{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:07:50Z","timestamp":1779084470506,"version":"3.51.4"},"reference-count":141,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82560522"],"award-info":[{"award-number":["82560522"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In recent years, immune checkpoint inhibitors have been widely adopted in cancer therapy. However, their use is frequently associated with the development of colitis. This study employs bibliometric methods to analyze the knowledge structure and current research trends in immune checkpoint inhibitors induced colitis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic literature search was conducted within the Web of Science Core Collection database. Data analysis and visualization were performed using CiteSpace, VOSViewer, and the Bibliometrix package in R software.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The present study collated 1,010 papers on ICI-induced colitis from Web of Science Core Collection, encompassing literature from 62 countries\/regions, 1,873 institutions, 7,385 authors, and 373 journals. The United States demonstrated leadership in two key metrics: publication volume, with a total of 470 publications, and total citations, with a total of 41,125 citations. The University of Texas MD Anderson Cancer Center produced the highest number of publications (n=83). Wang Yinghong (n=48) emerged as the most prolific author. The Journal for Immunotherapy of Cancer was the most widely disseminated publication in this field (n=60). An analysis of keywords identified research trends beyond ICI, colitis, and irAE, including Ipilimumab, immunotherapy, Nivolumab, melanoma, cancer, and Pembrolizumab.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study performed a visual analysis of the fundamental knowledge structure underlying immune checkpoint inhibitors mediated colitis. The results indicate that future research should prioritize the exploration of combination therapies, clinical case management strategies, underlying pathogenic mechanisms, fecal microbiota transplantation, and the identification of predictive and diagnostic biomarkers for adverse events.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1817557","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:42:41Z","timestamp":1779082961000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Research landscape, thematic evolution, and translational insights of immune checkpoint inhibitor-induced colitis: a bibliometric analysis (2006-2025)"],"prefix":"10.3389","volume":"17","author":[{"given":"Huiyong","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuang","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangteng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongliang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005841","article-title":"Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: case report and systematic review of the literature","volume":"11","author":"Liu","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.035","article-title":"A paradigm shift in cancer immunotherapy: from enhancement to normalization","volume":"175","author":"Sanmamed","year":"2018","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.001","article-title":"Immune checkpoint blockade: a common denominator approach to cancer therapy","volume":"27","author":"Topalian","year":"2015","journal-title":"Cancer Cell"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000383","article-title":"Immune checkpoint inhibitor-associated diarrhea and colitis: a systematic review and meta-analysis of observational studies","volume":"44","author":"Tran","year":"2021","journal-title":"J Immunother Hagerstown Md 1997"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1186\/s12885-020-07690-8","article-title":"Clinically relevant prognostic and predictive markers for immune-checkpoint-inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC)","volume":"20","author":"Brueckl","year":"2020","journal-title":"BMC Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1016\/j.ccell.2024.10.007","article-title":"Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: a prospective phase II trial","volume":"42","author":"Davar","year":"2024","journal-title":"Cancer Cell"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-024-02887-1","article-title":"Cancer and treatment specific incidence rates of immune-related adverse events induced by immune checkpoint inhibitors: a systematic review","volume":"132","author":"Jayathilaka","year":"2025","journal-title":"Br J Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1093\/annonc\/mdw534","article-title":"Next steps in immuno-oncology: enhancing antitumor effects through appropriate patient selection and rationally designed combination strategies","volume":"28","author":"Salama","year":"2017","journal-title":"Ann Oncol Off J Eur Soc Med Oncol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1007\/s00520-024-08889-2","article-title":"Immune checkpoint inhibitor-induced diarrhea and colitis: an overview","volume":"32","author":"Zoghbi","year":"2024","journal-title":"Support Care Cancer Off J Multinatl Assoc Support Care Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241411504","article-title":"Checkpoint