title: Preoperative dynamic contrast-enhanced MRI correlates with molecular markers of hypoxia and vascularity in specific areas of intratumoral microenvironment and is predictive of patient outcome.
abstract: BACKGROUND
  Measures of tumor vascularity and hypoxia have been correlated with glioma grade and outcome. Dynamic contrast-enhanced (DCE) MRI can noninvasively map tumor blood flow, vascularity, and permeability. In this prospective observational cohort pilot study, preoperative imaging was correlated with molecular markers of hypoxia, vascularity, proliferation, and progression-free and overall patient survival.
  
  
  METHODS
  Pharmacokinetic modeling methods were used to generate maps of tumor blood flow, extraction fraction, permeability-surface area product, transfer constant, washout rate, interstitial volume, blood volume, capillary transit time, and capillary heterogeneity from preoperative DCE-MRI data in human glioma patients. Tissue was obtained from areas of peritumoral edema, active tumor, hypoxic penumbra, and necrotic core and evaluated for vascularity, proliferation, and expression of hypoxia-regulated molecules. DCE-MRI parameter values were correlated with hypoxia-regulated protein expression at tissue sample sites.
  
  
  RESULTS
  Patient survival correlated with DCE parameters in 2 cases: capillary heterogeneity in active tumor and interstitial volume in areas of peritumoral edema. Statistically significant correlations were observed between several DCE parameters and tissue markers. In addition, MIB-1 index was predictive of overall survival (P = .044) and correlated with vascular endothelial growth factor expression in hypoxic penumbra (r = 0.7933, P = .0071) and peritumoral edema (r = 0.4546). Increased microvessel density correlated with worse patient outcome (P = .026).
  
  
  CONCLUSIONS
  Our findings suggest that DCE-MRI may facilitate noninvasive preoperative predictions of areas of tumor with increased hypoxia and proliferation. Both imaging and hypoxia biomarkers are predictive of patient outcome. This has the potential to allow unprecedented prognostic decisions and to guide therapies to specific tumor areas.
authors.affiliation: Corresponding author: Randy L. Jensen, MD, PhD, Huntsman Cancer Institute and Departments of Neurosurgery, Radiation Oncology, Oncological Sciences, Clinical Neuroscience Center, University of Utah, 175 North Medical Drive, Salt Lake City, Utah 84132. randy.jensen@hsc.utah.edu.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Jensen
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mumert
authors.forename: David L
authors.initials: DL
authors.lastname: Gillespie
authors.forename: Anita Y
authors.initials: AY
authors.lastname: Kinney
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Schabel
authors.forename: Karen L
authors.initials: KL
authors.lastname: Salzman
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D049109:Cell Proliferation; D003287:Contrast Media / Q000493:pharmacokinetics; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D010865:Pilot Projects; D011300:Preoperative Care; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D014018:Tissue Distribution; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D003287:Contrast Media; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495677:SLC2A1 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: DCE-MRI; HIF-1; VEGF.; hypoxia; vascularity