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This work describes 5 groups of tumours seen in routine neuropathological practice in Southampton between 1980 and 1986. The clinical and light microscopic findings in a total of 44 tumours are described. A panel of monoclonal and polyclonal antibodies was used in immunohistochemical studies on each group, and this made important contributions to the diagnosis and characterisation of these tumours. Six primary central nervous system lymphomas were shown to be 5 follicle centre cell lymphomas (Kiel-classification) and 1 T-cell lymphoma. 15 lymphomas causing spinal cord compression were typed as 11 follicle centre cell lymphomas, 3 T-cell lymphomas and 1 lymphoblastic lymphoma. T-cell lymphomas appear to be more likely to be localised in the spine and to have a better prognosis. In all these tumours admixed reactive cell populations were also identified immunohistochemically. Ten primitive neuroectodermal tumours of the cerebrum were examined and immunohistochemistry assisted in their distinction from lymphoma and metastatic carcinoma. It also showed evidence of differentiation in apparently poorly differentiated parts of the tumours. Immunohistochemical studies facilitated the distinction of pleomorphic xanthoastrocytoma from a monstrocellular astrocytoma and a meningeal malignant fibrous histiocytoma. The recognition of this first entity has important prognostic implications. In 10 cerebellar haemangioblastomas a panel of antibodies was used to investigate the histogenesis of the stromal cell component of these tumours. Endothelial and stromal cells were found to be antigenically distinct and neurone specific enolase activity was found in the latter. The implications of this finding are discussed. The studies confirm the important and increasing role played by immunohistochemistry in our understanding of central nervous system neoplasia.

Introduction: Many patients with brain tumours experience dysfunction in several cognitive domains. Given the limited survival times of the majority of patients with brain tumours, maintenance or improvement of quality of life is as important as increasing survival time. Impaired cognition has a negative impact on quality of life and as such, cognitive function is becoming an increasingly important endpoint in clinical trials in neuro-oncology. However, measuring cognition in patients with brain tumours is problematic for a number of reasons. Most intracranial tumours are initially treated with surgery and studies of neurosurgical morbidity often evaluate physical as opposed to cognitive domains, yet the latter can have a greater negative impact on the patient’s quality of life. This thesis therefore details cognition in brain tumour patients at the time of presentation (pre-operatively) and examines the effects of surgical intervention on cognitive function. Of particular interest is the potential utility of inspection time, a computer-based measure of the brain’s information processing efficiency, as a measure of brain slowing as a result of the tumour and as an indicator of response to surgical intervention. Methods: The study is based on a cohort of 118 newly-presenting patients with a supratentorial brain tumour who were to have surgery (biopsy or resection). Each patient was administered a comprehensive battery of cognitive tests prior to surgery (baseline). The battery comprised inspection time testing, other standardised cognitive measures and assessment of mood, quality of life and functional status. Post-operatively, each patient repeated the inspection time test in addition to a selected number of the other tests administered at baseline. For comparison, a group of patients admitted for elective spinal surgery (n = 85) were also tested pre- and post-operatively. A group of healthy volunteers provided a second control group by being tested twice (n = 80). Results: The brain tumour cohort were significantly impaired by comparison with both control groups at baseline (pre-operatively) on the majority of the cognitive measures, including inspection time. Baseline inspection time scores were significantly related to some scores on the EORTC Quality of Life Questionnaire in the brain tumour group, but not in the spinal surgery group. There was no significant difference between the brain tumour and spinal surgery groups in term of the levels of pre-operative anxiety and depression. The brain tumour cohort showed significantly greater relative deterioration on inspection time following surgery by comparison with both control groups. The brain tumour cohort also deteriorated significantly on several other measures postoperatively by comparison with the healthy control group. Detailed analyses were carried out to determine the differential effects of tumour type, location, and type of surgery (biopsy or resection) on inspection time and other functions in the brain tumour group. Conclusions: Tumour-related cognitive impairment appears to be common in a heterogeneous group of brain tumour patients with a variety of different tumours located throughout the brain. Surgical intervention has a negative impact on function in brain tumour patients, although this deterioration may be transient. General slowing of visual information processing appears to be common to brain tumour patients and the inspection time task provides a feasible and useful method of assessment in brain tumour patients. The task is sensitive to tumour-related brain slowing and can provide a reliable assessment of response to surgery. Given the task’s advantages over more commonly-used cognitive measures, it could be usefully incorporated into cognitive tests batteries in neuro-oncology.