inhibitor-induced colitis: from pathogenesis to management","volume":"24","author":"Terrin","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbusres.2021.04.070","article-title":"How to conduct a bibliometric analysis: an overview and guidelines","volume":"133","author":"Donthu","year":"2021","journal-title":"J Bus Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0223994","article-title":"Visualizing a field of research: a methodology of systematic scientometric reviews","volume":"14","author":"Chen","year":"2019","journal-title":"PloS One"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.joi.2017.08.007","article-title":"bibliometrix: an R-tool for comprehensive science mapping analysis","volume":"11","author":"Massimo","year":"2017","journal-title":"J Informetr"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/asi.20317","article-title":"CiteSpace II: Detecting and visualizing emerging trends and transient patterns in scientific literature","volume":"57","author":"Chen","year":""},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s11192-009-0146-3","article-title":"Software survey: VOSviewer, a computer program for bibliometric mapping","volume":"84","author":"van Eck","year":"2010","journal-title":"Scientometrics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1186\/s40425-019-0768-9","article-title":"The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors","volume":"7","author":"Davis","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajps.2024.100902","article-title":"Tumor microenvironment reprogramming by nanomedicine to enhance the effect of tumor immunotherapy","volume":"19","author":"Huang","year":"2024","journal-title":"Asian J Pharm Sci"},{"key":"B19","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1208\/s12248-021-00574-0","article-title":"Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics","volume":"23","author":"Twomey","year":"2021","journal-title":"AAPS J"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1908","DOI":"10.1007\/s12672-025-03769-5","article-title":"Knowledge mapping and visualization of immune checkpoint inhibitor-related pneumonitis: a bibliometric analysis","volume":"16","author":"Jiang","year":"2025","journal-title":"Discov Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1242336","article-title":"Bibliometric analysis of rheumatic immune related adverse events associated with immune checkpoint inhibitors","volume":"14","author":"Zeng","year":"2023","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1253832","article-title":"Research hot spots and trends in endocrine-related adverse events caused by immune checkpoint inhibitors: a bibliometric analysis and visualization research","volume":"15","author":"Zhao","year":"2024","journal-title":"Front Endocrinol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.08.063","article-title":"AGA clinical practice update on diagnosis and management of immune checkpoint inhibitor colitis and hepatitis: expert review","volume":"160","author":"Dougan","year":"2021","journal-title":"Gastroenterology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abq4006","article-title":"Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis","volume":"15","author":"Halsey","year":"2023","journal-title":"Sci Transl Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01440","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update","volume":"39","author":"Schneider","year":"2021","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.1038\/s41591-018-0238-9","article-title":"Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis","volume":"24","author":"Wang","year":"2018","journal-title":"Nat Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01655-5","article-title":"Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer","volume":"28","author":"Derosa","year":"2022","journal-title":"Nat Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002058","article-title":"Fecal calprotectin concentration to assess endoscopic and histologic remission in patients with cancer with immune-mediated diarrhea and colitis","volume":"9","author":"Zou","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-024-02647-1","article-title":"Anti-integrin \u03b1v\u03b26 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis","volume":"130","author":"Yokode","year":"2024","journal-title":"Br J Cancer"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1053\/j.gastro.2021.06.025","article-title":"Interferon-gamma-producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis","volume":"161","author":"Sasson","year":"2021","journal-title":"Gastroenterology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"6719","DOI":"10.1038\/s41467-023-41798-2","article-title":"Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23\/IFN\u03b3 axis","volume":"14","author":"Lo","year":"2023","journal-title":"Nat Commun"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02895-x","article-title":"Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis","volume":"30","author":"Thomas","year":"2024","journal-title":"Nat Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-23-0498","article-title":"Immune-related colitis is associated with fecal microbial dysbiosis and can be mitigated by fecal microbiota