - Sibylle Wolleb
- Division of Medical Oncology, Hospital of Uster, Uster, Switzerland
| | - Zsuzsanna Varga
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland
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Wang S, Tian B, Wang H. Risk Factors and Prognostic Analysis of Immune Checkpoint Inhibitor-Related Colitis in Lung Cancer. J Inflamm Res 2024; 17:7535-7542. [PMID: 39464335 PMCID: PMC11505368 DOI: 10.2147/jir.s482456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/21/2024] [Indexed: 10/29/2024] Open
Abstract
Objective This study aimed to investigate the risk factors for immune checkpoint inhibitor (ICI)-related colitis and its impact on prognosis in the treatment of lung cancer. Methods This retrospective, single-center, observational study included lung cancer patients who received ICIs treatment between January 2016 and January 2022. The correlation between immune-related colitis and prognosis was evaluated. Kaplan-Meier analysis was used to compare the median overall survival (OS). Results Among the lung cancer patients treated with ICIs, the incidence of colitis was 5.88% (35/595). The severity of colitis was graded as follows: grade 1 (8 cases), grade 2 (15 cases), grade 3 (9 cases), and grade 4 (3 cases). Except for the 1 case that resulted in death due to grade 4 adverse events, the remaining patients showed significant improvement after corticosteroid intervention. Among the 35 patients with ICI-related colitis, complete remission was not achieved. Partial remission was observed in 11 cases, disease stability in 16 cases, disease progression in 7 cases, and death in 1 case. Among the included patients, 19 chose to continue ICI treatment after symptom relief. The overall survival for all participants was 34 months (IQR: 24-36), while the overall survival for those who received ICI treatment again was 36 months (IQR: 32-NA), and for those who did not receive ICI treatment again was 32 months (IQR: 21-35). Kaplan-Meier survival curve analysis showed that patients who received ICI treatment again had significantly better overall survival compared to other patients. Conclusion Immune-related colitis remains a significant concern in lung cancer patients treated with ICIs and requires close monitoring and timely intervention. Restarting treatment after symptom relief can provide additional benefits for patients.
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Affiliation(s)
- Shiyang Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of China
| | - Binhe Tian
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of China
| | - Hanping Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of China
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Feakins RM. Inflammatory disorders of the large intestine. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:709-857. [DOI: 10.1002/9781119423195.ch35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chen R, Shi Y, Fang N, Shao C, Huang H, Pan R, Xu Y, Wang M, Liu X, Xu K, Zhu R, Wang M. Bronchoalveolar lavage fluid analysis in patients with checkpoint inhibitor pneumonitis. Cancer Immunol Immunother 2024; 73:235. [PMID: 39271538 PMCID: PMC11399518 DOI: 10.1007/s00262-024-03834-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] [Received: 06/07/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND Checkpoint inhibitor pneumonitis (CIP) is a relatively uncommon but potentially life-threatening immune-related adverse event (irAE). Lung biopsies have not been commonly performed for CIP patients. Bronchoalveolar lavage fluid (BALF) analysis is a useful diagnostic approach for interstitial lung disease. However, BALF features were inconsistent across different studies. METHODS We retrospectively reviewed the medical records of 154 patients with pathologically confirmed malignancies and suffering from CIPs between July 2018 and December 2022. Patients who had bronchoalveolar lavage (BAL) data available were enrolled in our study. Patient clinical, laboratory, radiological and follow-up data were reviewed and analyzed. RESULTS The BALF differential cell count and lymphocyte subset analysis were performed for 42 CIP patients. There were 32 males (76.2%). The mean age at diagnosis of CIP was 62.0 ± 10.4 (range: 31-78) years. The median time to onset of CIP was 98.5 days after the start of immunotherapy. There were 18 patients (42.9%) with low-grade CIPs and 24 patients (57.1%) with high-grade CIPs. The mean lymphocyte percentage was 36.7 ± 22.5%. There were 34 (81%) CIP patients with a lymphocytic cellular pattern. The median ratio of CD3+CD4+/CD3+CD8+ lymphocytes was 0.5 (0.3, 1.0). The ratio was less than 1.0 for 31 CIP patients (73.8%). However, there was no significant difference in the BALF features between patients with low-grade CIPs and those with high-grade CIPs. CONCLUSIONS The CD3+CD8+ lymphocytosis pattern was the main inflammatory profile in the BALF of CIP patients in this cohort. Targeting CD3+CD8+ lymphocytes might be a treatment option for CIPs.
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Affiliation(s)
- Ruxuan Chen
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China
| | - Yujie Shi
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China
| | - Nan Fang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Xian Nong Tan Street, Beijing, 100050, China
| | - Chi Shao
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China
| | - Hui Huang
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China.
| | - Ruili Pan
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China
| | - Yan Xu
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China
| | - Mengqi Wang
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China
| | - Xiangning Liu
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China
| | - Kai Xu
- Department of Radiology, Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, PekingBeijing, 100730, China
| | - Rui Zhu
- Department of Medical Records, Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, PekingBeijing, 100730, China
| | - Mengzhao Wang
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Dongcheng District, Beijing, 100730, China
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Del Gaudio A, Di Vincenzo F, Petito V, Giustiniani MC, Gasbarrini A, Scaldaferri F, Lopetuso LR. Focus on Immune Checkpoint Inhibitors-related Intestinal Inflammation: From Pathogenesis to Therapeutical Approach. Inflamm Bowel Dis 2024; 30:1018-1031. [PMID: 37801695 PMCID: PMC11144981 DOI: 10.1093/ibd/izad229] [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: 05/25/2023] [Indexed: 10/08/2023]
Abstract
Recently, antitumor immunotherapies have witnessed a breakthrough with the emergence of immune checkpoint inhibitors (ICIs) including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. Unfortunately, the use of ICIs has also led to the advent of a novel class of adverse events that differ from those of classic chemotherapeutics and are more reminiscent of autoimmune diseases, the immune-related adverse events (IRAEs). Herein, we performed an insight of the main IRAEs associated with ICIs, focusing on gastroenterological IRAEs and specifically on checkpoint inhibitor colitis, which represents the most widely reported IRAE to date. We comprehensively dissected the current evidence regarding pathogenesis, diagnosis, and management of ICIs-induced colitis, touching upon also on innovative therapies.
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Affiliation(s)
- Angelo Del Gaudio
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Federica Di Vincenzo
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Valentina Petito
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | | | - Antonio Gasbarrini
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Franco Scaldaferri
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Loris Riccardo Lopetuso
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, Chieti, 66100, Italy
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, 66100, Italy
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Wang J, Guo Z, Shen M, Xie Q, Xiang H. Potential application mechanism of traditional Chinese medicine in treating immune checkpoint inhibitor-induced colitis. Front Immunol 2024; 15:1366489. [PMID: 38660314 PMCID: PMC11039877 DOI: 10.3389/fimmu.2024.1366489] [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: 01/06/2024] [Accepted: 03/08/2024] [Indexed: 04/26/2024] Open
Abstract
Cancer ranks among the foremost causes of mortality worldwide, posing a significant threat to human lives. The advent of tumor immunotherapy has substantially transformed the therapeutic landscape for numerous advanced malignancies, notably non-small cell lung cancer and melanoma. However, as immune checkpoint inhibitors (ICIs) are increasingly applied in clinical settings, a spectrum of undesired reactions, termed immune-related adverse events (irAEs), has emerged. These adverse reactions are associated with immunotherapy and can result in varying degrees of harm to the human body. Among these reactions, Immune checkpoint inhibitor-induced colitis (ICIIC) stands out as one of the most prevalent clinical adverse events. In contemporary times, traditional Chinese medicine (TCM) has demonstrated remarkable efficacy in addressing various maladies. Consequently, investigating the potential application and mechanisms of Chinese medicine in countering immune checkpoint inhibitor-induced colitis assumes significant importance in the treatment of this condition.
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Affiliation(s)
- Jing Wang
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ziyue Guo
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Mengyi Shen
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shangdong First Medical University & Shangdong Academy of Medical Sciences, Jinan, China
| | - Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Hongjie Xiang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallego-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:401-432. [PMID: 38228461 DOI: 10.1016/j.gastrohep.2023.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/28/2023] [Accepted: 10/19/2023] [Indexed: 01/18/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
- Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona (UAB), Department of Medicine, Spain.
| | - Sabela Carballal
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Universitat de Barcelona, Spain
| | - Álvaro Díaz-González
- Gastroenterology Department, Grupo de Investigación Clínica y Traslacional en Enfermedades Digestivas, Instituto de Investigación Valdecilla (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Míriam Mañosa
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | | | - Joaquín Cubiella
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitario de Ourense, Grupo de Investigación en Oncología Digestiva-Ourense, Spain
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - María Varela
- Gastroenterology Department, Hospital Universitario Central de Asturias, IUOPA, ISPA, FINBA, University of Oviedo, Oviedo, Spain
| | - Luis Menchén
- Servicio de Aparato Digestivo - CEIMI, Instituto de Investigación Sanitaria Gregorio, Marañón, Spain; Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Cancer Center Clinica Universidad de Navarra, Pamplona-Madrid, Spain
| | - Ana Fernández-Montes
- Medical Oncology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Francisco Mesonero
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Universidad de Alcalá de Henares, Spain
| | - Miguel Ángel Rodríguez-Gandía
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS), Madrid, Spain
| | - Fernando Rivera
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - María-Carlota Londoño
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat de Barcelona, Spain; Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Spain
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8
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallgo-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:83-113. [PMID: 38226597 DOI: 10.17235/reed.2024.10250/2024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
| | | | | | - Miriam Mañosa
- Gastroenterology, Hospital Universitari Germans Trias i Pujol
| | | | | | | | - María Varela
- Gastroenterology, Hospital Universitario Central de Asturias
| | - Luis Menchén
- Digestive Diseases, Instituto de Investigación Sanitaria Gregorio Marañón
| | | | | | | | | | - Fernando Rivera
- Hospital Universitario Marqués de Valdecilla, Medical Oncology
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Mitchell JM, Karamchandani DM. Histopathologic Manifestations of Immune Checkpoint Inhibitor Therapy-Associated Gastrointestinal Tract Injury: A Practical Review. Surg Pathol Clin 2023; 16:703-718. [PMID: 37863561 DOI: 10.1016/j.path.2023.05.007] [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: 10/22/2023]
Abstract
Immune checkpoint inhibitors have revolutionized the management of many advanced cancers by producing robust remissions. They mostly target two immune regulatory pathways: cytotoxic T lymphocyte antigen-4 and programmed death-1 or its ligand. However, a flip side is the immune-related adverse events (irAEs) commonly affecting the gastrointestinal (GI) tract that can cause treatment interruptions or discontinuation. This practical review discusses the clinical and histopathologic findings of irAEs encountered in the luminal GI tract, along with histopathologic differentials that can mimic varied inflammatory, infectious, or other medication-associated etiologies and the importance of clinico-pathologic correlation for an accurate diagnosis.
