{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T12:14:39Z","timestamp":1770293679652,"version":"3.49.0"},"reference-count":13,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T00:00:00Z","timestamp":1633564800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Thoracic Cancer"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In advanced lung cancer treatment, immunotherapy provides durable responses in some patients. However, other patients experience progressive disease and the resistance mechanisms to immunotherapy have yet been fully elucidated. Small cell transformation of non\u2010small cell lung cancer (NSCLC) is commonly recognized as one of the resistance mechanisms to epidermal growth factor receptor (EGFR)\u2010tyrosine kinase inhibitors in <jats:italic>EGFR<\/jats:italic>\u2010mutant NSCLC treatment. As a resistant mechanism for immunotherapy, we report the first case of small cell transformation in 2017. Since then, eight similar cases have been reported and the concept of small cell transformation is now becoming more prevalent as a mechanism of immunotherapy resistance. In our facility, we have experienced four cases of small cell transformation after immunotherapy (including the reported case in 2017). The histology of each primary tumor was squamous cell carcinoma, large cell type neuroendocrine carcinoma, or poorly differentiated NSCLC. None had driver gene mutations. Nivolumab was administered in all four cases and atezolizumab was administered as a next line to nivolumab treatment in one case. The best response to immunotherapy was partial response or stable disease. There was a wide range of periods from the start of immunotherapy to confirmation of small cell transformation (from 2\u2009weeks to almost 3\u2009years). In conclusion, small cell transformation is an important resistance mechanism in cancer immunotherapy. When NSCLC progresses after immunotherapy, the possibility of small cell transformation and rebiopsy should always be encouraged, as it leads to clarification of the resistance mechanisms and frequency.<\/jats:p>","DOI":"10.1111\/1759-7714.14180","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T03:23:25Z","timestamp":1633749805000},"page":"3062-3067","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Small cell transformation of non\u2010small cell lung cancer under immunotherapy: Case series and literature review"],"prefix":"10.1111","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1246-2339","authenticated-orcid":false,"given":"Takuma","family":"Imakita","sequence":"first","affiliation":[{"name":"Division of Respiratory Medicine, Center for Respiratory Diseases, National Hospital Organization Kyoto Medical Center  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6902-9085","authenticated-orcid":false,"given":"Kohei","family":"Fujita","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Center for Respiratory Diseases, National Hospital Organization Kyoto Medical Center  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0736-3317","authenticated-orcid":false,"given":"Osamu","family":"Kanai","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Center for Respiratory Diseases, National Hospital Organization Kyoto Medical Center  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misato","family":"Okamura","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Center for Respiratory Diseases, National Hospital Organization Kyoto Medical Center  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Center for Respiratory Diseases, National Hospital Organization Kyoto Medical Center  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Nakatani","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Center for Respiratory Diseases, National Hospital Organization Kyoto Medical Center  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Sawai","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Center for Respiratory Diseases, National Hospital Organization Kyoto Medical Center  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadashi","family":"Mio","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Center for Respiratory Diseases, National Hospital Organization Kyoto Medical Center  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,7]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy275"},{"key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"S31","DOI":"10.1634\/theoncologist.2019-IO-S1-s05","article-title":"PD\u20101\/PD\u2010L1 blockade therapy in advanced non\u2010small\u2010cell lung cancer: current status and future directions","volume":"24","author":"Xia L","year":"2019","journal-title":"Oncologist"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)71180-5"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.05.4692"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904554"},{"key":"e_1_2_6_8_1","first-page":"52","article-title":"Small cell lung cancer transformation during immunotherapy with nivolumab: a case report","volume":"21","author":"Imakita T","year":"2017","journal-title":"Respir Med Case Rep"},{"key":"e_1_2_6_9_1","first-page":"85","article-title":"Non\u2010small cell to small cell lung cancer on PD\u20101 inhibitors: two cases on potential histologic transformation","volume":"9","author":"Abdallah N","year":"2018","journal-title":"Lung Cancer"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.2892-19"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2019.09.025"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2018.11.031"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000697"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2018.10.006"}],"container-title":["Thoracic Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1759-7714.14180","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/1759-7714.14180","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1759-7714.14180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T05:28:09Z","timestamp":1693200489000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/1759-7714.14180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,7]]},"references-count":13,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["10.1111\/1759-7714.14180"],"URL":"https:\/\/doi.org\/10.1111\/1759-7714.14180","archive":["Portico"],"relation":{},"ISSN":["1759-7706","1759-7714"],"issn-type":[{"value":"1759-7706","type":"print"},{"value":"1759-7714","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,7]]},"assertion":[{"value":"2021-08-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}