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Diffuse intrinsic pontine gliomas (DIPG) is an aggressive brain tumor and the leading cause of pediatric death caused by cancer. Despite great strides in understanding this disease, prognosis is dismal, with over 90% of patients dying within two years of diagnosis and a median overall survival time of 9-12 months. These grim statistics underscore that DIPG is an unmet clinical need. In this doctoral thesis, I have evaluated the local administration of an anti-TIM-3 antibody in anti-TIM-3 antibody in syngeneic orthotopic models of DIPG as a therapeutic approach for this disease. Our work uncovered, through in silico studies in patient datasets (whole RNAseq and scRNAseq) and samples (by multiplex IF) that TIM-3 was robustly expressed in tumor cells and tumor microenvironment, mainly in microglia and macrophages, suggesting this molecule as a potential therapeutic target in DIPGs. Mechanistic studies showed that TIM-3 provided intrinsic survival cues to the tumor cell while modulating the tumor microenvironment when expressed in the myeloid compartment. In vivo studies showed that TIM-3 blockade significantly increased the overall survival of DIPG immunocompetent orthotopic models, led to long-term survivors, and showed immune memory. TIM-3 inhibition resulted in an increase in the number and proliferative state of microglia, NK cells, and CD8+ T cells and higher levels of IFN, GrzB, and TNF&945; corresponding to NK and T-cell activate phenotypes. Interestingly, there was a decrease in the Treg population, which caused an increase in the pro-inflammatory CD8/Treg ratio. Chemokine studies demonstrated an augmentation of CCL5, CCL2 chemotactic chemokines, and CXCL10, IL-1;, and IFN- pro-inflammatory cytokines in the tumor microenvironment of treated mice. Additionally, DCs, CD4+, and CD8+ T cells were increased in treated draining lymph nodes and of functional significance, expressed higher amounts of pro-inflammatory cytokines than in control mice. Interestingly, the depletion of NK cells, CD4+, and CD8+ T cells immune populations did not completely abrogate the treatment efficacy. However, microglia and macrophages depletion with an anti-CSF1R resulted in a total loss due to a loss of microglia and CD8 T cells pro-inflammatory populations, chemokines, and cytokines indicating a critical role of these populations in the therapeutic effect of TIM-3 blockade. This study provides a new and previously unstudied view of DIPG treatment. TIM-3 blockade emerges as an exciting alternative to classical immune checkpoints, such as PD-1, that did not obtain the desired results in DIPG clinical trials. Moreover, the lack of other effective therapies for these devastating pediatric brain tumors makes these pre-clinical results especially promising and offers strong support for initiating a clinical trial with an anti-TIM-3 antibody for the treatment of DIPG.

Histotripsy is a non-thermal, non-invasive focused ultrasound therapy using controlled acoustic cavitation to mechanically disintegrate tissue into an acellular homogenate. Histotripsy applies microsecond-length, high pressure (> 10 MPa) pulses to initiate the rapid expansion and collapse of nuclei in a millimeter-scale focal region, applying large stresses and strains to targeted tissues. The cavitation "bubble cloud" generated during histotripsy treatment can be visualized in real time on ultrasound imaging, assisting with treatment guidance and monitoring. Past studies have demonstrated histotripsy's potential for a variety of applications, but histotripsy has not yet been investigated for superficial musculoskeletal tumor ablation. Additionally, preliminary investigations using histotripsy to ablate brain tumors are underway, but require advanced histotripsy devices capable of overcoming attenuation of the therapeutic ultrasound signal by the skull and rely on MRI for real-time guidance. As a result, open questions remain regarding ultrasound-guided histotripsy for brain tumors. Early evidence also suggests that histotripsy ablation may induce immunogenic changes in the tumor microenvironment. Continued research is needed to explain and corroborate these findings under conditions more immunologically representative of human cancers, such as in large animal models with spontaneous tumors. This dissertation investigates the safety and feasibility of using ultrasound-guided histotripsy to ablate superficial soft tissue sarcomas (STS), osteosarcomas (OS), and brain tumors and considers the immunological impacts of histotripsy treatment for STS and OS. The research described herein (1) investigates the ability of histotripsy to treat superficial STS tumors in companion animals with spontaneous tumors, (2) investigates the feasibility of treating bone tumors with histotripsy through a series of ex vivo and in vivo studies, and (3) applies histotripsy for the minimally invasive treatment of superficial brain tumors. The completion of this dissertation will provide significant insight into the ability of ultrasound-guided histotripsy to treat novel tumor types (i.e., STS, OS, and brain tumors) and the potential role of histotripsy in veterinary medicine. Future work will build upon the studies detailed in this dissertation to optimize ultrasound-guided histotripsy for the treatment of complete STS, OS, and brain tumors in veterinary and human patients.