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Affiliation(s)
- James Michael Mitchell
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. https://twitter.com/GIJamesMD
| | - Dipti M Karamchandani
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
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Lobatón T, Truyens M. Editorial: LAG-3-depleting monoclonal antibody: a potential treatment for patients with ulcerative colitis? Aliment Pharmacol Ther 2023; 58:359-360. [PMID: 37452596 DOI: 10.1111/apt.17604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Affiliation(s)
- Triana Lobatón
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Marie Truyens
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
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11
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Vlachos I, Karamanolis G, Vezakis A, Dellaportas D, Myoteri D. Nivolumab-Induced Colitis in a Patient With Esophageal Adenocarcinoma: A Case Report. Cureus 2023; 15:e42315. [PMID: 37614260 PMCID: PMC10442715 DOI: 10.7759/cureus.42315] [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] [Accepted: 07/22/2023] [Indexed: 08/25/2023] Open
Abstract
Nivolumab is an immune checkpoint inhibitor used in the treatment of several types of cancer. Among the adverse effects of this drug, immune-mediated colitis (IMC) has been described. However, in contrast to other checkpoint inhibitors, such as ipilimumab, drug-induced colitis due to nivolumab is not commonly reported. We report the case of a 59-year-old male who had undergone surgical resection for gastroesophageal junction adenocarcinoma, had been on nivolumab during the past five months, and presented with worsening diarrhea. Colonoscopy demonstrated local edema and mild colitis in a region of the colonic mucosa located 30 cm distal to the ileocecal valve. Biopsies revealed acute moderate colitis. The patient responded well to loperamide and dietary modifications. Although nivolumab rarely causes IMC, this occurrence requires proper management in order to avoid further complications.
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Affiliation(s)
- Iakovos Vlachos
- Department of Pathology, Aretaieion University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, GRC
| | - Georgios Karamanolis
- Department of Gastroenterology, School of Medicine, National and Kapodistrian University of Athens, Athens, GRC
| | - Antonios Vezakis
- 2nd Department of Surgery, Aretaieion University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, GRC
| | - Dionysios Dellaportas
- 3rd Department of Surgery, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, GRC
| | - Despoina Myoteri
- Department of Pathology, Aretaieion University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, GRC
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12
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Ohwada S, Ishigami K, Yokoyama Y, Kazama T, Masaki Y, Takahashi M, Yoshii S, Yamano HO, Chiba H, Nakase H. Immune-related colitis and pancreatitis treated with infliximab. Clin J Gastroenterol 2023; 16:73-80. [PMID: 36414888 DOI: 10.1007/s12328-022-01731-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/28/2022] [Indexed: 11/24/2022]
Abstract
Patients with various cancers benefit from immune checkpoint inhibitors. However, immune checkpoint inhibitor-induced adverse events have also been reported, such as colitis. Prednisolone is the first-line treatment for immune-related adverse events, but second-line therapy for patients refractory to steroids has not been established. Furthermore, the inflammatory cytokine expression pattern in the intestinal mucosa of patients with steroid-refractory immune-related colitis remains unclear. We present the case of a 48-year-old man diagnosed with immune-related colitis and pancreatitis induced by pembrolizumab for advanced lung cancer. First, we administered 50 mg/day of prednisolone, and the patient's abdominal symptoms improved. However, the pancreatic enzyme levels did not return to normal. Furthermore, the patient's diarrhea worsened and hematochezia appeared at a 40 mg/day prednisolone dose. A mucosal cytokine analysis identified a low interleukin-10 messenger RNA level, which has been associated with a poor response to prednisolone. Thus, we administered 5 mg/kg of infliximab; the patient's diarrhea and hematochezia immediately improved, and the pancreatic enzyme levels returned to normal. Infliximab was administered three times every 2 weeks. After, the patient's colitis and pancreatitis did not recur. To our knowledge, this is the first report demonstrating the effectiveness of infliximab for immune-related colitis and pancreatitis.
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Affiliation(s)
- Sae Ohwada
- Department of Gastroenterology, Muroran City General Hospital, Muroran, Japan.,Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Keisuke Ishigami
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Yoshihiro Yokoyama
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tomoe Kazama
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yoshiharu Masaki
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Mamoru Takahashi
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shinji Yoshii
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiro-O Yamano
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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13
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Drug-induced digestive tract injury: decoding some invisible offenders. Hum Pathol 2023; 132:135-148. [PMID: 35714837 DOI: 10.1016/j.humpath.2022.06.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/09/2022] [Indexed: 02/07/2023]
Abstract
There is an ever-growing list of pharmacological agents, several of which are attributed to cause clinically significant gastrointestinal (GI) injury. Many patients present with significant but nonspecific symptoms, that in conjunction with the absence of relevant drug history on the requisition slip can make the histopathologic diagnosis challenging. To complicate this, although some drugs have relatively characteristic histopathologic features (such as doxycycline), there exist many other drugs that exhibit wide and varying spectra of histopathologic findings (such as immune checkpoint inhibitors or olmesartan) and have histomorphologic overlap with many other commonly encountered disease entities. This review discusses the histopathologic features of some relatively recently described drugs causing GI tract injury, namely doxycycline, tacrolimus, mycophenolate, immune checkpoint inhibitors, and olmesartan. We also discuss the common mimics in histopathologic differential and some pearls that can help distinguish GI tract injury induced by the aforementioned drugs from its mimics. Awareness of the wide spectra of histopathologic changes associated with these drugs is crucial for practicing pathologists, to avoid misdiagnosis and guiding the clinician for an optimal patient management, which usually involves modifying or discontinuing the offending drug. Needless to say, once a diagnosis of drug-induced injury is suspected, clinicopathologic correlation including corroboration with the drug history is of utmost importance as is the exclusion of dual pathology in these patients.
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14
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Zhang P, Mao R, Zhang C, Qiu Y, Chen M. Gastrointestinal injury induced by immunomodulators: A review article. Therap Adv Gastroenterol 2023; 16:17562848231158549. [PMID: 37113189 PMCID: PMC10126616 DOI: 10.1177/17562848231158549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 02/02/2023] [Indexed: 04/29/2023] Open
Abstract
An increasing number of immunomodulators, either anti-inflammatory or immunity-enhancing, have brought about a revolutionary effect in the management of a variety of autoimmune disorders and malignancies. However, their ability to cause gastrointestinal (GI) injury and induce GI symptoms has been increasingly and unexpectedly recognized. GI injury associated with immunomodulators may demonstrate various histologic and endoscopic patterns. Optimal diagnosis and treatment require a multidisciplinary approach. This review aims to provide an overview of the literature on its pathogenesis, the clinical, endoscopic, and histologic features, and suggested approaches to manage these newly recognized immunomodulator-induced GI adverse effects (AEs). We also reviewed current biomarkers predictive of GI toxicity and potential risk factors to identify susceptible patients. In addition, these immune-mediated AEs were compared with inflammatory bowel disease, a well-documented form of inflammation-driven GI injury. We hope this review will raise awareness and vigilance among clinicians of these entities to increase early diagnosis and rapid referral to specialist care.
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Affiliation(s)
- Pingxin Zhang
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | - Ren Mao
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | - Chuhan Zhang
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | | | - Minhu Chen
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
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15
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Deng LR, Han Q, Zou M, Chen FJ, Huang CY, Zhong YM, Wu QY, Tomlinson B, Li YH. Identification of potential immunomodulators from Pulsatilla decoction that act on therapeutic targets for ulcerative colitis based on pharmacological activity, absorbed ingredients, and in-silico molecular docking. Chin Med 2022; 17:132. [PMID: 36434688 PMCID: PMC9701001 DOI: 10.1186/s13020-022-00684-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/03/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Pulsatilla decoction (Bai-Tou-Weng-Tang, BTWT) is a classic formula prescription of a traditional Chinese medicine that is used to treat ulcerative colitis (UC). However, its active components and underlying mechanism of action remain unclear. In the present study, we aimed to identify potential immunomodulators from BTWT that act at therapeutic targets for UC. METHODS The protective effects of BTWT granules were examined in mice with colitis induced by dextran sulfate sodium. The absorbed components of BTWT were identified using LC-MS, and selected protein targets of these components in UC were investigated using molecular docking. RESULTS Oral administration of BTWT granules significantly alleviated disease severity and colon shortening, and inhibited the inflammatory response in mice with chronic colitis. In these mice, 11 compounds from the BTWT granules were detected in the serum and/or colon. The molecular docking study demonstrated that compounds from Radix pulsatillae, such as anemoside A3, interacted with STAT3 and S1PR1; compounds from Rhizoma coptidis and/or Cortex phellodendri, such as palmatine, interacted with JAK3, PD-1, and PD-L1; and components of Cortex fraxini such as aesculin interacted with S1PR1, JAK3, STAT3 and PD-L1. Further in-vitro experiments showing that the compounds inhibited TNF-α and IL-6 production and STAT3 activation in RAW 264.7 cells suggested that these compounds have immunomodulatory activities. CONCLUSION We revealed for the first time that 11 absorbed ingredients from BTWT were immunomodulators against therapeutic targets for UC. These findings suggest that the identified compounds are the active components of BTWT, and the identified protein targets underlie the mechanism of action of BTWT against UC.
