Intensity Modulated Radiation Therapy (IMRT) is a complex form of radiation delivery for the treatment of malignant tumours and other diseases. In IMRT treatment planning, quantitative assessment is crucial to measure and improve the plan quality and treatment delivery. The search for simple and universal quantitative metrics to assess IMRT treatment plan quality has been identified as important but as yet not entirely successful. The aim of this thesis was to assess the IMRT treatment plan quality by establishing quantitative metrics for planning conformity and complexity. The metrics proposed in this work were simple, reproducible and universally applicable to all IMRT techniques, which included step-and-shoot IMRT (SSIMRT), volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT). Two metrics, conformity index (CI) and conformation number (CN) were adopted to quantify the plan conformity. The data used for CI and CN calculations were easily retrieved from dose volume histogram (DVH). By reporting both of these metrics, comprehensive information on target coverage and irradiation of normal tissues could be provided. For the quantification of planning complexity, a new and novel spatial complexity matrix (SCM) was introduced to measure the average dose gradient of a dose profile. In addition, the spatial frequency ratio (SFR) was established to explore the proportion of rapidly varying dose with distance in a treatment plan by using one-dimensional power spectral density (1D PSD). Virtual phantoms were developed for the initial quantitative assessment, in order to form a basis for treatment plan inter-comparisons amongst the different IMRT techniques. A series of multi organs at risk (OARs) phantoms was developed to simulate the planning target volume (PTV) and OARs for different configurations. A virtual prostate phantom was also designed to include a unique shape of PTV and the OAR in close proximity to PTV, in order to mimic clinical prostate case. Quantitative assessments were undertaken on all the IMRT plans generated using the virtual phantoms. The results of these phantom studies have shown for the first time, the feasibility of the developed quantitative metrics for assessing plan quality. Following the successful application of SCM and SFR on the phantom plans, verification work was undertaken to demonstrate the clinical relevance of these self-developed complexity metrics. A retrospective study was carried out to assess the complexity of plans for the treatment of prostate and head and neck tumours. The information contained in DICOM-RT objects were utilised to acquire dose data from the corresponding dose plane. A qualitative survey on plan complexity was also conducted amongst treatment planners, to demonstrate the correlation between the qualitative and quantitative results. These preliminary studies demonstrated the successful application of the self-developed complexity metrics on clinical IMRT treatment plans. In conclusion, the work in this thesis has demonstrated the successful establishment of quantitative metrics for assessing plan conformity and complexity of different IMRT techniques. These metrics were considered as universal tools for the inter-comparison of plan quality for different IMRT techniques and were successfully applied and translated from phantom studies to the clinical setting. Whilst the judgment and experience of the treatment planner undoubtedly remains paramount for making a final decision on the best plan in the interest of the patient, it is expected that the use of quantitative metrics will provide an effective means of benchmarking performance, minimising treatment plan variability and enhancing the quality of IMRT treatment planning.

Spin-exchange optical pumping (SEOP) is a hyperpolarisation method used in the hyperpolarisation of noble gases and can enhance nuclear spin polarisation by five orders of magnitude. Hyperpolarised (HP) 129-Xe has many properties that make it ideally suited to clinical lung imaging, but since its first demonstration in animals in 1994 and humans in 1996, translation to the clinic has been hampered by challenges associated with scaling up production. Within this thesis, construction and demonstration of a clinical-scale stopped-flow hyperpolariser is described, the design of which is based on the record holding XeUS and XeNA polarisers developed previously by our consortium, which had aimed to address the issue of production scale-up. Modifications enhancing the ease of operation and utility in-clinic are presented, as are modifications that reduce the capital cost of such a system. These include a re-design of the gas manifold and the development of a low-cost low-field NMR spectrometer which achieved an SNR of 125 at a cost of ~$300, a 13-fold improvement in cost/SNR compared with the existing spectrometer at a saving of ~$19,000. In continuous-flow 129-Xe polarisers there has long been a discrepancy in the polarisation achieved and that predicted by the standard model of SEOP which was shown recently to be due to the presence of rubidium clusters. Here, the standard model is applied to- and validated for the first time against the stopped-flow regime. The validated model is used to explore parameter space to identify the most effective ways to increase production yield in future stopped-flow polarisers. Stopped-flow SEOP in the xenon-rich regime presents unique thermal management problems due to the absence of gas flow and abundance of poorly thermally conductive, Rb spin destroying Xe. Raman spectroscopy is used to spatially examine in-cell thermal behaviour under steady-state and turbulent 'rubidium runaway' conditions as a function of temperature and Xe density and the beneficial impact of adding thermally conductive helium to the standard N2-Xe gas mix is demonstrated. Hybrid Rb-Cs-Xe SEOP is demonstrated for the first time and examined using in-situ NMR and Raman spectroscopies. High polarisations of ~50% were obtained. Finally, progress on the HP-Xe clinical trial is presented to illustrate the impact of the 4-fold increase in SNR that will come with the installation of the new N-XeUS stopped-flow polariser.

