{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T07:14:37Z","timestamp":1783581277676,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T00:00:00Z","timestamp":1704672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft"},{"name":"Deutsche Krebshilfe"},{"name":"F\u00f6rdergemeinschaft Kinderkrebs Zentrum Hamburg"},{"name":"F\u00f6rderkreis krebskranke Kinder Stuttgart"},{"name":"Helga und Heinrich Holzhauer Stiftung"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: To evaluate patient and tumour characteristics, treatment, and their impact on survival in patients with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma. Precedure: Eighty-three consecutive patients who presented with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma were retrospectively reviewed. In cases of curative intent, the Cooperative Osteosarcoma Study Group recommended surgical removal of all detectable metastases in addition to complete resection of the primary tumour and chemotherapy. Results: Eighty-three eligible patients (1.8%) were identified among a total of 4605 individuals with high-grade osteosarcoma. Nine (10.8%) of these achieved complete surgical remission, of whom seven later had recurrences. The median follow-up time was 12 (range, 1\u2013165) months for all patients. Actuarial event-free survival after 1, 2, and 5 years was 9.6 \u00b1 3.2%, 1.4 \u00b1 1.4%, and 1.4 \u00b1 1.4%, and overall survival was 54.0 \u00b1 5.6%, 23.2 \u00b1 4.9%, and 8.7 \u00b1 3.3%. In univariate analyses, elevated alkaline phosphatase before chemotherapy, pleural effusion, distant bones as metastatic sites, and more than one bone metastasis were negative prognostic factors. Among treatment-related factors, the microscopically complete resection of the primary tumour, a good response to first-line chemotherapy, the macroscopically complete resection of all affected tumour sites, and local treatment (surgery \u00b1 radiotherapy) of all bone metastases were associated with better outcomes. Tumour progression under first-line treatment significantly correlated with shorter survival times. Conclusion: The outlook for patients with multi-systemic primary metastases from osteosarcoma remains very poor. The utmost importance of surgical resection of all tumour sites was confirmed. For unresectable bone metastases, radiotherapy might be considered. In the patient group studied, standard chemotherapy was often insufficiently effective. In the case of such advanced disease, alternative treatment options are urgently required.<\/jats:p>","DOI":"10.3390\/cancers16020275","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T03:36:58Z","timestamp":1704771418000},"page":"275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Primary Multi-Systemic Metastases in Osteosarcoma: Presentation, Treatment, and Survival of 83 Patients of the Cooperative Osteosarcoma Study Group"],"prefix":"10.3390","volume":"16","author":[{"given":"Vanessa L.","family":"Mettmann","sequence":"first","affiliation":[{"name":"Cooperative Osteosarcoma Study Group, Paediatrics 5 (Oncology, Haematology, Immunology), Centre for Paediatric, Adolescent and Women\u2019s Medicine, and Stuttgart Cancer Centre, Klinikum Stuttgart\u2013Olgahospital, 70174 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Blattmann","sequence":"additional","affiliation":[{"name":"Cooperative Osteosarcoma Study Group, Paediatrics 5 (Oncology, Haematology, Immunology), Centre for Paediatric, Adolescent and Women\u2019s Medicine, and Stuttgart Cancer Centre, Klinikum Stuttgart\u2013Olgahospital, 70174 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Godehard","family":"Friedel","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Faculty of Science, University of Tubingen, 72076 Tubingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1195-7150","authenticated-orcid":false,"given":"Semi","family":"Harrabi","sequence":"additional","affiliation":[{"name":"Heidelberg Ion Beam Therapy Centre (HIT), Department of Radiation Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thekla","family":"von Kalle","sequence":"additional","affiliation":[{"name":"Radiologic Institute, Centre for Paediatric, Adolescent and Women\u2019s Medicine, Stuttgart Cancer Centre, Klinikum Stuttgart\u2013Olgahospital, 70174 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4954-6488","authenticated-orcid":false,"given":"Leo","family":"Kager","sequence":"additional","affiliation":[{"name":"St. Anna Children\u2019s Hospital, University Hospital for Paediatric and Adolescent Medicine of the Medical University and St. Anna Children\u2019s Cancer Research Institute (CCRI), 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Kevric","sequence":"additional","affiliation":[{"name":"Cooperative Osteosarcoma Study Group, Paediatrics 5 (Oncology, Haematology, Immunology), Centre