Gliomas are highly infiltrative, heterogenous brain tumors with poorly defined margin, and varying overall survival based on molecular subtype and grade. Despite recent developments in new diagnostic and treatment tools for gliomas, progression free survival and overall survival has only improved marginally for patients with glioma. Furthermore, treatment of glioma tends to be “one size fits all”, which can lead to either undertreating or overtreating the subclinical disease. Thus, the management of gliomas needs to be more patient-specific and more flexible over the course of the disease if the goal is to maximize both the longevity and quality of life of these patients.Recent advancement in MRI and radiation therapy research has opened the door for many opportunities to answer these questions. While the use of MRI in the clinic has been mostly limited to anatomical imaging, other MRI modalities have been gaining a lot of traction and have been proven to be able to provide clinical information not available in anatomical MRI. However, incorporating multimodal MRI in glioma management is a difficult task, because more advanced MRI acquisitions are not consistently acquired across institutions, and effectively understanding the consequences of changes observed on multimodal MRI over time is difficult even for trained radiologist. Artificial Intelligence has shown promise in making predictions from multi-parametric images, as multiple inputs can be given at the same time, and all processing and prediction tasks can be pre-trained and automatic applied. In this dissertation, we attempted to use multimodal MRI and artificial intelligence to improve both the diagnosis and treatment planning for patients with glioma. First, we developed an 1D deep learning based model that can help predict tumor histopathology noninvasively using the full spectrum of 1H MR Spectroscopic Imaging data. Then, we developed 3D segmentation-based deep learning model using multi-parametric MRI to redefine the clinical target volume for radiotherapy treatment planning and found that our model performed better than current practice, both in terms of better detecting subclinical disease and future progression, as well as sparing normal brain tissue. Finally, we highlighted the efficacy of using multi-parametric MRI in predicting a patient’s progression free and overall survival and improved the model performance by applying different types of masks.

The central nervous system (CNS) barriers, in particular the blood-brain barrier (BBB), play a critical role in the delivery, safety, and efficacy of drugs. The BBB prevents the distribution of a wide variety of molecules into brain, either due to the limited paracellular transport of large and hydrophilic molecules, or the active efflux of many small, lipophilic compounds with appreciable membrane permeability. Limited brain penetration of drugs can be an asset to the development of molecules for which dose-limiting toxicities are mediated within the CNS. This is of particular interest in the case of opioids, as their CNS side effects can be fatal. On the other hand, the limited delivery of drugs to the brain has been one of the greatest barriers to the development of novel therapies to treat diseases of the CNS, including brain tumors like glioblastoma (GBM). The objective of this dissertation was to assess how the BBB impacts the distribution of drugs in both of the aforementioned cases. In this dissertation, we utilized preclinical pharmacokinetic studies in wild-type and transgenic mice to characterize the CNS disposition of both opioids and antibody-drug conjugates (ADCs) following multiple routes of administration. This work shows that efflux by P-glycoprotein limits the CNS distribution of two opioid agonists with synergistic activity, loperamide and oxymorphindole, and indicates that their synergy is mediated in the peripheral nervous system. The subsequent work on the ADC, ABBV-221, shows that systemic administration of ADCs is unlikely to result in efficacious drug delivery to GBM tumors, but that administration by convection-enhanced delivery significantly enhances the exposure in brain. Together, these studies provide opposing perspectives on how CNS penetration can affect the safety and efficacy of novel therapeutics.

The goal of this dissertation is to improve our understanding of two important processes in carcinogenesis: First, the resistance mechanisms to tyrosine kinase inhibitors in glioblastoma (GBM). Second, the mechanisms involved in the metastatic spread of non-small cell lung cancer (NSCLC) to the brain. Malignant gliomas have a poor prognosis, as recurrence remains nearly inevitable despite aggressive treatment with a median survival time of 12-15 months. Primary GBM usually displays amplification or mutation of at least one receptor tyrosine kinase, most often the epidermal growth factor receptor (EGFR). Targeting EGFR for inhibition often provides an initial tumor response in patients, but recurrence is a main limitation of these therapies because secondary mutations emerge that lead to drug resistance. In this work, we identified a receptor tyrosine kinase, proto-oncogene ROS1 fusion, that drives the resistance to therapy and leads to tumorigenesis in GBM. In parallel, the aggressive metastatic phenotype is one of the hallmarks of recurrent tumors, and its estimated that 90% of all cancer deaths arise from the metastatic spread of primary tumors. Of all the processes involved in carcinogenesis, local invasion and the formation of metastases are clinically the most relevant, but the least well understood at the molecular level. This work also provides evidence for the use of circulating tumor cells as a biomarker for the metastatic spread of cancer, specifically in lung cancer. To uncover the molecular changes that govern the transition from a primary lung tumor to a secondary metastasis and specifically the mechanisms by which circulating tumor cells (CTCs) survive in circulation, we carried out whole genome sequencing of normal lung tissue, primary tumors, and the corresponding brain metastases from five patients with progressive metastatic NSCLC. We also isolated CTCs from patients with metastatic cancer and subjected them to whole genome amplification and Sanger sequencing of genes of interest. Whereas the primary tumors showed mutations in genes associated with cell adhesion and motility, brain metastases acquired mutations in adaptive, cytoprotective genes involved in the response to cellular stress, namely Kelch ECH associating protein (Keap1), nuclear factor erythroid 2-related factor 2 (NRF2), and P300, which are the key players of the Keap1-NRF2-ARE survival pathway. NRF2 is a transcriptional factor that translocates into the nucleus upon stress, binds to the antioxidant response elements (ARE), and drives the expression of antioxidant genes. The identified mutations affect regulatory domains in all three proteins, suggesting a functional role in providing a survival advantage to CTCs in the peripheral blood that allows their dissemination to distant organs. We identified a combination therapy strategy tailored to specific genetic alterations prevalent in primary GBM and identified novel targets for preventing cancer metastasis. We are the first to report ROS1-mediated gefitinib resistance in GBM cells and shown that these cells are remarkably sensitive to ROS1 inhibition in combination with gefitinib. Additionally, investigating mutations in the key players of the NRF2 antioxidant pathway that can be targeted therapeutically with NRF2 inhibitors is a promising approach to prevent cancer metastasis.

