title: Anti-VEGF antibodies mitigate the development of radiation necrosis in mouse brain.
abstract: OBJECTIVE
  To quantify the effectiveness of anti-VEGF antibodies (bevacizumab and B20-4.1.1) as mitigators of radiation-induced, central nervous system (brain) necrosis in a mouse model.
  
  
  METHODS
  Cohorts of mice were irradiated with single-fraction 50- or 60-Gy doses of radiation targeted to the left hemisphere (brain) using the Leksell Perfexion Gamma Knife. The onset and progression of radiation necrosis were monitored longitudinally by in vivo, small-animal MRI, beginning 4 weeks after irradiation. MRI-derived necrotic volumes for antibody (Ab)-treated and untreated mice were compared. MRI results were supported by correlative histology.
  
  
  RESULTS
  Hematoxylin and eosin-stained sections of brains from irradiated, non-Ab-treated mice confirmed profound tissue damage, including regions of fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, loss of neurons, and edema. Treatment with the murine anti-VEGF antibody B20-4.1.1 mitigated radiation-induced changes in an extraordinary, highly statistically significant manner. The development of radiation necrosis in mice under treatment with bevacizumab (a humanized anti-VEGF antibody) was intermediate between that for B20-4.1.1-treated and non-Ab-treated animals. MRI findings were validated by histologic assessment, which confirmed that anti-VEGF antibody treatment dramatically reduced late-onset necrosis in irradiated brain.
  
  
  CONCLUSIONS
  The single-hemispheric irradiation mouse model, with longitudinal MRI monitoring, provides a powerful platform for studying the onset and progression of radiation necrosis and for developing and testing new therapies. The observation that anti-VEGF antibodies are effective mitigants of necrosis in our mouse model will enable a wide variety of studies aimed at dose optimization and timing and mechanism of action with direct relevance to ongoing clinical trials of bevacizumab as a treatment for radiation necrosis.
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: John A
authors.initials: JA
authors.lastname: Engelbach
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Liya
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Cates
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, MissouriAuthors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, MissouriAuthors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Drzymala
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, MissouriAuthors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, MissouriAuthors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Rich
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, MissouriAuthors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, MissouriAuthors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, MissouriAuthors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Joseph J H
authors.initials: JJ
authors.lastname: Ackerman
authors.affiliation: Authors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, MissouriAuthors' Affiliations: Departments of Chemistry, Radiology, Neurosurgery, Radiation Oncology, Neuropathology, and Internal Medicine; Division of Biostatistics; and the Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri garbow@wustl.edu.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Garbow
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology*; D000068258:Bevacizumab; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D005260:Female; D005720:Gamma Rays; D008279:Magnetic Resonance Imaging; D008807:Mice, Inbred BALB C; D009336:Necrosis; D011833:Radiation Injuries, Experimental / Q000000981:diagnostic imaging / Q000517:prevention & control*; D011859:Radiography; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab