Introduction: The increased survival rates of children with brain tumors is the result of decades of advancement in diagnostic and therapeutic approaches, but brought the adverse long-term effects of the treatments and tumors on these children into focus. Survivors of childhood brain tumors (SCBT) are at an increased risk of cardiometabolic disorders and premature mortality. Obesity and excess adiposity are well-established risk factor for cardiometabolic risk in the general population, but its contribution to these outcomes in survivors is unknown. More recently, adiposity has emerged as a more robust predictor of cardiometabolic risk than body mass index, the most clinically used measure of obesity. The current thesis pursued four objectives: 1) to determine the prevalence of obesity and excess adiposity in SCBT 2) to explore adiposity and its determinants in SCBT 3) to investigate the determinants of obesity in SCBT and 4) to identify potentially effective interventions to manage obesity in SCBT. Methods: Systematic reviews and meta-analyses were used to evaluate the prevalence and interventions for overweight and obesity in SCBT while the determinants of adiposity and obesity were explored using primary data and regression analyses. General health information and brain tumors information were collected with standardized questionnaires and review of medical records. The overweight or obesity status of subjects was determined by body mass index (BMI), and adiposity profile was evaluated using percent body fat (%FM), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). Results: The results show no difference between the overweight and obesity rates in SCBT and non-cancer controls. However, SCBT have higher total and central adiposity. Birth weight is found to be a predictor of future BMI in SCBT, while a higher total adiposity in SCBT is predicted by having supratentorial tumors and receiving radiotherapy. Lastly, not enough evidence is available to conclude the effectiveness of lifestyle interventions, pharmacotherapy, and bariatric surgery on managing obesity in SCBT. Conclusions: Obesity, determined by BMI, is not enough to determine cardiometabolic risks in SCBT. Total and central adiposity should be measured as well to identify high-risk group. Special attention should be paid to SCBT with high birth weight, supratentorial tumors, and having received radiotherapy. Lastly, more randomized controlled trials are needed to provide high-quality evidence to determine the effectiveness of interventions to manage obesity and improve outcomes in SCBT. / Thesis / Master of Science (MSc) / Brain tumors are the most common solid tumors in children. The survival rates among children with brain tumors have increased significantly over the past four decades due to advances in early detection and treatment. However, these children are at increased risk of heart disease and type 2 diabetes, and early death. Evidence has suggested obesity and excess body fat as main reasons for cardiometabolic disorders in the general population, but it is not known if obesity and excess body fat contribute to diabetes and heart disease in survivors. Therefore, the current thesis aims to explore obesity and adiposity, their predictors and any existing treatments available to survivors of childhood brain tumors (SCBT) to see if outcomes can be improved. The results show that while survivors of childhood brain tumors have similar overweight and obesity rates to the general population when measured by the most common clinical measure, called body mass index (BMI), they in fact have higher fat mass. Furthermore, we identified birth weight as a predictor of obesity while the location of the tumors and receiving radiation therapy as predictors of the fat mass in SCBT. The results also show the lack of current effective interventions to manage obesity in SCBT. This data is critical to consider in the design and implementation of strategies to reduce heat disease and diabetes in survivors to improve their quality of life and lifespan.

Adult survivors of childhood posterior fossa tumors can experience reading difficulties related to white matter integrity. Previously, reading was shown to be related to cortical white matter tracts, however information transfer across the corpus callosum (CC) may also play a role in reading. The current study used both macro- and microstructural measures of the WM structure of the corpus callosum. The current study examined how white matter volume and fractional anisotropy (FA) in five divisions of the CC was related to degree of neurological risk and reading skill, and tested two mediation models predicting reading. Participants included 20 adult survivors of childhood posterior fossa tumor and 23 healthy controls. Volume and FA were measured in five divisions of the mid-sagittal corpus callosum. Total intracranial vault was used as a covariate in volume analyses. FA was reduced in CC1 and volume was reduced in each subregion in survivors. Volume but not FA was related to degree of neurological risk. Results identified that reduced volume in CC1 and CC5, and FA in CC5 appear to be specifically related to reading skill in line with the cortical reading regions that connect in these subregions of the CC. Mediation models indicate that processing speed is the mechanism by which volume is related to reading skill. These findings have implications for addressing processing speed in reading interventions in survivors and provide insight into the interhemispheric connections in the reading network.

