David G. Walker

Supportive care needs of people with brain tumours and their carers

Goals of workThe diagnosis and treatment of a brain tumour may result in long-term changes in a patient’s functional and social abilities and/or in a greatly reduced life span. A qualitative investigation was conducted to examine the supportive care needs of patients with brain tumour and their carers.Materials and methodsOverall, 18 patients and 18 carers participated in focus groups or telephone interviews, following a structured interview guide to elicit supportive care services of importance to these patients and carers.Main resultsSix major themes were identified using the framework analysis method, including needs for information and coping with uncertainty, practical support, support to return to pretreatment responsibilities or prepare for long-term care, support to deal with social isolation and organize respite care, support to overcome stigma/discrimination and support to discuss potentially reduced life expectancy.ConclusionsFive recommendations to improve service delivery include: assignment of a dedicated member of the care team or case manager; proactive dissemination of information, education and psychosocial support; access to objective assessment of neuropsychological functioning; facilitating easier access to welfare payments; and services facilitating communication about difficult illness-related topics. Provision of services along these recommendations could improve supportive care of brain tumour patients and their carers.

EphA3 Maintains Tumorigenicity and Is a Therapeutic Target in Glioblastoma Multiforme

Significant endeavor has been applied to identify functional therapeutic targets in glioblastoma (GBM) to halt the growth of this aggressive cancer. We show that the receptor tyrosine kinase EphA3 is frequently overexpressed in GBM and, in particular, in the most aggressive mesenchymal subtype. Importantly, EphA3 is highly expressed on the tumor-initiating cell population in glioma and appears critically involved in maintaining tumor cells in a less differentiated state by modulating mitogen-activated protein kinase signaling. EphA3 knockdown or depletion of EphA3-positive tumor cells reduced tumorigenic potential to a degree comparable to treatment with a therapeutic radiolabelled EphA3-specific monoclonal antibody. These results identify EphA3 as a functional, targetable receptor in GBM.

Autologous T cell Therapy for Cytomegalovirus as a Consolidative Treatment for Recurrent Glioblastoma

Glioblastoma multiforme (GBM) is one of the most aggressive human brain malignancies. Even with optimal treatment, median survival is less than 6 months for patients with recurrent GBM. Immune-based therapies have the potential to improve patient outcome by supplementing standard treatment. Expression of human cytomegalovirus (CMV) antigens in GBM tissues provides the unique opportunity to target viral antigens for GBM therapy. Here, we report findings of a formal clinical assessment of safety and potential clinical efficacy of autologous CMV-specific T-cell therapy as a consolidative treatment for recurrent GBM. From a total of 19 patients with recurrent GBM, CMV-specific T cells were successfully expanded from 13 patients (68.4%), 11 of whom received up to four T-cell infusions. Combination therapy based on T-cell infusion and chemotherapy was well tolerated, and we detected only minor adverse events. The overall survival of these patients since first recurrence ranged from 133 to 2,428 days, with a median overall survival of 403 days. Most importantly, 4 of 10 patients that completed the treatment remained progression free during the study period. Furthermore, molecular profiling of CMV-specific T-cell therapy from these patients revealed distinct gene expression signatures, which correlated with their clinical response. Our study suggests that a combination therapy with autologous CMV-specific T cells and chemotherapy is a safe novel treatment option and may offer clinical benefit for patients with recurrent GBM.

Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme

The frequent detection of human cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) has raised the possibility of exploiting CMV‐specific T‐cell immunotherapy to control this disease in CMV‐‐seropositive patients. Here, we have conducted a comprehensive ex vivo profiling of CMV‐specific CD8+ T‐cell responses in a cohort of GBM patients. Of the patients analyzed, approximately half exhibited serological evidence of past infection with CMV. Although no CMV‐specific CD8+ T‐cell responses could be detected in the serologically negative GBM patients, virus‐specific CD8+ T‐cell responses were detected in all seropositive GBM patients. Using major histocompatibility complex‐peptide multimers, the frequency of CMV‐specific T‐cells in the patients detected ranged from 0.1 to 22% of CD8+ T‐cells and a high proportion of these cells were positive for the human natural killer‐1 glycoprotein CD57. Furthermore, ex vivo polychromatic functional analysis of the CMV‐specific T‐cells from GBM patients revealed that large proportions of these cells were unable to produce multiple cytokines (macrophage inflammatory protein (MIP)‐1β, tumor necrosis factor (TNF)α and interferon (IFN)γ) and displayed limited cytolytic function (CD107a mobilization) following stimulation with CMV peptide epitopes. However, in vitro stimulation with CMV peptide epitopes in the presence of γC cytokine dramatically reversed the polyfunctional profile of these antigen‐specific T‐cells with high levels of MIP‐1β, TNFα, IFNγ and CD107a mobilization. Most importantly, adoptive transfer of these in vitro‐expanded T‐cells in combination with temozolomide (TMZ) therapy into a patient with recurrent GBM was coincident with a long‐term disease‐free survival. These studies provide an important platform for a formal assessment of combination therapies based on CMV‐specific T‐cells and TMZ for recurrent GBM.

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells

Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non‐homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia‐telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA‐dependent protein kinase inhibitor (DNA‐PKi) to inhibit NHEJ. Pre‐treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR‐mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA‐PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival.