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Affiliation(s)
- Li-rong Deng
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
| | - Qian Han
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
| | - Min Zou
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
| | - Fang-jun Chen
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
| | - Chang-yin Huang
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
| | - Yi-ming Zhong
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
| | - Qian-yan Wu
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
| | - Brian Tomlinson
- grid.259384.10000 0000 8945 4455Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau China
| | - Yan-hong Li
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
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16
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Immunotherapy-induced Colitis: A Comprehensive Review of Epidemiology, Clinical Presentation, Diagnostic Workup, and Management Plan. J Clin Gastroenterol 2022; 56:555-564. [PMID: 35470301 DOI: 10.1097/mcg.0000000000001705] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a variety of malignancies including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers among others. Since their introduction, there has been significant improvement in survival and prognosis in patients with advanced malignancies. Unfortunately, improved outcomes have come at a price of significant immune-related adverse events, with those of the gastrointestinal tract being the most common. Gastrointestinal immune-related adverse events frequently present as diarrhea and colitis, the severity of which can range from mild diarrhea to fulminant colitis with intestinal perforation. Currently, management of ICI-induced colitis is primarily guided by retrospective studies and expert opinion. A significant number of ICI-induced colitis responds to high-dose corticosteroids; however, some patients require further therapy with biologics. There is limited information on the factors which may predispose patients to ICI-induced colitis. Future research elucidating these risk factors along with development of a scoring system could allow for risk-stratification of patients before initiation of ICI therapy. Such a system may help clinicians and patients keep a high index of suspicion regarding ICI-induced colitis and could hopefully reduce the incidence of severe cases. Similarly, future studies should investigate protective factors against ICI-induced colitis, which could potentially allow more patients to safely benefit from ICI therapy.
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17
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Buch SA, Baba MR. Immune-Related Adverse Events (irAEs) in Cancer, with Inputs from a Nursing Expert: A Review. Indian J Med Paediatr Oncol 2022. [DOI: 10.1055/s-0042-1742442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
AbstractImmune checkpoint inhibitors (ICPis) belong to a group of immunotherapeutic agents that act on different immune cells and tumor cells and reactivate the suppressed immune system of the host. The emergence of immunotherapy has resulted in the successful management of many malignancies. High success rates with certain advanced cancers have attributed wide importance and relevance to the use of immunotherapy. Although ICPis have gained huge popularity, their use often leads to side effects that can affect almost any system; immune-related adverse events (irAEs). These adverse events occur due to unrestrained T cell activity that unsettles the immune homeostasis of the host. Although close monitoring for toxicities controls the events on most of the occasions, the inability to diagnose them early may prove fatal on some occasions due to their subtle and nonspecific symptoms. This review summarizes in brief the usual irAEs and their management, besides a very important nursing perspective, from a nursing expert about an overall insight into the routine irAEs.
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Affiliation(s)
- Sajad Ahmad Buch
- Department of Oral Medicine and Radiology, Yenepoya Dental College, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Mudasir Rashid Baba
- Yenepoya Physiotherapy College, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
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18
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Feakins R, Torres J, Borralho-Nunes P, Burisch J, Cúrdia Gonçalves T, De Ridder L, Driessen A, Lobatón T, Menchén L, Mookhoek A, Noor N, Svrcek M, Villanacci V, Zidar N, Tripathi M. ECCO Topical Review on Clinicopathological Spectrum and Differential Diagnosis of Inflammatory Bowel Disease. J Crohns Colitis 2022; 16:343-368. [PMID: 34346490 DOI: 10.1093/ecco-jcc/jjab141] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Many diseases can imitate inflammatory bowel disease [IBD] clinically and pathologically. This review outlines the differential diagnosis of IBD and discusses morphological pointers and ancillary techniques that assist with the distinction between IBD and its mimics. METHODS European Crohn's and Colitis Organisation [ECCO] Topical Reviews are the result of an expert consensus. For this review, ECCO announced an open call to its members and formed three working groups [WGs] to study clinical aspects, pathological considerations, and the value of ancillary techniques. All WGs performed a systematic literature search. RESULTS Each WG produced a draft text and drew up provisional Current Practice Position [CPP] statements that highlighted the most important conclusions. Discussions and a preliminary voting round took place, with subsequent revision of CPP statements and text and a further meeting to agree on final statements. CONCLUSIONS Clinicians and pathologists encounter a wide variety of mimics of IBD, including infection, drug-induced disease, vascular disorders, diverticular disease, diversion proctocolitis, radiation damage, and immune disorders. Reliable distinction requires a multidisciplinary approach.
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Affiliation(s)
- Roger Feakins
- Department of Cellular Pathology, Royal Free Hospital, London, and University College London, UK
| | - Joana Torres
- Department of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
| | - Paula Borralho-Nunes
- Department of Pathology, Hospital Cuf Descobertas, Lisboa and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Tiago Cúrdia Gonçalves
- Department of Gastroenterology, Hospital da Senhora da Oliveira, Guimarães, Portugal.,School of Medicine, University of Minho, Braga/Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Lissy De Ridder
- Department of Paediatric Gastroenterology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, The Netherlands
| | - Ann Driessen
- Department of Pathology, University Hospital Antwerp, University Antwerp, Edegem, Belgium
| | - Triana Lobatón
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Luis Menchén
- Department of Digestive System Medicine, Hospital General Universitario-Insitituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.,Department of Medicine, Universidad Complutense, Madrid, Spain.,Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - Aart Mookhoek
- Department of Pathology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Nurulamin Noor
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Magali Svrcek
- Department of Pathology, Sorbonne Université, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Vincenzo Villanacci
- Department of Histopathology, Spedali Civili and University of Brescia, Brescia, Italy
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Monika Tripathi
- Department of Histopathology, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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19
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Tang L, Wang J, Lin N, Zhou Y, He W, Liu J, Ma X. Immune Checkpoint Inhibitor-Associated Colitis: From Mechanism to Management. Front Immunol 2021; 12:800879. [PMID: 34992611 PMCID: PMC8724248 DOI: 10.3389/fimmu.2021.800879] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 11/29/2021] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs), as one of the innovative types of immunotherapies, including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, have obtained unprecedented benefit in multiple malignancies. However, the immune response activation in the body organs could arise immune-related adverse events (irAEs). Checkpoint inhibitor colitis (CIC) is the most widely reported irAEs. However, some obscure problems, such as the mechanism concerning gut microbiota, the confusing differential diagnosis with inflammatory bowel disease (IBD), the optimal steroid schedule, the reintroduction of ICIs, and the controversial prognosis features, influence the deep understanding and precise diagnosis and management of CIC. Herein, we based on these problems and comprehensively summarized the relevant studies of CIC in patients with NSCLC, further discussing the future research direction of this specific pattern of irAEs.
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Affiliation(s)
- Liansha Tang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jialing Wang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Nan Lin
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wenbo He
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jiyan Liu
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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20
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Yanai S, Toya Y, Sugai T, Matsumoto T. Gastrointestinal Adverse Events Induced by Immune-Checkpoint Inhibitors. Digestion 2021; 102:965-973. [PMID: 34515105 DOI: 10.1159/000518543] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/17/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND As immune-checkpoint inhibitors (ICI) are becoming standard therapies for malignant tumors, increasing attention has been paid to their associated immune-related adverse events (irAEs). The gastrointestinal tract is the major site of irAEs, and it has recently become evident that the large bowel is the most frequently affected region. The aim of this narrative review was to clarify the endoscopic and histopathologic findings of and treatments for ICI-induced colitis. SUMMARY Endoscopic findings of ICI-induced colitis include a reddish, edematous mucosa with increased mucous exudate, loss of normal vascularity, and a granular mucosa with or without mucosal breaks. Histopathologic findings of ICI-induced colitis are expansion of the lamina propria, intraepithelial infiltration of neutrophils, crypt architectural distortion, neutrophilic crypt abscess, and prominent apoptosis. The clinical, endoscopic, and histopathologic severity of ICI-induced colitis is diverse, but colonoscopy together with biopsy is necessary for diagnosis. While a certain proportion of patients with ICI-induced colitis have an intractable clinical course, management guidelines are based on retrospective analyses. Prospective studies are needed to assess the efficacy of various medications, including immunosuppressive regimens. Key Messages: Colonoscopy with biopsy is the gold standard for the diagnosis of ICI-induced colitis. Endoscopists should be aware of the clinical features and pathophysiology of ICI-induced colitis for prompt diagnosis and treatment planning.
