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published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK- Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-B dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.

Thesis (D.PT.)--Sage Colleges, 2010. / "May 2010." "A Capstone project for PTY 768 presented to the faculty of The Department of Physical Therapy Sage Graduate School in partial fulfillment of the requirements for the degree of Doctor of Physical Therapy." Includes bibliographical references.

Childhood brain tumours affect more learners in our schools today than is generally the perception. The late effects of the tumours and their treatments on the learner that has to cope at school are legion and often leads to individuals being excluded from educational activities. It is incumbent that these children have to be accommodated within our current educative system. The possible way in which a child with a brain tumour could be accommodated within an inclusive schooling community thus became the focus of this study. Prior to considering the ways in which a learner with a brain tumour can be accommodated within current schooling communities, the possible needs of learners with brain tumours in general were first investigated. From an ecosystemic approach the late effects of brain tumours and its influence on all the systems in an individual’s life were studied and possible support strategies within an inclusive whole school paradigm were investigated. Within this framework the investigation on a single learner with a brain tumour and the way in which she was accommodated within her schooling community was initiated. A case study was launched to investigate the ways in which a schooling community addressed the needs of a young girl with a brain tumour inclusively. Data was collected from various sources to substantiate the findings. Findings have revealed that the schooling community effectively accommodated the girl by ascertaining and meeting her individual needs, as well as the needs of her other systems, for example family and educators. Within a narrative these accommodations were identified and highlighted for the reader. The researcher recommends that the inclusive accommodative strategies implemented by her schooling community effectively addressed this learner’s physical, cognitive, emotional and wider systemic needs. / Mrs. J.V. Fourie

Introduction: Survivors of childhood brain tumors (SCBT) are an emerging group of cancer survivors that has an increased risk of cardiovascular disease, stroke, and type 2 diabetes. SCBT have equivalent obesity rates but excess fat mass (adiposity) when compared to the general population. As adiposity is an important and potentially modifiable risk factor for cardiometabolic outcomes in the general population, its measurement may allow for early stratification of adverse health outcomes in SCBT so that they can be targeted with prevention and treatment strategies designed to improve outcomes. However, measuring adiposity often requires specialized equipment that is not always readily available, and a clinical measure is needed to facilitate these measurements in a feasible fashion. Tri-ponderal Mass Index (TMI; kg/m3) is a superior measure of adiposity compared to Body Mass Index (BMI) z-score in healthy children. However, it has not been assessed in SCBT. The aim of this thesis was to validate TMI as an adiposity measure in SCBT compared to non-cancer controls. Methods: A cross-sectional analysis was completed from a cohort study sample including 44 SCBT (n=20 female) and 137 (n=64 female) healthy controls between 5-17 years of age. Total adiposity was determined by fat mass percentage (%FM) using bioelectrical impedance analysis and central adiposity was assessed by waist-to-hip (WHR) and waist-to-height (WHtR) ratios. Results: TMI demonstrated equally strong correlations with total adiposity and stronger association with WHtR compared to BMI z-score in SCBT and healthy control children. Conclusions: TMI may serve as a reliable and feasible clinical measure of adiposity in both SCBT and healthy children. The availability of TMI may allow for early stratification of survivors at risk of excess adiposity to allow early targeting with interventions to improve health outcomes. / Thesis / Master of Science in Medical Sciences (MSMS) / Over the last thirty years, childhood cancer survival rates have greatly improved. However, these rates decrease over the lifespan of survivors. Certain groups within the survivors of childhood cancer population, including survivors of childhood brain tumors (SCBT), are at a higher risk of obesity, heart disease and type 2 diabetes. Excess body fat is a major contributor to the development of these adverse health outcomes in the general population and may represent an entry point to prevent and treat these conditions in SCBT. However, measuring fat mass in the clinical setting requires specialized equipment that can be expensive, time-consuming and not readily available in all settings. Therefore, this thesis aims to explore measures of fat mass that are both feasible and reliable in a clinical setting in SCBT compared to the general pediatric population. We have identified the tri-ponderal mass index (TMI), defined as weight divided by height cubed (kg/m3) as a valid measure of the fat mass in both SCBT and healthy children. We conclude that TMI may serve as a reliable and feasible measure of adiposity in both SCBT and healthy children in clinical settings and assist in the early identification of survivors at risk of obesity and cardiometabolic outcomes to prioritize early interventions to improve outcomes.

Thesis (M.D.)—Boston University

Class of 2012 Abstract / Specific Aims: This study was aimed to evaluate inpatient clinical treatment characteristics associated with the use of intracranial implantation of chemotherapeutic wafers for malignant brain neoplasms within United States, and assess inpatient mortality and total charges regarding treatment with wafer versus without. Methods: A retrospective cohort investigation was conducted utilizing inpatient discharge records from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample from 2005 to 2009. From this nationally- representative sample, 9,455 adults aged 18 years or older were identified with malignant neoplasms of the brain treated with implantable chemotherapeutic wafers. Outcomes of inpatient mortality and charges were assessed via multivariate regression analysis, controlling for patient characteristics, hospital structure, comorbidities, and clinical complications. Main Results: The average age of patients with brain neoplasms was 56.6 (±16.5) years, and of those patients, 42.9% were female. The odds ratio for inpatient mortality of patients treated with implantable chemotherapeutic wafers was OR=0.380 (P<0.001), and patients that received wafer treatment had increased charges exp(b)=2.147 (P<0.001). Conclusions: Multiple factors were associated with inpatient mortality and charges among the 247,829 patients that were diagnosed with malignant brain neoplasms from 2005-2009. With regards to these patients, implantable chemotherapeutic wafers were associated with increased inpatient survival and increased charges.

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