Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Chemistry

Language

English (en)

Date of Award

10-31-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Joseph JH Ackerman

Abstract

Radiation necrosis is a severe, but late occurring type of injury to normal tissue, within and surrounding a radiation treatment field, which can lead to significant complications for neurooncology patients. Radiation necrosis is difficult to distinguish from recurrent tumor by either neurologic examination or clinical imaging protocols. Concerns for the development of radiation necrosis often limit therapeutic radiation doses. Current treatment options for radiation necrosis are limited. The development of solutions to these clinical challenges has been hampered by an appropriate animal model of radiation necrosis.

With a novel mouse model of radiation necrosis developed in our lab employing a Gamma Knife, which enables high-dose, fractionated, hemispherical irradiation in the mouse brain, the objectives were to i) optimise radiation dosing schemes: total dose, fractionation) for this Gamma-Knife mouse-model of radiation necrosis; ii) determine the efficacy of bevacizumab: Avastin) and its murine analog B20-4.1.1, both vascular endothelial growth factor: VEGF) inhibitors, as mitigators of radiation necrosis in mice; iii) validate the neuroprotective effect of SB 415286, an inhibitor of glycogen synthase kinase 3β;: GSK-3β), in mouse brain following high-dose radiation treatment; and iv) identify and validate the quantitative blood oxygen level dependent: qBOLD) method as an imaging marker of radiation necrosis.

For these purposes, a series of experiments were performed, including monitoring the onset and progression of radiation necrosis in mice receiving different dose schedules, comparing the development of radiation necrosis in irradiated mice with or without treatments, and mapping the irradiated and non-irradiated mouse brains using qBOLD method.

It was found that i) radiation dose schedules affect the onset and progression of radiation necrosis; ii) anti-VEGF antibodies slow the progression of radiation necrosis in irradiated brain tissue; iii) SB 415286 protects against and mitigates radiation necrosis in irradiated brain tissue; and iv) a high SNR: 400 at least) is required to decouple oxygen extraction fraction: OEF) and deoxyhemoglombin cerebral blood volume: dCBV) in mouse brain using qBOLD method. In qBOLD, the voxel spread function: VSF) reduces the effect of macroscopic magnetic field inhomogeneities. However, with current shimming methods, imaging parameters, and post-processing algorithms, the resulting OEF and dCBV maps in the mouse brain are not reliable.

These results demonstrated that the development of radiation necrosis in this Gamma Knife mouse model can be characterized by both anatomic MR imaging and histology. Both anti-VEGF therapy and GSK-3β inhibition could be potential therapeutic managements for radiation necrosis, but further studies are needed to optimize dosing schemes and treatment periods and elucidate mechanisms of action. Characterizing radiation necrosis in mouse brain using qBOLD remains a challenge due to the imperfect correction for macro magnetic field inhomogeneities.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7CV4FSG

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