{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T20:20:39Z","timestamp":1783369239572,"version":"3.54.6"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:00:00Z","timestamp":1733270400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:00:00Z","timestamp":1733270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002839","name":"Charit\u00e9 - Universit\u00e4tsmedizin Berlin","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002839","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurooncol"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Thyroid Transcription Factor-1 (TTF-1) expression in lung adenocarcinoma (LUAD) has been studied for its prognostic value in early-stage and metastatic disease. Its role in brain metastasis remains unexplored. This study investigates the predictive value and association of TTF-1 status with clinicopathological variables in patients with synchronous LUAD brain metastases.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Material and methods<\/jats:title>\n            <jats:p>In this bicentric retrospective study, 245 patients with newly diagnosed, treatment-na\u00efve brain metastasis undergoing resection were included. Patient data were retrieved from electronic records. Outcomes included overall and progression-free survival. Statistical analysis included Kaplan\u2013Meier estimates and Cox proportional hazards regression.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Mean Ki67 index in TTF-1 negative patients was 43% [95% CI 38\u201348%] compared to 32% [95% CI 29\u201335%] in TTF-1 positive (TTF-1\u2009+) patients (p\u2009&lt;\u20090.001). Tumor volume was significantly larger in TTF-1 negative (TTF-1-) patients (mean volume 24\u00a0mL [95% CI 18\u201331\u00a0mL]) vs. 15\u00a0mL [95% CI 12\u201317\u00a0mL] in TTF-1\u2009+\u2009patients (padjust\u2009=\u20090.003). Perifocal edema was smaller in TTF-1- patients (mean volume: 58\u00a0mL [95% CI 45\u201370\u00a0mL]) vs. 84\u00a0mL [95% CI 73\u201394\u00a0mL] in TTF-1\u2009+\u2009patients (padjust\u2009=\u20090.077). Tumor and edema volume did not correlate. TTF-1- patients showed worse overall, intracranial, and extracranial progression-free survival. In a multivariable Cox model, positive TTF-1 status was independently associated with improved outcomes. Negative TTF-1 status was associated with increased hazard for intracranial disease progression compared to extracranial progression.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>In synchronous LUAD brain metastases, TTF-1 negativity reflects an aggressive phenotype with larger proliferation capacity and tumor volume. Future research should explore the underlying cellular and molecular alterations of this phenotype.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s11060-024-04885-y","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T07:24:33Z","timestamp":1733297073000},"page":"637-649","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["TTF-1 negativity in synchronous M1b\/M1c wildtype lung adenocarcinoma brain metastases predicts worse survival with increased risk of intracranial progression"],"prefix":"10.1007","volume":"171","author":[{"given":"David","family":"Wasilewski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Araceli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Bischoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Fr\u00fch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rober","family":"Ates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selin","family":"Murad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Bukatz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majd","family":"Samman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Faust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"J\u00fcnger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Witzenrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Horst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atik","family":"Baborie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arend","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Capper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank L.","family":"Heppner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Radbruch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus J.","family":"Riemenschneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils Ole","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Vajkoczy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Proescholdt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Onken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaj","family":"Frost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"issue":"5","key":"4885_CR1","first-page":"407","volume":"39","author":"MA Vogelbaum","year":"2021","unstructured":"Vogelbaum MA, Brown PD, Messersmith H et al (2021) Treatment of brain metastases from lung cancer: a systematic review. J Clin Oncol 39(5):407\u2013422","journal-title":"J Clin Oncol"},{"key":"4885_CR2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.lungcan.2017.03.015","volume":"108","author":"JB Schilsky","year":"2017","unstructured":"Schilsky