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Affiliation(s)
- Shunichi Yanai
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Yosuke Toya
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
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21
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Khan J, Katona T. Immune Checkpoint Inhibitor-Induced Colitis Presenting As Lymphocytic Colitis. Cureus 2021; 13:e18085. [PMID: 34692300 PMCID: PMC8523195 DOI: 10.7759/cureus.18085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/18/2021] [Indexed: 11/15/2022] Open
Abstract
Checkpoint inhibitors (CPIs) are a new class of drugs that have changed the treatment and prognosis of several malignancies, even in their advanced stages. These drugs have increased patient survival rates. CPIs stimulate the immune system and include cytotoxic T-lymphocyte antigen-4 inhibitors (ipilimumab), programmed cell death inhibitors such as pembrolizumab, nivolumab, and avelumab, and programmed cell death protein ligand-1 inhibitors such as atezolizumab. Herein, we present a case of CPI-induced colitis in a 45-year-old woman with a history of melanoma. The melanoma was BRAF-positive with a V600 mutation. She had metastasis to the brain and the right 10th rib, which underwent surgery and radiation treatment, respectively. She was treated with nivolumab and denosumab. The patient presented with chronic watery diarrhea. Biopsy revealed lymphocytic colitis-like changes in the colon and terminal ileum. Thus, given the history of CPIs, a diagnosis of CPIS-induced colitis was made.
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Affiliation(s)
- Jaffar Khan
- Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, USA
| | - Terrence Katona
- Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, USA
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22
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Pembrolizumab-induced autoimmune side effects of colon and pancreas in a patient with lung cancer. Clin J Gastroenterol 2021; 14:1692-1699. [PMID: 34415552 DOI: 10.1007/s12328-021-01499-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/06/2021] [Indexed: 02/07/2023]
Abstract
Immune checkpoint inhibitors have been shown to be effective for treating many carcinomas. However, the activated immune response may lead to the development of multiple immune-related adverse events, including rare immune-mediated inflammation due to autoimmune mechanisms. An 82-year-old man was diagnosed with large cell lung cancer (T1aN3M1 stage IVB) and was treated with inhibitors of the programmed cell death receptor-1, pembrolizumab. Diarrhea and melena occurred after six doses of pembrolizumab, and colonoscopy revealed mucosal inflammation of the rectum and sigmoid colon in a continuous manner, resembling the typical endoscopic findings of ulcerative colitis. Subsequently, fever and hyperamylasemia appeared, and the patient was diagnosed with pancreatitis resembling type 2 autoimmune pancreatitis on imaging tests and cytological examination, which showed infiltration of inflammatory cells, mainly neutrophils. Steroid therapy was administered and both, colitis and pancreatitis markedly improved. Here, we present a patient who developed colitis and pancreatitis after ICI treatment for advanced lung cancer. Both are thought to be due to autoimmune side effects of pembrolizumab. Although pancreatitis is a rare irAE, clinicians should be aware of the development of pancreatitis, especially in the case of irAE colitis resembling ulcerative colitis.
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23
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Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8 + T cells and an infiltration pattern that resembles ulcerative colitis. Virchows Arch 2021; 479:1119-1129. [PMID: 34338882 PMCID: PMC8724151 DOI: 10.1007/s00428-021-03170-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/14/2021] [Accepted: 07/22/2021] [Indexed: 12/17/2022]
Abstract
Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn’s disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn’s disease.
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A case of immune checkpoint inhibitor-related colitis with a distinctive endoscopic finding of colonic pseudolipomatosis. Clin J Gastroenterol 2021; 14:1431-1436. [PMID: 34106395 DOI: 10.1007/s12328-021-01459-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/02/2021] [Indexed: 10/21/2022]
Abstract
A man in his 70s received anticancer chemotherapy with the anti-programmed cell death protein-ligand 1 antibody atezolizumab for non-small cell lung cancer. Ten days later, he developed diarrhea and skin rash, which were suspected to be due to immune-related adverse events, and was treated with prednisolone for 2 weeks. Five weeks after atezolizumab administration, he was admitted to our hospital for Common Terminology Criteria for Adverse Events Grade 3 diarrhea and hematochezia. Sigmoidoscopy revealed a dark red color in the mucosa of the transverse colon and multiple whitish mucosal plaques extending from the transverse colon to the rectum. Biopsy specimens revealed empty vacuoles in the lamina propria with infiltration of numerous inflammatory cells, including CD8+ T cells. Based on the findings of sigmoidoscopy and histology, the diagnosis was immune checkpoint inhibitor-related colitis with colonic pseudolipomatosis. The endoscopic findings and symptoms were markedly improved by prednisolone administration. We herein report the first case of immune checkpoint inhibitor-related colitis with characteristic endoscopic findings of colonic pseudolipomatosis. It is important to perform endoscopy and histological evaluation to determine the differential diagnosis and treatment strategy for patients treated with immune checkpoint inhibitors.
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Zheng X, Wei H. Organ-Specific Immune-Related Adverse Events for PD-1 Antibodies in Lung Cancer Treatment. Front Oncol 2021; 11:628243. [PMID: 34094910 PMCID: PMC8175899 DOI: 10.3389/fonc.2021.628243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 05/04/2021] [Indexed: 12/19/2022] Open
Abstract
Anti-PD-1 therapy has revolutionized the clinical treatment of lung cancer. With the increasing number of lung cancer patients being treated, there is also an increase in the number of immune-related adverse events (irAEs) being reported. These irAEs involve multiple organs and systems, mainly manifest as inflammatory side effects, and are different from the adverse events observed with traditional lung cancer treatment. These effects are often mild and treatable and reversible; however, in a few cases the side effects can be severe and lead to termination of immunotherapy. Management involves glucocorticoid-based related immunomodulators, which should be carefully prescribed to balance the efficacy and side effects of the PD-1 antibody treatment. This review will describe the characteristics and mechanisms of irAEs in specific organs, and will serve as a guide to help optimize treatment plans and improve patient outcomes.
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Affiliation(s)
- Xiaohu Zheng
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China.,Research Unit Of NK Cells, Chinese Academy Of Medical Sciences, Hefei, China
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He M, Yang T, Wang Y, Wang M, Chen X, Ding D, Zheng Y, Chen H. Immune Checkpoint Inhibitor-Based Strategies for Synergistic Cancer Therapy. Adv Healthc Mater 2021; 10:e2002104. [PMID: 33709564 DOI: 10.1002/adhm.202002104] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/26/2021] [Indexed: 12/16/2022]
Abstract
Immune checkpoint blockade therapy (ICBT) targeting checkpoints, such as, cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed death-1 (PD-1), or programmed death-ligand 1 (PD-L1), can yield durable immune response in various types of cancers and has gained constantly increasing research interests in recent years. However, the efficacy of ICBT alone is limited by low response rate and immune-related side effects. Emerging preclinical and clinical studies reveal that chemotherapy, radiotherapy, phototherapy, or other immunotherapies can reprogramm immunologically "cold" tumor microenvironment into a "hot" one, thus synergizing with ICBT. In this review, the working principle and current development of various immune checkpoint inhibitors are summarized, while the interactive mechanism and recent progress of ICBT-based synergistic therapies with other immunotherapy, chemotherapy, phototherapy, and radiotherapy in fundamental and clinical studies in the past 5 years are depicted and highlighted. Moreover, the potential issues in current studies of ICBT-based synergistic therapies and future perspectives are also discussed.
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Affiliation(s)
- Mengying He
- Jiangsu Key Laboratory of Neuropsychiatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China
| | - Tao Yang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China
| | - Yuhan Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China
| | - Mengyuan Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China
| | - Xingye Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China
| | - Dawei Ding
- Jiangsu Key Laboratory of Neuropsychiatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China
| | - Yiran Zheng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China
| | - Huabing Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China
- State Key Laboratory of Radiation Medicine and Protection Soochow University Suzhou 215123 China
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Patil PA, Zhang X. Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy. Arch Pathol Lab Med 2021; 145:571-582. [PMID: 32338534 DOI: 10.5858/arpa.2020-0070-ra] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2020] [Indexed: 02/05/2023]
Abstract
CONTEXT.— Immune checkpoint inhibitors (CPIs), including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, are being increasingly used for treating many advanced malignancies. However, CPI therapy is also associated with gastrointestinal and hepatobiliary adverse effects. OBJECTIVES.— To review the adverse effects of CPI therapy on the gastrointestinal tract and hepatobiliary system. To describe histopathologic patterns and discuss differential diagnostic considerations in the diagnosis of CPI injuries. DATA SOURCES.— Published peer-reviewed literature in the English language and personal experience in the diagnosis of CPI injuries. CONCLUSIONS.— The pathologic manifestations of CPI therapy-induced gastrointestinal and hepatobiliary injury are broad. The patterns of esophageal CPI injury include lymphocytic inflammation and ulcerative esophagitis, while those of gastric injury include chronic active gastritis, lymphocytic gastritis, focal enhancing gastritis, and periglandular inflammation. The duodenal injury may present as duodenitis with villous blunting and granulomas. We also noticed active colitis, microscopic colitis, chronic active colitis, increased apoptosis, ischemic colitis, and nonspecific inflammatory reactive changes in colonic injuries. The reported histologic features of hepatobiliary injuries are panlobular hepatitis, centrilobular necrosis, portal inflammation with bile duct injury, steatosis, nodular regenerative hyperplasia, and secondary sclerosing cholangitis. In summary, we discuss the pathologic features and differential diagnosis of CPI therapy-induced gastrointestinal and hepatobiliary injury. Recognition of CPI injury is important to determine the proper management that often includes cessation of CPI therapy, and administration of steroids or other immunosuppressive agents, based on severity of injury.
