title: A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis.
abstract: OBJECTIVE
  To develop a Gamma Knife-based mouse model of late time-to-onset, cerebral radiation necrosis (RN) with serial evaluation by magnetic resonance imaging (MRI) and histology.
  
  
  METHODS
  Mice were irradiated with the Leksell Gamma Knife® (GK) PerfexionTM (Elekta AB; Stockholm, Sweden) with total single-hemispheric radiation doses (TRD) of 45- to 60-Gy, delivered in one to three fractions. RN was measured using T2-weighted MR images, while confirmation of tissue damage was assessed histologically by hematoxylin & eosin, trichrome, and PTAH staining.
  
  
  RESULTS
  MRI measurements demonstrate that TRD is a more important determinant of both time-to-onset and progression of RN than fractionation. The development of RN is significantly slower in mice irradiated with 45-Gy than 50- or 60-Gy, where RN development is similar. Irradiated mouse brains demonstrate all of the pathologic features observed clinically in patients with confirmed RN. A semi-quantitative (0 to 3) histologic grading system, capturing both the extent and severity of injury, is described and illustrated. Tissue damage, as assessed by a histologic score, correlates well with total necrotic volume measured by MRI (correlation coefficient = 0.948, with p<0.0001), and with post-irradiation time (correlation coefficient = 0.508, with p<0.0001).
  
  
  CONCLUSIONS
  Following GK irradiation, mice develop late time-to-onset cerebral RN histology mirroring clinical observations. MR imaging provides reliable quantification of the necrotic volume that correlates well with histologic score. This mouse model of RN will provide a platform for mechanism of action studies, the identification of imaging biomarkers of RN, and the development of clinical studies for improved mitigation and neuroprotection.
authors.affiliation: Department of Chemistry, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Liya
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Radiology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: John A
authors.initials: JA
authors.lastname: Engelbach
authors.affiliation: Department of Radiation Oncology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Cates
authors.affiliation: Department of Radiology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Perez-Torres
authors.affiliation: Division of Biostatistics, Washington University, St. Louis, Missouri, United States of America; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Radiation Oncology, Washington University, St. Louis, Missouri, United States of America; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Thotala
authors.affiliation: Department of Neurosurgery, Washington University, St. Louis, Missouri, United States of America; Department of Radiation Oncology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Drzymala
authors.affiliation: Department of Neuropathology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Department of Neurosurgery, Washington University, St. Louis, Missouri, United States of America; Department of Radiation Oncology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Rich
authors.affiliation: Department of Radiation Oncology, Washington University, St. Louis, Missouri, United States of America; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
authors.affiliation: Department of Chemistry, Washington University, St. Louis, Missouri, United States of America; Department of Radiology, Washington University, St. Louis, Missouri, United States of America; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America; Department of Internal Medicine, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Joseph J H
authors.initials: JJ
authors.lastname: Ackerman
authors.affiliation: Department of Radiology, Washington University, St. Louis, Missouri, United States of America; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Garbow
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology* / Q000528:radiation effects; D019583:Dose Fractionation, Radiation; D005260:Female; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000473:pathology*; D011833:Radiation Injuries, Experimental / Q000473:pathology*; D016634:Radiosurgery