Proton magnetic resonance spectroscopy was investigated as a non-invasive technique to observe biochemical changes in the brains of children who had sustained perinatal hypoxic, ischaemic and haemorrhagic brain injury. Methods: Proton spectra were acquired from the centre of the brain in premature infants, and from the parieto-occipital region in older children. Phosphorus spectra were also collected and compared with the proton spectra. Unlocalized phosphorus spectra were acquired at different repetition times. Some children had localized phosphorus spectroscopy examinations with two and four dimensional chemical shift imaging. The children were between 33 weeks post-conceptional age and four years and three months postnatal age at the time of their initial spectroscopy examination. The ability of early proton spectroscopy to predict outcome was considered in relation to the clinical neurological state at eighteen months or more. Because certain assumptions were made about the proton spectra (e.g. no T2 measurements were made), proton spectra were acquired from adults with central nervous system tumours. At surgery, biopsies were taken from the tumours and from normal brain and were analysed with in vitro spectroscopy, histology and established biochemical techniques. The metabolite ratios were compared with those from the in vivo spectra. Modifications were made to commercially available monitoring and ventilation equipment to provide the same standards of care within the magnetic field for sick patients, as on the neonatal or intensive care units. Results: All the proton spectra had peaks attributable to N-Acetyl aspartate (NAA), choline containing compounds (Cho) and creatine plus phosphocreatine (Cr). The NAA/Cho and NAA/Cr peak height ratios increased with age, while the Cho/Cr ratio decreased. The NAA/Cr ratios were significantly decreased in all children with an abnormal neurological outcome when compared with the NAA/Cr ratios from children with a normal outcome. The NAA/Cho ratios were significantly decreased in those children with a moderate outcome but not in those with a severe neurological outcome. There were no significant changes in the Cho/Cr ratios. The phosphorus spectra showed changes; phosphocreatine (PCr) to inorganic phosphate (Pi) decreased after injury and there was a marked increase in pH in the children with the poorest outcome. The apparent Tl of Pi was increased in the first month after birth in the children with a severe outcome. Few changes were seen with localized phosphorus spectroscopy in children who had focal lesions. Phosphorus spectra returned to normal within weeks of birth, while the proton spectra remained abnormal. The adult tumour proton spectra compared well with the in vitro spectra and histology of the biopsies. The concentrations changes of metabolites in vivo, were consistent with the measurements made with established biochemical techniques. Discussion: Hypoxic-ischaemic injury produced changes in the proton spectrum from neonatal brain. These changes persisted with time. Some of these changes correlated with outcome. Phosphorus spectra showed acute changes in response to injury, but the changes resolved within weeks. NAA is located in neurons; the decrease in NAA could be due to failure of neurons to develop normally, or to areas of neuronal loss and gliosis resulting from hypoxic-ischaemic damage. Phosphorus spectra may return to normal because neurons and glia have similar phosphorus metabolite ratios. Proton spectroscopy combined with magnetic resonance imaging, may become a useful technique for studying the anatomy and biochemistry of the brain in children who have suffered brain injury.

No description available.

