title: A novel prognostic model for osteosarcoma using circulating CXCL10 and FLT3LG.
abstract: BACKGROUND
  Osteosarcoma (OS) is the most common malignant pediatric bone tumor. The identification of novel biomarkers for early prognostication will facilitate risk-based stratification and therapy. This study investigated the significance of circulating cytokines/chemokines for predicting the prognosis at the initial diagnosis.
  
  
  METHODS
  Luminex assays were used to measure cytokine/chemokine concentrations in blood samples from a discovery cohort of OS patients from Texas Children's Hospital (n = 37) and an independent validation cohort obtained from the Children's Oncology Group (n = 233). After the validation of the biomarkers, a multivariate model was constructed to stratify the patients into risk groups.
  
  
  RESULTS
  The circulating concentrations of C-X-C motif chemokine ligand 10 (CXCL10), Fms-related tyrosine kinase 3 ligand (FLT3LG), interferon γ (IFNG), and C-C motif chemokine ligand 4 (CCL4) were significantly associated with overall survival in both cohorts. Among these candidates, CXCL10 and FLT3LG were independent of the existing prognostic factor, metastasis at diagnosis, and CCL4 further discriminated cancer cases from controls. CXCL10, FLT3LG, and the metastatic status at diagnosis were combined to develop a multivariate model that significantly stratified the patients into 4 distinct risk groups (P = 1.6 × 10-8). The survival analysis showed that the 5-year overall survival rates for the low-, intermediate-, high-, and very high-risk groups were 77%, 54%, 47%, and 10%, respectively, whereas the 5-year event-free survival rates were 64%, 47%, 27%, and 0%, respectively. Neither CXCL10 nor FLT3LG tumor expression was significantly associated with survival.
  
  
  CONCLUSIONS
  High circulating levels of CXCL10 and FLT3LG predicted worse survival for patients with OS. Because both CXCL10 and FL3LG axes are potentially targetable, further study may lead to novel risk-based stratification and therapy for OS. Cancer 2017;144-154. © 2016 American Cancer Society.
authors.affiliation: Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Flores
authors.affiliation: Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Program of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Kelly
authors.affiliation: Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Li
authors.affiliation: Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Manjula
authors.initials: M
authors.lastname: Nakka
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.|Children's Oncology Group, Monrovia, California.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Barkauskas
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.|Children's Oncology Group, Monrovia, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.affiliation: Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Perlaky
authors.affiliation: Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.|Program of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.|Department of Pathology, Baylor College of Medicine, Houston, Texas.
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.|Program of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Tsz-Kwong
authors.initials: TK
authors.lastname: Man
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood; D001859:Bone Neoplasms / Q000097:blood* / Q000401:mortality / Q000473:pathology*; D054357:Chemokine CXCL10 / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000097:blood*; D012516:Osteosarcoma / Q000097:blood* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D012306:Risk; D016019:Survival Analysis; D015996:Survival Rate; D013781:Texas; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016207:Cytokines; D008565:Membrane Proteins; C084881:flt3 ligand protein
keywords: CXCL10; FLT3LG; Luminex; circulating biomarkers; metastasis; osteosarcoma; pediatric cancer and prognosis