transplantation","volume":"12","author":"Elkrief","year":"2024","journal-title":"Cancer Immunol Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1524695","article-title":"Clinical characterization of colitis arising from anti-PD-1 based therapy","volume":"8","author":"Wang","year":"2019","journal-title":"Oncoimmunology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000213","article-title":"The risk of diarrhea and colitis in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy: a systematic review and meta-analysis","volume":"41","author":"Tandon","year":"2018","journal-title":"J Immunother"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001488","article-title":"Clinicopathological characteristics and management of colitis with anti-PD1 immunotherapy alone or in combination with ipilimumab","volume":"8","author":"Nahar","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.804597","article-title":"Holistic approach to immune checkpoint inhibitor-related adverse events","volume":"13","author":"Poto","year":"2022","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nri3818","article-title":"The ins and outs of MHC class II-mediated antigen processing and presentation","volume":"15","author":"Roche","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s12943-023-01746-6","article-title":"Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy","volume":"22","author":"Zhou","year":"2023","journal-title":"Mol Cancer"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14010260","article-title":"Harnessing antitumor CD4+ T cells for cancer immunotherapy","volume":"14","author":"Ben Khelil","year":"2022","journal-title":"Cancers"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.11.001","article-title":"Neoadjuvant gene-mediated cytotoxic immunotherapy for non-small-cell lung cancer: safety and immunologic activity","volume":"29","author":"Predina","year":"2021","journal-title":"Mol Ther J Am Soc Gene Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2024.101177","article-title":"Why and how citrate may sensitize Malignant tumors to immunotherapy","volume":"78","author":"Icard","year":"2025","journal-title":"Drug Resist Update Rev Comm Antimicrob Anticancer Chemother"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","article-title":"Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death","volume":"11","author":"Ishida","year":"1992","journal-title":"EMBO J"},{"key":"B44","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","article-title":"PD-1 and its ligands in tolerance and immunity","volume":"26","author":"Keir","year":"2008","journal-title":"Annu Rev Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1292","article-title":"T cell costimulatory receptor CD28 is a primary target for PD-1\u2013mediated inhibition","volume":"355","author":"Hui","year":"2017","journal-title":"Science"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20231242","article-title":"TCR ligand potency differentially impacts PD-1 inhibitory effects on diverse signaling pathways","volume":"220","author":"Chan","year":"2023","journal-title":"J Exp Med"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2746","DOI":"10.1038\/s41467-021-22965-9","article-title":"PD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition","volume":"12","author":"Li","year":"2021","journal-title":"Nat Commun"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090847","article-title":"PD-L1 regulates the development, maintenance, and function of induced regulatory T cells","volume":"206","author":"Francisco","year":"2009","journal-title":"J Exp Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1387975","article-title":"Regulation of Treg cells by cytokine signaling and co-stimulatory molecules","volume":"15","author":"Zong","year":"2024","journal-title":"Front Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2008.02.011","article-title":"Ctla-4 trafficking and surface expression","volume":"29","author":"Valk","year":"2008","journal-title":"Trends Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.19.1.565","article-title":"Ctla-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy","volume":"19","author":"Chambers","year":"2001","journal-title":"Annu Rev Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.6.3321","article-title":"Tgf-beta requires ctla-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells","volume":"176","author":"Zheng","year":"2006","journal-title":"J Immunol Balt Md 1950"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.017","article-title":"B cells in the tumor microenvironment: Multi-faceted organizers, regulators, and effectors of anti-tumor immunity","volume":"41","author":"Laumont","year":"2023","journal-title":"Cancer Cell"},{"key":"B55","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.ccell.2024.04.010","article-title":"Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis","volume":"42","author":"Gupta","year":"2024","journal-title":"Cancer Cell"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007358","article-title":"Scrna-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis","volume":"11","author":"Mann","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B57","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.cell.2020.06.001","article-title":"Molecular