<p>Genetic and epigenetic variation is a key determinant of human diversity and has an impact on disease predisposition. Single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) are the main forms of genetic variation. The challenge is to distinguish normal variations from disease-associated changes. Combination of genetic and epigenetic alterations, often together with an environmental component, can cause cancer. In paper I, we investigated possible alterations affecting the transcriptional regulation of PDGFRα in patients affected with central nervous system tumors by characterizing the haplotype combinations in the <i>PDGFRA</i> gene promoter. A specific over-representation of one haplotype (H2δ) in primitive neuroectodermal tumors and ependymomas was observed, suggesting a functional role for the ZNF148/PDGFRα pathway in the tumor pathogenesis. In paper II, 50 glioblastomas were analyzed for DNA copy number variation with a chromosome 22 tiling genomic array. While 20% of tumors displayed monosomy 22, copy number variations affecting a portion of chromosome 22 were found in 14% of cases. This implies the presence of genes involved in glioblastoma development on 22q. Paper III described the analysis of copy number variation of 37 ependymomas using the same array. We detected monosomy in 51.5% of the samples. In addition, we identified two overlapping germline deletions of 2.2 Mb and 320 kb (the latter designated as Ep CNP). In order to investigate whether Ep CNP was a common polymorphism in the normal population or had an association with ependymoma development, we constructed a high-resolution PCR product-based microarray covering this locus (paper IV). For this purpose, we developed a program called <i>Sequence Allocator</i>, which automates the process of array design. This approach allowed assessment of copy number variation within regions of segmental duplications. Our results revealed that gains or deletions were identical in size and encompassed 290 kb. Therefore, papers I-IV suggest that some SNPs and CNPs can be regarded as tumor-associated polymorphisms. Finally, paper V describes variation of DNA methylation among fully differentiated tissues by using an array covering ~9% of the human genome. Major changes in the overall methylation were also found in colorectal cancer cell lines lacking one or two DNA methyltransferases.</p>

This paper presents the computer simulation results on the delivery of Etanidazole (radiosensitiser) to the brain tumor and examines several factors affecting the delivery. The simulation consists of a 3D model of tumor with poly (lactide-co-glycolide) (PLGA) wafers of 1% Etanidzole loading implanted in the resected cavity. A zero-order release device will produce a concentration profile in the tumor which increases with time until the drug in the carrier is depleted. This causes toxicity complications during the later stages of drug treatment. However, for wafers of similar loading, such release results in a higher drug penetration depth and therapeutic index as compared to the double drug burst profile. The numerical accuracy of the model was verified by the similar results obtained in the two-dimensional and three-dimensional models. / Singapore-MIT Alliance (SMA)

Genetic and epigenetic variation is a key determinant of human diversity and has an impact on disease predisposition. Single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) are the main forms of genetic variation. The challenge is to distinguish normal variations from disease-associated changes. Combination of genetic and epigenetic alterations, often together with an environmental component, can cause cancer. In paper I, we investigated possible alterations affecting the transcriptional regulation of PDGFRα in patients affected with central nervous system tumors by characterizing the haplotype combinations in the PDGFRA gene promoter. A specific over-representation of one haplotype (H2δ) in primitive neuroectodermal tumors and ependymomas was observed, suggesting a functional role for the ZNF148/PDGFRα pathway in the tumor pathogenesis. In paper II, 50 glioblastomas were analyzed for DNA copy number variation with a chromosome 22 tiling genomic array. While 20% of tumors displayed monosomy 22, copy number variations affecting a portion of chromosome 22 were found in 14% of cases. This implies the presence of genes involved in glioblastoma development on 22q. Paper III described the analysis of copy number variation of 37 ependymomas using the same array. We detected monosomy in 51.5% of the samples. In addition, we identified two overlapping germline deletions of 2.2 Mb and 320 kb (the latter designated as Ep CNP). In order to investigate whether Ep CNP was a common polymorphism in the normal population or had an association with ependymoma development, we constructed a high-resolution PCR product-based microarray covering this locus (paper IV). For this purpose, we developed a program called Sequence Allocator, which automates the process of array design. This approach allowed assessment of copy number variation within regions of segmental duplications. Our results revealed that gains or deletions were identical in size and encompassed 290 kb. Therefore, papers I-IV suggest that some SNPs and CNPs can be regarded as tumor-associated polymorphisms. Finally, paper V describes variation of DNA methylation among fully differentiated tissues by using an array covering ~9% of the human genome. Major changes in the overall methylation were also found in colorectal cancer cell lines lacking one or two DNA methyltransferases.