Meningiomas are the most common primary intracranial tumor with currentclassification offering limited therapeutic guidance. Here, we interrogatedmeningioma enhancer landscapes from 33 tumors to stratify patients based uponprognosis and identify novel meningioma-specific dependencies. Enhancersrobustlystratifiedmeningiomasintothreebiologicallydistinctgroups(adipogenesis/cholesterol, mesodermal and neural crest) distinguished bydistinct hormonal lineage transcriptional regulators. Meningioma landscapesclustered with intrinsic brain tumors and hormonally-responsive systemic cancerswith meningioma subgroups reflecting progesterone or androgen hormonalsignaling. Enhancer classification identified a subset of tumors with poorprognosis, irrespective of histological grading. Super enhancer signaturespredicted drug dependencies with superior in vitro efficacy to treatment basedupon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggablemeningioma target, impaired tumor growth in vivo. Collectively, epigeneticlandscapes empower meningioma classification and identification of noveltherapies.

Rationale. Patient, brain-tumor, and brain-tumor-treatment factors may negatively impact brain tumor patients’ health-related quality of life (HRQOL) and executive functioning (EF). Yet, in order to inform clinical decisions, more information is needed about what factors influence HRQOL and EF, the trajectories of HRQOL and EF overtime, and potential causal relationships between HRQOL and EF.Methods. Adults with primary brain tumors (N = 53) were enrolled in a prospective, longitudinal study evaluating the effects of radiation therapy (RT) over the first year following RT. All patients completed a self-report measure of HRQOL and objective EF assessments at baseline (pre-RT), and three months, six months, and 12 months following RT. Descriptive statistics and general linear model regression with contrast coding were used to characterize HRQOL and EF at baseline based on patient factors, tumor factors, and treatment factors. Linear mixed effects models were used to examine the trajectories of HRQOL and EF over time, controlling for significant characteristics previously identified. Cross-lagged panel model path analysis was used to examine the interrelationships between HRQOL and EF over time. Results. Patients in this study were primarily middle-aged, married, well-educated White men and women. Seizures, steroid use, and future RT type were related to HRQOL at baseline. Marital status, seizures, tumor laterality, steroid use, antiepileptic drug use, and future chemotherapy use were related to EF at baseline. HRQOL did not exhibit a trend over time. EF exhibited a cubic trend over time. There was one statistically causal pathway between HRQOL and EF; EF performance at six-month follow-up was predictive of HRQOL at 12-month follow-up. Conclusions. Findings suggest that patients who receive steroids and experience seizures prior to RT and who have left-sided tumors may benefit from HRQOL and EF monitoring and possibly intervention. Additionally, there was complex pattern of change in EF over time, with early deleterious effects being followed by improvement. Patients’ EF six months after RT may impact their HRQOL one-year post-RT completion. Although the mechanisms underlying this relationship remain unclear, it is possible that interventions to improve or preserve EF prior to six-months post RT may facilitate later improvements in HRQOL.

Glioblastoma multiforme (GBM) is the most common type of primary brain tumor, characterized by a short survival period after diagnosis. As with most other cancers, treatment and follow-up decisions are made largely based on observed changes in tumor size and appearance during imaging studies. The quantification of tumor measurements is problematic due to the systematic variability introduced while attempting to quantify tumor characteristics in uncertain regions. This issue is primarily observed around the tumor boundary, where it is often hard to differentiate whether a given region is part of the tumor (e.g., active, necrotic, edema, etc.) or part of normal brain tissue (e.g., grey matter, white matter). This problem has significant implications because this uncertainty can affect ensuing quantitative/computational analyses. Current approaches for the segmentation of glioblastoma multiforme still face multiple challenges, often failing to consistently identify the tumor region so as to be clinically useful and reliable; moreover, these different techniques tend to produce results that differ significantly from each other (i.e., measurement variability). To address these problems, this dissertation describes a framework to help characterize factors that influence variability in brain tumor boundaries and to optimize their performance through methods that calculate an estimate of expected variability arising from different automated segmentation approaches, setting the bases for the development of better knowledge-based methods. Additionally, a novel automated method was developed to generate more robust brain tumor segmentations by taking into consideration the inherent variability of brain tumors and statistical priors that provide context-relevant information about the different brain and tumor tissues.Altogether, this dissertation project provides further understanding of the sources of variability that arise in GBM across different image analysis methodologies and the integration of these insights into the development of tumor variability maps that can provide a better characterization of tumors.

