Functional assessment and development of treatment strategies for brain tumors: promoting neurorestoration and reducing harm to bystander cells and neuroplasticity
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Current treatment options for malignant brain tumors not only frequently fail to cure the disease due to local recurrence, but also may severely compromise quality of remaining life even when tumor mass is reduced in large part because they interfere with mechanisms of neuroplasticity and function of bystander tissue. The aims of this dissertation are to: (a) assess neurological impairments associated with rapid focal cortical tissue displacement; (b) evaluate the specific impact of conventional and novel treatments on neurorestoration while controlling tissue compression without the confound of related events linked to tumor physiology; (c) identify the behavioral change pattern during brain tumor progression and investigate the stealth nature of brain tumors; (d) demonstrate how anti-cancer treatments affect brain function especially when administered in the silent stages of brain tumors; and (e) develop treatment strategies that might improve therapeutic effectiveness and brain function. We adopted a new focal mass compression model providing rapid displacement of tissue in the underlying sensorimotor cortex, as well as the traditional rat and mouse glioma xenograft models that exhibit prominent tumor growth and invasion, given the varied aims and contexts of our different studies. Various conventional and novel brain tumor treatments were employed in this dissertation, including local and systemic chemotherapy, antiangiogenic agents, photodynamic therapy, and a glutamate antagonist. A neurorestorative therapy with atorvastatin was evaluated in its effects on functional recovery after photodynamic therapy. Functional outcomes were measured with an array of behavioral tests, which are sensitive to mild focal insults to the sensorimotor cortex and can detect recovery of function. Histopathological assessments consisted of Nissl staining, hematoxylin-andeosin (H&E) staining, and immunohistochemistry, depending on varied purposes, used in conjunction with a computer imaging analysis system. In clinical trials, functional outcome is as critical to gauging the success of a treatment as is patient survival time. Both preclinical screening of anti-cancer interventions for the ability to shrink tumors effectively with minimal disturbance of neuroplasticity and developing combination therapy with neurorestorative regimens following neurotoxic cancer treatments should allow for optimal promotion of plastic mechanisms in the remaining normal brain tissue.