{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T19:39:49Z","timestamp":1789933189627,"version":"4.0.1"},"reference-count":40,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2018,4,6]],"date-time":"2018-04-06T00:00:00Z","timestamp":1522972800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA154489"],"award-info":[{"award-number":["R01 CA154489"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA154947"],"award-info":[{"award-number":["CA154947"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UL1TR001857"],"award-info":[{"award-number":["UL1TR001857"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001445","name":"Alex's Lemonade Stand Foundation for Childhood Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001445","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006058","name":"St. Baldrick's Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006058","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2018,6,15]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Central nervous system Langerhans cell histiocytosis (CNS\u2010LCH) brain involvement may include mass lesions and\/or a neurodegenerative disease (LCH\u2010ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS\u2010LCH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular\n                      <jats:italic>BRAF<\/jats:italic>\n                      V600E DNA were analyzed in CSF from patients with CNS\u2010LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of\n                      <jats:italic>BRAF<\/jats:italic>\n                      V600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH\u2010ND patients, and the response to BRAF\u2010V600E inhibitor was evaluated in 4 patients with progressive disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Osteopontin was the only consistently elevated CSF protein in patients with CNS\u2010LCH compared with patients with other brain pathologies.\n                      <jats:italic>BRAF<\/jats:italic>\n                      V600E DNA was detected in CSF of only 2\/20 (10%) cases, both with LCH\u2010ND and active lesions outside the CNS. However, BRAF\n                      <jats:italic>\n                        V600E\n                        <jats:sup>+<\/jats:sup>\n                      <\/jats:italic>\n                      PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH\u2010ND. Brain biopsies of patients with LCH\u2010ND demonstrated diffuse perivascular infiltration by\n                      <jats:italic>BRAF<\/jats:italic>\n                      V600E\n                      <jats:sup>+<\/jats:sup>\n                      cells with monocyte phenotype (CD14\n                      <jats:sup>+<\/jats:sup>\n                      CD33\n                      <jats:sup>+<\/jats:sup>\n                      CD163\n                      <jats:sup>+<\/jats:sup>\n                      P2RY12\n                      <jats:sup>\u2010<\/jats:sup>\n                      ) and associated osteopontin expression. Three of 4 patients with LCH\u2010ND treated with BRAF\u2010V600E inhibitor experienced significant clinical and radiologic improvement.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      In LCH\u2010ND patients,\n                      <jats:italic>BRAF<\/jats:italic>\n                      V600E\n                      <jats:sup>+<\/jats:sup>\n                      cells in PBMCs and infiltrating myeloid\/monocytic cells in the brain is consistent with LCH\u2010ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207\n                      <jats:sup>+<\/jats:sup>\n                      cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH\u2010ND.\n                      <jats:bold>\n                        <jats:italic>Cancer<\/jats:italic>\n                        2018;124:2607\u201020\n                      <\/jats:bold>\n                      . \u00a9\n                      <jats:italic>2018 American Cancer Society<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cncr.31348","type":"journal-article","created":{"date-parts":[[2018,4,6]],"date-time":"2018-04-06T17:36:27Z","timestamp":1523036187000},"page":"2607-2620","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":120,"title":["CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH\u2010associated neurodegeneration and mass lesions"],"prefix":"10.1002","volume":"124","author":[{"given":"Kenneth L.","family":"McClain","sequence":"first","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Picarsic","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikhia","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Zinn","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Lin","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harshal","family":"Abhyankar","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooks","family":"Scull","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Shih","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen Phaik Har","family":"Lim","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"},{"name":"Graduate Program in Translational Biology and Molecular Medicine Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olive","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Lubega","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tricia L.","family":"Peters","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"},{"name":"Department of Pathology Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Olea","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Burke","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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