{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:50:51Z","timestamp":1789519851932,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,11]],"date-time":"2024-05-11T00:00:00Z","timestamp":1715385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chang Gung Memorial Hospital","award":["CMRPG6C0111"],"award-info":[{"award-number":["CMRPG6C0111"]}]},{"name":"Chang Gung Memorial Hospital","award":["CMRPG6I0111"],"award-info":[{"award-number":["CMRPG6I0111"]}]},{"name":"Chang Gung Memorial Hospital","award":["CMRPG6I0112"],"award-info":[{"award-number":["CMRPG6I0112"]}]},{"name":"Chang Gung Memorial Hospital","award":["CMRPG6I0113"],"award-info":[{"award-number":["CMRPG6I0113"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Spheroids generated by tumor cells collected from malignant pleural effusion (MPE) were shown to retain the characteristics of the original tumors. This ex vivo model might be used to predict the response of non-small cell lung cancer (NSCLC) to anticancer treatments. Methods: The characteristics, epidermal growth factor receptor (EGFR) mutation status, and clinical response to EGFR-TKIs treatment of enrolled patients were recorded. The viability of the spheroids generated from MPE of enrolled patients were evaluated by visualization of the formazan product of the MTT assay. Results: Spheroids were generated from 14 patients with NSCLC-related MPE. Patients with EGFR L861Q, L858R, or Exon 19 deletion all received EGFR-TKIs, and five of these seven patients responded to treatment. The viability of the spheroids generated from MPE of these five patients who responded to EGFR-TKIs treatment was significantly reduced after gefitinib treatment. On the other hand, gefitinib treatment did not reduce the viability of the spheroids generated from MPE of patients with EGFR wild type, Exon 20 insertion, or patients with sensitive EGFR mutation but did not respond to EGFR-TKIs treatment. Conclusion: Multicellular spheroids generated from NSCLC-related MPE might be used to predict the response of NSCLC to treatment.<\/jats:p>","DOI":"10.3390\/diagnostics14100998","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T06:59:32Z","timestamp":1715756372000},"page":"998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Spheroids Generated from Malignant Pleural Effusion as a Tool to Predict the Response of Non-Small Cell Lung Cancer to Treatment"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9241-2816","authenticated-orcid":false,"given":"Tsung-Ming","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 333423, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hung","family":"Fang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi 613016, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieh-Mo","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao-Fen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4500-0878","authenticated-orcid":false,"given":"Chun-Liang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Bray","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/cac2.12505","article-title":"Management of locally advanced non-small cell lung cancer: State of the art and future directions","volume":"44","author":"Miao","year":"2024","journal-title":"Cancer Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s00408-020-00407-5","article-title":"Update 2020: Management of non-small cell lung cancer","volume":"198","author":"Alexander","year":"2020","journal-title":"Lung"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/cncr.32468","article-title":"Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (nsclc)","volume":"126","author":"Bodor","year":"2020","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1200\/JCO.21.01626","article-title":"Targeted therapies for lung cancer patients with oncogenic driver molecular alterations","volume":"40","author":"Tan","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.hoc.2016.08.006","article-title":"Lung cancer biomarkers","volume":"31","author":"Villalobos","year":"2017","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1056\/NEJMoa1713137","article-title":"Osimertinib in untreated egfr-mutated advanced non-small-cell lung cancer","volume":"378","author":"Soria","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4592","DOI":"10.1158\/1078-0432.CCR-18-1538","article-title":"Immunotherapy in non-small cell lung cancer: Facts and hopes","volume":"25","author":"Doroshow","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0140-6736(16)30958-8","article-title":"Lung cancer: Current therapies and new targeted treatments","volume":"389","author":"Hirsch","year":"2017","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.tibtech.2009.12.001","article-title":"Can tissue engineering concepts advance tumor biology research?","volume":"28","author":"Hutmacher","year":"2010","journal-title":"Trends Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/978-1-4939-9145-7_10","article-title":"3d-3 tumor models in drug discovery for analysis of immune cell infiltration","volume":"1953","author":"Osswald","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s13577-021-00642-9","article-title":"3d modeling in cancer studies","volume":"35","author":"Atat","year":"2022","journal-title":"Human Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Basak, S.K., Veena, M.S., Oh, S., Huang, G., Srivatsan, E., Huang, M., Sharma, S., and Batra, R.K. (2009). The malignant pleural effusion as a model to investigate intratumoral heterogeneity in lung cancer. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005884"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/s41588-018-0209-6","article-title":"Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy","volume":"50","author":"Lee","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1158\/1078-0432.CCR-19-1844","article-title":"Use of ex vivo patient-derived tumor organotypic spheroids to identify combination therapies for her2 mutant non-small cell lung cancer","volume":"26","author":"Ivanova","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_16","first-page":"187","article-title":"Role of epidermal growth factor receptor in lung cancer and targeted therapies","volume":"7","author":"Liu","year":"2017","journal-title":"Am. J. