BACKGROUND: Gliomas are the most common primary brain malignancy, with more than 16,000 patients diagnosed every year (Ostrom, et al., 2015). Outcomes vary widely depending on tumor grade and treatment, and have been steadily improving with the advent of new therapeutics. Glioma patients frequently undergo chemotherapy to remove residual tumor after surgery, and many of these cytotoxic therapies are known to affect rapidly dividing cells such as ovarian follicles (Vassilakopoulou et al., 2016). The negative effects of chemotherapy on fertility have been demonstrated in patients with breast and colorectal cancer (Bines, et al., 1996; Avastin Prescribing Information). Additionally, infertility has been linked with decreased quality of life, primarily in women (O’Moore et al., 1983; Greil, 1997). Fertility treatments are available for women undergoing cancer treatment, however it is unknown whether these treatments are routinely discussed with glioma patients before initiating chemotherapy. OBJECTIVE: The primary goal of this study was to assess whether female glioma patients are being effectively counselled on their possible loss of fertility and their choices for fertility treatment prior to beginning chemotherapy. To this end, it was also important to understand the barriers preventing patients from obtaining information related to their fertility. Another principle goal of this study was to describe the effects of chemotherapy on a sample of women with glioma. Finally, this study sought to understand the priorities of women with glioma in regards to family planning, and to address these priorities in the context of a comprehensive fertility preservation discussion. METHODS: To assess these endpoints, a survey was designed and delivered to patients being treated at the Neuro-oncology clinic of the University of California, San Francisco. Eligible candidates were identified prior to a clinic visit, and patients were asked whether they would like to participate in the survey. Consenting patients then completed the survey at home or in the clinic. Seventy two women completed the survey. Data was analyzed using STATA Software Version 10.0. RESULTS: Analysis of the survey results showed that only 35% of women receiving chemotherapy reported having a discussion regarding fertility preservation prior to beginning treatment. Of those who reported having this discussion, only 80% were aware that chemotherapy could negatively affect their fertility. Many women reported that while fertility preservation was not important to them at the time of diagnosis, it was a priority for them at the time of survey completion. Most women surveyed expressed a desire to have a fertility preservation discussion with a reproductive specialist. CONCLUSIONS: The data obtained in this study suggest a lack of understanding of the negative effects of chemotherapy which may be addressed with a more comprehensive fertility discussion with glioma patients prior to beginning treatment. Although interest in having children tends to decrease after cancer treatment, the majority of respondents still report wanting a child after treatment. The priorities of women in the study reflect a concern for the health of their future offspring which may be best addressed prior to beginning treatment in order to increase their chances of conceiving at a later date.

Medulloblastoma is the most common brain tumor in children, accounting for 10-20% of primary central nervous system (CNS) neoplasms and approximately 40% of all posterior fossa tumors. It is a highly invasive embryonal neuroepithelial tumor that typically arises in the cerebellar vermis and has a tendency to disseminate throughout the CNS early in its course. The molecular mechanisms of the disease largely remain uncharacterized, as the clinical treatment is still associated with mortality and severe side effects. The development of a clinically relevant in vivo model is important not only to further understand the disease but also to provide a method with which to test novel therapeutics. This study quantified the volumetric growth of a human medulloblastoma (VC312) in the athymic nude mouse cerebellum using Gd- enhanced T1-weighed MRI scans. Additionally, a medulloblastoma flank tumor model was used to explore the in vivo effect of the oral anti-cancer agent that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway. In the orthotopic intracerebellar tumor model, perifosine significantly increased the survival of treated mice while qualitatively reducing leptomeningeal dissemination. In the flank model, perifosine effectively suppressed the volumetric growth, decreased activation of the AKT pathway and reduced cellular proliferation in treated mice.

While researchers have explored many important aspects of living with childhood cancer, including the multitude of strains on family members and their reactions, very little is known about the experiences of children with brain tumours and their parents. Grounded theory methods were utilized to explore the unique and shared elements of the experiences of childhood brain tumours, from the perspectives of these children and their parents. Woven throughout their stories were expressions of grief and uncertainty related to the tumour and its effects on their lives. Children and parents tried to maintain a positive outlook and a sense of normalcy, in order to cope and to adapt to the struggles and the changes in their lives. A substantive theory of Balancing Grief and Survival was developed, offering a lens through which to view the children’s and parents’ complex experiences, struggles and coping strategies as integrated, dynamic processes.

This qualitative multi case research asks how the needs of caregivers of primary malignant brain tumour (PMBT) patients are met through structured neuro-oncology programs in Canadian centres. Utilizing telephone interviews with eleven social workers and one psychologist the study analyses their perspectives on the scope and nature of services to brain tumour patients and their caregivers. PMBT is a rare and palliative disease often with neurocognitive and neurobehavioral effects posing special challenges for caregivers. Health care system reliance on family caregivers has resulted in significant implications for their emotional and physical risk. Findings show exclusive patient focused health care in ambulatory programs with fragmented care resulting in marginalization and invisibility of caregivers. This approach is inconsistent with current literature promoting collaborative family centered care, recommended for continuity of care throughout the illness trajectory. Recommendations focus on systemic caregiver service improvements.