pathways of colon inflammation induced by cancer immunotherapy","volume":"182","author":"Luoma","year":"2020","journal-title":"Cell"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107891","article-title":"Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor colitis","volume":"26","author":"van Eijs","year":"2023","journal-title":"iScience"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1177\/17562848241309445","article-title":"Cd8+ cell dominance in immune checkpoint inhibitor-induced colitis and its heterogeneity across endoscopic features","volume":"17","author":"Kim","year":"2024","journal-title":"Ther Adv Gastroenterol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-008628","article-title":"Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis","volume":"12","author":"He","year":"2024","journal-title":"J Immunother Cancer"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1209615","article-title":"Evaluation of immune infiltration in the colonic mucosa of patients with ipilimumab-related colitis","volume":"5","author":"Arriola","year":"2016","journal-title":"Oncoimmunology"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01623-z","article-title":"T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma","volume":"28","author":"Lozano","year":"2022","journal-title":"Nat Med"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjx081","article-title":"Colon immune-related adverse events: Anti-ctla-4 and anti-pd-1 blockade induce distinct immunopathological entities","volume":"11","author":"Coutzac","year":"2017","journal-title":"J Crohns Colitis"},{"key":"B64","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/imr.13239","article-title":"Gastrointestinal mucosal toxicities from immune checkpoint inhibitors: Current understanding and future directions","volume":"318","author":"Dougan","year":"2023","journal-title":"Immunol Rev"},{"key":"B65","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1126\/science.adh8342","article-title":"Microbiota-dependent activation of CD4+ T cells induces ctla-4 blockade-associated colitis via Fc\u03b3 receptors","volume":"383","author":"Lo","year":"2024","journal-title":"Science"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(24)00390-X","article-title":"The intestinal barrier: a pivotal role in health, inflammation, and cancer","volume":"10","author":"Neurath","year":"2025","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00768-1","article-title":"Il-12 and il-23 pathway inhibition in inflammatory bowel disease","volume":"20","author":"Verstockt","year":"2023","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B68","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.chom.2023.03.019","article-title":"Beneficial effects of fecal microbiota transplantation in recurrent Clostridioides difficile infection","volume":"31","author":"Yadegar","year":"2023","journal-title":"Cell Host Microbe"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ads3530","article-title":"Th17 cells regulate chemokine expression in epithelial cells through C\/EBP\u03b2 and dictate host sensitivity to colitis and cancer immunity","volume":"11","author":"Xing","year":"2025","journal-title":"Sci Adv"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.04.010","article-title":"Il-6 blockade in cancer patients treated with immune checkpoint blockade: A win-win strategy","volume":"40","author":"Delyon","year":"2022","journal-title":"Cancer Cell"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20221333","article-title":"Intestinal toxicity to ctla-4 blockade driven by il-6 and myeloid infiltration","volume":"220","author":"Zhou","year":"2023","journal-title":"J Exp Med"},{"key":"B72","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.ccell.2022.04.004","article-title":"Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity","volume":"40","author":"Hailemichael","year":"2022","journal-title":"Cancer Cell"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.987568","article-title":"Serological biomarkers predict immune-related adverse events and clinical benefit in patients with advanced gastrointestinal cancers","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1080\/07357907.2017.1324032","article-title":"Immunological characteristics of colitis associated with anti-ctla-4 antibody therapy","volume":"35","author":"Bamias","year":"2017","journal-title":"Cancer Invest"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01022-z","article-title":"Versatile roles of innate lymphoid cells at the mucosal barrier: from homeostasis to pathological inflammation","volume":"55","author":"Ryu","year":"2023","journal-title":"Exp Mol Med"},{"key":"B76","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s40425-015-0081-1","article-title":"Baseline circulating il-17 predicts toxicity while tgf-\u03b21 and il-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma","volume":"3","author":"Tarhini","year":"2015","journal-title":"J Immunother Cancer"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001895","article-title":"Blocking il-17a enhances tumor response to anti-pd-1 immunotherapy in microsatellite stable colorectal cancer","volume":"9","author":"Liu","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-009345","article-title":"Prophylactic