title: Diffusion-Weighted MRI as a Biomarker of Tumor Radiation Treatment Response Heterogeneity: A Comparative Study of Whole-Volume Histogram Analysis versus Voxel-Based Functional Diffusion Map Analysis.
abstract: BACKGROUND
  Treatment of glioblastoma (GBM) remains challenging due in part to its histologic intratumoral heterogeneity that contributes to its overall poor treatment response. Our goal was to evaluate a voxel-based biomarker, the functional diffusion map (fDM), as an imaging biomarker to detect heterogeneity of tumor response in a radiation dose escalation protocol using a genetically engineered murine GBM model.
  
  
  METHODS
  Twenty-four genetically engineered murine GBM models [Ink4a-Arf(-/-)/Pten(loxp/loxp)/Ntv-a RCAS/PDGF(+)/Cre(+)] were randomized in four treatment groups (n = 6 per group) consisting of daily doses of 0, 1, 2, and 4 Gy delivered for 5 days. Contrast-enhanced T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scans were acquired for tumor delineation and quantification of apparent diffusion coefficient (ADC) maps, respectively. MRI experiments were performed daily for a week and every 2 days thereafter. For each animal, the area under the curve (AUC) of the percentage change of the ADC (AUCADC) and that of the increase in fDM values (AUCfDM+) were determined within the first 5 days following therapy initiation.
  
  
  RESULTS
  Animal survival increased with increasing radiation dose. Treatment induced a dose-dependent increase in tumor ADC values. The strongest correlation between survival and ADC measurements was observed using the AUCfDM+ metric (R (2) = 0.88).
  
  
  CONCLUSIONS
  This study showed that the efficacy of a voxel-based imaging biomarker (fDM) was able to detect spatially varying changes in tumors, which were determined to be a more sensitive predictor of overall response versus whole-volume tumor measurements (AUCADC). Finally, fDM provided for visualization of treatment-associated spatial heterogeneity within the tumor.
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lemasson
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Galbán
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Boes
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Heist
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Johnson
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Chenevert
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross