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Purpose Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. The standard method for assessing lung function in COPD is spirometry, which provides global lung function information but is a poor predictor of disability and quality of life. The overall aim of this thesis is to develop utility of hyperpolarised xenon gas magnetic resonance imaging (HP 129Xe-MRI) as a technique to evaluate regional lung function. Methods Studies were approved by the National Research Ethics Service (NRES). Eleven volunteers and 25 patients with COPD underwent HP 129Xe-MRI, pulmonary function tests (PFTs) and quantitative computerised tomography (QCT). Gravitational-dependent gradients of HP 129Xe-MRI were compared between prone and supine postures in healthy volunteers. Lobar quantification of HP 129Xe-MRI was completed in COPD patients, who also underwent time-resolved HP 129Xe-MRI and HP 129Xe-MRI pre- and post-salbutamol to determine feasibility of detecting regional delayed ventilation and post-intervention change. The relationship between study measures was assessed using Pearson's correlation coefficient. Results HP 129Xe-MR ventilation gradients were more marked in the supine than prone posture in healthy volunteers, whereas diffusion-weighted gradients were more uniform. HP 129Xe-MRI was successfully quantified according to pulmonary lobes and correlated with lobar lung anatomy (QCT) and global functional transfer capability (TLCO) (r=-0.61, p<0.005). Delayed ventilation was observed with time-resolved breath-hold HP 129Xe-MRI. Differential regional ventilation change was detected with HP 129Xe-MRI post-salbutamol. Conclusion These data demonstrate technical optimisation of HP 129Xe-MRI in healthy volunteers and COPD patients. Successful generation of lobar HP 129Xe-MRI parameters offers an automated analysis method that can be adopted into the clinical workflow. Finally proof-of-principle data have identified roles for HP 129Xe-MRI in evaluating regional treatments and assessing therapeutic response. Future work will evaluate the role of HP 129Xe-MRI in patient selection for lung volume reduction therapy and as a surrogate end-point in drug development studies.

Chemotherapy forms the mainstay of treatment for patients with liver tumours, which has a number of significant side effects. Treatment response is often assessed some time after commencement of treatment. A quantitative method to detect early liver tumour response to chemotherapy would be beneficial to facilitate termination of ineffective treatment and to minimise unnecessary side effects. This thesis investigated firstly whether fractal analysis of contrast enhanced computed tomography (ceCT) images of colorectal liver metastases could be used to detect early response to chemotherapy. Secondly, a technique based on Nakagami imaging of ultrasound radio-frequency (RF) signals was developed, initially using data from a xenograft mouse tumour model, as a potential early predictor of tumour response. This was subsequently tested using clinical ultrasound data collected from patients undergoing chemotherapy treatment for liver tumours. Mean fractal dimension (FD) obtained from fractal analysis of volumetric ceCT images of colorectal liver metastases was confirmed as a reliable quantitative parameter to detect tumour tissue changes. There was however no significant difference in the interval change of mean FD from baseline between responding and non-responding metastases. Based on the current study, fractal analysis is unable to detect early liver tumour response to chemotherapy. Development of an ultrasound-based tissue assessment technique was then performed, owing to the advantages of ultrasound imaging. A Nakagami imaging-based volumetric tissue assessment technique was developed using backscattered RF ultrasound data from xenograft mice tumour treated in an investigation of high intensity focused ultrasound mediated chemotherapy delivery. The percentage of pre- Rayleigh regions (%PRR) obtained from the new analysis technique demonstrated an indirect correlation with the tumour volume. Interval reduction in %PRR from baseline was also found to be significantly greater in tumours that responded to treatment. These observations confirmed the potential of Nakagami imaging-based techniques to detect early tumour response to treatment. The technique was subsequently used to analyse volumetric ultrasound datasets collected from patients undergoing chemotherapy treatment for liver tumours. The %PRR was found to indirectly correlate with the axial diameter of the liver tumour. Additionally, interval increase in the %PRR between follow-up and baseline study was found to be significantly higher in responding compared to non-responding tumours. These preliminary results demonstrated the potential of the Nakagami imaging-based volumetric tissue assessment technique to detect early response of liver tumour to chemotherapy. Further work is recommended prior to translation into clinical practice.

Angiogenesis is a fundamental process in the survival, growth and spread of cancers. In recent years several therapies have been developed to interfere with this process. Despite initial optimism these agents have rarely provided durable clinical responses. Methods capable of assessing angiogenesis are required to help develop effective anti-angiogenic approaches. Radionuclide imaging is one potential method of assessing angiogenesis. VEGF and integrin expression are two key factors in regulation of angiogenesis in tumours and provide potential targets for radionuclide imaging of angiogenesis. This thesis investigates whether targeting of VEGF and integrins can be performed to image angiogenesis and if treatment with antiangiogenic therapy can be detected viasuch imaging. VEGF imaging was successfully performed by radiolabelling bevacizumab, a monoclonal antibody directed against all isoforms of VEGF, with 111Indium for SPECT imaging. This agent was validated in vitro and in vivo mouse xenograft models, and appears to bind to matrix and cell membrane associated VEGF within tumours. Integrin imaging was attempted using 99mTc-maraciclatide, another SPECT imaging agent. This is a commercial agent based on the RGD tripeptide sequence and binds primarily to αvβ3 and αvβ5 integrins. It was assessed in a clinical trial and compared with histological markers of angiogenesis in patients with colorectal, renal and breast tumours. There was an inverse relationship between 99mTc-maraciclatide uptake and β3 vascular density but no correlation with other angiogenic markers. Both tracers were investigated in a preclinical xenograft model with antiangiogenic therapies. Rapamycin, an mTOR inhibitor, increased uptake of 111In-bnDTPA-bevacizumab and decreased uptake of 99mTc-maraciclatide. These responses corresponded with an increase in VEGF and decrease in β3 integrin levels in the tumours. Rapamycin therapy was also associated with reduction in blood vessel number and changes in perfusion as demonstrated by DCE-MRI. The effect of bevacizumab therapy on 99mTc-maraciclatide uptake was also investigated. Bevacizumab had no significant effect on either 99mTc-maraciclatide uptake or β3 integrin levels. These preliminary results demonstrate that both radiotracers have potential for imaging angiogenesis and detecting response to angiogenic therapies. They also highlight the complex nature of the angiogenic process and that further work is necessary to determine the clinical usefulness of these agents.