{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T23:31:49Z","timestamp":1787700709518,"version":"build-2784847793"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin J Gastroenterol"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Combination immunotherapy, particularly the STRIDE regimen (durvalumab plus tremelimumab), is recommended as first-line treatment for advanced hepatocellular carcinoma (HCC). Cytokine release syndrome (CRS), while rare, can be a life-threatening adverse event associated with immune checkpoint inhibitors (ICIs). The relationship between CRS and antitumor activity remains unclear; however, some studies suggest that the occurrence of immune-related adverse events (irAEs) may be indicative of enhanced immune activation. We report a case in which severe CRS following ICI therapy led to marked tumor shrinkage and enabled conversion surgery.  <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Case presentation<\/jats:title>\n            <jats:p>An 85-year-old woman presented with a 100\u00a0mm HCC in the right hepatic lobe with intrahepatic metastases, initially deemed unresectable. She received the STRIDE regimen and developed Grade 3 CRS with fever, hypotension, and multi-organ dysfunction. Corticosteroid therapy led to rapid clinical improvement. Three months post-treatment, imaging revealed tumor regression (from 100\u00a0mm to 60\u00a0mm) and significant decline in tumor markers (AFP 1550\u2013110\u00a0ng\/mL; PIVKA-2 32,600 to 79\u00a0AU\/mL). Extended anterior sectionectomy was performed, with histopathology showing 90% tumor necrosis. The postoperative course was uneventful, and the patient was discharged on postoperative day 16.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>CRS is a potentially severe irAE that may also signal favorable immune activation. Early recognition and appropriate management of CRS are essential, and in select cases, ICI-induced CRS may facilitate curative conversion surgery in advanced HCC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s12328-025-02155-6","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T15:04:26Z","timestamp":1749654266000},"page":"739-745","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Conversion surgery following severe cytokine release syndrome induced by immune checkpoint inhibitors doublet in advanced hepatocellular carcinoma"],"prefix":"10.1007","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9143-256X","authenticated-orcid":false,"given":"Haruki","family":"Mori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromitsu","family":"Maehira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhito","family":"Nitta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Miyake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Kaida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsushi","family":"Takebayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatsugu","family":"Kojima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Nishina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaji","family":"Tani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"issue":"2","key":"2155_CR1","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1053\/j.gastro.2018.08.065","volume":"156","author":"L Kulik","year":"2019","unstructured":"Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477-91.e1.","journal-title":"Gastroenterology"},{"issue":"1","key":"2155_CR2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","volume":"7","author":"JM Llovet","year":"2021","unstructured":"Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.","journal-title":"Nat Rev Dis Primers"},{"issue":"10","key":"2155_CR3","first-page":"1144","volume":"23","author":"JM Llovet","year":"2022","unstructured":"Llovet JM, Kelley RK, Villanueva A, et al. Himalaya: a randomized, phase 3 study of durvalumab (anti-PD-L1) with or without tremelimumab (anti-CTLA-4) versus sorafenib in advanced hepatocellular carcinoma. Lancet Oncol. 2022;23(10):1144\u201357.","journal-title":"Lancet Oncol"},{"issue":"2","key":"2155_CR4","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1056\/NEJMra1703481","volume":"378","author":"MA Postow","year":"2018","unstructured":"Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158\u201368.","journal-title":"N Engl J Med"},{"issue":"2","key":"2155_CR5","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3390\/cancers14020277","volume":"14","author":"A Casadei-Gardini","year":"2022","unstructured":"Casadei-Gardini A, Rimassa L, Salvagni S, et al. The evolving role of conversion therapy in advanced hepatocellular carcinoma in the era of immune checkpoint inhibitors. Cancers (Basel). 2022;14(2):277.","journal-title":"Cancers (Basel)"},{"issue":"2","key":"2155_CR6","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1182\/blood-2014-05-552729","volume":"124","author":"DW Lee","year":"2014","unstructured":"Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188\u201395.","journal-title":"Blood"},{"issue":"6","key":"2155_CR7","first-page":"345","volume":"32","author":"JN Brudno","year":"2016","unstructured":"Brudno JN, Kochenderfer JN. Recent advances in CAR-T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. 