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However, the biological basis for this therapeutic resistance remains poorly understood. Furthermore, the effectiveness of temozolomide (TMZ) and the role of surgery in pediatric patients remain uncertain. Therefore, we performed a multi-institutional retrospective analysis of the clinical, imaging, and molecular characteristics of 36 pediatric (\u2264\u200918\u00a0years) patients with newly diagnosed H3 G34-mutant DHG. The median age of the cohort was 14\u00a0years (8\u201318\u00a0years). The median progression-free survival (PFS) was 0.7\u00a0years (95% CI 0.4\u20131.2\u00a0years), and the median overall survival (OS) was 1.8\u00a0years (95% CI 1.1\u20133.2\u00a0years). Gross total resection (GTR) was associated with improved PFS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0046). Infiltration of three or more brain lobes (gliomatosis cerebri) was noted in 22.6% (7\/31) of patients at presentation. Twenty-one patients (58.3%) received frontline TMZ and had improved PFS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0049) compared to those who did not. Low\n                    <jats:italic>MGMT<\/jats:italic>\n                    expression was associated with better PFS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0039) and better OS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). In pediatric DHG, gene body\/intronic CpG methylation, rather than promoter methylation, correlated with\n                    <jats:italic>MGMT<\/jats:italic>\n                    expression (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001).\n                    <jats:italic>MGMT<\/jats:italic>\n                    promoter methylation was not significantly associated with PFS or OS.\n                    <jats:italic>PDGFRA<\/jats:italic>\n                    alterations (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200913) were associated with inferior OS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0035). Post-radiation local (\u00b1\u2009distant) recurrence occurred in 81.0% (17\/21) of patients. Our findings reaffirm the dismal outcomes of pediatric H3 G34-mutant DHG, which exhibits radiation resistance, frequent widespread disease, and a novel mechanism of\n                    <jats:italic>MGMT<\/jats:italic>\n                    regulation. Our data support the use of frontline TMZ in pediatric patients and underscore the importance of GTR when feasible.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-02992-w","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T05:39:19Z","timestamp":1772429959000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pediatric H3 G34-mutant diffuse hemispheric glioma: clinical, imaging and molecular prognostic factors, MGMT expression, and temozolomide response"],"prefix":"10.1007","volume":"151","author":[{"given":"Dana","family":"Tlais","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan T.","family":"Roach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Tinkle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayatullah","family":"Mostafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Moreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene Y.","family":"McNall-Knapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Z.","family":"Rush","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian H.","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Sinno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apeksha","family":"Ramnarayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin F.","family":"Ginn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Partap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arzu","family":"Onar-Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa V.","family":"Furtado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asim K.","family":"Bag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"2992_CR1","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.jmoldx.2015.11.009","volume":"18","author":"P Bady","year":"2016","unstructured":"Bady P, Delorenzi M, Hegi ME (2016) Sensitivity analysis of the MGMT-STP27 model and impact of genetic and epigenetic context to predict the MGMT methylation status in gliomas and other tumors. 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