There is increasing interest in the use of small field of view (SFOV) portable gamma cameras in medical imaging. A novel hybrid optical-gamma camera (HGC) has been developed through a collaboration between the Universities of Leicester and Nottingham. This system offers high resolution gamma and optical imaging and shows potential for use at the patient bedside, or in the operating theatre. The aim of this thesis was to translate the HGC technology from in vitro laboratory studies to clinical use in human subjects. Pilot studies were undertaken with the HGC as part of this thesis. Furthermore, efforts have been made to transform the HGC technologies into a new medical device, known as Nebuleye. Initial physical evaluation of the pre-production prototype camera was carried out as part of the device developmental process, highlighting some aspects of the design that require further modification. A complete and rigorous testing scheme to assess the pre-production prototype camera has been developed and successfully implemented. The newly introduced tests enabled the system uniformity, system sensitivity, detector head shielding leakage, optical-gamma image alignment and optical image quality of the hybrid camera to be assessed objectively. This harmonised testing scheme allows characterisation and direct comparison of SFOV gamma cameras. In vitro and in vivo preclinical imaging was undertaken to examine the performance of the SFOV gamma cameras for experimental animal studies. The results of animal study have shown for the first time the feasibility and performance of these SFOV gamma cameras for imaging mice injected with a newly developed 111In labelled hybrid tracer. Further investigations are needed to improve the system resolution and prepare the camera system for combined gamma-near infrared fluorescence imaging in future. A systematic in vitro laboratory assessment method has been established to examine the imaging performance of the SFOV gamma camera in radioguided sentinel lymph node biopsy (SLNB) and radioactive seed localisation procedures for breast cancer surgery. Further preparatory work was undertaken to carry out a pilot clinical trial of the use of the pre-production prototype camera in sentinel node localisation procedures during breast cancer surgery. The clinical study protocol and routine quality control procedures have been established and are suitable for future use. Baseline data on the camera performance assessed using the routine quality control scheme have been obtained. Finally, the capabilities of the SFOV gamma camera were assessed. This has provided baseline data on user feedback and the imaging consequences on operator motion effects, as well as examining the detectability of a range of radionuclides, including 99mTc, 111In, 123I, 125I and 75Se. The first clinical results of the use of the HGC in clinical hybrid optical-gamma imaging in patients administered with 99mTc and 123I labelled radiopharmaceuticals have been reported. This clinical study has demonstrated the feasibility and capability of HGC in various clinical applications performed at the patient bedside, which included patients undergoing bone, thyroid, lacrimal drainage and lymphatic imaging as well as DaTscan studies. In conclusion, the work in this thesis has demonstrated the successful translation of an SFOV hybrid gamma camera for clinical use. This system would be ideally suited for use in the operating theatre for radioguided procedures such as sentinel node detection and tumour localisation. This system also offers potential for use with the new generation of hybrid fluorescent-radionuclide tracers currently under development.

