{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T01:05:17Z","timestamp":1773277517004,"version":"3.50.1"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"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":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pleural effusion is a rare immune-related adverse event for lung cancer patients receiving immune checkpoint inhibitors (ICIs). We enrolled 281 lung cancer patients treated with ICIs and 17 were analyzed. We categorized the formation of pleural effusion into 3 patterns: type 1, rapid and massive; type 2, slow and indolent; and type 3, with disease progression. CD4\/CD8 ratio of 1.93 was selected as the cutoff threshold to predict survival. Most patients of types 1 and 2 effusions possessed pleural effusion with CD4\/CD8 ratios\u2009\u2265\u20091.93. The median OS time in type 1, 2, and 3 patients were not reached, 24.8, and 2.6\u00a0months, respectively. The median PFS time in type 1, 2, and 3 patients were 35.5, 30.2, and 1.4\u00a0months, respectively. The median OS for the group with pleural effusion CD4\/CD8\u2009\u2265\u20091.93 and\u2009&lt;\u20091.93 were not reached and 2.6\u00a0months. The median PFS of those with pleural effusion CD4\/CD8\u2009\u2265\u20091.93 and\u2009&lt;\u20091.93 were 18.4 and 1.2\u00a0months. In conclusion, patients with type 1 and 2 effusion patterns had better survival than those with type 3. Type 1 might be interpreted as pseudoprogression of malignant pleural effusion. CD4\/CD8 ratio\u2009\u2265\u20091.93 in pleural effusion is a good predicting factor for PFS.<\/jats:p>","DOI":"10.1038\/s41598-021-89043-4","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T10:04:45Z","timestamp":1619777085000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Higher CD4\/CD8 ratio of pleural effusion predicts better survival for lung cancer patients receiving immune checkpoint inhibitors"],"prefix":"10.1038","volume":"11","author":[{"given":"Po-Hsin","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsung-Ying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun-Chieh","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Hsiang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeng-Sen","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuo-Hsuan","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Chen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ko-Jiunn","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gee-Chen","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,30]]},"reference":[{"key":"89043_CR1","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.jtho.2018.12.011","volume":"14","author":"R Ferrara","year":"2019","unstructured":"Ferrara, R., Caramella, C., Besse, B. & Champiat, S. Pseudoprogression in non-small cell lung cancer upon immunotherapy: Few drops in the ocean?. J. Thorac. Oncol. 14, 328\u2013331 (2019).","journal-title":"J. Thorac. Oncol."},{"key":"89043_CR2","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s40425-016-0185-2","volume":"4","author":"BC Kolla","year":"2016","unstructured":"Kolla, B. C. & Patel, M. R. Recurrent pleural effusions and cardiac tamponade as possible manifestations of pseudoprogression associated with nivolumab therapy\u2014A report of two cases. J. Immunother. Cancer 4, 80 (2016).","journal-title":"J. Immunother. Cancer"},{"key":"89043_CR3","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1056\/NEJMra1703481","volume":"378","author":"MA Postow","year":"2018","unstructured":"Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158\u2013168 (2018).","journal-title":"N. Engl. J. Med."},{"key":"89043_CR4","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1056\/NEJMoa1609214","volume":"375","author":"DB Johnson","year":"2016","unstructured":"Johnson, D. B. et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375, 1749\u20131755 (2016).","journal-title":"N. Engl. J. Med."},{"key":"89043_CR5","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1186\/s40425-019-0760-4","volume":"7","author":"S Anastasia","year":"2019","unstructured":"Anastasia, S. et al. Pericardial effusion under nivolumab: Case-reports and review of the literature. J. Immunother. Cancer 7, 266 (2019).","journal-title":"J. Immunother. Cancer"},{"key":"89043_CR6","doi-asserted-by":"publisher","first-page":"3426","DOI":"10.1200\/JCO.1998.16.10.3426","volume":"16","author":"KA Semb","year":"1998","unstructured":"Semb, K. A., Aamdal, S. & Oian, P. Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. J. Clin. Oncol. 16, 3426\u20133432 (1998).","journal-title":"J. Clin. Oncol."},{"key":"89043_CR7","doi-asserted-by":"publisher","first-page":"e0120852","DOI":"10.1371\/journal.pone.0120852","volume":"10","author":"K-H Hsu","year":"2015","unstructured":"Hsu, K.-H. et al. Identification of five driver gene mutations in patients with treatment-naive lung adenocarcinoma in Taiwan. PLoS ONE 10, e0120852 (2015).","journal-title":"PLoS ONE"},{"key":"89043_CR8","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1056\/NEJMoa1501824","volume":"372","author":"EB Garon","year":"2015","unstructured":"Garon, E. B. et al. Pembrolizumab for the treatment of non\u2013small-cell lung cancer. N. Engl. J. Med. 372, 2018\u20132028 (2015).","journal-title":"N. Engl. J. Med."},{"key":"89043_CR9","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","volume":"375","author":"M Reck","year":"2016","unstructured":"Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1\u2013positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823\u20131833 (2016).","journal-title":"N. Engl. J. Med."},{"key":"89043_CR10","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.1016\/S0140-6736(18)32409-7","volume":"393","author":"TS Mok","year":"2019","unstructured":"Mok, T. S. et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 393, 1819\u20131830 (2019).","journal-title":"Lancet"},{"key":"89043_CR11","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.ejca.2018.06.031","volume":"101","author":"L Horn","year":"2018","unstructured":"Horn, L. et al. Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: Final results from a phase I study. Eur. J. Cancer 101, 201\u2013209 (2018).","journal-title":"Eur. J. Cancer"},{"key":"89043_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-35840-3","volume":"9","author":"JC Nieto","year":"2019","unstructured":"Nieto, J. C. et al. Migrated t lymphocytes into malignant pleural effusions: An indicator of good prognosis in lung adenocarcinoma patients. Sci. Rep. 9, 1\u201311 (2019).","journal-title":"Sci. Rep."},{"key":"89043_CR13","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1200\/JCO.2014.58.3708","volume":"33","author":"SN Gettinger","year":"2015","unstructured":"Gettinger, S. N. et al. Overall survival and long-term safety of nivolumab (anti\u2013programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non\u2013small-cell lung cancer. J. Clin. Oncol. 33, 2004 (2015).","journal-title":"J. Clin. Oncol."},{"key":"89043_CR14","doi-asserted-by":"publisher","first-page":"4671","DOI":"10.1158\/1078-0432.CCR-17-0114","volume":"23","author":"M Nishino","year":"2017","unstructured":"Nishino, M. et al. Immune-related tumor response dynamics in melanoma patients treated with pembrolizumab: Identifying markers for clinical outcome and treatment decisions. Clin. Cancer Res. 23, 4671\u20134679 (2017).","journal-title":"Clin. Cancer Res."},{"key":"89043_CR15","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.ejca.2017.10.017","volume":"88","author":"M Tazdait","year":"2018","unstructured":"Tazdait, M. et al. Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: Comparison of RECIST 1.1, irRECIST and iRECIST criteria. Eur. J. Cancer 88, 38\u201347 (2018).","journal-title":"Eur. J. Cancer"},{"key":"89043_CR16","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.jtho.2018.10.167","volume":"14","author":"D Fujimoto","year":"2019","unstructured":"Fujimoto, D. et al. Pseudoprogression in previously treated patients with non-small cell lung cancer who received nivolumab monotherapy. J. Thorac. Oncol. 14, 468\u2013474 (2019).","journal-title":"J. Thorac. Oncol."},{"key":"89043_CR17","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1111\/1759-7714.13004","volume":"10","author":"R Shibaki","year":"2019","unstructured":"Shibaki, R. et al. Malignant pleural effusion as a predictor of the efficacy of anti-PD-1 antibody in patients with non-small cell lung cancer. Thorac. Cancer 10, 815\u2013822 (2019).","journal-title":"Thorac. Cancer"},{"key":"89043_CR18","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.ejca.2020.04.025","volume":"134","author":"O Nigro","year":"2020","unstructured":"Nigro, O. et al. Late immune-related adverse events in long-term responders to PD-1\/PD-L1 checkpoint inhibitors: A multicentre study. Eur. J. Cancer 134, 19\u201328 (2020).","journal-title":"Eur. J. Cancer"},{"key":"89043_CR19","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1186\/1471-2407-13-324","volume":"13","author":"A Scherpereel","year":"2013","unstructured":"Scherpereel, A. et al. Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid. BMC Cancer 13, 324 (2013).","journal-title":"BMC Cancer"},{"key":"89043_CR20","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1590\/S1807-59322008000500012","volume":"63","author":"LMZD Aguiar","year":"2008","unstructured":"Aguiar, L. M. Z. D. et al. Malignant and tuberculous pleural effusions: Immunophenotypic cellular characterization. Clinics 63, 637\u2013644 (2008).","journal-title":"Clinics"},{"key":"89043_CR21","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/s41416-018-0155-1","volume":"120","author":"S Khan","year":"2019","unstructured":"Khan, S. et al. Immune dysregulation in cancer patients developing immune-related adverse events. Br. J. Cancer 120, 63\u201368 (2019).","journal-title":"Br. J. Cancer"},{"key":"89043_CR22","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1158\/1078-0432.CCR-18-2795","volume":"25","author":"SY Lim","year":"2019","unstructured":"Lim, S. Y. et al. Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy. Clin. Cancer Res. 25, 1557\u20131563 (2019).","journal-title":"Clin. Cancer Res."},{"key":"89043_CR23","doi-asserted-by":"publisher","first-page":"2254","DOI":"10.3389\/fimmu.2019.02254","volume":"10","author":"R Anderson","year":"2019","unstructured":"Anderson, R., Theron, A. J. & Rapoport, B. L. Immunopathogenesis of immune checkpoint inhibitor-related adverse events: Roles of the intestinal microbiome and Th17 cells. Front. Immunol. 10, 2254 (2019).","journal-title":"Front. Immunol."},{"key":"89043_CR24","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1111\/1759-7714.13341","volume":"11","author":"W Ke","year":"2020","unstructured":"Ke, W., Zhang, L. & Dai, Y. The role of IL-6 in immunotherapy of non-small cell lung cancer (NSCLC) with immune-related adverse events (irAEs). Thorac. Cancer 11, 835\u2013839 (2020).","journal-title":"Thorac. Cancer"},{"key":"89043_CR25","doi-asserted-by":"publisher","first-page":"3924","DOI":"10.1158\/1078-0432.CCR-15-2463","volume":"22","author":"C Alfaro","year":"2016","unstructured":"Alfaro, C. et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin. Cancer Res. 22, 3924\u20133936 (2016).","journal-title":"Clin. Cancer Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89043-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89043-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89043-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T07:32:43Z","timestamp":1670052763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89043-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,30]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["89043"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-89043-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,30]]},"assertion":[{"value":"11 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9381"}}