The efficacy of a weight-reducing programme depends on the extent and composition of the weight loss, and the associated changes in body function. The aim of the thesis was to assess the value of BioImpedance Spectroscopy (BIS) to predict changes in total body water (TBW) and whole body and regional body composition in obese subjects (BMI 30-45kg/m2) using deuterium dilution and a four-compartment model as the reference methods. First, equations were created for the prediction of TBW from impedance (SEE: 1.99 kg (males), 1.37 kg (females)). The acceptable level of mean agreement for the prediction of TBW was set at 1.5 kg. Bias SD for males was found to be - 0.283 2.680 kg and bias for females was found to be 0.128 1.705 kg before weight loss. After weight loss bias SD for males was found to be - 0.004 1.963 kg and for females the bias was 0.003 1.349 kg. Therefore the acceptable level of agreement was met for both males and females. Second, fat free mass (FFM) was predicted using the hydration fraction (HF) of fat free mass obtained by the four- compartment model. This HF was found to be 0.756 0.028, with approximately half of the variability due to methodology and the other half to physiology. BIS satisfactorily predicted whole body composition before (bias SD; males -0.942 1.973 kg and females 0.077 2.660 kg) and after weight loss (males -0.238 2.934 kg and females -0.342 1.755 kg) when compared to the four-compartment model (the acceptable level of agreement was set at 2 kg). Approximately 80% of the mean weight loss was due to fat mass and 20% to FFM. Bias ( SD) for change in FFM was -0.687 1.893 kg for males and 0.714 1.904 kg for females. Bias ( SD) for the change in %BF was 0.674 2.116 for males and -0.843 1.843 for females. Therefore, the acceptable level of the mean agreement in change in FFM between BIS and the four-compartment model (set at 0.5 kg FFM) was not met in this study. In other words in this subjects studied in this project BIS did not satisfactorily predict the change in FFM compared to the four-compartment model. Third, BIS satisfactorily predicted regional body composition as validated by magnetic resonance imaging (MRI) before (arm SEE 0.33 kg and leg SEE 0.93 kg) and after weight loss (arm SEE 0.27 kg and leg SEE 0.86 kg). The acceptable level of mean agreement for the assessment of fat mass in the arm and leg were set as 0.25 kg and 0.75 kg respectively. Before weight loss bias SD for males in the arm was found to be 0.02 0.26 kg and for females bias was found to be - 0.02 0.41 kg. After weight loss bias for the arm was found to be 0.02 0.20 kg for males and - 0.00 0.25 kg for females. The bias for the prediction of fat mass in the leg was found to be 0.03 0.26 kg for males and - 0.19 1.02 kg for females before weight loss. After weight loss the bias SD for males was 0.00 0.77 kg and bias for females was 0.00 .42 kg. Therefore the acceptable levels of agreement were met for both males and females. Furthermore, a novel impedance method (site-specific impedance) predicted MRI skinfold thickness (sum of four skinfolds) better than the traditional calipers (r=0.84 v r=-0.21; P0.05). It is concluded that BIS is of value in assessing TBW, whole body and regional composition and skinfold thickness and that the composition of weight loss was predominantly fat.

Positron emission tomography (PET) allows the accurate quantitation of blood flow measurement non-invasively. Four mathematical methods of calculating blood flow from PET scan data of H215O bolus injections were implemented. No gold standard method for determining blood flow exists, so the accuracy and precision of estimates must be found using alternative methods. To this end a computer model of the scanner was used to study various effects on flow including the arterial time delay and dispersion, tissue inhomogeneity, incorrect partition coefficient estimation, scan duration and weighting functions. However, computer models do not adequately describe all of the physical problems. Physical models were therefore built and imaged in an analogous manner to patients. They highlighted some of the physical problems with data collection, including deadtime of both the arterial -detector and the PET scanner. Suitable correction procedures were developed and implemented. The physical models were used to determine the optimal scan duration. For the autoradiographic method, the optimal scan duration is 132 seconds and for the weighted methods, 264 seconds. The best weighting functions for the weighted methods were 1 and t . Sophisticated optimisation methods were unable to give consistent optimal weights. The estimates of flow for the physical models were typically within 5&'37 of the true values. When flows were calculated from patient data, the flow estimates fell as the scan duration increased. This was due to a blood volume component where the activity in the blood does not diffuse into the tissue spaces. The conclusion is that the single compartment tissue model enables blood flow to be estimated with an accuracy of about 10&'37, but for higher accuracy, the non-exchanging blood volume component must be considered.

No description available.

There is an urgent need to develop sensitive and specific biomarkers of response to treatment in oncology. This thesis explores the utility of three novel positron emission tomography (PET) radiotracers: [18F]-3'deoxy-3'fluorothymidine (FLT), [11C]choline and [18F]-AH111585. All patients in the PET studies had breast cancer. Aims: 1) To quantify the uptake and retention of [18F]FLT, [11C]choiine and [18F]-AH111585 in breast cancer, and evaluate the role of mathematical modelling compared to standard techniques for quantifying tracer uptake. 2) To correlate [18F]FLT and [11C]choiine PET data with immunohistochemical markers of proliferation. 3) To establish if [18F]FLT and [11C]choline PET are reproducible in breast cancer. 4) To determine the effect of anti-cancer treatment on [18F]FLT and [11C]choline PET. 5) To evaluate the diagnostic utility of [18F]-AH111585, a novel avps imaging agent, in breast cancer. Methods: 15 patients with primary and metastatic breast cancer were studied with [18F] FLT-PET at baseline, 2-7 days later, and then 7 days post-chemotherapy. [11C]Choline-PET was evaluated in 21 separate breast cancer patients, 13 for repeatability and 8 for response to trastuzumab. Finally, in 7 further patients [18F]-AH111585-PET was used to monitor angiogenesis in metastatic breast cancer. Findings: All tumour lesions had positive uptake of FLT, which correlated with cell proliferation, FLT uptake was found to have good repeatability, and patients who clinically responded to chemotherapy also demonstrated significant early changes in FLT uptake. In the choline studies, all tumour lesions demonstrated significant uptake compared to normal tissue, and patients who clinically responded to trastuzumab also had a decrease in choline retention parameters. In seven patients studied with [18F]-AH111585-PET all but one lesion had significant retention of the tracer, suggesting that this agent may be promising for imaging angiogenesis.