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"141","DOI":"10.21037\/atm.2017.11.34","article-title":"Treating alk-positive non-small cell lung cancer","volume":"6","author":"Ziogas","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.lungcan.2018.01.002","article-title":"Tumor biomarker testing in non-small-cell lung cancer: A decade of change","volume":"116","author":"VanderLaan","year":"2018","journal-title":"Lung Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/annonc\/mdw611","article-title":"Afatinib versus gefitinib in patients with egfr mutation-positive advanced non-small-cell lung cancer: Overall survival data from the phase iib lux-lung 7 trial","volume":"28","author":"Tan","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S1470-2045(16)30033-X","article-title":"Afatinib versus gefitinib as first-line treatment of patients with egfr mutation-positive non-small-cell lung cancer (lux-lung 7): A phase 2b, open-label, randomised controlled trial","volume":"17","author":"Park","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/cncr.31891","article-title":"Osimertinib in patients with t790m mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies","volume":"125","author":"Ahn","year":"2019","journal-title":"Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/s43018-023-00515-0","article-title":"Alk-positive lung cancer: A moving target","volume":"4","author":"Schneider","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1056\/NEJMoa1408440","article-title":"First-line crizotinib versus chemotherapy in alk-positive lung cancer","volume":"371","author":"Solomon","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S0140-6736(17)30123-X","article-title":"First-line ceritinib versus platinum-based chemotherapy in advanced alk-rearranged non-small-cell lung cancer (ascend-4): A randomised, open-label, phase 3 study","volume":"389","author":"Soria","year":"2017","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1056\/NEJMoa1704795","article-title":"Alectinib versus crizotinib in untreated alk-positive non-small-cell lung cancer","volume":"377","author":"Peters","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1056\/NEJMoa1810171","article-title":"Brigatinib versus crizotinib in alk-positive non-small-cell lung cancer","volume":"379","author":"Camidge","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1056\/NEJMoa2027187","article-title":"First-line lorlatinib or crizotinib in advanced alk-positive lung cancer","volume":"383","author":"Shaw","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e006464","DOI":"10.1136\/jitc-2022-006464","article-title":"Predictive biomarkers for pd-1\/pd-l1 checkpoint inhibitor response in nsclc: An analysis of clinical trial and real-world data","volume":"11","author":"So","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/03936155231214273","article-title":"Pd-l1 assessment in lung cancer biopsies-pitfalls and limitations","volume":"39","author":"Gompelmann","year":"2024","journal-title":"Int. J. Biol. Markers"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103374","DOI":"10.1016\/j.critrevonc.2021.103374","article-title":"Tmb or not tmb as a biomarker: That is the question","volume":"163","author":"Addeo","year":"2021","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e000536","DOI":"10.1136\/esmoopen-2019-000536","article-title":"Ex vivo lung cancer spheroids resemble treatment response of a patient with nsclc to chemotherapy and immunotherapy: Case report and translational study","volume":"4","author":"Ciaramella","year":"2019","journal-title":"ESMO Open"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/JTO.0b013e3182779ccf","article-title":"Spheroid culture of primary lung cancer cells with neuregulin 1\/her3 pathway activation","volume":"8","author":"Endo","year":"2013","journal-title":"J. Thorac. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107533","DOI":"10.1016\/j.lungcan.2024.107533","article-title":"Ex vivo drug testing of patient-derived lung organoids to predict treatment responses for personalized medicine","volume":"190","author":"Taverna","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.1038\/s41467-018-05388-x","article-title":"Contact inhibition controls cell survival and proliferation via yap\/taz-autophagy axis","volume":"9","author":"Pavel","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_35","first-page":"e51998","article-title":"The soft agar colony formation assay","volume":"92","author":"Borowicz","year":"2014","journal-title":"J. Vis. Exp."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"van Tonder, A., Joubert, A.M., and Cromarty, A.D. (2015). Limitations of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2h-tetrazolium bromide (mtt) assay when compared to three commonly used cell enumeration assays. BMC Res. Notes, 8.","DOI":"10.1186\/s13104-015-1000-8"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1089\/adt.2011.391","article-title":"The xtt cell proliferation assay applied to cell layers embedded in three-dimensional matrix","volume":"10","author":"Huyck","year":"2012","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_38","first-page":"e59714","article-title":"Assessing cell viability and death in 3d spheroid cultures of cancer cells","volume":"148","author":"Rolver","year":"2019","journal-title":"J. Vis. Exp."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/10\/998\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:44:21Z","timestamp":1760107461000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/10\/998"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,11]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["diagnostics14100998"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics14100998","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,11]]}}}