Background: Malignant cerebral glioma is a rare cancer but has a devastating impact on patients and their families. In Scotland each year, around 450 people are diagnosed with glioma. Prognosis is generally poor and treatment is essentially palliative. There is a growing recognition that non-clinical aspects of care for both patients and their families need to be acknowledged and integrated into health care provision in line with a patient-focused ethos of care. Currently, there is relatively little research exploring the psychosocial issues and needs of this patient group. Aims: To give patients being investigated for malignant cerebral glioma and their families the opportunity to describe their shared experiences of their illness journey and voice their concerns and unmet needs. To examine how these experiences and needs change over time as the patient progresses through the illness journey. To ascertain the extent to which these needs are recognised and supported, taking into accounts professionals’ views and making suggestions for steps forward in improving patients’ psychosocial care. Methods: A total of 80 qualitative prospective longitudinal interviews (30 paired and 50 separate) were conducted with 26 people with a suspected or confirmed diagnosis of malignant cerebral glioma being treated at a regional hospital and 24 primary relative/informal carers. Patients and carers were interviewed at the following five times: leading up to diagnosis; following a formal diagnosis; around the end of initial treatment (radiotherapy); at a designated six-month follow-up stage; and bereavement interviews with carers. One-off interviews were carried out with 66 health professionals (19 case-linked GPs and 47 other health, health-related and social care professionals involved in patients' care). Interviews were recorded and transcribed verbatim and analysed using the constant comparative method from a grounded theory approach assisted by QSR NVivo Version 7. Findings: Distress, anxiety and shock were overwhelming reactions in the period leading up to a diagnosis of glioma, making it difficult for participants to make sense of their experience. Over time, participants employed a range of strategies in order to cope with their diagnosis. Social and emotional support from professionals and friends, family and other patients were vital in many cases but support often felt inadequate. The role of information and the manner in which it was communicated was closely linked to participants’ ability to cope. Information needs were variable but on the whole patients and carers did not feel well informed. Dealing with cognitive and physical symptoms of their illness and side effects of treatment inhibited patients’ ability to resume their everyday activities. The lives of relatives were also affected as they struggled to care for their loved ones. People with a diagnosis of glioma were faced with the possibility of death from an early point in their illness trajectory and awareness of this, coupled with ability to make sense of existential issues, varied across participants. Issues around support, communication, information and palliative care were considered to be important among health professionals involved in the care of people with a diagnosis of glioma but provision fell short. Conclusions: Concerns regarding information, communication and support reported elsewhere in the literature are enduring in glioma patients and their relatives. Reporting of unmet psychosocial and supportive care issues by patients and recognition by professionals of the need to improve these dimensions of care for people affected by glioma emphasises previous recommendations yet to be fully implemented into patient care.

This collection of studies begins by exploring the development of recognition memory in a group of healthy children and adolescents using experimental memory tests developed as part of this thesis. Various versions of these recognition memory tests were trialled in order to establish age appropriate tests for children aged 6-14 years. In keeping with previous literature in this area, these tests showed relatively stable familiarity memory throughout childhood compared to a steep developmental course for recollection memory. Paediatric brain tumour survivors are known to suffer from significant memory deficits following treatment. However, a clear description of this clinical group’s deficits, in terms of recognition and recall (and therefore also familiarity and recollection), has not previously been established. Using standard clinical memory assessments, the current body of work contributes to this area by characterising this population’s memory deficits as primarily recall-based, particularly when recalling information presented as prose. A sex difference is also noted; with female brain tumour survivors being significantly more impaired than their age-matched male counterparts. This finding is discussed with respect to the differing neural development of males and females. The experimental memory tests developed with normal children were also administered to a group of paediatric brain tumour patients. They were found to have a varied pattern of performance, including auditory recognition impairments but intact visual recognition, even when the test format incorporated similar foils. Associative memory tests revealed impairments in recollection-based recognition; this effect was dependant on the type of information being associated and the length of the encoding-test delay. A learning intervention was developed (and trialled with healthy children), using a method known as the ‘testing effect’, in an attempt to enhance recall of prose at long delays in a group of paediatric brain tumour survivors. Structured repeated retrieval was compared to repeated study for prose passages. This was found, with some patients, to be a successful method of improving recall after a delay of one week. Taken together, the work described in this thesis provides further understanding of recognition memory development in healthy children, novel insights into the residual memory function of paediatric brain tumour survivors and an exciting foundation on which to build a rehabilitation programme for this vulnerable group.