To study potential hyperactivity and hyperconnectivity based on the latent resource hypothesis, this study assessed functional connectivity in survivors of childhood brain tumors compared to their healthy peers during an attention task using psychophysiological interaction (PPI) analyses and evaluated for a relationship with performance. Twenty-three survivors and 23 healthy controls completed a letter n-back task in the scanner. An empirically-based seed was placed in the parietal lobe, a theoretical seed was placed in the hippocampus, and a control seed was placed in the occipital lobe. Differences in both performance and functional connectivity networks from each seed emerged between groups, with some findings supporting the latent resource hypothesis and other networks showing compensatory function in survivors. Attention networks, phonological networks, and executive function networks were all found to differ between controls and survivors.

Purpose: To study the relationships between body mass index (BMI), symptom distress, anxiety, and quality of life (QOL) among patients with brain tumors. Design: Descriptive correlational design. Methods: The sample composed of 115 patients with brain tumors who were admitted to Bach Mai Hospital, Hanoi, Vietnam. Data were collected using 4 questionnaires: 1) Demographic data and illness information, 2) the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) scale, 3) the Hamilton Anxiety Rating Scale (HAM-A), and 4) the Functional Assessment of Cancer Therapy-Brain (FACT-Br). Spearman’s Rho was employed to test the relationship among studied variables. Main findings: The findings revealed that symptom distress and anxiety were negatively related to QOL (rs = - .665, p < .05; rs = - .702, p < .05); while BMI was not related to the QOL (p > .05). Conclusion and recommendations: Nurses should pay attention to the patients’ anxiety and symptom distress by conducting routine assessment. Clinical practice guideline to reduce anxiety and manage symptom should be developed and implemented to improve QOL among patients with brain tumors.

The literature has clearly demonstrated that the cerebellum serves as a major processing center in the brain for many complex functional pathways ranging from attention and learning to emotions and affect. Research is now emphasizing the importance of connectivity between the cerebellum and other brain regions, and has begun highlighting the need to understand the impact of damage to distinct regions on functional pathways throughout the brain. One particular type of cerebellar damage, caused by posterior fossa tumors, has received substantial attention in the medical and neuropsychological literature in recent years. Tumors of the posterior fossa, which includes the cerebellum and brain stem structures, account for over 15% of brain tumors in children. Due to advances in treatment, survival rates have increased dramatically for individuals with posterior fossa tumors, leading to a greater need for long-term medical and psychosocial care. Treatments for these tumors, including chemotherapy and cranial radiation, are known to produce long-term deficits in a variety of neurocognitive domains. These deficits are referred to as “neurocognitive late effects,” and can be seen as impaired performance in the areas of attention, memory, executive functioning, visual-spatial processing, and processing speed. Neurocognitive late effects can be especially pronounced in patients with localized cranial radiation, as is common with malignant brain tumors. Research has clearly shown that different regions of the cerebellum uniquely contribute to various neurocognitive functions. Additionally, much research has assessed the neurocognitive implications of posterior fossa tumors in children. However, little work has examined the unique relationship between specific tumor locations within the cerebellum and later neurocognitive outcomes. The purpose of this document is to propose a study to determine whether the particular location of tumors in the cerebellum can predict neurocognitive functioning in the domains of attention and executive functioning in children with these tumors.

Primary and metastatic brain tumors have limited treatment options and long term survival is rare. Cyclin-dependent kinases (CDKs) are major regulators of the cell cycle and are commonly altered in tumors. The CDK4/6 pathway regulates the checkpoint between G1 and S phase of the cell cycle. When altered, cells are able to proliferate rapidly and independent of this checkpoint. The blood-brain barrier (BBB) is a network of cells and proteins that prevent the paracellular and transcellular passage of many therapeutic agents from systemic circulation into the brain. The efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) actively transport substrates back into systemic circulation. Previous studies have demonstrated that numerous molecularly-targeted agents are substrates of P-gp and/or BCRP and that these transporters are responsible for the limited brain delivery. The objective of this work was to evaluate the role of efflux transport at the BBB in the brain delivery of CDK4/6 inhibitors and assess the relationship between brain delivery and efficacy in a glioblastoma (GBM) patient-derived xenograft. There are three CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, currently in clinical development for the treatment of a variety of solid tumors. We show that palbociclib has limited brain delivery to active efflux transport by P-gp and BCRP at the BBB. Furthermore, we demonstrate that the concentrations of palbociclib reaching the brain are also subtherapeutic in the treatment of a subcutaneous GBM tumor. We then used a pharmacological inhibitor of efflux transport and improved the brain delivery of palbociclib in tumor-naïve and tumor-bearing mice. We demonstrated that chronic use of this combination therapy was well tolerated and significantly improved the brain delivery of palbociclib in an intracranial tumor model to the same levels that were achieved in the subcutaneous GBM model. Despite improving the brain delivery of palbociclib, there was no improvement in efficacy. Using the in situ brain perfusion technique, we compared the brain delivery of palbociclib, ribociclib and abemaciclib and the data suggest that abemaciclib may saturate efflux at lower concentrations that palbociclib or ribociclib and have improved brain delivery. These studies show that improving the brain delivery of palbociclib alone is not sufficient to improve survival in the intracranial GBM model. Future studies that reveal other factors besides delivery that are altered in subcutaneous models of brain tumors will be essential in understanding the use of preclinical models to study experimental GBM therapies.

Magnetic Resonance Imaging is a non-invasive imaging technique that is widely used in medicine. Conventionally, MRI contrasts rely on differences in longitudinal or transverse relaxation times of different tissues and the resulting images display primarily anatomical information of the tissues. With progress in MRI techniques, image contrasts that provide functional or physiological information are now available. Tissue susceptibility is one of this kind and recently has been gaining interest in MRI, especially at high MR field strengths. To generate susceptibility contrast, MR phase and susceptibility-weighted imaging (SWI) are currently two imaging modalities that are used most often. In this work, we focused on using these imaging methods to study abnormal iron accumulation in multiple sclerosis (MS) and radiation-treated brain tumors. We first report in this dissertation a serial phase imaging study of chronic MS lesions in which the phase contrast, presumed due to iron deposition in the lesions, was investigated longitudinally. The observations from the study contribute to a better knowledge of the mechanism of the phase contrast in MS lesions and their evolution. Then we present a comparison study of SWI of iron-containing cerebral microbleeds (CMBs) between 3 Tesla and 7 Tesla MR scanners for patients who had brain tumors and received radiation therapy. This study was aimed at knowing how much sensitivity gain can be achieved when choosing 7T over 3T for detection of CMBs. Followed by the study, a gradient-echo sequence with multiple echoes is introduced, which is able to acquire MR angiography and susceptibility-weighted images simultaneously. This sequence provides a way to characterize CMBs together with veins and arteries in the brain. In addition, by integrating data from several echoes, the SWI can be made more flexible and its imaging quality of CMBs can be improved compared to sing-echo SWI. Finally, an automated CMB detection algorithm is developed, which is able to identify CMBs on images from SWI with a high sensitivity. Its high accuracy and fast speed significantly reduces radiological time burden in identifying CMBs, which will speed up the exploring of the clinical relevance of CMBs.

Nanomedicine has recently emerged as an exciting tool able to improve the early diagnosis and treatment of a variety of intractable or age-related brain disorders. The most relevant properties of nanomaterials are that they can be engineered in such a way that they can cross the blood brain barrier, with the final aim of targeting specific cells and molecules and to act as vehicles for drugs. Potentially beneficial properties of nanotherapeutics derived from its unique characteristics include improved efficacy, safety, sensitivity and personalization compared to conventional medicines. In this review, recent advances in available nanostructures and nanomaterials for brain applications will be described. Then, the latest nanotechnological applications for the treatment and diagnosis of neurological disorders, mainly brain tumors and neurodegenerative diseases, will be reviewed. Recent investigations of the neurotoxicity of the nanomaterial both in vitro and in vivo will be summarized. Finally, the ongoing challenges that have to be meet if new nanomedical products are to be put on the market will be discussed and some future directions will be outlined.

Tumor cell vaccination is a promising strategy for patients with primary brain tumors. Cell-derived vaccines have been developed and tested in patients with many cancers, resulting in objective responses in a minority of cases. Tumor cells are often harvested from tissue culture, where phenotype can shift in response to many factors. Oxygen affects expression of thousands of genes, yet its impact on immunogenicity in culture was unknown until recently. Compared to atmospheric oxygen levels, physiologic (5%) oxygen increases the adjuvant properties and efficacy of glioma vaccines. These studies determined the impact of oxygen on cell-mediated and humoral immunity with regard to its potential for improving efficacy in brain tumor patients. Immunogenicity and oxygen were first investigated over a broader oxygen range, with 5% oxygen still yielding the greatest extension of survival. With the effort to maximize immunogenicity, primary autologous meningioma cells from pet dogs were cultured in 5% oxygen for vaccine production. Dogs vaccinated with lysate/adjuvant vaccines based on these cells induced robust antibody responses and survived a median of three-fold longer than historic controls. Further studies in mice led to the discovery that glioma cells cultured in 5% oxygen upregulated a "danger" signal, annexin II. Monomeric annexin II enhanced dendritic cell cross presentation, CD8 T cell priming, and extended survival of murine breast carcinoma and plasmacytoma. Enriching for endogenous danger signals by decreasing tissue culture oxygen is a simple means to enhance the immunogenicity of brain tumor cultures.