This qualitative multi case research asks how the needs of caregivers of primary malignant brain tumour (PMBT) patients are met through structured neuro-oncology programs in Canadian centres. Utilizing telephone interviews with eleven social workers and one psychologist the study analyses their perspectives on the scope and nature of services to brain tumour patients and their caregivers. PMBT is a rare and palliative disease often with neurocognitive and neurobehavioral effects posing special challenges for caregivers. Health care system reliance on family caregivers has resulted in significant implications for their emotional and physical risk. Findings show exclusive patient focused health care in ambulatory programs with fragmented care resulting in marginalization and invisibility of caregivers. This approach is inconsistent with current literature promoting collaborative family centered care, recommended for continuity of care throughout the illness trajectory. Recommendations focus on systemic caregiver service improvements.

INTRODUCTION: Cancers of the gastrointestinal tract are the second most prevalent malignancy with 289,610 new cases last year and the second most common cause of cancer-related death with 150,000 deaths last year in the United States. Prognosis for patients with these malignancies is poor and worsens significantly once the cancer has metastasized to the brain. We evaluated the outcome of patients following Stereotactic Radiosurgery (SRS) for brain metastases (BM) in individuals with GI cancers to identify safety and effectivity of treatment and we assessed prognostic factors that affect tumor control and survival. OBJECTIVES: By the conclusion of this session, participants should be able to: 1) Identify an effective treatment for brain metastases from GI cancers in terms of increasing survival; 2) Identify which treatment provides the best local and distant control of CNS disease; 3) Discuss the effects of different prognostic factors on local control and survival. METHODS: This is a retrospective analysis of 58 brain metastases from 18 consecutive patients who underwent SRS treatment at BIDMC between 2006 and 2013. 11/18 patients underwent prior microsurgical resection for their metastases and 3/18 patients had undergone Whole Brain Radiation Therapy (WBRT). Overall Survival (OS), Local Control (LC), Distal control (DC), and prognostic factors such as age, number of brain metastases (BM), Karnofsky Performance Status (KPS), Recursive Partition Analysis (RPA) and Disease Specific Graded Prognostic Assessment (Ds-GPA) class were evaluated. RESULTS: The median overall survival (mOS) for the entire cohort was 14 months after the diagnosis of BM. The mOS for patients receiving only SRS, Surgical Resection + SRS, and WBXRT + SRS were 8 months, 18 months, and 13 months respectively. The difference in overall survival between treatment groups was not found to be statistically significant. Increasing number of BM was a factor shown to negatively influence survival. Local control was achieved in 55% of lesions after SRS, and in 75% of lesions that were surgically resected followed by SRS boost to the resection cavity. The difference in local control between SRS alone vs. Surgery + SRS was found to be statistically significant (p = 0.013). CONCLUSION: With a higher overall survival and significantly better local control rates, Surgery followed by SRS boost to the resection cavity should be considered as the treatment of choice in this specific subgroup of cancer patients as this study shows that they benefit from this more aggressive treatment option.

Complex network models of functional connectivity have emerged as a paradigm shift in brain mapping over the past decade. Despite significant attention within the neuroimaging and cognitive neuroscience communities, these approaches have hitherto not been extensively explored in neurosurgery. The aim of this thesis is to investigate how the field of connectomics can contribute to understanding the effects of focal brain lesions and to functional brain mapping in neurosurgery. This datasets for this thesis include a clinical population with focal brain tumours and a cohort focused on healthy adolescent brain development. Multiple network analyses of increasing complexity are performed based upon resting state functional MRI. In patients with focal brain tumours, the full complement of resting state networks were apparent, while also suggesting putative patterns of network plasticity. Connectome analysis was able to identify potential signatures of node robustness and connections at risk that could be used to individually plan surgery. Focal lesions induced the formation of new hubs while down regulating previously established hubs. Overall these data are consistent with a dynamic rather than a static response to the presence of focal lesions. Adolescent brain development demonstrated discrete dynamics with distinct gender specific and age-gender interactions. Network architecture also became more robust, particularly to random removal of nodes and edges. Overall these data provide evidence for the early vulnerability rather than enhanced plasticity of brain networks. In summary, this thesis presents a combined analysis of pathological and healthy development datasets focused on understanding the functional effects of focal brain lesions at a network level. The coda serves as an introduction to a forthcoming study, known as Connectomics and Electrical Stimulation for Augmenting Resection (CAESAR), which is an evolution of the results and methods herein.

