title: The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma.
abstract: BACKGROUND
  Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process.
  
  
  METHODS
  Serial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed.
  
  
  RESULTS
  The number of microbleeds increased with time for all patients, with initial onset occurring at 8-22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01).
  
  
  CONCLUSIONS
  We have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California (J.M.L., E.E.-B., S.C., S.J.N.); Department of Neurosurgery, University of California San Francisco, San Francisco, California (A.M.M., N.B., S.M.C., S.C.); Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California (A.M.M.); Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California (S.J.N.).
authors.forename: Janine M
authors.initials: JM
authors.lastname: Lupo
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California (J.M.L., E.E.-B., S.C., S.J.N.); Department of Neurosurgery, University of California San Francisco, San Francisco, California (A.M.M., N.B., S.M.C., S.C.); Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California (A.M.M.); Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California (S.J.N.).
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California (J.M.L., E.E.-B., S.C., S.J.N.); Department of Neurosurgery, University of California San Francisco, San Francisco, California (A.M.M., N.B., S.M.C., S.C.); Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California (A.M.M.); Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California (S.J.N.).
authors.forename: Emma
authors.initials: E
authors.lastname: Essock-Burns
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California (J.M.L., E.E.-B., S.C., S.J.N.); Department of Neurosurgery, University of California San Francisco, San Francisco, California (A.M.M., N.B., S.M.C., S.C.); Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California (A.M.M.); Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California (S.J.N.).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Butowski
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California (J.M.L., E.E.-B., S.C., S.J.N.); Department of Neurosurgery, University of California San Francisco, San Francisco, California (A.M.M., N.B., S.M.C., S.C.); Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California (A.M.M.); Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California (S.J.N.).
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California (J.M.L., E.E.-B., S.C., S.J.N.); Department of Neurosurgery, University of California San Francisco, San Francisco, California (A.M.M., N.B., S.M.C., S.C.); Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California (A.M.M.); Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California (S.J.N.).
authors.forename: Soonmee
authors.initials: S
authors.lastname: Cha
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California (J.M.L., E.E.-B., S.C., S.J.N.); Department of Neurosurgery, University of California San Francisco, San Francisco, California (A.M.M., N.B., S.M.C., S.C.); Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California (A.M.M.); Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California (S.J.N.).
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000473:pathology* / Q000532:radiotherapy; D002543:Cerebral Hemorrhage / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005910:Glioma / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011878:Radiotherapy / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; C504878:enzastaurin
keywords: anti-angiogenic therapy; glioma; microbleeds; radiation therapy; susceptibility-weighted imaging; treatment effects