Positron emission tomography (PET) is a unique and powerful imaging technique that is used to visualize and quantify various biological processes in living subjects in health and disease. PET imaging can also provide biological information for the assessment of therapies. In this dissertation, we will cover three projects that utilize the quantitative capability of PET for studying two neurological disorders: Alzheimer's disease and brain tumors.One of the goals in PET imaging is to produce an image volume that accurately describes the true distribution of the injected radioactivity. The correction factor that has the most significant impact on the quantitative aspects of a PET image is attenuation correction. Without it, the reconstructed images will give a distorted view of the true activity distribution. Head movement during a PET scan (especially a dynamic scan) can also lead to a loss in the information content contained in a PET image. This is especially true when scanning patients with dementia or movement disorders. The transmission scan, which is typically acquired at the start of a PET study, corrects for photon attenuation in each of the serial emission scans that are acquired afterwards.In the first project of this dissertation, we developed a retrospective image-based movement correction (MC) method and evaluated its implementation on dynamic 18F-FDDNP PET images of cognitively intact control subjects and patients with Alzheimer's disease (AD), each with varying degrees of head movement. 18F-FDDNP is a PET probe that binds to beta-amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of AD. The MC method corrected for transmission-emission misalignments as well as for emission-emission misalignments that might have been present in the dynamic PET scan. The image quality, tracer kinetics, and diagnostic accuracy of the 18F-FDDNP PET images were significantly improved after applying the MC method.In the second project of this dissertation, we investigated whether changes in 18F-FLT kinetic parameters, taken early after the start of therapy, could predict overall survival and progression-free survival in patients with recurrent malignant glioma undergoing treatment with bevacizumab (an angiogenesis inhibitor) and irinotecan (a chemotherapeutic agent). 18F-FLT is a radiotracer used in PET to measure cellular proliferation. We found that when a group of optimal kinetic parameter changes are incorporated into a linear discriminant function, one could accurately classify patients into their known survival groups. This method is advantageous because by reliably identifying short- and long-term survivors early during therapy, clinicians can discontinue ineffective treatment strategies and switch to more advanced treatment regimens that could improve patient outcome.Our third project expanded on what we did in our second project in that we acquired longitudinal 18F-FDOPA PET scans in addition to 18F-FLT PET scans. We also tried to predict overall survival as a continuous outcome variable using multiple linear regression (as opposed to a dichotomous categorical variable with discriminant analysis from before). In brain tumors, 18F-FDOPA is used to image amino acid transport. We found that in patients with recurrent malignant glioma, kinetic information from 18F-FLT alone was more predictive than using information from 18F-FDOPA alone. Using both probes combined provided comparable results to using 18F-FLT alone, suggesting that a single tracer may provide sufficient information for predicting OS with reasonable accuracy.The studies reported in this dissertation have demonstrated in three examples that the utility of kinetic quantification can significantly improve the value of PET for imaging biological functions in brain tissues in vivo. The developed methodologies in these examples are also expected to be useful in other quantitative brain PET imaging studies – for other applications or using other tracers.

Two-thirds of children diagnosed with brain tumors achieve long-term survival, and increasingly, children younger than 5-6 years at diagnosis are treated with high-dose chemotherapy protocols, delaying or foregoing cranial radiation. Intrathecal chemotherapy is associated with white matter loss, with systemic administration of certain agents also damaging healthy brain tissue. However, effects of systemic chemotherapy on the brain in children with tumors are unclear. Our first objective was to compare structural neural integrity with magnetic resonance imaging procedures in children with brain tumors (n = 7, mean age 8.3 years), treated with chemotherapy a mean of 5.4 years earlier, to age- and gender-matched healthy controls (n = 9, mean age 9.3 years). We also sought to explore the relationship between tissue loss, memory and executive functioning and quality of life (QOL) effects. Magnetic resonance imaging data were collected using a diffusion tensor imaging protocol to evaluate tissue integrity throughout the brain, and in specific regions of interest. Voxel-based morphometry was used to determine differences between groups. In addition, we used neurocognitive, behavioral and QOL assessments. Mean diffusivity and fractional anisotropy maps were obtained from normalized, smoothed images, and the two groups were compared using analysis of covariance, with age and gender as covariates. Higher mean diffusivity values emerged in patients over controls (p < 0.05, corrected for multiple comparisons), and were especially apparent in the central thalamus, internal and external capsules, putamen, globus pallidus and pons. No significant differences emerged in fractional anisotropy values between groups. The patient group had lower brain-to-CSF ratio (p = .03), assessed with volumetric analyses. Overall QOL, school functioning, and psychosocial functioning were significantly lower in patients. The majority of patients scored within the average range on memory and executive functioning tests, and behavior assessment did not differ from controls. Significantly higher mean diffusivity, indicating long-term damage, appeared in multiple areas in patients 5 years after treatment with chemotherapy. Early intervention may provide neuroprotection or repair to alleviate the long-term consequences of the original trauma and chemotherapy-related damage.

Rapid advances in wireless technology have increased the number of users of mobile devices. As of 2011, the number of cell phone subscribers have reached 5.3 billion worldwide. Mobile devices have saturated our environment with radio frequency (RF) signals. This situation has created public concern over the effect of such signals on human health. This dissertation focuses on the correlation of RF signals emitted by cell phones with male infertility. A thorough discussion is provided on the effects of RF signals on the development of central nervous system (CNS) neoplasm, the design of these mobile devices, the range of the RF frequencies they emit, the power with which they operate, their specific absorption rate (SAR), the distance between the user and the device while in use, how and where the devices are used, the duration of usage, and the accumulated exposure associated with the use of multiple RF devices. The results of our reviews and experimental in vitro studies show a significant correlation between the usage of mobile phones and human semen parameters, with a decrease in motility and viability, and an increase in the reactive oxygen species (ROS) score. However, in daily usage, a cell phone kept in proximity to the groin is separated from the testes by multiple layers of tissue. To explore this effect, a computational model of scrotal tissues was designed. Our results show that during in vitro experimentation, an effect equivalent to real-life conditions can be obtained by placing the cell phone a few centimeters farther away from the semen sample. The results of our study can be used to calculate the equivalent distance between a radiation source and a semen sample, and to set up in vitro experiments that mimic real-life conditions.

