{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T22:13:39Z","timestamp":1782339219164,"version":"3.54.5"},"reference-count":39,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Leptomeningeal disease (LMD) in diffuse midline gliomas (DMGs) can lead to devastating symptoms such as severe pain, urinary incontinence, and tetraparesis, with limited treatment options. We determined whether detecting <jats:italic>H3F3A<\/jats:italic> K27M\u2010mutant droplets in cerebrospinal fluid (CSF) circulating tumor deoxyribonucleic acid (ctDNA) could be a biomarker for detecting LMD in DMGs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty\u2010five CSF samples were obtained from 22 DMG patients. Histological confirmation of <jats:italic>H3F3A<\/jats:italic> K27M mutation was obtained in 10 (45.5%) cases. ctDNA was extracted from CSF, and <jats:italic>H3F3A<\/jats:italic> K27M\u2010mutant and wildtype droplets were detected using digital droplet polymerase chain reaction (ddPCR). LMD was diagnosed by CSF cytology and pre\u2010 and post\u2010contrast head and spine magnetic resonance (MR) imaging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The number of <jats:italic>H3F3A<\/jats:italic> K27M\u2010mutant droplets (median 27 [range: 1\u2013379] vs. median 0 [range: 0\u20131]; <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001) and variant allele frequency (VAF) (median 48.9% [range: 7.5%\u201387.5%] vs. median 0.0% [range: 0.0%\u201350.0%]; <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001) were significantly higher in the LMD\/early\u2010LMD group compared to no\u2010LMD group. In two cases (Cases 4 and 11) without clinical evidence of LMD, multiple <jats:italic>H3F3A<\/jats:italic> K27M\u2010mutant droplets were detected in CSF ctDNA. In those cases, extensive spinal dissemination was detected 6\u00a0months after the initial liquid biopsy. One case (Case 15) with high Schlafen11 (SLFN11) expression responded well to treatment for LMD and survived for 532\u00a0days after the diagnosis of LMD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study provides evidence that detecting <jats:italic>H3F3A<\/jats:italic> K27M\u2010mutant droplets in CSF ctDNA is diagnostic for LMD and is more sensitive than traditional methods such as CSF cytology and MR imaging.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.31535","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T05:40:36Z","timestamp":1736487636000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Diagnosis of Leptomeningeal Disease in Diffuse Midline Gliomas by Detection of <i>H3F3A<\/i> K27M Mutation in Circulating Tumor DNA of Cerebrospinal Fluid"],"prefix":"10.1002","volume":"72","author":[{"given":"Satoshi","family":"Shibuma","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jotaro","family":"On","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Natsumeda","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"},{"name":"Advanced Treatment of Neurological Diseases Branch, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihide","family":"Koyama","sequence":"additional","affiliation":[{"name":"Department of Legal Medicine, Graduate School of Medical and Dental Science Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Mitobe","sequence":"additional","affiliation":[{"name":"Department of Hematology, Endocrinology and Metabolism Niigata University Faculty of Medicine  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Nakata","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Gunma University Graduate School of Medicine  Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brain Research Institute Niigata University  Niigata Japan"},{"name":"Department of Orthopedic Surgery Niigata University Graduate School of Medical and Dental Sciences, Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayasu","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"},{"name":"Department of Brain Tumor Biology, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Tada","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichi","family":"Oya","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Gunma University Graduate School of Medicine  Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Murai","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Ehime University Graduate School of Medicine  Toon Ehime Japan"},{"name":"Division of Cell Growth and Tumor Regulation Proteo\u2010Science Center (PROS)  Toon Ehime Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouichirou","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Niigata University Graduate School of Medical and Dental Sciences, Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiyoshi","family":"Kakita","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Oishi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"World Health Organization Classification of Tumours of the central Nervous System","author":"Louis D. N.","year":"2021"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3171\/2017.2.PEDS1665"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(06)70615-5"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1319-6"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6603402"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-005-9029-5"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2176\/nmc.43.375"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1307-x"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-010-0301-y"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2019.1639169"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/po.18.00308"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics11040681"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1936-6"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-017-0436-6"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noac030"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0882-3"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3800"},{"key":"e_1_2_10_19_1","first-page":"9704","article-title":"Detection of Tumor\u2010derived DNA in Cerebrospinal Fluid of Patients With Primary Tumors of the Brain and Spinal Cord","volume":"112","author":"Wang Y.","year":"2015","journal-title":"P"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01568"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1789.2010.01197.x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlae084"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noac243"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1227\/00006123-199312000-00010"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/jon.12905"},{"key":"e_1_2_10_26_1","first-page":"15030","article-title":"Putative DNA\/RNA Helicase Schlafen\u201011 (SLFN11) Sensitizes Cancer Cells to DNA\u2010Damaging Agents","volume":"109","author":"Zoppoli G.","year":"2012","journal-title":"P"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01199-4"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-024-04582-w"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000216"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-012-0973-6"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.18758"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17357"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2489"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15133"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.66.6487"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdac178"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1478-0"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02194-y"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.3171\/2022.2.JNS211920"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11195548"}],"container-title":["Pediatric Blood &amp; Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.31535","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T06:19:56Z","timestamp":1741760396000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pbc.31535"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,9]]},"references-count":39,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1002\/pbc.31535"],"URL":"https:\/\/doi.org\/10.1002\/pbc.31535","archive":["Portico"],"relation":{},"ISSN":["1545-5009","1545-5017"],"issn-type":[{"value":"1545-5009","type":"print"},{"value":"1545-5017","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,9]]},"assertion":[{"value":"2024-10-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e31535"}}