{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:18:05Z","timestamp":1792721885309,"version":"4.5.0"},"reference-count":46,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,7,10]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder driven by mitogen-activated protein kinase (MAPK) activation in hematopoietic cells. Historically, LCH has been staged according to involvement of \u201crisk organs\u201d (bone marrow, liver, and spleen), based on risk of death. With improvements in supportive care and efficacy of MAPK pathway inhibitors, patients with LCH now rarely die. However, most patients with LCH with multisystem disease are not cured with current front-line chemotherapy, and treatment failure is associated with long-term morbidity, including LCH-associated neurodegeneration (LCH-ND). In this study, we evaluated the impact of extent of LCH at presentation, tumor genotype, and BRAFV600E in pretherapy peripheral blood mononuclear cells (PBMCs) and bone marrow on systemic and central nervous system outcomes in a cohort of 385 pediatric patients with LCH and 115 adults with LCH, followed up for a median of 4 years (range, 0.02-18 years). Five-year event-free survival was 50.7% for pediatric patients and 32.7% for adult patients with LCH. In the pediatric cohort, presence of BRAFV600E PBMC was strongly associated with front-line treatment failure (hazard ratio [HR], 7.7). Remarkably, BRAFV600E PBMC at diagnosis also identified patients at the highest risk of developing LCH-ND (HR, 23.1). These findings support an updated model of pediatric LCH pathogenesis in which persistence of disease reservoir and cell of origin determine extent of disease and clinical risks. We, therefore, propose a major revision of pediatric LCH diagnostic staging, shifting from focus on historical risk of death to risks of systemic treatment failure and LCH-ND based on lesion location, lesion genotype, and peripheral LCH reservoir (eg, BRAFV600E PBMC).<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024026671","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T16:56:25Z","timestamp":1743699385000},"page":"206-218","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":20,"title":["<i>BRAF<\/i>\n          V600E-positive mononuclear cells in blood at diagnosis portend treatment failure and neurodegeneration in pediatric LCH"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0847-904X","authenticated-orcid":false,"given":"Howard","family":"Lin","sequence":"first","affiliation":[{"name":"1Department of Genetics and Genomics, Baylor 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Department of Pediatrics, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Zinn","sequence":"additional","affiliation":[{"name":"2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX"},{"name":"3Texas Children\u2019s Cancer Center, Texas Children\u2019s Hospital, Houston, TX"},{"name":"5Division of Pediatric Hematology\/Oncology, Department of Pediatrics, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, NH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olive S.","family":"Eckstein","sequence":"additional","affiliation":[{"name":"2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX"},{"name":"3Texas Children\u2019s Cancer Center, Texas Children\u2019s Hospital, Houston, 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John","family":"Hicks","sequence":"additional","affiliation":[{"name":"8Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin E.","family":"Fisher","sequence":"additional","affiliation":[{"name":"8Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4783-6991","authenticated-orcid":false,"given":"Choladda V.","family":"Curry","sequence":"additional","affiliation":[{"name":"8Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angshumoy","family":"Roy","sequence":"additional","affiliation":[{"name":"8Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3154-8987","authenticated-orcid":false,"given":"Deborah","family":"Schiff","sequence":"additional","affiliation":[{"name":"9University of California School of Medicine, La Jolla, CA"},{"name":"10Rady Children\u2019s Hospital, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth M.","family":"Heym","sequence":"additional","affiliation":[{"name":"11Department of Pediatric Hematology and Oncology, Cook Children\u2019s Medical Center, Fort Worth, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Scheurer","sequence":"additional","affiliation":[{"name":"2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX"},{"name":"3Texas Children\u2019s Cancer Center, Texas Children\u2019s Hospital, Houston, TX"},{"name":"4Center for Epidemiology and Population Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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