Brain tumors are highly lethal, most often resulting in a terminal prognosis. Today's standard-of-care has not significantly altered patient survival time. The status quo indicates the need for a more targeted, multi-functional therapeutic approach. Nanotechnology has been implicated as a potential magic bullet drug carrier solution to cancer, with magnetic iron oxide nanoparticles (MNPs) representing a unique, magnetically responsive type of nanomaterial. MNPs have been targeted to brain tumors by applying an external magnetic field to lesions. The short circulation times of preferred MNPs, though, limits their availability for targeting, and, thus, tumor delivery. If plasma residence were enhanced, the question then arises: would targeting efficiency improve? This dissertation aimed to develop long-circulating MNPs suitable for enhanced magnetic brain tumor targeting. Aminosilane (A) and cross-linked starch coated, polyethylene glycol (PEG) conjugated MNP candidates were synthesized using N-hydroxysuccinimide chemistry and characterized. Candidates were similar in size (140--190 nm) and PEG content, (up to 1.5 mol %) and deemed magnetically suitable for targeting. Candidates were subjected to in vitro reticuloendothelial system simulations to predict long-circulating behavior in vivo. Unlike the A-platform, cross-linked starch PEG-MNPs (D5/D20) performed well in vitro showing sustained size stability in cell culture medium and up to 10-fold reduced uptake in RAW 264.7 macrophages, when compared to previously studied starch-coated MNPs (D). Simulations predicted improved circulation behavior, with intravenously administered D5/D20 (12 mg Fe/kg) showing up to an estimated 150-fold increase in tumor exposure over D in 9L-glioma bearing rats. Validated electron spin resonance methodology was used to study biodistribution of D5/D20 in tissues of elimination. MNP concentrations in the spleen were high, and, unexpectedly, appeared attenuated in the liver. Improved exposure of MNPs to rat 9L-glioma lesions resulted in enhanced magnetic brain tumor targeting (t=1 hr) with up to 1.0% injected dose (ID)/g tissue (200 g animal) delivery achieved, a 15-fold improvement over targeted D (0.07% ID/g tissue). Magnetic resonance imaging confirmed targeting enhancements. Results achieve proof-of-concept that long-circulating MNPs permit enhanced magnetic targeting of nanoparticles to brain tumors, warranting further development of the materials and strategy studied.

In this dissertation, we outline our efforts to introduce an advanced MRI imaging technique called Diffusion Tensor Imaging (DTI) to the pediatric brain tumor population. We discuss the theory and application of DTI as it was performed in a series of translational investigations at St. Jude Children’s Research Hospital. We present evidence of how the introduction of this technique impacted diagnosis, and treatment. And finally, we demonstrate how DTI was used to investigate cognitive morbidities associated with cancer treatment and how this research provided insight into the underlying pathophysiology involved in the development of these treatment sequela. This research has generated important insights into the fundamental causes of neuroanatomical and cognitive deficits associated with cancer and cancer therapy. The use of DTI has permitted us to identify potential targets for improved radiological and surgical techniques as well as targets for pharmacological and behavioral interventions that might improve cognitive function in cancer survivors. The discoveries here afford us an opportunity to reduce the negative effects of cancer therapy on patients treated in the future while maintaining successful survival rates.

Brain tumors inflict a heavy burden of morbidity and high risk of death. Currently employed treatment modalities fail to substantially improve these dismal outcomes. Proteins have recently emerged as a new class of agent with potent anti-glioma activity. However, their therapeutic potential has been limited by formidable challenges in their delivery to brain tumor sites. This dissertation research investigated the feasibility of utilizing magnetic nanoparticles as a carrier for delivery of proteins to brain tumor lesions. Magnetic nanoparticles composed of a superparamagnetic core and a biocompatible polymeric shell presented a promising platform for this application. The core provided high saturation magnetization of 108 emu/g Fe, suggesting that the particles would be amenable to capture within a tumor lesion by an external magnetic field, a strategy termed magnetic targeting. Moreover, high T2 relaxivity of 43 s-1mM -1 indicated a possibility for non-invasive monitoring of nanocarrier delivery to the target site by in vivo T2 MRI. Furthermore, the polysaccharide shell of the nanoparticles allowed successful loading of a model protein, beta-Galactosidase (betaGal), with a high loading capacity of 7.5% w/w. To deliver the nanocarriers to brain tumor lesions in vivo, an improved magnetic targeting methodology has been developed. This methodology involved administration of nanoparticles via carotid artery, optimization of the magnet configuration, and MRI-guided animal alignment with respect to mapped magnetic field topography. Animal studies in rats harboring 9L-gliosarcomas revealed that utilization of the developed methodology provided a 4.7-fold increase in tumor betaGal activity (636 +/- 42 muU/g tissue) compared to non-targeted control animals (134 +/- 46 muU/g tissue). In addition, high tumor selectivity of protein localization was observed, as tumor tissues displayed 7.5-fold higher betaGal activity (636 +/- 42 muU/g tissue) than the contra-lateral brain (85 +/- 30 muU/g tissue). Moreover, the delivery of the betaGal-loaded nanocarrier to the target site was successfully validated and quantified with non-invasive T2 MRI. In conclusion, this work established the plausibility of protein delivery to brain tumor lesions using MRI-monitored magnetically-responsive nanoplatform in conjunction with developed magnetic targeting methodology. This accomplishment may pave the way to realization of efficacious protein-based therapies for brain cancer treatment.

