title: Magnetic resonance perfusion image features uncover an angiogenic subgroup of glioblastoma patients with poor survival and better response to antiangiogenic treatment.
abstract: BACKGROUND
  In previous clinical trials, antiangiogenic therapies such as bevacizumab did not show efficacy in patients with newly diagnosed glioblastoma (GBM). This may be a result of the heterogeneity of GBM, which has a variety of imaging-based phenotypes and gene expression patterns. In this study, we sought to identify a phenotypic subtype of GBM patients who have distinct tumor-image features and molecular activities and who may benefit from antiangiogenic therapies.
  
  
  METHODS
  Quantitative image features characterizing subregions of tumors and the whole tumor were extracted from preoperative and pretherapy perfusion magnetic resonance (MR) images of 117 GBM patients in 2 independent cohorts. Unsupervised consensus clustering was performed to identify robust clusters of GBM in each cohort. Cox survival and gene set enrichment analyses were conducted to characterize the clinical significance and molecular pathway activities of the clusters. The differential treatment efficacy of antiangiogenic therapy between the clusters was evaluated.
  
  
  RESULTS
  A subgroup of patients with elevated perfusion features was identified and was significantly associated with poor patient survival after accounting for other clinical covariates (P values <.01; hazard ratios > 3) consistently found in both cohorts. Angiogenesis and hypoxia pathways were enriched in this subgroup of patients, suggesting the potential efficacy of antiangiogenic therapy. Patients of the angiogenic subgroups pooled from both cohorts, who had chemotherapy information available, had significantly longer survival when treated with antiangiogenic therapy (log-rank P=.022).
  
  
  CONCLUSIONS
  Our findings suggest that an angiogenic subtype of GBM patients may benefit from antiangiogenic therapy with improved overall survival.
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Tiffany T
authors.initials: TT
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Achal S
authors.initials: AS
authors.lastname: Achrol
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Lex A
authors.initials: LA
authors.lastname: Mitchell
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rodriguez
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Feroze
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Iv
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Navjot
authors.initials: N
authors.lastname: Chaudhary
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gevaert
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Josh M
authors.initials: JM
authors.lastname: Stuart
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Griffith R
authors.initials: GR
authors.lastname: Harsh
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Chang
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Rubin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D005909:Glioblastoma / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors
keywords: angiogenesis; antiangiogenic therapy; patient stratification; quantitative perfusion-weighted imaging; radiogenomic analysis