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Affiliation(s)
- Pallavi A Patil
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Xuchen Zhang
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
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28
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Iaquinto G, Panico L, Luongo G, Tenneriello V, Iaquinto S, Giardullo N, Rotondi Aufiero V, Mazzarella G, Rispoli R, Lucariello A, Perna A, De Luca A. Adult autoimmune enteropathy in autoimmune hepatitis patient. Case report and literature review. Clin Res Hepatol Gastroenterol 2021; 45:101673. [PMID: 33744411 DOI: 10.1016/j.clinre.2021.101673] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 01/25/2021] [Accepted: 03/02/2021] [Indexed: 02/04/2023]
Abstract
Autoimmune enteropathy (AIE) is a rare disease characterized by prolonged diarrhea, vomiting and weight loss; although it is mainly a rare pediatric disease, over the years a number of adults have also been found to be affected. In this study, we present a case report of a 73-year-old woman with a history of autoimmune hepatitis, antinuclear (ANA) and positive anti-enterocyte antibodies (AEA), who has suffered two months of intractable diarrhea, nausea, anorexia and severe weight loss. The histological examination of the endoscopic duodenal mucosa biopsies revealed severe shortening and flattening of the villi, resulting in mucosal atrophy. The immunohistochemical study revealed a polymorphic lymphoid population, exhibiting a B cell (CD20+) phenotype in follicles and a T cell phenotype (CD3+) in the diffuse component within the lamina propria. Our patient had a complete recovery after two weeks of taking prednisone and following a gluten-rich diet. To our knowledge this is the first case of autoimmune enteropathy in adults with ANA and AEA 7 years after a diagnosis of autoimmune hepatitis. To date, the patient is still in clinical remission on a low dose of orally administered predinisone without any additional immunosuppression.
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Affiliation(s)
- Gaetano Iaquinto
- Division of Gastroenterology, Department of Internal Medicine, S. Rita Hospital, Atripalda, Avellino, Italy.
| | - Luigi Panico
- Department of Pathology, AORN dei Colli, Monaldi Hospital, Naples, Italy
| | - Gelsomina Luongo
- Department of Pathology, San G. Moscati Hospital, Avellino, Italy
| | | | | | - Nicola Giardullo
- Division of Gastroenterology, San G. Moscati Hospital, Avellino, Italy
| | | | | | - Raffaella Rispoli
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Angela Lucariello
- Department of Sport Sciences and Wellness, University of Naples "Parthenope", Naples, Italy
| | - Angelica Perna
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy
| | - Antonio De Luca
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania "Luigi Vanvitelli", Naples, Italy
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Kichloo A, Albosta M, Dahiya D, Guidi JC, Aljadah M, Singh J, Shaka H, Wani F, Kumar A, Lekkala M. Systemic adverse effects and toxicities associated with immunotherapy: A review. World J Clin Oncol 2021; 12:150-163. [PMID: 33767971 PMCID: PMC7968107 DOI: 10.5306/wjco.v12.i3.150] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/21/2021] [Accepted: 02/20/2021] [Indexed: 02/06/2023] Open
Abstract
Immunotherapy is rapidly evolving secondary to the advent of newer immunotherapeutic agents and increasing approval of the current agents by the United States Food and Drug Administration to treat a wide spectrum of cancers. Immunotherapeutic agents have gained immense popularity due to their tumor-specific action. Immunotherapy is slowly transforming into a separate therapeutic entity, and the fifth pillar of management for cancers alongside surgery, radiotherapy, chemotherapy, and targeted therapy. However, like any therapeutic entity it has its own adverse effects. With the increasing use of immuno-therapeutic agents, it is vital for physicians to acquaint themselves with these adverse effects. The aim of this review is to investigate the common systemic adverse effects and toxicities associated with the use of different classes of immunotherapeutic agents. We provide an overview of potential adverse effects and toxicities associated with different classes of immunotherapeutic agents organized by organ systems, as well as an extensive discussion of the current recommendations for treatment and clinical trial data. As we continue to see increasing usage of these agents in clinical practice, it is vital for physicians to familiarize themselves with these effects.
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Affiliation(s)
- Asim Kichloo
- Department of Internal Medicine, Central Michigan University, Saginaw, MI 48603, United States
- Department of Internal Medicine, Samaritan Medical Center, Watertown, NY 13601, United States
| | - Michael Albosta
- Department of Internal Medicine, Central Michigan University, Saginaw, MI 48603, United States
| | - Dushyant Dahiya
- Department of Internal Medicine, Central Michigan University, Saginaw, MI 48603, United States
| | - Jean Claude Guidi
- Department of Internal Medicine, Samaritan Medical Center, Watertown, NY 13601, United States
| | - Michael Aljadah
- Department of Internal Medicine, Medical College of Wisconsin, Milwaukee, WI 53201, United States
| | - Jagmeet Singh
- Department of Nephrology, Guthrie Robert Packer Hospital, Sayre, PA 18840, United States
| | - Hafeez Shaka
- Department of Internal Medicine, John H Stroger Jr. Hospital of Cook County, Chicago, IL 60612, United States
| | - Farah Wani
- Department of Family Medicine, Samaritan Medical Center, Watertown, NY 13601, United States
| | - Akshay Kumar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Manidhar Lekkala
- Department of Hematology and Oncology, University of Rochester Medical Center, Rochester, NY 14642, United States
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30
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Irshaid L, Robert ME, Zhang X. Immune Checkpoint Inhibitor-Induced Upper Gastrointestinal Tract Inflammation Shows Morphologic Similarities to, but Is Immunologically Distinct From, Helicobacter pylori Gastritis and Celiac Disease. Arch Pathol Lab Med 2021; 145:191-200. [PMID: 33501492 DOI: 10.5858/arpa.2019-0700-oa] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2020] [Indexed: 02/05/2023]
Abstract
CONTEXT.— Immune checkpoint inhibitor (CPI) therapies are associated with multi-organ immune-related adverse events. Although colonic mucosal changes have been described, inflammatory changes incited by CPIs in the upper gastrointestinal tract have not been well characterized. OBJECTIVE.— To investigate morphologic and immunologic changes incited by CPI therapy in the upper gastrointestinal tract. DESIGN.— We compared the morphology and immune cell phenotype of gastric and duodenal biopsies from patients treated with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or anti-programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) antibodies with biopsies from patients with Helicobacter pylori gastritis, patients with celiac disease, and normal controls. RESULTS.— Gastric biopsies from patients on CPIs showed chronic gastritis mimicking H pylori gastritis. However, CPI gastritis demonstrated greater numbers of CD8+ intraepithelial lymphocytes, less lamina propria inflammation, fewer plasma cells and CD20+ B cells, fewer lymphoid aggregates, and reduced CD4:CD8 ratio in both the lamina propria and the epithelial layer. There were no differences between anti-CTLA-4 and anti-PD-1/PD-L1 gastritis, except for more lymphoid aggregates in anti-PD-1/PD-L1 gastritis. Duodenal biopsies from patients on CPIs revealed chronic duodenitis with villous blunting, mimicking celiac disease. Compared with celiac disease, CPI duodenitis demonstrated higher prevalence of neutrophilic infiltrates and erosions, increased lamina propria CD3 and CD8 T cells, and reduced CD4:CD8 ratio. Upper gastrointestinal biopsies were more inflamed than concomitant colonic biopsies in the majority of patients. CONCLUSIONS.— The morphologic and immunophenotypic distinctions between CPI-associated upper gastrointestinal injuries and common infectious and autoimmune diseases may provide useful discriminators when clinicians are confronted with gastric and duodenal inflammatory changes in patients receiving CPI therapy.
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Affiliation(s)
- Lina Irshaid
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Marie E Robert
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Xuchen Zhang
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
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31
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Dahiya DS, Kichloo A, Singh J, Albosta M, Lekkala M. Current immunotherapy in gastrointestinal malignancies A Review. J Investig Med 2021; 69:689-696. [PMID: 33443046 DOI: 10.1136/jim-2020-001654] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2020] [Indexed: 12/24/2022]
Abstract
Immunotherapy is an extremely important breakthrough and an exciting new modality of treatment for a wide spectrum of cancers. It is focused around developing agents to stimulate or suppress the immune system, in a specific manner, to fight off a wide spectrum of diseases, particularly cancers. Traditional therapies available for the treatment of cancers include surgical intervention, chemotherapy, radiation therapy or a combination of these, which tend to be very non-specific. However, immunotherapy shows a stark difference from conventional therapy, in fact, that it has a high level of specificity for the tumor-specific antigens. The recent success of cancer immunotherapies in clinical trials is slowly revolutionizing the landscape for cancer therapy. The US Food and Drug Administration has approved numerous agents, after clinical trials showed promising results, for the treatment of multiple cancers. The role of immunotherapy in gastrointestinal cancers has also been very promising, particularly in patients with advanced metastatic disease or malignancies refractory to initial treatment. In this review of literature, we detail and discuss the immunotherapy agents approved for the treatment of GI cancers and glance at the future of immunotherapy for patients with these cancers.
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Affiliation(s)
| | - Asim Kichloo
- Department of Internal Medicine, CMU Medical Education Partners, Saginaw, Michigan, USA .,Department of Internal Medicine, Samaritan Medical Center, Watertown, New York, USA
| | - Jagmeet Singh
- Internal Medicine, Guthrie Healthcare System, Sayre, Pennsylvania, USA.,Department of Internal Medicine, Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania, USA
| | - Michael Albosta
- Internal Medicine, Central Michigan University, Saginaw, Michigan, USA
| | - Manidhar Lekkala
- Hematology and Oncology, University of Rochester Medical Center, Rochester, New York, USA
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Dahiya DS, Wani F, Guidi JC, Kichloo A. Gastrointestinal Adverse Effects of Immunotherapeutic Agents: A Systematic Review. Gastroenterology Res 2020; 13:227-232. [PMID: 33447301 PMCID: PMC7781271 DOI: 10.14740/gr1340] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/05/2020] [Indexed: 12/26/2022] Open
Abstract
The utilization of immunotherapy is increasing to the point of becoming the fifth pillar of management alongside surgical intervention, chemotherapy, radiotherapy and targeted therapy. However, gastrointestinal adverse effects and toxicities have been frequently cited with its use. As per literature, the most common adverse effect of immune checkpoint inhibitors is watery and non-bloody diarrhea. Adoptive cell therapy can lead to delayed, on-target but off-tumor adverse effects which are unknown and may be life-threatening. The use of anti-angiogenic monoclonal antibodies can lead to bowel perforations, whereas epidermal growth factor receptor inhibitors and anti-HER2 agents are frequently associated with diarrhea. Minimal adverse effects have been associated with therapeutic cancer vaccines; however, additional studies are needed to determine their efficacy and potential toxicities. To provide an in-depth review of the gastrointestinal side effects of immunotherapeutic agents, we performed a thorough literature search using multiple online search engines such as PubMed, Google Scholar and Ovid MEDLINE, along with a review of the guidelines from the United States Food and Drug Administration (FDA) and the Cancer Research Institute on immunotherapy. In this systematic review, we detail the gastrointestinal adverse effects of immunotherapy and describe their management. With the advent of newer immunotherapeutic agents and the consistent approval of current agents by FDA for a wide spectrum of cancers, it is vital for physicians to familiarize themselves with their adverse effects for prompt diagnosis and early intervention to decrease adverse outcomes.
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Affiliation(s)
| | - Farah Wani
- Department of Family Medicine, Samaritan Medical Center, Watertown, NY, USA
| | - Jean Claude Guidi
- Department of Internal Medicine, Samaritan Medical Center, Watertown, NY, USA
| | - Asim Kichloo
- Department of Internal Medicine, Central Michigan University, Saginaw, MI, USA.,Department of Internal Medicine, Samaritan Medical Center, Watertown, NY, USA
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Cassol CA, Owen D, Kendra K, Braga JR, Frankel WL, Arnold CA. Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression in PD-1 inhibitor-associated colitis and its mimics. Histopathology 2020; 77:240-249. [PMID: 32298485 DOI: 10.1111/his.14115] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/17/2022]
Abstract
AIMS Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of advanced malignancies by boosting immune-mediated destruction of neoplastic cells, but are associated with side effects stemming from generalised immune system activation against normal tissues. Checkpoint ligand expression in non-tumoral cells of tissues affected by immune-related adverse effects has been described in ICI-associated hypophysitis, myocarditis, and acute interstitial nephritis. We aimed to investigate the tissue expression of the immune checkpoint receptor programmed cell death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), in PD-1 inhibitor-associated colitis (PD1i colitis). METHODS AND RESULTS PD-1 and PD-L1 immunohistochemical expression levels were analysed in 15 cases of PD1i colitis and potential mimics-infectious colitis and inflammatory bowel disease (IBD). Increased epithelial expression of PD-L1 was observed in PD1i colitis as compared with normal colon and infectious colitis, but the expression level was lower than that in IBD. Conversely, PD-1 expression in inflammatory cells was higher in infectious colitis, intermediate in IBD, and minimal or absent in normal colon and in patients receiving PD-1 inhibitors. CONCLUSIONS Although our results do not justify the use of PD-L1 as a discriminatory marker of PD1i colitis against other entities within the differential diagnosis, they support the concept that PD1i colitis and IBD have similar pathogenetic mechanisms. They also highlight the fact that PD-L1 epithelial overexpression is a commonly used mechanism of the gastrointestinal tract mucosa to protect itself from inflammatory-mediated damage resulting from different aetiologies, which probably underpins the high incidence of gastrointestinal immune-related adverse effects in patients receiving ICI therapies, in whom this mechanism is disrupted.
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Affiliation(s)
- Clarissa A Cassol
- Department of Pathology, Division of Medical Oncology, Ohio State University, Columbus, OH, USA
| | - Dwight Owen
- Department of Internal Medicine, Division of Medical Oncology, Ohio State University, Columbus, OH, USA
| | - Kari Kendra
- Department of Internal Medicine, Division of Medical Oncology, Ohio State University, Columbus, OH, USA
| | - Juarez R Braga
- Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Wendy L Frankel
- Department of Pathology, Division of Medical Oncology, Ohio State University, Columbus, OH, USA
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Pugh MR, Leopold GD, Morgan M, Christian AD, Hewett R, Durai D, Wagstaff J, Harris D, Dojcinov SD. Epstein-Barr Virus-Positive Mucocutaneous Ulcers Complicate Colitis Caused by Immune Checkpoint Regulator Therapy and Associate With Colon Perforation. Clin Gastroenterol Hepatol 2020; 18:1785-1795.e3. [PMID: 31610336 DOI: 10.1016/j.cgh.2019.09.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/08/2019] [Accepted: 09/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Cancer therapy with immune checkpoint inhibitors can cause colitis and colon perforation. We investigated whether infection with Epstein Barr virus (EBV) associates with development and severity of colitis in patients receiving immune checkpoint inhibitor therapies. METHODS We performed a retrospective analysis of fixed colon tissues from 16 patients (12 men, 4 women, median age, 69.5 y) with colitis after immune checkpoint inhibitor therapy (9 patients treated with anti-CTLA4, 3 patients treated with anti-PD1, and 4 patients received a combination). Ten tissue samples were biopsies and 6 were collected during resection (4 surgeries for colon perforation). Patients were treated between 2010 and 2018 in the United Kingdom. The tissues were analyzed by pathology, in situ hybridization (to detect EBV-encoded small RNAs [EBERs]), and immunohistochemistry. Clinical data were also collected. RESULTS Colon tissues from 4 of the 13 patients who received anti-CTLA4 (alone or in combination, 4 with colon perforation) had EBV-positive lymphoproliferations that manifested as florid ulcers associated with polymorphous infiltrates containing EBV-positive blasts (CD30+ or CD30-negative, CD20+, CD3-negative, and EBER+), plasma cells (CD138+, CD20-negative, and EBER+ or EBER-negative), and small B cells (CD20+, CD3-negative, and EBER+ or EBER-negative), consistent with EBV-positive mucocutaneous ulcers (EBVMCUs). In analyses of biopsies collected from 2 patients with EBVMCUs over multiple time points, we found that earlier biopsies had no or only a few EBV-positive cells, whereas 1 later biopsy had EBVMCU and co-infection with cytomegalovirus. EBVMCUs were associated with steroid-refractory colitis (100% of EBV-positive patients vs 12.5% of EBV-negative patients; P = .008) and colon perforation (100% of EBV-positive patients vs no EBV-negative patients; P = .001). CONCLUSIONS We found that colon tissues from 4/13 patients with colitis after anti-CTLA4 therapy (4/6 patients who underwent resection and 4/4 patients with colon perforation) contained EBVMCUs. EBVMCUs seem to arise secondarily in areas of inflamed colon due to immunosuppressive treatment for colitis. EBVMCUs are associated with steroid-refractory colitis and colon perforation.
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Affiliation(s)
- Matthew R Pugh
- Department of Cellular Pathology, University Hospital of Wales, Cardiff, United Kingdom
| | | | - Meleri Morgan
- Department of Cellular Pathology, University Hospital of Wales, Cardiff, United Kingdom
| | - Adam D Christian
- Department of Cellular Pathology, University Hospital of Wales, Cardiff, United Kingdom
| | - Rhys Hewett
- Department of Cellular Pathology, University Hospital of Wales, Cardiff, United Kingdom; Department of Gastroenterology, University Hospital of Wales, Cardiff, United Kingdom
| | - Dharmaraj Durai
- Department of Cellular Pathology, University Hospital of Wales, Cardiff, United Kingdom; Department of Gastroenterology, University Hospital of Wales, Cardiff, United Kingdom
| | - John Wagstaff
- College of Medicine, Swansea University, Swansea, United Kingdom
| | - Dean Harris
- Department of General Surgery, Morriston Hospital, Swansea, United Kingdom
| | - Stefan D Dojcinov
- All Wales Lymphoma Panel, University Hospital of Wales, Cardiff, United Kingdom.
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Kooshkaki O, Derakhshani A, Hosseinkhani N, Torabi M, Safaei S, Brunetti O, Racanelli V, Silvestris N, Baradaran B. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials. Int J Mol Sci 2020; 21:ijms21124427. [PMID: 32580338 PMCID: PMC7352976 DOI: 10.3390/ijms21124427] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/15/2020] [Accepted: 06/18/2020] [Indexed: 12/13/2022] Open
Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells’ responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.
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Affiliation(s)
- Omid Kooshkaki
- Student research committee, Birjand University of Medical Sciences, Birjand 9717853577, Iran;
- Department of Immunology, Birjand University of Medical Sciences, Birjand 9717853577, Iran
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (A.D.); (S.S.)
| | - Negar Hosseinkhani
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran;
| | - Mitra Torabi
- Student research committee, Tabriz University of medical sciences, Tabriz 5165665811, Iran;
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (A.D.); (S.S.)
| | - Oronzo Brunetti
- Medical Oncology Unit, IRCCS IstitutoTumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Nicola Silvestris
- Medical Oncology Unit, IRCCS IstitutoTumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy;
- Correspondence: (N.S.); (B.B.)