Tumors have several important hallmarks; anomalous and heterogeneous behaviors of their vascular structures, and high angiogenesis and neovascularization. Tumor tissue presents high blood flow (F) and extraction ratio (E) of contrast molecules. Consequently there is growing interest in non invasive methods for characterizing changes in tumor vasculature. Toft's model has been extensively used in the past in order to calculate Ktrans maps which take into consideration both F and E. However, in this thesis we argue that for accurate tumor characterization we need a model able to compute both F and E in tissue plasma. This project has been developed as part of a larger project, working toward building a Clinical Decision Support System (CDSS): an interactive expert computer software, that helps doctors and other health professionals make decisions regarding patient treatment progress. Using the Gamma Capillary Transit Time (GCTT) pharmacokinetic model we calculate F and E separately in a more realistic framework; unlike other models it takes into account the heterogeneity of the tumor, which depends on parameter a-1. a-1 is the width of the distribution of the capillary transit times within a tissue voxel. In more detail, a-1 expresses the heterogeneity of tissue microcirculation and microvasculature. We studied 9 patients pathologically diagnosed with glioblastoma multiforme (GBM), a common malignant type of brain tumor. Several physiological parameters including the blood flow and extraction ratio distributions were calculated for each patient. Then we investigated if these parameters can characterize early the patients' responsiveness to current treatment; we assessed the classification potential based on the actual therapy outcome. To this end, we present a novel analysis framework which exploits the new parameter a-1 and organizes each voxel into four sub-region. Our results indicate that early characterization of response based on GCCT can be significantly improved by focusing on tumor voxels from a specific sub-region.

Malignant brain tumors are among the deadliest of human cancers. Despit recent advancements in conventional therapies, glioblastomas remain incurable, largel y due to their ability to invade surrounding tissue. Matrix metalloproteinases are thought to contribute to the invaseive phenotype of human gliomas. Absent in normal brain, matrix metalloproteinase-1 (MMP-1) has been shown to be present in gliomas, and in particular in glioblastoma multiforme (GBM). To begin to examine the role of MMP-1 in these tumore, two human glioma cell lines were stably transfected with MMP-1 cDNA. Confirmation of MMP-1 over-expression in these cells was achieved through real-time PCR and Western blot analysis. The functional consequences of MMP-1 over-expression were analyzed using a collagen type-I invasion assay along with clonogenic and ATP viability assays. Data presented demonstrate that MMP-1 over-expressing cells were more invasive in both cell types and interestingly more clonogenic in on of the glioma cell lines, supporting a possible role for MMP-1 in glioma growth and invasion.

A brain tumor diagnosis is traumatic and has a devastating impact upon the caregiver and the family unit. The effects of the tumor growth and treatment often cause significant neurologic injury and dramatically affect the quality of life (QOL) for the patient and their entire family unit. Caregivers are constantly challenged to provide care, yet they feel untrained and underprepared as they struggle to adjust to new roles and responsibilities. The purpose of this study is to gain an understanding of the lived experiences of caregivers of individuals with primary benign brain tumor (PBBT). An interpretive phenomenological analysis approach was used to explore the experiences of 10 caregivers. Bowen's family systems theory provided an understanding of how families respond to changes in their family system resulting from a member of the family having a PBBT. A nonprobability sampling technique was used to recruit participants from 2 virtual support groups. Data were collected through semistructured interviews guided by an interview template. Interviews were transcribed and analyzed following the Smith tradition of inquiry until data saturation was reached. Three major themes emerged from the data: experiencing new challenges, responding to initial diagnosis, and facing challenges with family and friends. Caregivers experience a wide variety of responsibilities that are physically and psychologically challenging, which can negatively affect the QOL for the caregiver and the patient. These findings can be used by healthcare providers to identify resources to alleviate the unanticipated demands caregivers experience. Future studies are needed to explore how best to decrease challenges experienced by caregivers of individuals with PBBT.

