Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT), which provides transient symptomatic relief and limited survival advantage. Successful implementation of radiosensitization strategies in DMG remains elusive. In this project, we identify Napabucasin, an NAD(P)H Quinone Dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS) inducer, as a potent radiosensitizer in DMG both in vitro and in vivo. We show Napabucasin-mediated ROS production and cytotoxicity are dependent on NQO1, and establish the novel safety, feasibility, and survival benefit of convection-enhanced drug delivery (CED) of Napabucasin to circumvent the blood-brain barrier (BBB) concurrent with RT in an orthotopic DMG mouse model. Using this multi-modality strategy, we identify a promising treatment paradigm in DMG that may also be utilized to develop novel therapeutic treatments for other brain tumors.

Children who have received radiation therapy for the treatment of brain tumors have been shown to experience neurocognitive deficits which appear to increase over time. The purpose of this study was to examine the memory functioning of 22 children irradiated for brain tumor and 22 healthy children of the same age who had not received irradiation. Subjects were administered a brief form of the WISC-III, to obtain an IQ, and the Wide Range Assessment of Memory and Learning (WRAML), to evaluate visual and verbal memory. Results indicated that, although there were no significant differences between the IQ scores of healthy children and children who had been irradiated, children who have received radiation therapy for brain tumor evidence memory deficits which effect visual and verbal memory abilities. Among the children who had been irradiated, as time since treatment increased, visual memory and overall memory functioning appeared to decline. Findings also suggested that children who received total tumor resection may evidence greater memory deficits than those who received only a partial resection. Visual memory was more closely related to IQ in the children irradiated for brain tumor than in the healthy children. The overall importance of research with this population lies in refining the understanding of memory deficits and strengths in order to formulate more effective remediation compensation, strategies.

Functional proton-beam stereotactic radiosurgery requires sub-millimeter alignment accuracy. A patient tracking system called Sequential Alignment and Position Verification System (SAVPS) is under development at Loma Linda University Medical Center. An optical positioning system (OPS), manufactured by Vicon Peak, has been chosen to verify the correct alignment of the target with the proton beam axis. The main objective of this thesis is to optimize an existing version of SAVPS by conducting error analysis. An image processing algorithm was developed and applied to estimate the error introduced by the Patient Positioning System (PPS) in order to derive the true error of the SAVPS.