La radiomique suppose que des informations pertinentes non repérables visuellement peuvent être trouvées en calculant une grande quantité d’indices quantitatifs à partir des images médicales. En cancérologie, ces informations pourraient caractériser le phénotype de la tumeur et définir le pronostic du patient. Le GITC est une tumeur pédiatrique rare diagnostiquée d'après des signes cliniques et son apparence en IRM. Cette thèse présente les premières études radiomiques pour des patients atteints de GITC. Comme les intensités en IRM clinique sont exprimées en unités arbitraires, la première étape de l’étude a été la standardisation des images. Une méthode de normalisation basée sur l'estimation de l'intensité dans la matière blanche d'apparence normale s’est avérée efficace sur plus de 1500 volumes d'images. Des études méthodologiques sur le calcul des indices de texture ont abouti aux recommandations suivantes : (a) discrétiser les niveaux de gris avec une largeur constante pour tous les patients, (b) utiliser un volume d'intérêt constant ou faire attention au biais introduit par des volumes de taille et forme différentes. En s’appuyant sur ces recommandations, les indices radiomiques issus de 4 modalités d'IRM ont été systématiquement analysés en vue de prédire les principales mutations génétiques associées aux GITC et la survie globale des patients au moment du diagnostic. Un pipeline de sélection d’indices a été proposé et différentes méthodes d’apprentissage automatique avec validation croisée ont été mises en oeuvre pour les deux tâches de prédiction. La combinaison des indices cliniques avec les indices d’imagerie est plus efficace que les indices cliniques ou d’imagerie seuls pour la prédiction des deux principales mutations de l’histone H3 (H3.1 versus H3.3) associées au GITC. Comme certaines modalités d'imagerie étaient manquantes, une méthodologie adaptée à l’analyse des bases de données d’imagerie multi-modales avec données manquantes a été proposée pour pallier les limites de recueil des données d'imagerie. Cette approche permet d'intégrer de nouveaux patients. Les résultats du test externe de prédiction des deux principales mutations de l’histone H3 sont encourageants. Concernant la survie, certains indices radiomiques semblent informatifs. Toutefois, le faible nombre de patients n'a pas permis d'établir les performances des prédicteurs proposés. Enfin, ces premières études radiomiques suggèrent la pertinence des indices radiomiques pour la prise en charge des patients atteints de GITC en absence de biopsie mais l’augmentation de la base de données est nécessaire pour confirmer ces résultats. La méthodologie proposée dans cette thèse peut être appliquée à d'autres études cliniques. / Radiomics is based on the assumption that relevant, non-visually identifiable information can be found by calculating a large amount of quantitative indices from medical images. In oncology, this information could characterize the phenotype of the tumor and define the prognosis of the patient. DIPG is a rare pediatric tumor diagnosed by clinical signs and MRI appearance. This work presents the first radiomic studies for patients with DIPG. Since clinical MRI intensities are expressed in arbitrary units, the first step in the study was image standardization. A normalization method based on intensity estimation of the normal-appearing white matter has been shown to be effective on more than 1500 image volumes. Methodological studies on the calculation of texture indices have then defined the following recommendations: (a) discretize gray levels with a constant width for all patients, (b) use a constant volume of interest or pay attention to the bias introduced by volumes of different size and shape. Based on these recommendations, radiomic indices from four MRI modalities were systematically analyzed to predict the main genetic mutations associated with DIPG and the overall survival of patients at the time of diagnosis. An index selection pipeline was proposed and different cross-validated machine learning methods were implemented for both prediction tasks. The combination of clinical indices with imaging indices is more effective than the clinical or imaging indices alone for the prediction of the two main mutations in histone H3 (H3.1 versus H3.3) associated with DIPG. As some imaging modalities were missing, a methodology adapted to the analysis of multi-modal imaging databases with missing data was proposed to overcome the limitations of the collection of imaging data. This approach made it possible to integrate new patients. The results of the external prediction test for the two main mutations of H3 histone are encouraging. Regarding survival, some radiomic indices seem to be informative. However, the small number of patients did not make it possible to establish the performance of the proposed predictors. Finally, these first radiomic studies suggest the relevance of the radiomic indices for the management of patients with DIPG in the absence of biopsy but the database need to be increased in order to confirm these results. The proposed methodology can be applied to other studies.

No description available.

Pediatric medulloblastoma (MB) is a cerebellar brain tumor namely characterized by its origination in early development, as early as embryogenesis. MB is thought to originate from the highly heterogeneous granular neuron precursor (GNP) cell population that resides within the rhombic lip of the dorsal hindbrain region, and is particularly susceptible to the effects of the oncogenic Sonic Hedgehog (SHH) signaling pathway. Patched 1 (Ptch1), typically a transmembrane SHH pathway tumor suppressor gene, is mutated in 20% of MB cases, otherwise known as SHH-group MBs. This mutation in MB presents as a loss of heterozygosity (LOH), where the wild type allele of Ptch 1 is deleted. Ptch 1 receptor silencing activates downstream target genes such as proto-oncogene Smoothened (Smo) and allows for the initiation of tumorigenesis. However, the molecular basis for Ptch1 LOH in MB remains elusive. We have discovered a cancer-testis antigen, Protamine 1 (Prm 1), that is present in the Ptch 1 locus in SHH-group MB tumors. By utilization of the RNAscope technique, we confirm mRNA expression of Prm 1 in cerebellar tumor tissue, predominantly from tumor cells, but not in stromal cells. These studies reveal that tumor cells highjack the promoter of Ptch 1 to express Prm 1, promoting tumor progression. These findings establish the mechanism for Ptch 1 LOH in SHH-group MB, and provide the rationale to define the cell of origin for SHH group MB based on Prm 1 expression. / Biomedical Sciences