il-23 blockade uncouples efficacy and toxicity in dual ctla-4 and pd-1 immunotherapy","volume":"12","author":"Ju","year":"2024","journal-title":"J Immunother Cancer"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-018-0155-1","article-title":"Immune dysregulation in cancer patients developing immune-related adverse events","volume":"120","author":"Khan","year":"2019","journal-title":"Br J Cancer"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01406-6","article-title":"Gut microbiota signatures are associated with toxicity to combined ctla-4 and pd-1 blockade","volume":"27","author":"Andrews","year":"2021","journal-title":"Nat Med"},{"key":"B81","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.immuni.2010.03.001","article-title":"Interferon-\u03b3 regulates intestinal epithelial homeostasis through converging \u03b2-catenin signaling pathways","volume":"32","author":"Nava","year":"2010","journal-title":"Immunity"},{"key":"B82","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/s41571-025-01026-w","article-title":"Roles of the gut microbiota in immune-related adverse events: mechanisms and therapeutic intervention","volume":"22","author":"Gao","year":"2025","journal-title":"Nat Rev Clin Oncol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-0605","article-title":"Faecalibacterium prausnitzii abrogates intestinal toxicity and promotes tumor immunity to increase the efficacy of dual ctla4 and pd-1 checkpoint blockade","volume":"83","author":"Gao","year":"2023","journal-title":"Cancer Res"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20232079","article-title":"Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis","volume":"222","author":"Shang","year":"2025","journal-title":"J Exp Med"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10391","article-title":"Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis","volume":"7","author":"Dubin","year":"2016","journal-title":"Nat Commun"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx108","article-title":"Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab","volume":"28","author":"Chaput","year":"2017","journal-title":"Ann Oncol Off J Eur Soc Med Oncol"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad1329","article-title":"Anticancer immunotherapy by ctla-4 blockade relies on the gut microbiota","volume":"350","author":"V\u00e9tizou","year":"2015","journal-title":"Science"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.216038","article-title":"Immune checkpoint inhibitor resistance in hepatocellular carcinoma","volume":"555","author":"Wang","year":"2023","journal-title":"Cancer Lett"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(22)00197-8","article-title":"Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study","volume":"23","author":"Diaz","year":"2022","journal-title":"Lancet Oncol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2392","article-title":"Immunology beats cancer: a blueprint for successful translation","volume":"13","author":"Pardoll","year":"2012","journal-title":"Nat Immunol"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2018.3923","article-title":"Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis","volume":"4","author":"Wang","year":"2018","journal-title":"JAMA Oncol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30388-2","article-title":"Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study","volume":"20","author":"Robert","year":"2019","journal-title":"Lancet Oncol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx286","article-title":"Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review","volume":"28","author":"Khoja","year":"2017","journal-title":"Ann Oncol Off J Eur Soc Med Oncol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.36","article-title":"Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy","volume":"16","author":"Topalian","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30366-7","article-title":"Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial","volume":"17","author":"Hodi","year":"2016","journal-title":"Lancet Oncol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.1051","article-title":"Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review","volume":"2","author":"Friedman","year":"2016","journal-title":"JAMA Oncol"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30700-9","article-title":"Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial","volume":"19","author":"Hodi","year":"2018","journal-title":"Lancet Oncol"},{"key":"B98","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1038\/s41392-023-01522-4","article-title":"Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends","volume":"8","author":"Sun","year":"2023","journal-title":"Signal Transd Targ Ther"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.24.01124","article-title":"Three-year overall survival with nivolumab plus relatlimab in advanced melanoma from RELATIVITY-047","volume":"43","author":"Tawbi","year":"2025","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00152-2","article-title":"Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial","volume":"22","author":"Powles","year":"2021","journal-title":"Lancet