This thesis is autobiographical in nature and follows my life experiences relating to the development and subsequent removal of a large epidermoid brain tumour. The resultant impairment of my faculties, and its effect on my vocational, emotional and spiritual life is outlined. My main means of expressing my journey from illness to partial recovery and self-renewal is through art-making. This art-making (a form of art self-therapy) is recorded in my paintings; included in my thesis as my main means of expression taking the place of the printed word, as my capacity to write and type is somewhat impaired. The main value of my thesis relates to recounting the experience, for others of the renewal of my life, following a major illness. Most brain tumours are fatal or severely limit the ability of a person to communicate, or limit their intellectual functioning. I was fortunate in that I could still communicate through using the visual arts; an area where I had retained my competencies. My thesis then, is aimed at increasing the understanding of illness, recovery and renewal for those in the helping and medical professions; also to give hope of life renewal through art expression and art therapy in cases where verbal and written means of communication are limited. The field of my thesis is adult education and personal learning through experience. This learning has focussed on using creative painting experiences as a way of self-healing. Those paintings that were significant in my recovery and renewal are exhibited in the Art Gallery section of this thesis. By viewing these artworks, you can share in, and understand my journey through illness, recovery and renewal through art-making, self-therapy.

We recently discovered a high-level amplicon spanning the chr19q13.41 microRNA cluster in CNS Primitive Neuroectodermal Tumour, which results in striking upregulation of miR-520g. Constitutive over-expression of miR-520g in untransformed human neural stem cells enhanced cell growth, restricted differentiation down the neuronal lineage, and promoted expression of neural stem/progenitor cell markers. We thus hypothesize that ectopic miR-520g expression promotes tumourigenesis in part by inhibiting cellular differentiation. Consistent with this proposition, miR-520g is silenced upon embryonic stem cell differentiation and its expression is absent from most adult tissues. Moreover, expression analysis of miR-520g overexpressing cells revealed significant dysregulation of developmental signalling pathways. Further efforts focused on elucidating mechanisms of miR-520g function led to the identification of a cell cycle inhibitor, p21, as an important candidate target. These findings collectively suggest that miR-520g may modulate differentiation by regulating developmental signalling pathways and cell cycle exit of neural stem/progenitor cells.

Medulloblastoma is the most common malignant paediatric brain tumour. Similar to other tumours, medulloblastoma pathogenesis involves abnormal regulation of several developmental growth pathways. As my thesis project, I studied the effects of aberrant HGF/MET signalling on medulloblastoma formation in two ways. In my first objective, I investigated the role that mutations play in activated HGF/MET signalling in medulloblastoma by searching for mutations in HGF/MET pathway genes, SPINT1, SPINT2, and MET, within primary medulloblastoma specimens. This screen identified several single nucleotide polymorphisms (SNPs) and two novel variations, one in each SPINT1 and SPINT2 genes. In my second objective, I generated a transgenic mouse model with cerebellar-specific aberrant MET signalling. These mice developed extensive cerebellar abnormalities but formed no tumours. These results indicate that mutations in the HGF/MET pathway components alone are not sufficient to initiate medulloblastoma formation and must coincide with additional genetic insults to promote tumour formation, maintenance, and progression.

We recently discovered a high-level amplicon spanning the chr19q13.41 microRNA cluster in CNS Primitive Neuroectodermal Tumour, which results in striking upregulation of miR-520g. Constitutive over-expression of miR-520g in untransformed human neural stem cells enhanced cell growth, restricted differentiation down the neuronal lineage, and promoted expression of neural stem/progenitor cell markers. We thus hypothesize that ectopic miR-520g expression promotes tumourigenesis in part by inhibiting cellular differentiation. Consistent with this proposition, miR-520g is silenced upon embryonic stem cell differentiation and its expression is absent from most adult tissues. Moreover, expression analysis of miR-520g overexpressing cells revealed significant dysregulation of developmental signalling pathways. Further efforts focused on elucidating mechanisms of miR-520g function led to the identification of a cell cycle inhibitor, p21, as an important candidate target. These findings collectively suggest that miR-520g may modulate differentiation by regulating developmental signalling pathways and cell cycle exit of neural stem/progenitor cells.

Medulloblastoma is the most common malignant paediatric brain tumour. Similar to other tumours, medulloblastoma pathogenesis involves abnormal regulation of several developmental growth pathways. As my thesis project, I studied the effects of aberrant HGF/MET signalling on medulloblastoma formation in two ways. In my first objective, I investigated the role that mutations play in activated HGF/MET signalling in medulloblastoma by searching for mutations in HGF/MET pathway genes, SPINT1, SPINT2, and MET, within primary medulloblastoma specimens. This screen identified several single nucleotide polymorphisms (SNPs) and two novel variations, one in each SPINT1 and SPINT2 genes. In my second objective, I generated a transgenic mouse model with cerebellar-specific aberrant MET signalling. These mice developed extensive cerebellar abnormalities but formed no tumours. These results indicate that mutations in the HGF/MET pathway components alone are not sufficient to initiate medulloblastoma formation and must coincide with additional genetic insults to promote tumour formation, maintenance, and progression.