{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:36:19Z","timestamp":1792798579695,"version":"4.5.0"},"reference-count":20,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"unspecified","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UK Medical Research Council and the University of Bristol","award":["MC_UU_00011\/3"],"award-info":[{"award-number":["MC_UU_00011\/3"]}],"id":[{"id":"https:\/\/ror.org\/0524sp257","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100006244","name":"Stichting Kinderen Kankervrij","doi-asserted-by":"publisher","award":["163"],"award-info":[{"award-number":["163"]}],"id":[{"id":"10.13039\/501100006244","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Investigating the effect of prognostic factors in a multistate framework on survival in a large population of patients with osteosarcoma. Of interest is how prognostic factors affect different disease stages after surgery, with stages of local recurrence (LR), new metastatic disease (NM), LR+NM, secondary malignancy, a second NM, and death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>An open-label, international, phase 3 randomised controlled trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>325 sites in 17 countries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>The subset of 1631 metastases-free patients from 1965 patients with high-grade resectable osteosarcoma, from the European and American Osteosarcoma Study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main outcome measures<\/jats:title>\n                    <jats:p>The effect of prognostic factors on different disease stages, expressed as HRs; predictions of disease progression on an individual patient basis, according to patient-specific characteristics and history of intermediate events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 1631 patients, 526 experienced an intermediate event, and 305 died by the end of follow-up. An axial tumour site substantially increased the risk of LR after surgery (HR=10.84, 95% CI 8.46 to 13.86) and death after LR (HR=11.54, 95% CI 6.11 to 21.8). A poor histological increased the risk of NM (HR=5.81, 95% CI 5.31 to 6.36), which sharply declined after 3 years since surgery. Young patients (&lt;12 years) had a lower intermediate event risk (eg, for LR: HR=0.66, 95% CI 0.51 to 0.86), when compared with adolescents (12\u201318 years), but had an increased risk of subsequent death, while patients aged &gt;18 had a decreased risk of death after event (eg, for death after LR: HR=2.40, 95% CI 1.52 to 3.90; HR=0.35, 95% CI 0.21 to 0.56, respectively).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that patients with axial tumours should be monitored for LR and patients with poor histological response for NM, and that for young patients (&lt;12) with an LR additional treatment options should be investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT00134030\">NCT00134030<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-053083","type":"journal-article","created":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T11:21:16Z","timestamp":1646392876000},"page":"e053083","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Disease progression in osteosarcoma: a multistate model for the EURAMOS-1 (European and American Osteosarcoma Study) randomised clinical trial"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct00134030","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct00134030","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6923-4388","authenticated-orcid":false,"given":"Audinga-Dea","family":"Hazewinkel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Lancia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Anninga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"van de Sande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6793-5722","authenticated-orcid":false,"given":"Jeremy","family":"Whelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Gelderblom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Fiocco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"2022030408101428000_12.3.e053083.1","first-page":"1015","volume-title":"Principles and practice of pediatric oncology","volume":"Vol 6","author":"Gorlick","year":"2011"},{"key":"2022030408101428000_12.3.e053083.2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.4895"},{"key":"2022030408101428000_12.3.e053083.3","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu526"},{"key":"2022030408101428000_12.3.e053083.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.60.0734"},{"key":"2022030408101428000_12.3.e053083.5","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1016\/S1470-2045(16)30214-5","article-title":"Comparison of MAPIE versus map in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial","volume":"17","author":"Marina","year":"2016","journal-title":"Lancet Oncol"},{"key":"2022030408101428000_12.3.e053083.6","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.ejca.2018.11.027","article-title":"Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American osteosarcoma study) cohort","volume":"109","author":"Smeland","year":"2019","journal-title":"Eur J Cancer"},{"key":"2022030408101428000_12.3.e053083.7","doi-asserted-by":"publisher","DOI":"10.1002\/sim.2712"},{"key":"2022030408101428000_12.3.e053083.8","doi-asserted-by":"publisher","DOI":"10.2307\/2291635"},{"key":"2022030408101428000_12.3.e053083.9","unstructured":"R foundation for statistical computing . 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