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Neuro Oncol. 2016 Jan;18(1):87-95. doi: 10.1093/neuonc/nov128. Epub 2015 Jul 22.

The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma.

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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.).



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.


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.


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).


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.


anti-angiogenic therapy; glioma; microbleeds; radiation therapy; susceptibility-weighted imaging; treatment effects

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