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Title: Advanced imaging biomarkers for the characterisation of glioma
Author: Thompson, Gerard
ISNI:       0000 0004 2740 0258
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Glioblastoma multiform (GBM) is an aggressive primary brain tumour. Despite treatment advances in recent years, outcomes remain poor. Disease progression tends to occur adjacent to the original tumour or surgical resection bed, usually within the radiotherapy planning field. This local recurrence and progression is believed to be the result of invasive disease in the surrounding tissue at the time of diagnosis and treatment, which is not currently detectable by conventional non-invasive methods. A number of novel therapies are currently under development which target specific aspects of the tumour behaviour, to try and improve outcomes from this devastating disease. Imaging biomarkers are under development, therefore, in order to provide a non-invasive assessment of tumour extent and behaviour, to provide bespoke image-guided therapies, and detect recurrence or treatment failure at the earliest opportunity. These are also of value in the context of novel therapeutics, which may have a very specific affect on an aspect of tumour behaviour that is not readily apparent on standard clinical imaging. Key to the progression of GBM is the invasion into surrounding white matter. This is followed by a period of tumour growth and subsequent angiogenesis in which microvasculature is produce that is distinct from the highly regulated blood-brain barrier. This thesis covers the development of suite of advanced magnetic resonance imaging (MRI) techniques aimed at characterising those very traits of GBM responsible for the aggressiveness and treatment resistance. Repeatability studies are undertaken to determine the performance of the biomarkers in healthy tissues, and also in a range of gliomas. Dynamic Contrast Enhanced (DCE-) and dynamic susceptibility-enhanced (DSC-)MRI are used to provide estimates of perfusion and permeability in the tumour. In order to address the reasons behind preferential invasion of the corpus callosum, they are used in conjunction with ASL to non-invasively map perfusion territories and watershed regions in the brain through perfusion timing parameters. Diffusion Tensor Imaging (DTI) and quantitative magnetisation transfer (qMT) are used to provide complementary information about white matter integrity, in order to identify changes occurring with glioma invasion as early as possible and direct image-guided treatments at presentation. Their complementary nature is assessed by comparing the two parameters simultaneously in white matter. Additionally, one of the qMT parameters which may be related to tissue pH is shown to be sensitive and specific for the detection of high-grade tumour tissue. Finally, a novel multiparametric imaging biomarker is introduced. Tumour surface mapping assesses the boundary between the solid tumour and surrounding tissue in order to identify areas of potential aggressiveness and invasion. Multiple imaging parameters can be combined to improve specificity and sensitivity. Using the diffusion-weighted imaging parameter, mean diffusivity (MD - also referred to as the apparent diffusion coefficient (ADC)), it is shown to be predictive of clinical outcome in a retrospective and prospective study, while a multiparametric example is given indicating the utility as a predicative biomarker for regions of progression and recurrence, and as potential spatial discriminator for image-guided therapies.
Supervisor: Jackson, Alan; Parker, Geoffrey Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: glioma ; biomarker ; imaging ; permeability ; perfusion ; qMT ; DTI ; ASL ; DCE-MRI ; DSC-MRI ; glioblastoma ; multiforme ; watershed ; edge ; invasion