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (A.D.); (S.S.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran;
- Correspondence: (N.S.); (B.B.)
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Parthymos I, Liamis G, Dounousi E, Pentheroudakis G, Mauri D, Zarkavelis G, Florentin M. Metabolic consequences of immune checkpoint inhibitors: A new challenge in clinical practice. Crit Rev Oncol Hematol 2020; 151:102979. [PMID: 32480349 DOI: 10.1016/j.critrevonc.2020.102979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 02/29/2020] [Accepted: 05/03/2020] [Indexed: 12/13/2022] Open
Abstract
Treatment of oncologic patients has progressed greatly the last few years with the development of immune checkpoint inhibitors (ICPIs). These drugs are associated with the immune system and, thus, may cause side effects of immune origin, the so called immune related adverse events (irAEs). Immune related AEs may actually affect all organs and systems and frequently resemble clinical entities commonly encountered in clinical practice. As ICPIs have improved both quality of life and life expectancy, clinicians of various specialties may need to deal with irAEs in their everyday practice. Therefore, they should be able to recognize them timely and treat them accordingly. Herein, we review the pathophysiology, clinical manifestations and treatment of irAEs.
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Affiliation(s)
- Ioannis Parthymos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
| | - George Liamis
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Evangelia Dounousi
- Department of Internal Medicine, Division of Nephrology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - George Pentheroudakis
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
| | - Davide Mauri
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
| | - George Zarkavelis
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
| | - Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece.
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Complete Recovery of Immune Checkpoint Inhibitor–induced Colitis by Diverting Loop Ileostomy. J Immunother 2020; 43:145-148. [DOI: 10.1097/cji.0000000000000309] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Beaubier N, Tell R, Lau D, Parsons JR, Bush S, Perera J, Sorrells S, Baker T, Chang A, Michuda J, Iguartua C, MacNeil S, Shah K, Ellis P, Yeatts K, Mahon B, Taxter T, Bontrager M, Khan A, Huether R, Lefkofsky E, White KP. Clinical validation of the tempus xT next-generation targeted oncology sequencing assay. Oncotarget 2019; 10:2384-2396. [PMID: 31040929 PMCID: PMC6481324 DOI: 10.18632/oncotarget.26797] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 02/03/2019] [Indexed: 12/13/2022] Open
Abstract
We developed and clinically validated a hybrid capture next generation sequencing assay to detect somatic alterations and microsatellite instability in solid tumors and hematologic malignancies. This targeted oncology assay utilizes tumor-normal matched samples for highly accurate somatic alteration calling and whole transcriptome RNA sequencing for unbiased identification of gene fusion events. The assay was validated with a combination of clinical specimens and cell lines, and recorded a sensitivity of 99.1% for single nucleotide variants, 98.1% for indels, 99.9% for gene rearrangements, 98.4% for copy number variations, and 99.9% for microsatellite instability detection. This assay presents a wide array of data for clinical management and clinical trial enrollment while conserving limited tissue.
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Affiliation(s)
| | | | - Denise Lau
- Tempus Labs Inc., Chicago, IL 60654, USA
| | | | | | | | | | | | - Alan Chang
- Tempus Labs Inc., Chicago, IL 60654, USA
| | | | | | | | | | | | | | | | | | | | - Aly Khan
- Tempus Labs Inc., Chicago, IL 60654, USA
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Pawłowska A, Suszczyk D, Okła K, Barczyński B, Kotarski J, Wertel I. Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment. Clin Exp Immunol 2019; 195:334-344. [PMID: 30582756 PMCID: PMC6378380 DOI: 10.1111/cei.13255] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2018] [Indexed: 12/12/2022] Open
Abstract
Immunotherapies based on anti-programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway inhibitors may turn out effective in ovarian cancer (OC) treatment. They can be used in combination with standard therapy and are especially promising in recurrent and platinum-resistant OC. There is growing evidence that the mechanism of the PD-1/PD-L1 pathway can be specific for a particular histological cancer type. Interestingly, the data have shown that the PD-1/PD-L1 pathway blockade may be effective, especially in the endometrioid type of OC. It is important to identify the cause of anti-tumor immune response suppression and exclude its other mechanisms in OC patients. It is also necessary to conduct subsequent studies to confirm in which OC cases the treatment is effective and how to select patients and combine drugs to improve patient survival.
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Affiliation(s)
- A. Pawłowska
- Tumor Immunology Laboratory, 1st Chair and Department of Oncological Gynaecology and GynaecologyMedical University of LublinLublinPoland
| | - D. Suszczyk
- Tumor Immunology Laboratory, 1st Chair and Department of Oncological Gynaecology and GynaecologyMedical University of LublinLublinPoland
| | - K. Okła
- Tumor Immunology Laboratory, 1st Chair and Department of Oncological Gynaecology and GynaecologyMedical University of LublinLublinPoland
| | - B. Barczyński
- Tumor Immunology Laboratory, 1st Chair and Department of Oncological Gynaecology and GynaecologyMedical University of LublinLublinPoland
| | - J. Kotarski
- Tumor Immunology Laboratory, 1st Chair and Department of Oncological Gynaecology and GynaecologyMedical University of LublinLublinPoland
| | - I. Wertel
- Tumor Immunology Laboratory, 1st Chair and Department of Oncological Gynaecology and GynaecologyMedical University of LublinLublinPoland
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Ahmed Z, Imdad A, Connelly JA, Acra S. Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy. Dig Dis Sci 2019; 64:643-654. [PMID: 30415406 PMCID: PMC8260026 DOI: 10.1007/s10620-018-5364-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 11/01/2018] [Indexed: 12/12/2022]
Abstract
Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition.
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Affiliation(s)
- Zunirah Ahmed
- School of Medicine, University of Alabama, Montgomery Campus, 2055 E South Blvd Ste 202, Montgomery, AL, 36116, USA
| | - Aamer Imdad
- Division of Pediatric Gastroenterology, SUNY Upstate Medical University, 725 Irving Street, Suite 501, Syracuse, NY, 13210, USA
| | - James A Connelly
- Division of Pediatric Hematology-Oncology, Vanderbilt University Medical Center, 2100 Children's Way, Nashville, TN, 37212, USA
| | - Sari Acra
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2100 Children's Way, Nashville, TN, 37212, USA.
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42
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Zhou C, Klionsky Y, Treasure ME, Bruno DS. Pembrolizumab-Induced Immune-Mediated Colitis in a Patient with Concurrent Clostridium Difficile Infection. Case Rep Oncol 2019; 12:164-170. [PMID: 31043955 PMCID: PMC6477466 DOI: 10.1159/000497155] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 01/22/2019] [Indexed: 12/11/2022] Open
Abstract
Pembrolizumab is a programmed death receptor-1 (PD-1) inhibitor that has been approved for treatment of a wide variety of malignancies. Immune-mediated colitis is a known but uncommon adverse effect of pembrolizumab. Symptoms of immune-mediated colitis can be similar to those of many other gastrointestinal illnesses, including Clostridium difficile infection (CDI). If not recognized and treated in a timely fashion, immune-mediated colitis can lead to significant morbidity in cancer patients. We report the case of a 56-year-old woman on pembrolizumab for metastatic non-small cell lung cancer (NSCLC) who presented with severe colitis symptoms and initially tested positive for CDI. Her colitis symptoms worsened despite appropriate treatment for CDI but later improved rapidly after systemic corticosteroid was started for suspected immune-mediated colitis. To our knowledge, this is the first reported case of concurrent pembrolizumab-induced colitis and CDI. Immune-mediated colitis should be considered in the differential diagnoses in patients on pembrolizumab or other immune checkpoint inhibitors who present with colitis symptoms, even when a concurrent infectious etiology is suspected.
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Affiliation(s)
- Cheng Zhou
- Department of Medicine-Pediatrics, MetroHealth Medical Center, Cleveland, Ohio, USA
| | - Yael Klionsky
- Department of Internal Medicine, MetroHealth Medical Center, Cleveland, Ohio, USA
| | - Michelle E Treasure
- Department of Internal Medicine, Hematology and Oncology Division, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Debora S Bruno
- Department of Internal Medicine, Hematology and Oncology Division, University Hospitals - Seidman Cancer Center, Cleveland, Ohio, USA
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43
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Blood and Guts: Diarrhea from Colonic Involvement in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Dig Dis Sci 2019; 64:345-348. [PMID: 30155841 DOI: 10.1007/s10620-018-5264-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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44
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Choi K, Abu-Sbeih H, Samdani R, Nogueras Gonzalez G, Raju GS, Richards DM, Gao J, Subudhi S, Stroehlein J, Wang Y. Can Immune Checkpoint Inhibitors Induce Microscopic Colitis or a Brand New Entity? Inflamm Bowel Dis 2019; 25:385-393. [PMID: 30169584 PMCID: PMC7534361 DOI: 10.1093/ibd/izy240] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Indexed: 12/13/2022]
Abstract
Background Microscopic colitis (MC) has been described as 1 pattern of injury in immune checkpoint inhibitor (ICPI)-induced colitis. The main objective of this study was to characterize ICPI-induced MC by exploring the differences in risk factors, colitis treatments, endoscopic features, and clinical outcomes between cancer and noncancer patients with MC with and without exposure to ICPIs. Methods A retrospective chart review was conducted among patients diagnosed with MC from our institutional pathology database from January 2012 to January 2018. Patients were categorized into MC in cancer patients with or without ICPI exposure and in noncancer patients. Risk factors (use of tobacco and certain medications), colitis treatments (antidiarrheals and immunosuppressants), endoscopic features (with or without mucosal abnormality), and clinical outcomes (diarrhea recurrence, hospitalization, mortality) were collected and compared among the 3 groups. Results Of the 65 eligible patients with MC, 15 cancer patients had exposure to ICPI, 39 cancer patients had no exposure to ICPI, and 11 had no cancer diagnosis. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040). Furthermore, in this population, mucosal abnormality was the most common endoscopic feature compared with normal findings in the non-ICPI-induced MC groups (P = 0.106). Patients with ICPI-induced MC required more treatments with oral and intravenous steroids and nonsteroidal immunosuppressive agents (all P < 0.001) and had a higher rate of hospitalization (P < 0.001). Conclusion This study suggests that despite some similarities between MC with and without exposure to ICPIs, ICPI-induced MC has a more aggressive disease course that requires more potent immunosuppressive treatment regimens and greater need for hospitalization. 10.1093/ibd/izy240_video1izy240.video15828223597001.