The purpose of this study was to investigate the relationship between word reading and white matter (WM) integrity in the reading system and test a theory-based moderated mediation model such that relationship of WM integrity with word reading is mediated by processing speed and indirect effect is moderated by group. Thirty-seven adult survivors of childhood brain tumor and typically developing adults participated (mean age=24.19(4.51) years, 62% female). Tractography identified the WM tract for three reading system connections. Fractional anisotropy of the IFOF and PT-OT tracts were significantly correlated with word reading in survivors (r=.55, .46, respectively; p

Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor. The ability of glioma cells to rapidly disperse and invade healthy brain tissue, coupled with their high resistance to chemotherapy and radiation have resulted in extremely poor prognoses among patients. In recent years, nitric oxide (NO) has been discovered to play a ubiquitous of role in human physiology and studies have shown that, at sufficient concentrations, NO is able to induce apoptosis as well as chemosensitization in tumor cells. This thesis discusses the synthesis and characterization of targeted NO donors for the treatment of GBM. Two glioma targeting biomolecules, Chlorotoxin (CTX) and VTWTPQAWFQWVGGGSKKKKK (VTW) were reacted with NO gas to synthesize NO donors. These NO donors, CTX-NO and VTW-NO, released NO for over 3 days and were able to induce cytotoxicity in a dose dependent manner in glioma cells. The biggest advantage, a result of the targeted delivery of NO, was that the NO donors did not have toxic effects on astrocytes and endothelial cells. To characterize the chemosensitizing effects of CTX-NO, cells were incubated with CTX-NO prior to exposure to temozolomide (TMZ) or carmustine (BCNU). These drugs are the most popular chemotherapeutics used in the treatment of GBM, but have only shown modest improvements in patient survival. Viability studies showed that CTX-NO selectively elicited chemosensitivity in glioma cells, whereas the chemosensitivty of astrocytes and endothelial cells remained unaffected. Further investigation showed that CTX-NO pretreatment decreased O6-methylguanine DNA methyltransferase (MGMT) and p53 levels, suggesting that a decrease in DNA repair ability may be the mechanism by which chemosensitivity is induced. Lastly, the effects of CTX-NO on glioma cell invasion and migration were studied using Boyden chamber and modified scratch assays. Non-toxic doses of CTX-NO decreased glioma cell invasion in a dose dependent manner. Studies quantifying matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) surface expression demonstrated that while MMP-2 expression was decreased by both CTX and CTX-NO, MMP-9 expression was decreased only by CTX-NO. Furthermore quantifying MMP-2 and MMP-9 activity levels showed that NO and CTX work synergistically to decrease the activity of the enzymes. These studies demonstrate that the decrease in glioma invasion resulting from CTX-NO treatment was partially a consequence of decreased levels of surface and activated MMP-2 and MMP-9. The work presented in this thesis describes a novel approach to treating GBM that can be modified to develop treatments for various other tumors. Furthermore this is the first study to develop glioma-targeting NO donors.

There is mounting evidence to support combined therapy with radiation (RT) and antiangiogenic agents (AA) for the treatment of brain tumors. However, the therapeutic benefit of this combined treatment hinges on the specific dose, schedule, and duration of each treatment. Early biomarkers that reflect tumor physiological responses provide key information that could guide these aspects of treatment. Pre-clinical tumor models are invaluable tools for identifying potential biomarkers, their optimal timing for measurement and their ability to guide therapy in clinical translation. This thesis demonstrates the feasibility and potential of serial MRI to guide the design, delivery and measure of early response to combined AA and RT in a murine intracranial glioma model. We identified promising biomarker changes reflecting early treatment response that may ultimately facilitate individualized spatio-temporal delivery of radiotherapy (RT) and anti-angiogenic agents (AA) for brain tumors.

There is mounting evidence to support combined therapy with radiation (RT) and antiangiogenic agents (AA) for the treatment of brain tumors. However, the therapeutic benefit of this combined treatment hinges on the specific dose, schedule, and duration of each treatment. Early biomarkers that reflect tumor physiological responses provide key information that could guide these aspects of treatment. Pre-clinical tumor models are invaluable tools for identifying potential biomarkers, their optimal timing for measurement and their ability to guide therapy in clinical translation. This thesis demonstrates the feasibility and potential of serial MRI to guide the design, delivery and measure of early response to combined AA and RT in a murine intracranial glioma model. We identified promising biomarker changes reflecting early treatment response that may ultimately facilitate individualized spatio-temporal delivery of radiotherapy (RT) and anti-angiogenic agents (AA) for brain tumors.