JB, Ni A, Ahn L et al (2017) Thyroid transcription factor-1 represses the expression of Ki-67 and enhances the expression of BubR1. Lung Cancer 108:14\u201321","journal-title":"Lung Cancer"},{"issue":"1","key":"4885_CR3","first-page":"5","volume":"12","author":"AL Folpe","year":"1999","unstructured":"Folpe AL, Gown AM, Lamps LW et al (1999) Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors. Mod Pathol 12(1):5\u20138","journal-title":"Mod Pathol"},{"issue":"1","key":"4885_CR4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1097\/PAS.0b013e3182036d05","volume":"36","author":"S Mukhopadhyay","year":"2012","unstructured":"Mukhopadhyay S, Katzenstein AL (2012) Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5\/6. Am J Surg Pathol 36(1):15\u201325","journal-title":"Am J Surg Pathol"},{"issue":"1","key":"4885_CR5","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1309\/AJCP50RDXSCSBTBO","volume":"140","author":"H Brunnstrom","year":"2013","unstructured":"Brunnstrom H, Johansson A, Westbom-Fremer S et al (2013) Immunohistochemistry in the differential diagnostics of primary lung cancer: an investigation within the Southern Swedish lung cancer study. Am J Clin Pathol 140(1):37\u201346","journal-title":"Am J Clin Pathol"},{"issue":"10","key":"4885_CR6","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1053\/hupa.2002.126874","volume":"33","author":"M Srodon","year":"2002","unstructured":"Srodon M, Westra WH (2002) Immunohistochemical staining for thyroid transcription factor-1 on cytologic preparations as a diagnostic aid for lung cancer. Hum Pathol 33(10):1016\u20131020","journal-title":"Hum Pathol"},{"issue":"4","key":"4885_CR7","first-page":"930","volume":"131","author":"PL Sun","year":"2006","unstructured":"Sun PL, Seol H, Lee HJ et al (2006) High TTF-1 expression is associated with improved survival in patients with non-small cell lung cancers. J Thorac Cardiovasc Surg 131(4):930\u2013935","journal-title":"J Thorac Cardiovasc Surg"},{"issue":"1","key":"4885_CR8","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/s41598-023-28409-2","volume":"13","author":"E Kut","year":"2023","unstructured":"Kut E, Menekse S (2023) The prognostic importance of thyroid transcription factor 1 in patients with non-small cell lung cancer with brain metastases. Sci Rep 13(1):1234","journal-title":"Sci Rep"},{"issue":"2","key":"4885_CR9","doi-asserted-by":"publisher","first-page":"101042831769118","DOI":"10.1177\/1010428317691186","volume":"39","author":"O Fiala","year":"2017","unstructured":"Fiala O, Pesek M, Skrickova J et al (2017) Thyroid transcription factor 1 expression is associated with outcome of patients with non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. Tumor Biol 39(2):1010428317691186","journal-title":"Tumor Biol"},{"key":"4885_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2020.05.014","author":"N Frost","year":"2020","unstructured":"Frost N, Zhamurashvili T, von Laffert M et al (2020) Pemetrexed-based chemotherapy is inferior to pemetrexed-free regimens in thyroid transcription factor 1 (TTF-1)-negative, EGFR\/ALK-negative lung adenocarcinoma: a propensity score matched pairs analysis. Clin Lung Cancer. https:\/\/doi.org\/10.1016\/j.cllc.2020.05.014","journal-title":"Clin Lung Cancer"},{"key":"4885_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2023.113474","volume":"197","author":"S Schallenberg","year":"2024","unstructured":"Schallenberg S, Tsourlakis MC, Kuempers C et al (2024) TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading. Eur J Cancer 197:113474","journal-title":"Eur J Cancer"},{"issue":"4","key":"4885_CR12","first-page":"491","volume":"4","author":"PL Sun","year":"2009","unstructured":"Sun PL, Jin Y, Kim H et al (2009) The impact of expression of thyroid transcription factor-1 on outcomes in patients with non-small-cell lung cancer. J Thorac Oncol 4(4):491\u2013498","journal-title":"J Thorac Oncol"},{"issue":"2","key":"4885_CR13","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1200\/JCO.2008.17.0043","volume":"27","author":"VK Anagnostou","year":"2009","unstructured":"Anagnostou VK, Syrigos KN, Bepler G, Homer RJ, Rimm DL (2009) Thyroid transcription factor 1 is an independent prognostic factor for patients with stage I lung adenocarcinoma. J Clin Oncol 27(2):271\u2013278. https:\/\/doi.org\/10.1200\/JCO.2008.17.0043","journal-title":"J Clin Oncol"},{"key":"4885_CR14","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.lungcan.2018.12.027","volume":"129","author":"B Yang","year":"2019","unstructured":"Yang B, Lee H, Um SW et al (2019) Incidence of brain metastasis in lung adenocarcinoma at initial diagnosis on the basis of stage and genetic alterations. Lung Cancer 129:28\u201334","journal-title":"Lung Cancer"},{"key":"4885_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2020.07.011","author":"XR Chen","year":"2021","unstructured":"Chen XR, Hou X, Li DL et al (2021) Management of non-small-cell lung cancer patients initially diagnosed with 1 to 3 synchronous brain-only metastases: a retrospective study. Clin Lung Cancer. https:\/\/doi.org\/10.1016\/j.cllc.2020.07.011","journal-title":"Clin Lung