Gliomas are the most common and aggressive primary brain tumors. The most common treatment protocols for these brain tumors are combinations of surgery, chemotherapy and radiotherapy. However, even with the most aggressive combination of surgery and radiotherapy and/or chemotherapy schedules, gliomas almost always recur resulting in a median survival time for patients of not more than 12 months. This highly diffusive and invasive nature of brain tumors makes it very important to study the effects of these combined therapeutic strategies in an effort to improve the survival time of patients. It is also important to study the tumor microenvironment, since the complex nature of the cerebral vasculature, including the blood brain barrier and several other tumor-induced conditions such as hypoxia, high interstitial pressure, and cerebral edema affect drug delivery as well as the effectiveness of radiotherapy. Recently, a novel strategy using antiangiogenic therapy has been studied for the treatment of brain tumors. Antiangiogenic therapy interferes with the development of tumor vasculature and indirectly helps in the control of tumor growth. Recent clinical trials suggest that anti-angiogenic therapy is usually more effective when given in combination with other therapeutic strategies. In an effort to study the effects of the aforementioned therapeutic strategies, a spatio-temporal model is considered here that incorporates the tumor cell growth and the effects of radiotherapy and chemotherapy. The effects of different schedules of radiation therapy is then studied using a generalized linear quadratic model and compared against the published clinical data. The model is then extended to include the interactions of tumor vasculature and oxygen concentration, to explain tumor hypoxia and to study various methods of hypoxia characterizations including biomarker estimates and needle electrode measurements. The model predicted hypoxia is also used to analyze the effects of tumor oxygenation status on radiation response as it is known that tumor hypoxia negatively influences the radiotherapy outcome. This thesis also presents a detailed analysis of the effects of heterogenous tumor vasculature on tumor interstitial fluid pressure and interstitial fluid velocity. A mathematical modeling approach is then used to analyze the changes in interstitial fluid pressure with or without antiangiogenic therapy.

Sleep impairments for caregivers are multifactorial. Assumptions are that caregivers of those with primary malignant brain tumors (PMBT) are similar to caregivers of persons with dementia as cognitive impairments are present at diagnosis. The shorter trajectory of PMBTs and rapid deterioration of recipients’ health may influence sleep in caregivers of persons with a PMBT. The purposes of this study were to use a sleep impairment model to characterize caregiver sleep using objective and subjective measures, and to examine sleep loss effects on psychosocial and physiologic health outcomes. A secondary data analysis using baseline data from a larger study of mind-body interactions in caregivers of family members with PMBTs was used. Caregiver data included standardized questionnaires, serum blood draw, and three-day sleep-wake activity data from an accelerometer. Analyses included descriptive statistics, correlations, t-tests, and hierarchical regression models. Caregivers (N = 133) were White (94%), female (69.2%) spouses (75.2) and on average 52 years old (SD = 11.8). Care recipients were mainly White males of similar age with a highly malignant glioma (57.4%). Sleep latency was longer (35 min, SD = 34.5), with shorter total sleep time (TST) (357 min, SD = 84.6) and more frequent wake after sleep onset (WASO; 15.1%, SD = 9.2) than in the general population. Caregivers reported high anxiety (59.4%). Caregiver comorbidities and care recipient functioning explained higher perceptions of health (R2 = 26, F(2, 84) = 14.94, p < .001). Whereas, longer TST, more WASO and poorer sleep quality explained poorer quality of life (R2 = .27, F(4, 66) = 6.19, p < .001). Sleep loss variables explained little variance in physical health status, interleukin-1ra and interleukin-6 levels, fatigue, depressive symptoms, spiritual health, social support, and work limitations. Nurses need to assist caregivers with anxiety management and ways to improve sleep at time of PMBT diagnosis. Sleep impairments place these caregivers at risk for physical and mental health problems, and compromise their ability to continue in the role.

Malign hjärntumör är en vanlig sjukdom som ger olika former av symtom beroende på var tumören är lokaliserad och behandlingsformerna kan ge olika komplikationer. Det finns inga tydliga riktlinjer för hur omvårdnaden kring patienten med malign hjärntumör ska bedrivas. Syftet med denna studie var därför att sammanställa ett kunskapsunderlag angående omvårdnadsåtgärder för patienter med malign hjärntumör. Metoden som användes var en litteraturstudie i form av en granskning av vetenskapliga artiklar, vårdprogram, kandidat- och magisteruppsatser och böcker. Resultatet visade vem, hur, var, vad och när information ska ges till patienten. Det visade också vilka åtgärder sjuksköterskan ska beakta i samband med läkemedelshantering vid cytostatikabehandling, kortisonbehandling och epileptiskt anfall. Sjuksköterskan ska ha kunskap om hur observationer/övervakningar ska genomföras samt hur den speciella omvårdnaden bör genomföras vid strålbehandling, illamående, malnutrition, trötthet/depression och febertillstånd. Även kontaktsjuksköterskans roll i stöd och samordning behandlas. Kunskapsunderlaget visade vilka omvårdnadsåtgärder patienter med malign hjärntumör är i behov av. Implementeringen av kunskapsunderlaget medför en evidensbaserad grund för omvårdnadsarbetet och en ökad patientsäkerhet. Studien visar att det behövs mer omvårdnadsforskning inriktad på patienter med hjärntumör för att kunna ge en evidensbaserad omvårdnad till dessa patienter. / Malign brain tumor is a common illness which gives different kinds of symptoms depending upon where the tumor is located. The treatment can give complications with many different symptoms. There are no clear guidelines how to practice nursing of the patient with a malign brain tumor. The aim of the study was therefore to compile knowledge about nursing interventions for patients with malign brain tumor. The study´s method was a review of literature of scientific articles, care programs, bachelor- and master´s thesis and books. Findings showed whom, how, where, what and when information should be given and how to manage the medication when patient was given chemotherapy, cortisone and epileptic seizures. Nurses must have knowledge of how observation/monitoring must be carried out. How nursing should be carried out at radiotherapy, nausea, malnutrition, fatigue/depression and at fever. One specific nurse is responsible for contacts and her role is to support and coordinate for the patient. The knowledge shows which nursing interventions the patient with a malign brain tumor needs. Implementation of the knowledge-based guidelines involves an evidence-based foundation for the nursing practice and an increased patient safety. More nursing research is needed in the future of patients with brain tumor.