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Affiliation(s)
- Kati Choi
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
| | - Hamzah Abu-Sbeih
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rashmi Samdani
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Gottumukkala Subba Raju
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David M Richards
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jianjun Gao
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sumit Subudhi
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - John Stroehlein
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
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45
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Ahmed M. Checkpoint inhibitors: What gastroenterologists need to know. World J Gastroenterol 2018; 24:5433-5438. [PMID: 30622372 PMCID: PMC6319137 DOI: 10.3748/wjg.v24.i48.5433] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/07/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
Checkpoint inhibitors are increasingly being used in clinical practice. They can cause various gastrointestinal, hepatic and pancreatic side effects. As these side effects can be serious, appropriate management is essential. The different checkpoint inhibitors with their mechanisms of action and indications, as well as evaluation and management of gastrointestinal, hepatic and pancreatic side effects, are discussed in this article.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
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46
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Rocha M, Correia de Sousa J, Salgado M, Araújo A, Pedroto I. Management of Gastrointestinal Toxicity from Immune Checkpoint Inhibitor. GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2018; 26:268-274. [PMID: 31328141 DOI: 10.1159/000494569] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Accepted: 10/09/2018] [Indexed: 12/14/2022]
Abstract
Immune checkpoint inhibitors have shown anti-tumour activity in cancers such as melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma, colorectal cancer, and Hodgkin's lymphoma. Though immune checkpoint inhibitors have revolutionized the treatment and prognosis of some advanced malignancies, they are also associated with a significant risk of immune-related adverse events. These adverse events can occur in any organ system, but gastrointestinal side effects are among the most commonly reported, with manifestations ranging from mild diarrhoea to severe colitis, sharing some features with inflammatory bowel disease. Anticipating a greater use of these drugs in the future, gastroenterologists should expect to be increasingly faced with gastrointestinal immune-related adverse events. Knowledge of these toxicities, as well as effective management algorithms, is essential to enable early diagnosis and treatment, decreasing morbidity and mortality. We reviewed the currently available literature on gastrointestinal toxicity induced by immune checkpoint inhibitors, namely the clinical features, diagnosis, and management.
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Affiliation(s)
- Marta Rocha
- Department of Gastroenterology, Hospital de Santo António/Centro Hospitalar do Porto, Porto, Portugal
| | - João Correia de Sousa
- Department of Gastroenterology, Hospital de Santo António/Centro Hospitalar do Porto, Porto, Portugal
| | - Marta Salgado
- Department of Gastroenterology, Hospital de Santo António/Centro Hospitalar do Porto, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, Porto, Portugal
| | - António Araújo
- Department of Medical Oncology, Hospital de Santo António/Centro Hospitalar do Porto, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, Porto, Portugal
| | - Isabel Pedroto
- Department of Gastroenterology, Hospital de Santo António/Centro Hospitalar do Porto, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, Porto, Portugal
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Majenka P, Hoffmann M, Rötzer I, Dimitrakopoulou-Strauss A, Koschny R, Longerich T, Enk A, Hassel JC. Diet-dependent toxicity of ipilimumab in metastatic melanoma. Eur J Cancer 2018; 106:220-224. [PMID: 30528806 DOI: 10.1016/j.ejca.2018.10.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 10/03/2018] [Accepted: 10/27/2018] [Indexed: 11/25/2022]
Affiliation(s)
- P Majenka
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
| | - M Hoffmann
- Department of Nutrition Therapy, National Center for Tumor Diseases, Heidelberg, Germany
| | - I Rötzer
- Department of Nutrition Therapy, National Center for Tumor Diseases, Heidelberg, Germany
| | - A Dimitrakopoulou-Strauss
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - R Koschny
- Department of Gastroenterology, Infection and Intoxication, University Hospital Heidelberg, Heidelberg, Germany
| | - T Longerich
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - A Enk
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - J C Hassel
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
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48
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Soularue E, Lepage P, Colombel JF, Coutzac C, Faleck D, Marthey L, Collins M, Chaput N, Robert C, Carbonnel F. Enterocolitis due to immune checkpoint inhibitors: a systematic review. Gut 2018; 67:2056-2067. [PMID: 30131322 DOI: 10.1136/gutjnl-2018-316948] [Citation(s) in RCA: 178] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 07/11/2018] [Accepted: 07/19/2018] [Indexed: 12/14/2022]
Abstract
Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD-1)/ligand are increasingly used to treat several types of cancer. These drugs enhance antitumour T-cell activity and therefore induce immune-related adverse effects (irAE), of which gastrointestinal (GI) irAE are among the most frequent and severe. This systematic literature review summarises the clinical manifestations, management and pathophysiology of GI irAE due to immune checkpoint inhibitors. GI irAE induced by anti-CTLA-4 are frequent, potentially severe and resemble IBD, whereas those induced by PD-1 blockade seem to be less frequent and clinically more diverse. Baseline symbiotic gut microbiota is associated with an enhanced antitumour response to immune checkpoint inhibitors and an increased susceptibility to developing enterocolitis, in patients treated with anti-CTLA-4. These findings open new perspectives for possible manipulation of the gut microbiota in order to better identify responders to immune checkpoint inhibitors and to increase their efficacy and safety.
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Affiliation(s)
- Emilie Soularue
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.,Faculté de Médecine, University Paris-Saclay, Le Kremlin Bicêtre, France
| | - Patricia Lepage
- Micalis Institute, INRA, AgroParisTech, University Paris-Saclay, Jouy-en- Josas, France
| | - Jean Frederic Colombel
- Helmsley Inflammatory Bowel Disease Center, Icahn Medical School of Medicine at Mount Sinai, New York, USA
| | - Clelia Coutzac
- Laboratory of Immunomonitoring in Oncology and CNRS-UMS 3655 and INSERM-US23, Villejuif, France
| | - David Faleck
- Helmsley Inflammatory Bowel Disease Center, Icahn Medical School of Medicine at Mount Sinai, New York, USA
| | - Lysiane Marthey
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France
| | - Michael Collins
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.,Faculté de Médecine, University Paris-Saclay, Le Kremlin Bicêtre, France
| | - Nathalie Chaput
- Laboratory of Immunomonitoring in Oncology and CNRS-UMS 3655 and INSERM-US23, Villejuif, France.,Faculté de Pharmacie, University Paris-Saclay, Chatenay-Malabry, France
| | - Caroline Robert
- Faculté de Médecine, University Paris-Saclay, Le Kremlin Bicêtre, France.,Départment of Medecine, Dermatology Unit, Villejuif, France
| | - Franck Carbonnel
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.,Faculté de Médecine, University Paris-Saclay, Le Kremlin Bicêtre, France
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49
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Karamchandani DM, Chetty R. Apoptotic colopathy: a pragmatic approach to diagnosis. J Clin Pathol 2018; 71:1033-1040. [DOI: 10.1136/jclinpath-2018-205388] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 08/27/2018] [Indexed: 12/17/2022]
Abstract
‘Apoptotic colopathy’ is an umbrella term signifying a pattern of injury where the gastrointestinal biopsy shows a colitic picture with apoptosis as the predominant histological feature. Although the entities within apoptotic colopathy share a common histological feature— ‘apoptosis’, there is a list of varied clinical differential diagnoses that produce this similar histological pattern of injury. These include graft-versus-host disease, drug-induced injury due to multiple drugs (in particular, mycophenolate mofetil, check point inhibitor therapy and some others), infections (particularly cytomegalovirus, adenovirus and some others), immune disorders and other miscellaneous causes. However, the management of these varied differentials is strikingly different, thus necessitating an algorithmic approach for accurate diagnosis and optimal patient management. A definitive diagnosis requires interpretation of varied histological findings in the appropriate clinical context including clinical history, drug history and laboratory findings. This review will focus on the histopathological findings of varied entities that can manifest as ‘apoptotic colopathy’ on assessment of colonic biopsies.
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Sarofim M, Winn R. Rare case of delayed onset colitis due to immunotherapy for malignant melanoma. ANZ J Surg 2018; 89:E472-E473. [PMID: 30136350 DOI: 10.1111/ans.14768] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 06/15/2018] [Accepted: 06/19/2018] [Indexed: 12/25/2022]
Affiliation(s)
- Mina Sarofim
- Department of Colorectal Surgery, Wollongong Hospital, Sydney, New South Wales, Australia.,The University of New South Wales, Sydney, New South Wales, Australia
| | - Robert Winn
- Department of Colorectal Surgery, Wollongong Hospital, Sydney, New South Wales, Australia
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