Oncol"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.6601","article-title":"Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer","volume":"34","author":"Reck","year":"2016","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70334-1","article-title":"Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study","volume":"11","author":"Wolchok","year":"2010","journal-title":"Lancet Oncol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003277","article-title":"Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in patients with cancer: a two-center observational study","volume":"9","author":"Zou","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B104","article-title":"Treatment of Immune Checkpoint Inhibitor-Related Colitis With Infliximab or Vedolizumab: A Randomized Trial","volume-title":"clinicaltrials.gov","year":"2025"},{"key":"B105","article-title":"Fecal Microbiota Transplantation in Treating Immune-Checkpoint Inhibitor Induced-Diarrhea or Colitis in Genitourinary Cancer Patients","volume-title":"clinicaltrials.gov","year":"2026"},{"key":"B106","article-title":"Efficacy and Safety of Fecal Microbiota Transplantation in Patients With Intestinal Dysbiosis -A Pilot Study","volume-title":"clinicaltrials.gov","year":"2021"},{"key":"B107","article-title":"FMT in Checkpoint Inhibitor-mediated Diarrhea and Colitis (Immunobiome)","volume-title":"clinicaltrials.gov","year":"2025"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.683419","article-title":"FDA-approved and emerging next generation predictive biomarkers for immune checkpoint inhibitors in cancer patients","volume":"11","author":"Wang","year":"2021","journal-title":"Front Oncol"},{"key":"B109","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.jtho.2019.12.107","article-title":"PD-L1 testing for lung cancer in 2019: perspective from the IASLC Pathology Committee","volume":"15","author":"Lantuejoul","year":"2020","journal-title":"J Thorac Oncol Off Publ Int Assoc Study Lung Cancer"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1501824","article-title":"Pembrolizumab for the treatment of non-small-cell lung cancer","volume":"372","author":"Garon","year":"2015","journal-title":"N Engl J Med"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1038\/nature14011","article-title":"Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients","volume":"515","author":"Herbst","year":"2014","journal-title":"Nature"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.euf.2021.01.003","article-title":"Expression of programmed cell death ligand 1 as a predictive biomarker in metastatic urothelial carcinoma patients treated with first-line immune checkpoint inhibitors versus chemotherapy: a systematic review and meta-analysis","volume":"8","author":"Rizzo","year":"2022","journal-title":"Eur Urol Focus"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2020.1846901","article-title":"Soluble forms of PD-L1 and PD-1 as prognostic and predictive markers of sunitinib efficacy in patients with metastatic clear cell renal cell carcinoma","volume":"9","author":"Montemagno","year":"2020","journal-title":"Oncoimmunology"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2019.06.011","article-title":"A novel next-generation sequencing approach to detecting microsatellite instability and pan-tumor characterization of 1000 microsatellite instability\u2013high cases in 67,000 patient samples","volume":"21","author":"Trabucco","year":"2019","journal-title":"J Mol Diagn JMD"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2016.02.003","article-title":"Mismatch repair and colon cancer: mechanisms and therapies explored","volume":"22","author":"Li","year":"2016","journal-title":"Trends Mol Med"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2020.102024","article-title":"MSI as a predictive factor for treatment outcome of gastroesophageal adenocarcinoma","volume":"86","author":"van Velzen","year":"2020","journal-title":"Cancer Treat Rev"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1032314","article-title":"Predictive biomarkers of colon cancer immunotherapy: present and future","volume":"13","author":"Hou","year":"2022","journal-title":"Front Immunol"},{"key":"B118","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1093\/gastro\/goz061","article-title":"Immunotherapy with immune checkpoint inhibitors in colorectal cancer: what is the future beyond deficient mismatch-repair tumours","volume":"8","author":"Huyghe","year":"2019","journal-title":"Gastroenterol Rep"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2018.4942","article-title":"Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status","volume":"5","author":"Cohen","year":"2019","journal-title":"JAMA Oncol"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz116","article-title":"ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1\/PD-L1 expression and tumour mutational burden: a systematic review-based approach","volume":"30","author":"Luchini","year":"2019","journal-title":"Ann Oncol Off J Eur Soc Med Oncol"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-3054","article-title":"Tumor mutational burden as a predictor of immunotherapy response: is more always better","volume":"27","author":"Strickler","year":"2021","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1038\/nature12477","article-title":"Signatures