Cancer"},{"key":"4885_CR16","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2018-0596","author":"H Park","year":"2019","unstructured":"Park H, Dahlberg SE, Lydon CA et al (2019) M1b disease in the 8th edition of TNM staging of lung cancer: pattern of single extrathoracic metastasis and clinical outcome. Oncologist. https:\/\/doi.org\/10.1634\/theoncologist.2018-0596","journal-title":"Oncologist"},{"issue":"5","key":"4885_CR17","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1093\/neuonc\/noac193","volume":"25","author":"P Karschnia","year":"2023","unstructured":"Karschnia P, Young JS, Dono A et al (2023) Prognostic validation of a new classification system for extent of resection in glioblastoma: a report of the RANO resect group. Neuro Oncol 25(5):940\u2013954. https:\/\/doi.org\/10.1093\/neuonc\/noac193","journal-title":"Neuro Oncol"},{"key":"4885_CR18","doi-asserted-by":"publisher","first-page":"1149628","DOI":"10.3389\/fonc.2023.1149628","volume":"13","author":"L Baumgart","year":"2023","unstructured":"Baumgart L, Aftahy AK, Anetsberger A et al (2023) Brain metastases in the elderly\u2014impact of residual tumor volume on overall survival. Front Oncol 13:1149628. https:\/\/doi.org\/10.3389\/fonc.2023.1149628","journal-title":"Front Oncol"},{"issue":"6","key":"4885_CR19","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1111\/nan.12741","volume":"47","author":"L Schweizer","year":"2021","unstructured":"Schweizer L, Thierfelder F, Thomas C et al (2021) Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours. Neuropathol Appl Neurobiol 47(6):756\u2013767. https:\/\/doi.org\/10.1111\/nan.12741","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"5","key":"4885_CR20","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.3892\/or.2012.2009","volume":"28","author":"YF Zu","year":"2012","unstructured":"Zu YF, Wang XC, Chen Y et al (2012) Thyroid transcription factor 1 represses the expression of Ki-67 and induces apoptosis in non-small cell lung cancer. Oncol Rep 28(5):1544\u20131550. https:\/\/doi.org\/10.3892\/or.2012.2009","journal-title":"Oncol Rep"},{"issue":"4","key":"4885_CR21","doi-asserted-by":"publisher","first-page":"494","DOI":"10.3346\/jkms.2003.18.4.494","volume":"18","author":"NH Myong","year":"2003","unstructured":"Myong NH (2003) Thyroid transcription factor-1 (TTF-1) expression in human lung carcinomas: its prognostic implication and relationship with expressions of p53 and Ki-67 proteins. J Korean Med Sci 18(4):494\u2013500. https:\/\/doi.org\/10.3346\/jkms.2003.18.4.494","journal-title":"J Korean Med Sci"},{"issue":"1","key":"4885_CR22","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/s40425-019-0684-z","volume":"7","author":"TT Tran","year":"2019","unstructured":"Tran TT, Mahajan A, Chiang VL et al (2019) Perilesional edema in brain metastases: potential causes and implications for treatment with immune therapy. J Immunother Cancer 7(1):200. https:\/\/doi.org\/10.1186\/s40425-019-0684-z","journal-title":"J Immunother Cancer"},{"key":"4885_CR23","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2015.1057388","author":"AS Berghoff","year":"2016","unstructured":"Berghoff AS, Fuchs E, Ricken G et al (2016) Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology. https:\/\/doi.org\/10.1080\/2162402X.2015.1057388","journal-title":"Oncoimmunology"},{"issue":"1","key":"4885_CR24","doi-asserted-by":"publisher","first-page":"4980","DOI":"10.1038\/s41467-023-40793-x","volume":"14","author":"A Skakodub","year":"2023","unstructured":"Skakodub A, Walch H, Tringale KR et al (2023) Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis. Nat Commun 14(1):4980. https:\/\/doi.org\/10.1038\/s41467-023-40793-x","journal-title":"Nat Commun"}],"container-title":["Journal of Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11060-024-04885-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11060-024-04885-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11060-024-04885-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T16:06:15Z","timestamp":1736784375000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11060-024-04885-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,4]]},"references-count":24,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["4885"],"URL":"https:\/\/doi.org\/10.1007\/s11060-024-04885-y","relation":{},"ISSN":["0167-594X","1573-7373"],"issn-type":[{"value":"0167-594X","type":"print"},{"value":"1573-7373","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,4]]},"assertion":[{"value":"12 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2024","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 declare no\u00a0relevant financial or non-financial interests. There were no competing interests with respect to this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the local institutional review boards (EA1\/399\/20 and 20-1799-101).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Portions of this work were presented at the annual meeting of the European Association of Neurosurgical Societies (EANS), Sofia, Bulgaria, October 13\u201317, 2024.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Previous presentations"}}]}}