{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:05:58Z","timestamp":1781712358204,"version":"3.54.5"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Immune checkpoint inhibitors have provided significant clinical benefits to many patients with advanced cancer; however, severe immune-related adverse events (irAEs) have occurred. Detecting and treating irAEs early could improve patient prognoses. Therefore, clinicians and patients should understand that these irAEs exist, especially those that are rare and serious.<\/jats:p><jats:p><jats:bold>Case Presentation:<\/jats:bold> In this report, an 86-year-old male patient, diagnosed with metastatic gastric cancer involving the peritoneum and retroperitoneal lymph nodes was treated with 5-cycle pembrolizumab therapy (100 mg q 2 weeks), achieving a partial response. However, the patient developed Grade 3 cholestatic hepatitis and delayed pneumonia 10 days and 2 months after the final pembrolizumab dose, respectively. After discontinuing the pembrolizumab therapy and excluding obstructive jaundice with imaging studies, the patient received steroid therapy, with a gradual symptom improvement. However, the patient developed delayed pneumonia with type 1 respiratory failure 1-month post-discharge. Several microbiologic tests were negative, and immune-associated pneumonia was suspected, but we could not exclude an opportunistic infection. The patient recovered with steroids and antibiotics and remained in partial remission 5 months after pembrolizumab withdrawal.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> Cholestatic hepatitis is a rarely reported toxicity of immune checkpoint inhibitors, which should be suspected and addressed once obstructive jaundice is ruled out. In addition, clinicians should be aware that irAEs can occur at any time in patients treated with immune checkpoint inhibitors and that a timely diagnosis should be made.<\/jats:p>","DOI":"10.3389\/fmed.2021.719236","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T17:22:59Z","timestamp":1634145779000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Case Report: Severe Immune-Related Cholestatic Hepatitis and Subsequent Pneumonia After Pembrolizumab Therapy in a Geriatic Patient With Metastic Gastric Cancer"],"prefix":"10.3389","volume":"8","author":[{"given":"Hui","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenfei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liting","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011"},{"key":"B2","doi-asserted-by":"publisher","first-page":"6580","DOI":"10.1158\/1078-0432.CCR-12-1362","article-title":"Molecular pathways: next-generation immunotherapy\u2013inhibiting programmed death-ligand 1 and programmed death-1","volume":"18","author":"Chen","year":"2012","journal-title":"Clin Cancer Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1093\/annonc\/mdw141","article-title":"Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies","volume":"27","author":"Naidoo","year":"2016","journal-title":"Ann Oncol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1007\/s11739-020-02295-2","article-title":"Management of immune-related adverse events associated with immune checkpoint inhibitors in cancer patients: a patient-centred approach","volume":"15","author":"de La Rochefoucauld","year":"2020","journal-title":"Intern Emerg Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.ejca.2015.11.016","article-title":"Immune-related adverse events with immune checkpoint blockade: a comprehensive review","volume":"54","author":"Michot","year":"2016","journal-title":"Eur J Cancer."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1001\/jamaoncol.2020.3370","article-title":"Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial","volume":"6","author":"Shitara","year":"2020","journal-title":"JAMA Oncol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1200\/JCO.2015.66.1389","article-title":"Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma","volume":"35","author":"Weber","year":"2017","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1186\/s40425-019-0805-8","article-title":"Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors","volume":"7","author":"Das","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1016\/j.jhep.2018.08.014","article-title":"Incidence of grade 3-4 liver injury under immune checkpoints inhibitors: a retrospective study","volume":"69","author":"Parlati","year":"2018","journal-title":"J Hepatol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1002\/ijc.30678","article-title":"Risk of hepatotoxicity in cancer patients treatedwith immune checkpoint inhibitors: a systematic review and meta-analysis of published data","volume":"141","author":"Wang","year":"2017","journal-title":"Int J Cancer."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1097\/PAS.0000000000000453","article-title":"Ipilimumab-associated hepatitis: clinicopathologic characterization in a series of 11 cases","volume":"39","author":"Johncilla","year":"2015","journal-title":"Am J Surg Pathol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1038\/s41379-018-0013-y","article-title":"Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury","volume":"31","author":"Zen","year":"2018","journal-title":"Mod Pathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2994","DOI":"10.3748\/wjg.v27.i22.2994","article-title":"Hepatocellular carcinoma in viral and autoimmune liver diseases: role of CD4+ CD25+ Foxp3+ regulatory T cells in the immune microenvironment","volume":"27","author":"Granito","year":"2021","journal-title":"World J Gastroenterol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1384","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":"B15","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1002\/hep.28965","article-title":"The ascending pathophysiology of cholestatic liver disease","volume":"65","author":"Jansen","year":"2017","journal-title":"Hepatology."},{"key":"B16","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1146\/annurev-pharmtox-010818-021059","article-title":"Drug therapies for chronic cholestatic liver diseases","volume":"60","author":"Wagner","year":"2020","journal-title":"Annu Rev Pharmacol Toxicol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.jhep.2020.04.036","article-title":"Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults","volume":"73","author":"Stattermayer","year":"2020","journal-title":"J Hepatol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1200\/JCO.2017.77.6385","article-title":"Management of immunerelated adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline","volume":"36","author":"Brahmer","year":"2018","journal-title":"J Clin Oncol."},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.1093\/annonc\/mdx225","article-title":"Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up","volume-title":"Ann Oncol","author":"Haanen","year":"2017"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1002\/cncr.27969","article-title":"Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma","volume":"119","author":"Weber","year":"2013","journal-title":"Cancer"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2018","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":"B22","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1200\/JCO.2016.68.2005","article-title":"Pneumonitis in patients treated with anti-programmed death-1\/programmed death ligand 1 therapy","volume":"35","author":"Naidoo","year":"2017","journal-title":"J Clin Oncol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1700050","DOI":"10.1183\/13993003.00050-2017","article-title":"Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients","volume":"50","author":"Delaunay","year":"2017","journal-title":"Eur Respir J."},{"key":"B24","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1158\/2326-6066.CIR-15-0267","article-title":"Anti-PD-1 inhibitorrelated pneumonitis in non-small cell lung cancer","volume":"4","author":"Nishino","year":"2016","journal-title":"Cancer Immunol Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1952","DOI":"10.1001\/jamaoncol.2020.5012","article-title":"Multisystem immunerelated adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer","volume":"6","author":"Shankar","year":"2020","journal-title":"JAMA Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ejca.2018.11.009","article-title":"Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors","volume":"107","author":"Hasan Ali","year":"2019","journal-title":"Eur J Cancer."},{"key":"B27","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1126\/scitranslmed.3008002","article-title":"Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody","volume":"6","author":"Iwama","year":"2014","journal-title":"Sci Transl Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.719236\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T17:23:04Z","timestamp":1634145784000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.719236\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,12]]},"references-count":27,"alternative-id":["10.3389\/fmed.2021.719236"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.719236","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,12]]},"article-number":"719236"}}