When performing nuclear magnetic resonance (NMR) it is desirable to maximise the available polarisation of the spin system in order to achieve optimal signal-to-noise ratios. One method of achieving this is via the process of spin-exchange optical pumping (SEOP). SEOP can be used to produce hyperpolarised (HP) noble gases, which possess numerous applications in the fields of science and medicine, ranging from spectroscopic imaging of porous media to Magnetic Resonance Imaging (MRI) of the human lungs. The SEOP process involves transfer of angular momentum from circularly polarised laser photons to the electrons of an alkali metal vapour. Noble gas nuclei can then be polarised via collisions with the alkali metal vapour. Ultra-low frequency Raman Spectroscopy may be used to perform rotational temperature measurements of a nitrogen buffer gas in these SEOP experiments in real-time, in an attempt to understand the poorly understood and highly complex system dynamics and energy transport processes. The work contained in this thesis aims to investigate the co-dependence of these dynamics, in order to characterise the SEOP process in greater detail for a variety of gas mixtures, temperatures and alkali metal targets. With this, it is hoped that HP noble gases may be produced with greater efficiency, achieving faster build-up rates and higher net magnetisation. In addition to in situ Raman spectroscopy, additional diagnostic techniques were implemented in order to illustrate the co-dependence of variables during the thermal exchange processes present in SEOP. Low-field NMR spectroscopy was utilised to determine the 129Xe net spin polarisation (P_Xe) as a function of time and position within the SEOP vessel, whilst near-infra-red (NIR) optical absorption spectroscopy allowed an estimate of the alkali metal polarisation and global pump laser power absorption to be determined. Additionally, initial studies into the use of optical absorption spectroscopy at various wavelengths for determination of the alkali metal number density are discussed. A chronology of experiments conducted using an `in-line', optically filtered Raman probe arrangement will be presented, culminating in the development of a fully automated, single-axis translational stage to perform rapid measurement of the rotational nitrogen temperature (T_N2) within the optical pumping cell with a high degree of temporal and spatial precision. The automated nature of the system facilitates a >3-fold improvement in the rate of thermal data acquisition, with greater ease and reliability than the previous manual method. In addition to pure rubidium, rotational temperature determination via Raman spectroscopy is demonstrated in a variety of rubidium/caesium hybrid alloy mixtures. In this way it may be possible to more efficiently utilise the greater spin exchange rate of caesium with 129Xe to achieve hybrid Rb/Cs cross-polarisation. The result of this is the first observation of 129Xe polarisation in a hybrid Rb/Cs system exceeding that of an equivalent pure Rb system under otherwise identical experimental conditions.

Hyperpolarized 83Kr has previously demonstrated MRI contrast that is sensitive to the chemical composition of the surface in a porous model system. One-dimensional nuclear magnetic resonance spectroscopy of hyperpolarized 83Kr has also revealed distinctive longitudinal relaxation times from selected regions of an ex vivo rat lung originating from differences in surface to volume ratio. However, at the time, MRI using longitudinal relaxation for contrast was not attempted due to limited signal intensities. Methodological advances of the spin exchange optical pumping process have led to a substantial increase in the 83Kr hyperpolarization and the resulting signal intensity. This methodology originates from a below-ambient pressure hyperpolarization technique explored and developed in this work. Using the improved methodology for spin exchange optical pumping of isotopically enriched 83Kr has resolved anatomical details of ex vivo rodent lungs using hyperpolarized 83Kr MRI for the first time. Different 83Kr longitudinal relaxation times were found between the main bronchi and the parenchymal regions of the lung. The T1 weighted hyperpolarized 83Kr MRI provided the first demonstration of surface quadrupolar relaxation pulmonary MRI contrast. Novel hyperpolarization techniques of 129Xe have also been explored resulting a study into the combustion process of methane. Using 129Xe as a probe into the combustion process permitted the first in situ MRI of combustion and enabled spatial-velocity profiles.