2016;32(6):345\u201356.","journal-title":"Blood Rev"},{"issue":"4","key":"2155_CR8","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.bbmt.2018.12.758","volume":"23","author":"DW Lee","year":"2017","unstructured":"Lee DW, Santomasso BD, Locke FL, et al. ASBMT\u2013ASTCT consensus grading for cytokine release syndrome and neurotoxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2017;23(4):625\u201338.","journal-title":"Biol Blood Marrow Transplant"},{"issue":"1","key":"2155_CR9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nrclinonc.2017.148","volume":"15","author":"SS Neelapu","year":"2018","unstructured":"Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy\u2014assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47\u201362.","journal-title":"Nat Rev Clin Oncol"},{"issue":"4","key":"2155_CR10","first-page":"1234","volume":"25","author":"L Goyal","year":"2019","unstructured":"Goyal L, Zheng Y, Ma L, et al. A novel immune microenvironment in hepatocellular carcinoma and its implications for therapy. Clin Cancer Res. 2019;25(4):1234\u201344.","journal-title":"Clin Cancer Res"},{"issue":"10","key":"2155_CR11","doi-asserted-by":"publisher","first-page":"e2340695","DOI":"10.1001\/jamanetworkopen.2023.40695","volume":"6","author":"I Van Buren","year":"2023","unstructured":"Van Buren I, Madison C, Kohn A, et al. Survival among veterans receiving steroids for immune-related adverse events after immune checkpoint inhibitor therapy. JAMA Netw Open. 2023;6(10):e2340695.","journal-title":"JAMA Netw Open"},{"issue":"1","key":"2155_CR12","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s40425-018-0343-9","volume":"6","author":"A Shimabukuro-Vornhagen","year":"2018","unstructured":"Shimabukuro-Vornhagen A, G\u00f6del P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56.","journal-title":"J Immunother Cancer"},{"issue":"12","key":"2155_CR13","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1038\/nrc3380","volume":"12","author":"DV Krysko","year":"2012","unstructured":"Krysko DV, Garg AD, Kaczmarek A, et al. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012;12(12):860\u201375.","journal-title":"Nat Rev Cancer"},{"key":"2155_CR14","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.14088","author":"T Ozaki","year":"2024","unstructured":"Ozaki T, Tanaka S, Yamamoto M, et al. Cytokine release syndrome following durvalumab and tremelimumab in advanced hepatocellular carcinoma: a case report with cytokine and damage-associated molecular pattern analysis. Hepatol Res. 2024. https:\/\/doi.org\/10.1111\/hepr.14088.","journal-title":"Hepatol Res"},{"issue":"8","key":"2155_CR15","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1634\/theoncologist.2018-0028","volume":"23","author":"RQ Le","year":"2018","unstructured":"Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for the treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943\u20137.","journal-title":"Oncologist"},{"key":"2155_CR16","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.ejca.2015.11.016","volume":"54","author":"JM Michot","year":"2016","unstructured":"Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139\u201348.","journal-title":"Eur J Cancer"},{"issue":"20","key":"2155_CR17","first-page":"4183","volume":"5","author":"F Chen","year":"2021","unstructured":"Chen F, Teachey DT, Pequignot E, et al. Measuring IL-6 and IL-6 signaling pathway biomarkers to predict CRS. Blood Adv. 2021;5(20):4183\u201390.","journal-title":"Blood Adv"},{"issue":"4","key":"2155_CR18","first-page":"156","volume":"43","author":"JBAG Haanen","year":"2020","unstructured":"Haanen JBAG, Thienen JV, de Bruyn M, et al. Immune checkpoint inhibitor-related adverse events in cancer patients: a new frontier in medical management. Oncol Res Treat. 2020;43(4):156\u201364.","journal-title":"Oncol Res Treat"},{"issue":"7854","key":"2155_CR19","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/s41586-021-03362-0","volume":"592","author":"D Pfister","year":"2021","unstructured":"Pfister D, Nunez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592(7854):450\u20136.","journal-title":"Nature"}],"container-title":["Clinical Journal of Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12328-025-02155-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12328-025-02155-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12328-025-02155-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T19:14:50Z","timestamp":1757186090000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12328-025-02155-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,11]]},"references-count":19,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["2155"],"URL":"https:\/\/doi.org\/10.1007\/s12328-025-02155-6","relation":{},"ISSN":["1865-7257","1865-7265"],"issn-type":[{"value":"1865-7257","type":"print"},{"value":"1865-7265","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,11]]},"assertion":[{"value":"19 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participation"}},{"value":"Written informed consent was obtained from the patient for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}