title: Pulsed low-dose irradiation of orthotopic glioblastoma multiforme (GBM) in a pre-clinical model: effects on vascularization and tumor control.
abstract: OBJECTIVE
  To compare dose-escalated pulsed low-dose radiation therapy (PLRT) and standard radiation therapy (SRT).
  
  
  METHODS
  Intracranial U87MG GBM tumors were established in nude mice. Animals received whole brain irradiation with daily 2-Gy fractions given continuously (SRT) or in ten 0.2-Gy pulses separated by 3-min intervals (PLRT). Tumor response was evaluated using weekly CT and [(18)F]-FDG-PET scans. Brain tissue was subjected to immunohistochemistry and cytokine bead array to assess tumor and normal tissue effects.
  
  
  RESULTS
  Median survival for untreated animals was 18 (SE±0.5) days. A significant difference in median survival was seen between SRT (29±1.8days) and PLRT (34.2±1.9days). Compared to SRT, PLRT resulted in a 31% (p<0.01), 38% (p<0.01), and 53% (p=0.01) reduction in normalized tumor volume and a 48% (p<0.01), 51% (p<0.01), and 70% (p<0.01) reduction in tumor growth rate following the administration of 10Gy, 20Gy, and 30Gy, respectively. Compared to untreated tumors, PLRT resulted in similar tumor vascular density, while SRT produced a 40% reduction in tumor vascular density (p=0.05). Compared to SRT, PLRT was associated with a 28% reduction in degenerating neurons in the surrounding brain parenchyma (p=0.05).
  
  
  CONCLUSIONS
  Compared to SRT, PLRT resulted in greater inhibition of tumor growth and improved survival, which may be attributable to preservation of vascular density.
authors.affiliation: Department of Radiation Oncology, Beaumont Health System, Royal Oak, MI 48073, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Dilworth
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Krueger
authors.forename: Mohamad
authors.initials: M
authors.lastname: Dabjan
authors.forename: Inga S
authors.initials: IS
authors.lastname: Grills
authors.forename: John
authors.initials: J
authors.lastname: Torma
authors.forename: George D
authors.initials: GD
authors.lastname: Wilson
authors.forename: Brian
authors.initials: B
authors.lastname: Marples
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D011879:Radiotherapy Dosage
keywords: Animal model; Glioblastoma multiforme; Orthotopic; PLRT; Pulsed radiation