Ever since the inception of Diffusion Tensor Imaging (DTI), unabated advancements in its capabilities and applications have been spearheaded by a vibrant research effort to devise dedicated acquisition sequences, protocols and hardware. In translational research, however, the transition of these innovations into the arenas of biomedical research, and ultimately clinical practice is frequently hampered by practical considerations. These include the availability of appropriate expertise, time and resources for their implementation, and considerations of compatibility with established techniques and results reported in literature. Such concerns provide the impetus to maximize the utility of existing protocols before attempting the development of novel dedicated techniques. In this thesis, three investigations, each targeting a different DTI application, are presented. The strategy implemented throughout involves assessing the suitability of existing sequences for the intended task, and determining any limiting factors, evaluating whether appropriate modifications of the acquisition protocols used are capable of alleviating limitations, and developing novel, dedicated protocols wherever necessary. The value and, importantly, the wide scope of this approach in answering important research questions is exemplified through the breadth of the studies presented. The first study presents, for the first time, a quantitative evaluation of the effects of cardiac pulsation on prevalent DTI metrics acquired with a specific acquisition protocol used routinely in clinical practice. Findings inform the on-going debate on whether the investment in cardiac gating is merited by improvements in data quality. Effects were observed during only 6 % of the cardiac cycle, and not 20 % as previously reported. The impact of cardiac pulsation on selected diffusion Tensor indices was minimal in group studies, but of potential practical relevance in individual cases. Methods to predict which individuals may benefit from gating have also been suggested. Secondly, the feasibility of post-mortem DTI was established through the successful acquisition, also for the first time, of DTI data on a chemically fixed whole human post-mortem brain using a clinical sequence. Previous failed attempts have been attributed to insufficient SNR. In this study scanner stability and distortion are found to be the main limiting factors, and mitigated using appropriate averaging and co-registration strategies. The third study assessed the potential of ultra-high field strength DTI by identifying and optimizing the potential strengths of DTI at 7T. Subsequent to optimization with respect to SNR, the main sources of artefact were found to be B1 inhomogeneity and inadequate fat suppression. Both were alleviated by modification of the available acquisition protocol, resulting in higher SNR and data quality than previously reported. Finally, in developing appropriate data quality measures, the ‘Difference method’, commonly used for the quantification of SNR, was found to be unsuitable for in vivo DTI acquisitions at 7 T, leading to the proposal, and successful implementation and validation of an alternative.

Hyperpolarized (hp) gases such 129Xe and 83Kr (spin I = 1/2 and I = 9/2 respectively) can allow for significantly enhanced signal in a number of magnetic resonance applications. As a result there has been a growing interest in recent years to advance hp noble gas technology to non-invasively image the airspace of lungs, with the goal of developing a helpful probe for lung pathologies. 83Kr longitudinal relaxation (T1) has been shown to be sensitive to various surface properties, and may prove to be an interesting for identifying certain diseases including those that change surface chemistry (such as cystic fibrosis) or the surface-to-volume ratio in the lung (like in emphysema). This thesis contains several studies furthering 83Kr lung imaging, while also exploring methods for 129Xe imaging. A major focus has been on increasing spin polarization of the noble gases, as an increased polarization yields a greater MR signal strength. A novel low-pressure spin-exchange optical pumping technique has been utilized in this work allowing for 83Kr polarizations exceeding 17.5 %; as opposed to 4.4 % previously reported in literature. Gas produced in this fashion must be pressurized to above ambient before it is possible for it to be delivered to a lung. Two methodologies for pressurizing the noble gas via compression are explored and optimized for hp gas delivery to excised lungs with 83Kr polarizations as high as 13.8 % achievable after compression. This ultimately allowed for the first ever coronal 83Kr lung images in an ex vivo lung model. Further work repeated with isotopically enriched 83Kr achieved a surface-sensitive T1 relaxation map in this system. Finally gas handling techniques where created to allow for efficient and thorough mixing of the hp noble gases and O2 while minimizing relaxation effects. This is vital for any future in vivo studies.