Prior research suggests aggressive cancer treatments contribute to cognitive impairments in children diagnosed with pediatric brain tumors. The literature also suggests that younger age at diagnosis (AAD) and treatment may result in disrupted cognitive trajectories due to limited brain plasticity. In line with this research, we hypothesized an interaction between radiation therapy (RT) and young AAD of brain tumors, where young AAD and RT results in lower standard scores on the WRAT-R Reading Comprehension Subtest. Analyses included archival data; the sample consists of 134 children diagnosed with pediatric brain tumors with multiple assessments resulting in 487 cases for analysis. Participants were diagnosed with mixed tumor types and locations. A two level multilevel model was used to analyze reading trajectories while taking into account AAD, time since diagnosis, socioeconomic status (SES), and RT. Results detected a positive interaction between AAD and RT (γ =2.08, p=.02). For participants with RT, younger AAD was associated with lower reading scores, whereas AAD had no effect for participants without RT. Results also detected a negative interaction between radiation and time (γ =-2.29, p=.00) indicating that children treated with RT have reading scores that decrease over time. These data suggested that children diagnosed with pediatric brain tumors treated with RT are at higher risk of reading impairment as reflected in their reading scores.

To date, the effect of planning ability on adaptive functioning has not been extensively examined in children treated for brain tumors. Findings indicate that individuals with brain tumors are more likely to experience poor planning ability (Boyd & Sautter, 1993) and that children with even mild neurological complications demonstrate impairments in adaptive functioning (Fletcher et al., 1990). The purpose of this study is to assess spatial planning and to examine its utility in predicting adaptive and cognitive functional impairment in children diagnosed and treated for brain tumors. Forty children diagnosed with a brain tumor (mean age at diagnosis 8.6 years) were administered the Rey-Osterrieth Complex Figure (ROCF) task, the Vineland Adaptive Behavior Scale (VABS), and the Stanford-Binet Intelligence Scale: Fourth Edition (SB:IV) at an average of one year post diagnosis (post acute) and again at two years post diagnosis (long term). The results of this investigation did not support the use of spatial planning skills as a predictor of adaptive functioning at one year or two years post diagnosis. However, spatial planning skill was an important predictor of cognitive functioning, accounting for a significant amount of variance at both one year and two years post diagnosis. These results were not expected and therefore further analyses were performed in order to better understand the data and results. Additional analyses suggest that it is spatial skill and not spatial planning that predicts adaptive functioning. Further research should continue to ask questions that will impact how we understand executive, adaptive, and cognitive functioning outcomes in children diagnosed with brain tumors.

Varje år drabbas cirka 1100 personer av någon form av hjärntumör i Sverige. Patienterna drabbas av fysiska, psykiska och kognitiva inskränkningar som förändrar individen. Förändringarna påverkar inte enbart patienterna utan även de närstående. Därför är det viktigt att sjuksköterskan uppmärksammar vilka behov patienter och närstående har samt hur sjuksköterskan kan underlätta för familjerna under sjukdomstiden. Syftet med litteraturstudien var att beskriva hur patienter med diagnosen hjärntumör och deras närstående upplever sjukdomen och dess konsekvenser samt utvärdera vilken funktion sjuksköterskan hade för dem. Utifrån bearbetningen av 19 vetenskapliga artiklar framkom fyra tydliga kategorier. Patientens försämrade förmåga innebar en förändring av roller och relationer inom familjen och en ökad börda på de närstående, som ofta axlade rollen som vårdare. Hur sjukdomen hanterades skiljde sig till viss del mellan patienter och närstående, vilket även resulterade i att behovet av stöd varierade. De närstående kände sig ofta osäkra i rollen som vårdare vilket tyder på att de behöver mer utbildning. Mer utbildning behöver också ges till sjuksköterskan för att kunna tillgodose de behov som patienter och närstående uttryckt. Sjuksköterskan bör uppmärksammas på att närstående är de som känner patienten bäst och genom att se dessa som en resurs underlättas sjuksköterskans arbete och resulterar i att vården blir mer individanpassad. / Each year around 1100 people in Sweden get some form of brain tumor. Patients suffer from physical, mental and cognitive limitations that change the individual. The changes do not only affect the patients but also the next of kin. Therefore it is important that the nurse pay attention to the needs of patients and next of kin and how the nurse can help the families during their illness. The aim of the literature study was to describe how patients with brain tumor and their next of kin experience the illness and its consequences and evaluate the nurses’ function for them. Based on the processing of 19 scientific articles four distinct categories were revealed. The patients’ decreased ability resulted in a change of roles and relationships within the family and an increased burden on the next of kin who often took on the role as caregiver. How the disease was handled differed to some extent between patients’ and next of kin which also resulted in that the need for support varied. The next of kin often felt insecure in the role as caregiver which is suggesting that they need more education. More education also needs to be given to the nurse to be able to meet the needs expressed by patients’ and next of kin. Nurses should pay attention to that the next of kin is the one that knows the patient best and seeing them as a resource makes the nurse’s job easier and result in that healthcare becomes more personalized.