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<jats:title>Abstract<\/jats:title>\n                    <jats:p>BackgroundCurrent treatment strategies for pediatric intracranial ependymoma do not consider molecular heterogeneity. Here, we evaluated molecular group-specific determinants of outcome and developed an improved risk stratification model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients aged 0-21 years with localized intracranial ependymoma were enrolled into the prospective clinical trial E-HIT2000. Treatment included maximum safe surgery, local radiotherapy, and chemotherapy, stratified according to age, histology and, following a major amendment, residual tumor. Clinical data were analyzed in a pooled molecularly annotated cohort with data from patients treated analogously within subsequent registries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>For 291 trial patients, the 5-year progression-free survival (PFS) and overall survival (OS) were 62\u2009\u00b1\u20093% and 81\u2009\u00b1\u20092%, respectively. For the molecularly annotated pooled cohort (n\u2009=\u2009228), 5-year PFS\/OS were: posterior-fossa group A ependymoma (EPN-PFA) (n\u2009=\u2009146): 45\u2009\u00b1\u20094%\/77\u2009\u00b1\u20094%; posterior-fossa group B ependymoma (EPN-PFB) (n\u2009=\u200919): 90\u2009\u00b1\u20097%\/100%; supratentorial ependymoma, ZFTA fusion-positive (EPN-ZFTA) (n\u2009=\u200959): 64\u2009\u00b1\u20097%\/86\u2009\u00b1\u20095%; supratentorial ependymoma, YAP1 fusion-positive (EPN-YAP1) (n\u2009=\u20094): 50\u2009\u00b1\u200925%\/100%. Patients with EPN-PFA without molecular risk factors (1q gain, and\/or subtype EPN-PFA1c\/d\/e, 2a), with complete resection, and postoperative radiotherapy showed favorable outcomes (5-year PFS\/OS 75\u2009\u00b1\u200910%\/92\u2009\u00b1\u20097%). For patients with EPN-PFA with molecular risk factors, prognosis was poor irrespective of residual tumor status (5-year PFS\/OS: 33\u2009\u00b1\u20096%\/64\u2009\u00b1\u20096%). Among EPN-ZFTA, 11\/59 tumors were classified as EPN-ZFTA with alternative fusions, associated with inferior PFS (5-year PFS\/OS: 36\u2009\u00b1\u200915%\/91\u2009\u00b1\u20099%). For EPN-ZFTA-RELA, homozygous deletions of CDKN2A were associated with unfavorable outcomes (4-year PFS\/OS: 19\u2009\u00b1\u200916%\/57\u2009\u00b1\u200918% vs. 79\u2009\u00b1\u20097%\/97\u2009\u00b1\u20093%, P\u2009=\u2009.0001). Finally, we developed a novel stratification model that discriminates standard and intermediate risk patients from those at high risk (P\u2009&amp;lt;\u2009.0001 for PFS and OS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results strongly suggest the inclusion of molecular parameters into stratification and the use of distinct treatment strategies within future ependymoma trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noaf218","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T11:59:23Z","timestamp":1757591963000},"source":"Crossref","is-referenced-by-count":6,"title":["Developing an advanced risk stratification model for pediatric intracranial ependymoma based on the prospective trial E-HIT2000 and subsequent registries"],"prefix":"10.1093","author":[{"given":"Katja","family":"von Hoff","sequence":"first","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg,","place":["Germany"]},{"name":"Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, and Department of Clinical Medicine, University of Aarhus , Aarhus,","place":["Denmark"]},{"name":"Department of Pediatric Oncology and Hematology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Berlin,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3216-8452","authenticated-orcid":false,"given":"Denise","family":"Obrecht-Sturm","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , 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