of mutational processes in human cancer","volume":"500","author":"Alexandrov","year":"2013","journal-title":"Nature"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30445-9","article-title":"Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study","volume":"21","author":"Marabelle","year":"2020","journal-title":"Lancet Oncol"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)00561-4","article-title":"Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial","volume":"387","author":"Rosenberg","year":"2016","journal-title":"Lancet Lond Engl"},{"key":"B125","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.ccell.2018.04.001","article-title":"Tumor mutation burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small cell lung cancer","volume":"33","author":"Hellmann","year":"2018","journal-title":"Cancer Cell"},{"key":"B126","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.ccell.2018.03.018","article-title":"Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer","volume":"33","author":"Hellmann","year":"2018","journal-title":"Cancer Cell"},{"key":"B127","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cell.2016.02.065","article-title":"Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma","volume":"165","author":"Hugo","year":"2016","journal-title":"Cell"},{"key":"B128","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1126\/science.aan4236","article-title":"Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients","volume":"359","author":"Gopalakrishnan","year":"2018","journal-title":"Science"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-20-0196","article-title":"The gut microbiome associates with immune checkpoint inhibition outcomes in patients with advanced non-small cell lung cancer","volume":"8","author":"Hakozaki","year":"2020","journal-title":"Cancer Immunol Res"},{"key":"B130","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/j.eururo.2020.07.011","article-title":"Stool microbiome profiling of patients with metastatic renal cell carcinoma receiving anti-PD-1 immune checkpoint inhibitors","volume":"78","author":"Salgia","year":"2020","journal-title":"Eur Urol"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01698-2","article-title":"Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1","volume":"28","author":"McCulloch","year":"2022","journal-title":"Nat Med"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.140940","article-title":"Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma","volume":"5","author":"Limeta","year":"2020","journal-title":"JCI Insight"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-317220","article-title":"Microbiota and cancer immunotherapy: in search of microbial signals","volume":"68","author":"Gharaibeh","year":"2019","journal-title":"Gut"},{"key":"B134","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan3706","article-title":"Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors","volume":"359","author":"Routy","year":"2018","journal-title":"Science"},{"key":"B135","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1038\/s41591-022-02189-0","article-title":"Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial","volume":"29","author":"Cascone","year":"2023","journal-title":"Nat Med"},{"key":"B136","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.11680","article-title":"Antibiotic use does not appear to influence response to nivolumab","volume":"37","author":"Kaderbhai","year":"2017","journal-title":"Anticancer Res"},{"key":"B137","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01695-5","article-title":"Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma","volume":"28","author":"Lee","year":"2022","journal-title":"Nat Med"},{"key":"B138","doi-asserted-by":"publisher","first-page":"7421","DOI":"10.1038\/s41467-023-42997-7","article-title":"Gut microbial structural variation associates with immune checkpoint inhibitor response","volume":"14","author":"Liu","year":"2023","journal-title":"Nat Commun"},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1528594","article-title":"Tumor Akkermansia muciniphila predicts clinical response to immune checkpoint inhibitors in non-small-cell lung cancer patients with low PD-L1 expression","volume":"16","author":"Shimizu","year":"2025","journal-title":"Front Immunol"},{"key":"B140","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2022.12.007","article-title":"AGA clinical practice guideline on the role of biomarkers for the management of ulcerative colitis","volume":"164","author":"Singh","year":"2023","journal-title":"Gastroenterology"},{"key":"B141","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb5920","article-title":"Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients","volume":"371","author":"Baruch","year":"2021","journal-title":"Science"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1817557\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:42:43Z","timestamp":1779082963000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1817557\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":141,"alternative-id":["10.3389\/fimmu.2026.1817557"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1817557","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]},"article-number":"1817557"}}