A biopsychosocial perspective on adjustment and quality of life following brain tumor: A systematic evaluation of the literature

Purpose. To systematically evaluate the literature on quality of life and adjustment to brain tumor from a biopsychosocial perspective. Methods. On the basis of the cancer and brain injury literature, a biopsychosocial organisational framework was initially developed to support an evaluative review of the brain tumor literature. This framework consisted of four themes relating to pre-illness characteristics, neuropathology, personal appraisals and reactions and social support. Electronic searches of Medline, PsycINFO and CINAHL databases identified 48 empirical studies (1980–2007) that investigated factors associated with quality of life or the adjustment of adults with brain tumor. A review of studies within each theme appraised these findings and evaluated the quality of methodology and extent to which biopsychosocial perspectives have guided investigations. Results. Overall, the review identified consistent associations between depression, performance status, fatigue and quality of life. Seven multivariate studies with strong methodology that adopted a biopsychosocial perspective were found. In general, the relationships among pre-illness and brain tumor characteristics, psychosocial variables and quality of life were unclear and various gaps in the literature emerged. Conclusions. Empirical findings within a biopsychosocial perspective may guide the development and delivery of support services for individuals with brain tumor; however, many important areas exist for future research.

Verbal suppression and strategy use: a role for the right lateral prefrontal cortex?

Verbal initiation, suppression and strategy generation/use are cognitive processes widely held to be supported by the frontal cortex. The Hayling Test was designed to tap these cognitive processes within the same sentence completion task. There are few studies specifically investigating the neural correlates of the Hayling Test but it has been primarily used to detect frontal lobe damage. This study investigates the components of the Hayling Test in a large sample of patients with unselected focal frontal (n = 60) and posterior (n = 30) lesions. Patients and controls (n = 40) matched for education, age and sex were administered the Hayling Test as well as background cognitive tests. The standard Hayling Test clinical measures (initiation response time, suppression response time, suppression errors and overall score), composite errors scores and strategy-based responses were calculated. Lesions were analysed by classical frontal/posterior subdivisions as well as a finer-grained frontal localization method and a specific contrast method that is somewhat analogous to voxel-based lesion mapping methods. Thus, patients with right lateral, left lateral and superior medial lesions were compared to controls and patients with right lateral lesions were compared to all other patients. The results show that all four standard Hayling Test clinical measures are sensitive to frontal lobe damage although only the suppression error and overall scores were specific to the frontal region. Although all frontal patients produced blatant suppression errors, a specific right lateral frontal effect was revealed for producing errors that were subtly wrong. In addition, frontal patients overall produced fewer correct responses indicative of developing an appropriate strategy but only the right lateral group showed a significant deficit. This problem in strategy attainment and implementation could explain, at least in part, the suppression error impairment. Contrary to previous studies there was no specific frontal effect for verbal initiation. Overall, our results support a role for the right lateral frontal region in verbal suppression and, for the first time, in strategy generation/use.

Diagnosis and management of astrocytomas, oligodendrogliomas and mixed gliomas: a review.

Low-grade gliomas are a diverse group of neoplasms which, as the name implies, are thought to arise from glial cells. Common among this group are astrocytomas (low-grade astrocytoma; LGA), oligodendrogliomas and mixed gliomas. Among these, LGA is the commonest low-grade glioma and, occasionally, although incorrectly, the terms are used interchangeably. Advances in imaging technology have improved the accuracy of preoperative diagnosis. The management of low-grade gliomas is controversial. Recent evidence suggests that previously considered standard therapy (i.e. surgery plus radiotherapy) may not be in the patients best interests. A review of the available published research concerning low-grade gliomas is therefore timely.

A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells

Glioblastoma multiforme (GBM) is the most common form of brain tumor with a poor prognosis and resistance to radiotherapy. Recent evidence suggests that glioma-initiating cells play a central role in radioresistance through DNA damage checkpoint activation and enhanced DNA repair. To investigate this in more detail, we compared the DNA damage response in nontumor forming neural progenitor cells (NPC) and glioma-initiating cells isolated from GBM patient specimens. As observed for GBM tumors, initial characterization showed that glioma-initiating cells have long-term self-renewal capacity. They express markers identical to NPCs and have the ability to form tumors in an animal model. In addition, these cells are radioresistant to varying degrees, which could not be explained by enhanced nonhomologous end joining (NHEJ). Indeed, NHEJ in glioma-initiating cells was equivalent, or in some cases reduced, as compared with NPCs. However, there was evidence for more efficient homologous recombination repair in glioma-initiating cells. We did not observe a prolonged cell cycle nor enhanced basal activation of checkpoint proteins as reported previously. Rather, cell-cycle defects in the G1–S and S-phase checkpoints were observed by determining entry into S-phase and radioresistant DNA synthesis following irradiation. These data suggest that homologous recombination and cell-cycle checkpoint abnormalities may contribute to the radioresistance of glioma-initiating cells and that both processes may be suitable targets for therapy. Mol Cancer Ther; 11(9); 1863–72. ©2012 AACR.

T-cell apoptosis in human glioblastoma multiforme: Implications for immunotherapy

We used immunohistochemistry and flow cytometry to assess apoptosis in human glioblastoma multiforme (GBM). Our immunohistochemical study revealed apoptosis of glioma cells expressing glial fibrillary acidic protein and of CD3(+) T cells infiltrating GBM. To quantify and phenotype the apoptotic T cells, we performed flow cytometry on lymphocytes separated from GBM. The cells were stained with annexin-V-FLUOS/propidium iodide to identify apoptosis. We found that high proportions of both the CD4(+) and CD8(+) T cells were apoptotic. In particular, we found that T cells expressing Fas ligand (Fas-L, CD95L) were eight times more vulnerable to apoptosis than those not expressing Fas-L, which suggests that the T-cell apoptosis is induced by overactivation of the T-cell receptor, possibly in the absence of appropriate costimulation. Our results have implications for the design of immunotherapies for GBM.