{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T13:32:23Z","timestamp":1758807143093,"version":"3.41.2"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,3,30]],"date-time":"2018-03-30T00:00:00Z","timestamp":1522368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100008634","name":"Neuroblastoma UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008634","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C5651\/A9663"],"award-info":[{"award-number":["C5651\/A9663"]}],"id":[{"id":"10.13039\/501100000289","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":[[2018,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (\u226412 months of age at diagnosis, <jats:italic>MYCN<\/jats:italic> amplified) and toddlers (between 12 and 18 months, any <jats:italic>MYCN<\/jats:italic> status) predict event\u2010free survival (EFS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Bone marrow aspirates and peripheral blood samples from 97 infants\/toddlers enrolled in the European High\u2010Risk Neuroblastoma trial were collected at diagnosis in PAXgene<jats:sup>\u2122<\/jats:sup> blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bone marrow tyrosine hydroxylase (TH) or paired\u2010like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and <jats:italic>MYCN<\/jats:italic> status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p\u00a0=\u00a00.015), and identified 20 (23%) infants\/toddlers with 5\u2010year EFS of 20% (95%CI: 4%\u201344%). Prognostic significance was maintained after adjusting for over\u2010fitting bias (p\u00a0=\u00a00.038), age and <jats:italic>MYCN<\/jats:italic> status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two\u2010fold increased risk of an event (p\u00a0=\u00a00.032), and identified 23 (34%) infants\/toddlers with 5\u2010year EFS of 29% (95%CI: 12%\u201348%). Time\u2010dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow\u2010up.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high\u2010risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.27052","type":"journal-article","created":{"date-parts":[[2018,3,31]],"date-time":"2018-03-31T01:16:22Z","timestamp":1522458982000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Event\u2010free survival of infants and toddlers enrolled in the HR\u2010NBL\u20101\/SIOPEN trial is associated with the level of neuroblastoma mRNAs at diagnosis"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7316-0772","authenticated-orcid":false,"given":"Maria V.","family":"Corrias","sequence":"first","affiliation":[{"name":"Unit of Experimental Therapy in Oncology Istituto Giannina Gaslini  Genoa Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Parodi","sequence":"additional","affiliation":[{"name":"Unit 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