Gliomas are the most common and aggressive primary brain tumors. The most common treatment protocols for these brain tumors are combinations of surgery, chemotherapy and radiotherapy. However, even with the most aggressive combination of surgery and radiotherapy and/or chemotherapy schedules, gliomas almost always recur resulting in a median survival time for patients of not more than 12 months. This highly diffusive and invasive nature of brain tumors makes it very important to study the effects of these combined therapeutic strategies in an effort to improve the survival time of patients. It is also important to study the tumor microenvironment, since the complex nature of the cerebral vasculature, including the blood brain barrier and several other tumor-induced conditions such as hypoxia, high interstitial pressure, and cerebral edema affect drug delivery as well as the effectiveness of radiotherapy. Recently, a novel strategy using antiangiogenic therapy has been studied for the treatment of brain tumors. Antiangiogenic therapy interferes with the development of tumor vasculature and indirectly helps in the control of tumor growth. Recent clinical trials suggest that anti-angiogenic therapy is usually more effective when given in combination with other therapeutic strategies. In an effort to study the effects of the aforementioned therapeutic strategies, a spatio-temporal model is considered here that incorporates the tumor cell growth and the effects of radiotherapy and chemotherapy. The effects of different schedules of radiation therapy is then studied using a generalized linear quadratic model and compared against the published clinical data. The model is then extended to include the interactions of tumor vasculature and oxygen concentration, to explain tumor hypoxia and to study various methods of hypoxia characterizations including biomarker estimates and needle electrode measurements. The model predicted hypoxia is also used to analyze the effects of tumor oxygenation status on radiation response as it is known that tumor hypoxia negatively influences the radiotherapy outcome. This thesis also presents a detailed analysis of the effects of heterogenous tumor vasculature on tumor interstitial fluid pressure and interstitial fluid velocity. A mathematical modeling approach is then used to analyze the changes in interstitial fluid pressure with or without antiangiogenic therapy.

Brain tumors are abnormal tissue masses found, either malignant or benign in nature. Medulloblastoma is a brain tumor subtype found to arise in the hind region of the brain, which is highly malignant and has poor long term prospects in general. On the basis of the driving force behind the tumor, medulloblastoma is further subgrouped into 4 categories: WNT; SHH; Group 3 and Group 4 tumors. Group 3 tumors show a high expression of N-Myc protein which is seen in certain types of cancerous cells. The cell cycle is regulated at several checkpoints by cyclin/cdk inhibitors. The primary cilium is an organelle found on the cellular surface, which has functions in cell growth, differentiation and neurogenesis. Aurora kinase is a protein kinase involved in the regulation and maintainence of the cilium. Often the cilium gets deleted from the cellular surface in tumors coupled with an increase in the kinase level inside the cells. Hence aurora kinase is found to be a viable target for therapy. Aurora kinase is also involved in stabilizing the MYCN gene by protecting it from degradation. In this project, the primary cilum was studied in neural stem cells and followed by study of its presence on tumor cells in culture. The gene involved in cilium development i.e. Kif3a was mutated and its aggressive nature was compared with that of the tumor cells. Aurora kinase was commonly found to be over-expressed in both the tumors and the mutants whereas N-Myc over-expression was seen only in tumors. Experiments suggest that cilia repression in Kif3a mutants takes place via an aurora kinase dependent pathway.