for Paediatric, Adolescent and Women\u2019s Medicine, and Stuttgart Cancer Centre, Klinikum Stuttgart\u2013Olgahospital, 70174 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7387-7028","authenticated-orcid":false,"given":"Thomas","family":"K\u00fchne","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Nathrath","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Children\u2019s Cancer Research Centre, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany"},{"name":"Paediatric Haematology and Oncology, Klinikum Kassel, 34125 Kassel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Sorg","sequence":"additional","affiliation":[{"name":"Cooperative Osteosarcoma Study Group, Paediatrics 5 (Oncology, Haematology, Immunology), Centre for Paediatric, Adolescent and Women\u2019s Medicine, and Stuttgart Cancer Centre, Klinikum Stuttgart\u2013Olgahospital, 70174 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Werner","sequence":"additional","affiliation":[{"name":"Osteopathology Reference Centre, Institute of Pathology, Vivantes Klinikum im Friedrichshein, 10249 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2144-3153","authenticated-orcid":false,"given":"Stefan S.","family":"Bielack","sequence":"additional","affiliation":[{"name":"Cooperative Osteosarcoma Study Group, Paediatrics 5 (Oncology, Haematology, Immunology), Centre for Paediatric, Adolescent and Women\u2019s Medicine, and Stuttgart Cancer Centre, Klinikum Stuttgart\u2013Olgahospital, 70174 Stuttgart, Germany"},{"name":"Department for Paediatric Haematology and Oncology, University\u2019s Children\u2019s Hospital Muenster, 48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Hecker-Nolting","sequence":"additional","affiliation":[{"name":"Cooperative Osteosarcoma Study Group, Paediatrics 5 (Oncology, Haematology, Immunology), Centre for Paediatric, Adolescent and Women\u2019s Medicine, and Stuttgart Cancer Centre, Klinikum Stuttgart\u2013Olgahospital, 70174 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1002\/pbc.25963","article-title":"Prevalence of Metastasis at Diagnosis of Osteosarcoma: An International Comparison","volume":"63","author":"Marko","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1200\/JCO.2002.20.3.776","article-title":"Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols","volume":"20","author":"Bielack","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1002\/(SICI)1097-0142(19991015)86:8<1602::AID-CNCR31>3.0.CO;2-R","article-title":"Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis: Imaging features","volume":"86","author":"Kaste","year":"1999","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/00043426-200201000-00008","article-title":"High-grade osteosarcoma of the extremity: Differences between localized and metastatic tumors at presentation","volume":"24","author":"Bacci","year":"2002","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e89","DOI":"10.2106\/JBJS.L.01189","article-title":"Risk factors for metastatic disease at presentation with osteosarcoma: An analysis of the SEER database","volume":"95","author":"Miller","year":"2013","journal-title":"J. Bone Joint Surg. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.canep.2015.05.001","article-title":"Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database","volume":"39","author":"Duchman","year":"2015","journal-title":"Cancer Epidemiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1200\/JCO.2003.08.132","article-title":"Primary metastatic osteosarcoma: Presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols","volume":"21","author":"Kager","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1200\/JCO.1993.11.3.449","article-title":"Osteogenic sarcoma with clinically detectable metastasis at initial presentation","volume":"11","author":"Meyers","year":"1993","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3641","DOI":"10.1200\/JCO.1998.16.11.3641","article-title":"Treatment of metastatic osteosarcoma at diagnosis: A Pediatric Oncology Group Study","volume":"16","author":"Harris","year":"1998","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e345","DOI":"10.3928\/01477447-20200721-05","article-title":"Current Treatment Considerations for Osteosarcoma Metastatic at Presentation","volume":"43","author":"Tsukamoto","year":"2020","journal-title":"Orthopedics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1016\/j.annonc.2021.08.1995","article-title":"Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"32","author":"Strauss","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e28352","DOI":"10.1002\/pbc.28352","article-title":"Osteosarcoma","volume":"68","author":"Eaton","year":"2021","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"vii320","DOI":"10.1093\/annonc\/mdq276","article-title":"Osteosarcoma","volume":"21","author":"Ritter","year":"2010","journal-title":"Ann. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1002\/cncr.21263","article-title":"Metastatic osteosarcoma at diagnosis: Prognostic factors and long-term outcome--the French pediatric experience","volume":"104","author":"Mialou","year":"2005","journal-title":"Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jpedsurg.2014.10.038","article-title":"Effect of concurrent metastatic disease on survival in children and adolescents undergoing lung resection for metastatic osteosarcoma","volume":"50","author":"Slade","year":"2015","journal-title":"J. Pediatr. Surg."},{"key":"ref_16","first-page":"135","article-title":"Determination of the degree of morphological regression following chemotherapy in malignant bone tumors","volume":"4","author":"Brand","year":"1983","journal-title":"Pathologe"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1080\/01621459.1958.10501452","article-title":"Nonparametric Estimation from Incomplete Observations","volume":"53","author":"Kaplan","year":"1958","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_18","first-page":"163","article-title":"Evaluation of survival data and two new rank order statistics arising in its consideration","volume":"50","author":"Mantel","year":"1966","journal-title":"Cancer Chemother. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1302\/0301-620X.88B8.17809","article-title":"Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients","volume":"88","author":"Bacci","year":"2006","journal-title":"J. Bone Joint Surg. Br."},{"key":"ref_20","first-page":"171","article-title":"The prognostic value of serum alkaline phosphatase in osteosarcoma of the limbs","volume":"77","author":"Bacci","year":"1992","journal-title":"Chir. Organi Mov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7043","DOI":"10.3390\/curroncol30070511","article-title":"The Prognostic Value of Serum Biomarkers for Survival of Children with Osteosarcoma of the Extremities","volume":"30","author":"Basoli","year":"2023","journal-title":"Curr. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jbo.2015.09.002","article-title":"Pre-treatment serum lactate dehydrogenase and alkaline phosphatase as predictors of metastases in extremity osteosarcoma","volume":"4","author":"Marais","year":"2015","journal-title":"J. Bone Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jasc.2023.01.005","article-title":"Metastatic sarcomas to pleural effusion: A 10-year large tertiary care center experience with emphasis on clinical features and cytomorphologic characteristics","volume":"12","author":"Saoud","year":"2023","journal-title":"J. Am. Soc. Cytopathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/pbc.22293","article-title":"Prognostic factors in pulmonary metastasized high-grade osteosarcoma","volume":"54","author":"Buddingh","year":"2010","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.ejcts.2008.07.032","article-title":"Prognostic factors of pulmonary metastasectomy for osteosarcomas of the extremities","volume":"34","author":"Chen","year":"2008","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3470","DOI":"10.1200\/JCO.2002.11.028","article-title":"Effect of timing of pulmonary metastases identification on prognosis of patients with osteosarcoma: The Japanese Musculoskeletal Oncology Group study","volume":"20","author":"Tsuchiya","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1093\/jjco\/hyaa204","article-title":"Surgical resection of the primary lesion for osteosarcoma patients with metastasis at initial diagnosis","volume":"51","author":"Zhang","year":"2021","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jpedsurg.2005.10.024","article-title":"Computed tomographic scan of the chest underestimates the number of metastatic lesions in osteosarcoma","volume":"41","author":"Kayton","year":"2006","journal-title":"J. Pediatr. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1016\/j.ejrad.2015.09.022","article-title":"The many faces of pulmonary metastases of osteosarcoma: Retrospective study on 283 lesions submitted to surgery","volume":"84","author":"Ciccarese","year":"2015","journal-title":"Eur. J. Radiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3578","DOI":"10.21037\/jtd.2019.07.65","article-title":"Necessity of thoracotomy in pulmonary metastasis of osteosarcoma","volume":"11","author":"Gao","year":"2019","journal-title":"J. Thorac. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.jpedsurg.2003.11.030","article-title":"Surgical management and outcome of osteosarcoma patients with unilateral pulmonary metastases","volume":"39","author":"Su","year":"2004","journal-title":"J. Pediatr. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jpedsurg.2016.10.034","article-title":"A 20-year retrospective analysis of CT-based pre-operative identification of pulmonary metastases in patients with osteosarcoma: A single-center review","volume":"52","author":"Heaton","year":"2017","journal-title":"J. Pediatr. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/978-1-4419-0284-9_8","article-title":"Osteosarcoma lung metastases detection and principles of multimodal therapy","volume":"152","author":"Carrle","year":"2009","journal-title":"Cancer Treat. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4522","DOI":"10.1002\/cncr.26037","article-title":"Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma","volume":"117","author":"Ciernik","year":"2011","journal-title":"Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4466","DOI":"10.1200\/JCO.2002.10.050","article-title":"Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas","volume":"20","author":"Kamada","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.radonc.2021.01.029","article-title":"The role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma","volume":"159","author":"Seidensaal","year":"2021","journal-title":"Radiother. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/978-1-4419-0284-9_7","article-title":"The role of radiotherapy in oseosarcoma","volume":"152","author":"Schwarz","year":"2009","journal-title":"Pediatr. Adolesc. Osteosarcoma"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4555","DOI":"10.1002\/cncr.27451","article-title":"Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk","volume":"118","author":"Matsunobu","year":"2012","journal-title":"Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00586-015-4202-9","article-title":"Carbon-ion radiotherapy of spinal osteosarcoma with long-term follow","volume":"25","author":"Zhang","year":"2016","journal-title":"Eur. Spine J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/978-3-319-04843-7_16","article-title":"Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: Samarium-153-EDTMP and radium-223","volume":"804","author":"Anderson","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1093\/annonc\/mdr542","article-title":"153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients","volume":"23","author":"Berger","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/S1470-2045(19)30825-3","article-title":"Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): A multicentre, single-arm, phase 2 trial","volume":"21","author":"Italiano","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1200\/JCO.18.02374","article-title":"Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma","volume":"37","author":"Davis","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/S1470-2045(18)30742-3","article-title":"Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: A non-comparative, randomised, double-blind, placebo-controlled, phase 2 study","volume":"20","author":"Duffaud","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1093\/annonc\/mdr151","article-title":"A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: An Italian Sarcoma Group study","volume":"23","author":"Grignani","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/S1470-2045(14)71136-2","article-title":"Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: A non-randomised phase 2 clinical trial","volume":"16","author":"Grignani","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41572-022-00409-y","article-title":"Osteosarcoma","volume":"8","author":"Beird","year":"2022","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1177\/15353702211067718","article-title":"Innovative approaches for treatment of osteosarcoma","volume":"247","author":"Rothzerg","year":"2022","journal-title":"Exp. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Harris, M.A., and Hawkins, C.J. (2022). Recent and Ongoing Research into Metastatic Osteosarcoma Treatments. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073817"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Pilavaki, P., Gahanbani Ardakani, A., Gikas, P., and Constantinidou, A. (2023). Osteosarcoma: Current Concepts and Evolutions in Management Principles. J. Clin. Med., 12.","DOI":"10.3390\/jcm12082785"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Gazouli, I., Kyriazoglou, A., Kotsantis, I., Anastasiou, M., Pantazopoulos, A., Prevezanou, M., Chatzidakis, I., Kavourakis, G., Economopoulou, P., and Kontogeorgakos, V. (2021). Systematic Review of Recurrent Osteosarcoma Systemic Therapy. Cancers, 13.","DOI":"10.3390\/cancers13081757"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/2\/275\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:42:23Z","timestamp":1760103743000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/2\/275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,8]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["cancers16020275"],"URL":"https:\/\/doi.org\/10.3390\/cancers16020275","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,8]]}}}