Diffusion weighted Magnetic Resonance Imaging has been shown to be very useful for the clinical evaluation of patients with stroke. Although the acquisition of such data is a common feature on most MR scanners, the implication of the parameters that it uses are often not appreciated by the oncology community, especially for the application to patients with gliomas. The potential for providing quantitative information that describes the biological properties of tumor and surrounding brain parenchyma has therefore not been fully explored. The goal of this thesis was to characterize the variations in diffusion imaging parameters and determine how they may be used for the management of patients with brain tumors throughout the treatment of their disease. This thesis utilized MR spectroscopic imaging (MRSI) techniques to provide adjunct metabolic information. The relationship between the apparent diffusion coefficient (ADC) from DTI and levels of choline containing compounds from MRSI, both of which have been suggested to correlate to cell density, was assessed by grade and subtype within the anatomically heterogeneous tumor regions. There was evidence of a relationship between ADC and choline in some regions of grade IV gliomas but within no regions of grade II gliomas. This suggested independent information to be acquired from both DTI and MRSI. A method to assess deviation from mono-exponential decay in a clinically relevant scan time was developed as another possible method of assessing abnormality in grade IV glioma. Previously observed variations in grade II glioma subtypes was further assessed. A difference in ADC was evident and based on these findings, a method of visualizing this variation was developed using RGB color maps. This technique was applied on a new cohort of grade II gliomas and histopathology was assessed by image-guided biopsies to examine the histopathological variations. Diffusion parameters during treatment were evaluated for early non-invasive biomarkers. The ADC changes from mid- to post-treatment suggest such a possible early non-invasive biomarker. The results of this dissertation suggest that diffusion parameters play an important role in assessing gliomas. These are very important steps towards increasing the utilization of imaging in the management of patients with brain tumors.

The third ventricle region houses several neuroanatomical structures that are primary components of the human memory system, and provides pathways through which these brain regions communicate with critical regions of the frontal and medial temporal lobes. Archival data was obtained for 42 children with cerebellar or third ventricle tumors, and was examined for tumor and treatment related confounds. Children with third ventricle tumors were hypothesized to exhibit; 1) better performance on a measure of auditory attention, 2) greater impairment in learning across trials, 3) greater memory loss over a 20-minute delay, and 4) greater impairment across delayed memory tests than the cerebellar group. Children with third ventricle tumors demonstrated significantly better auditory attention, but greater impairments in verbal learning, and greater verbal memory loss following a 20-minute delay. In contrast, children with third ventricle tumors did not demonstrate significantly greater memory impairments across long delay memory tests.

In survival analysis, a linear model often provides an adequate approximation to the survival times and covariates after a suitable transformation. This dissertation is devoted to a systematic investigation of semiparametric regression methods for estimating the regression parameter in the context of linear regression without specifying the error distribution, where the response is right-censored. The method uses the random-sieve likelihood, which combines the benefits of semiparametric likelihood with estimating equations and constraints. A method of estimating the parameters is developed and inferential procedures based on the asymptotic distributions of the estimated regression parameters and of the profile likelihood ratios are derived. The small sample operating characteristics of the proposed method are examined via simulations and illustrated on a data set from a study of ganglioside of primary brain tumors and a data set from bone marrow transplant study. This dissertation proposes an estimation method as well as an inference procedure, for a general linear model, allowing for right-censoring and an unspecified error distribution. The proposed methodology yields an easily interpreted regression estimate, and is especially useful when the proportionality assumption doesn't hold for Cox regression models. However, how to determine the best transformation of the response or how to select the best model from the class studied are left for future work.

Within a stress-coping-adaptation framework, a path analytic model was hypothesized to explain the interrelationships among the variables of gender, age, duration of illness, steroid dosage, social support, perceived health status limitations, and coping skills, and their subsequent effect on body image appraisal in the population of subjects undergoing treatment for a malignant brain tumor. The many potential changes in physical appearance and functional abilities, including the loss of hair, the onset of Cushing's syndrome and varied physical disabilities, may cause devastating alterations in body image, requiring tremendous coping skills for adaptation in these individuals. One hundred and ten subjects were assisted, during home or clinic visits, to complete a demographic questionnaire, the Sickness Impact Profile Scale (SIPS) to assess perceived health status limitations, the PRQ-85 social support instrument, the Revised Jalowiec Coping Scale, the Body Cathexis/Self-Cathexis Scale to measure body attitude, and the Modified Topographic Device to measure body perception. The data were analyzed using descriptive statistics along with bivariate and multiple regression techniques to explain the greatest amount of variance in the causal model. The simplified model contained 12 significant direct effects and two significant indirect effects for predicting the dependent variables. In the post hoc analysis, differences were found between the low grade tumor group and the high grade tumor group in terms of their impact on causal relationships within the model. The variables with the strongest ability to predict body image appraisal in the high grade tumor group included steroid dosage and physical health status limitations. Conversely, the variables able to explain the greatest amount of variance in body image appraisal for the low grade tumor group included confrontive coping, duration of illness, and social support through confrontive coping. Among both groups, male gender and age negatively influenced body attitude, while male gender was predictive of a positive body perception. Knowledge about the concept/construct of body image has implications for the practice, research and theoretical realms of nursing. Spanning the scope of all nursing settings and populations, and applicable within nursing conceptual frameworks, body image should impact the arenas of the clinical practitioners, researchers and educators within our profession.

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.