Introduction Cerebral glioma is the most prevalent primary brain tumour, of which the majority are high grade gliomas. High grade gliomas possess a poor prognosis, and glioblastoma patients survive less than one year after diagnosis. To date, histological grading is used as the standard technique for diagnosis and survival prediction. Previous studies using advanced techniques such as MR Perfusion have achieved a high sensitivity but a low specificity in identifying high grade gliomas. Moreover, they have failed to distinguish glioblastoma from anaplastic glioma. The purpose of the study presented here is to assess the diagnostic and prognostic value for cerebral glioma of cerebral blood volume maps derived from MR perfusion. Methods This retrospective study was approved by the local research ethics committee and clinical audit office. This study included 123 patients with newly diagnosed cerebral glioma, of all grades. Histological diagnosis was used as the standard reference for all potential patients. The relative tumour blood volume (rTBVmax) derived from MR perfusion was used for radiological grading of cerebral glioma. Receiver operating characteristics (ROC) were used to define the best threshold value in distinguishing the glioma grades and in determining the accuracy values (sensitivity, specificity, and positive and negative predictive values). For survival analysis, Kaplan-Meier was used to illustrate and compare the discriminatory value of the histological and radiological classifications. A multiple Cox regression model was used to assess the prognostic value of both classifications in addition to other tested demographic and clinical variables. Finally, the influence of potential moderators was assessed using ANOVA, to assess whether the variation in rTBVmax was only due to the difference in tumour grades. Results A model data set (n = 50) produced a 7-fold increase of TBVmax in tumour versus white matter and provided sensitivity and specificity of 97% and 94%, respectively, in distinguishing high versus low grade glioma. Moreover, a threshold value of 9.6 provided sensitivity and specificity of 100% and 56% in differentiating glioblastoma within the group of high grade gliomas. These threshold values were applied to the second group (n = 73) and provided sensitivity and specificity of 96% and 95% in distinguishing high versus low grade glioma, and 97% and 73% in differentiating, within the high grade gliomas, glioblastoma from anaplastic glioma. Using these two thresholds for a three-tier radiological classification, both the Kaplan-Meier plots and the multiple Cox regression showed that radiological classification was the most independent predictor of survival and tumour progression. The proposed radiological classification system was better than histological classification in predicting glioma patients survival especially noted in a group of moderately hyperaemic rTBVmax. Conclusion MR perfusion is a non-invasive and robust technique in glioma grading and survival prediction. The diagnostic value of rTBVmax derived from MR perfusion in differentiating high versus low grade glioma is promising. It may have a role in the future in defining the appropriate treatment. However, the proposed radiological classification was inferior in differentiating anaplastic glioma from glioblastoma multiforme. In the future, a more advanced multimodal MR, such as MR spectroscopy and MR diffusion, may be studied, besides MR perfusion, in order to improve this diagnostic accuracy.

Molecular magnetic resonance imaging (MRI) methods have the potential to provide detailed information regarding cellular and molecular processes at small scales within the human body. Nuclear signals from chemical samples can be probed using specialised MRI techniques, to highlight molecular contrast from particular enzymes or metabolites. The aim of the work described in this thesis is to investigate both exogenous and endogenous contrast mechanisms using fluorine MRI and chemical exchange saturation transfer (CEST) respectively, in order to detect molecular changes in vitro. Initial theoretical work investigates the factors which affect fluorine MRI signals and provides a theoretical framework to determine the sensitivity of such experiments. A novel paramagnetic fluorine sensor to detect enzyme activity is then characterised using high field nuclear magnetic resonance (NMR), showing 60 to 70–fold increases in T1 relaxation values upon enzyme interaction. The effects on the fluorine lineshape from varying sample temperature and solvent were investigated. The possibility of imaging is demonstrated, but further investigations using the theoretical framework found pre–clinical implementation of the sensor is limited by the achievable experimental sensitivity. Efforts then focussed on CEST molecular methods, which are not limited by sensitivity. A protocol is developed to target amide protons in an in vitro cancer cell model, with parameters optimised following simulation of the expected contrast. Analysis of CEST results were aided through use of a support vector machine (SVM) to distinguish group differences between cancer cells and control samples. A linear classifier was found to be suitable to discriminate between samples.