No description available.

This doctoral thesis is a practice-led enquiry into the value of 3-D Computer Generated Imagery (CGI) in the visualisation and animation of clinical radiological scan data. The aim of this work is to develop an alternative pathway to visualising clinical data that augments and challenges the existing medical imaging aesthetic. It questions the integrity of the author?s arts-based interpretation of the radiological scan data and its relevance in the realworld context of enhancement of doctor-patient communication and interaction.The thesis starts by exploring current pathways for visualising the inner body, in particular biomedical animation, TV documentary, clinical 3-D visualisation and fine art practice inmedical imaging. This analysis is followed by an interrogation of the literature in the field of doctor-patient interaction, resulting in a small qualitative study with patients. This helps to define the opportunity for a new visualisation pathway that brings together the visual and narrative approaches of a 3-D computer animation aesthetic and the detail embedded inclinical radiological scan data.A multi-method approach is used to address the research questions. Informed by a collaborative two-year residency at Ninewells Hospital, NHS Tayside, Dundee, the author creates a series of 3-D CGI works that define this hybrid visualisation pathway. The resulting bandwidth of interpretative works is then investigated in a qualitative study involving semistructured interviews with professionals from the arts and clinical imaging. Overall, the study suggests that image integrity is tethered to context and purpose, contextualising the potential application of the author?s 3-D CGI works. The author concludes that his original contribution to knowledge is this alternative visualisation pathway, as developed through thebandwidth of interpretation. This is achieved through the exposition and use of the author?s tacit knowledge, and the collaborative approach. This provides a transferable model ofworking, for the future visualisation of medical scan data.

In recent years measurements of cerebral perfusion using bolus-tracking MRI have become common clinical practice in the diagnosis and management of patients with stroke and cerebrovascular disease. An active area of research is the development of methods to identify brain tissue that is at risk of irreversible damage, but amenable to salvage using reperfusion treatments, such as thrombolysis. However, the specificity and sensitivity of these methods are limited by the inaccuracies in the perfusion data. Accurate measurements of perfusion are difficult to obtain, especially in patients with cerebrovascular diseases. In particular, if the bolus of MR contrast is delayed and/or dispersed due to cerebral arterial abnormalities, perfusion is likely to be underestimated using the standard analysis techniques. The potential for such underestimation is often overlooked when using the perfusion maps to assess stroke patients. Since thrombolysis can increase the risk of haemorrhage, a misidentification of 'at-risk' tissue has potentially dangerous clinical implications. This thesis presents several methodologies which aim to improve the accuracy and interpretation of the analysed bolus-tracking data. Two novel data analysis techniques are proposed, which enable the identification of brain regions where delay and dispersion of the bolus are likely to bias the perfusion measurements. In this way true hypoperfusion can be distinguished from erroneously low perfusion estimates. The size of the perfusion measurement errors are investigated in vivo, and a parameterised characterisation of the bolus delay and dispersion is obtained. Such information is valuable for the interpretation of in vivo data, and for further investigation into the effects of abnormal vasculature on perfusion estimates. Finally, methodology is presented to minimise the perfusion measurement errors prevalent in patients with cerebrovascular diseases. The in vivo application of this method highlights the dangers of interpreting perfusion values independently of the bolus delay and dispersion.

Background: The mortality of pancreatico-biliary tumours (PBT) is high. The majority of patients present with advanced disease and poor performance status; thus palliative treatment plays a very important role. There is no standard palliative approach for PBT. The role of chemotherapy (CHT) and/or radiotherapy (RT) and/or molecular agents remains to be established in clinical trials. Molecular analysis of tumours may help to predict in whom the disease will remain localised for a significant time. With functional imaging techniques, it may be possible to assess response to anti-cancer drugs. These approaches could help triage patients for single or combined modality therapy. Aims: 1) To evaluate the results of treatment with concurrent cetuximab and RT in locally advanced pancreatic cancer (LAPC) patients in the PACER trial. 2) To develop a quality assurance (QA) strategy for RT in PACER. 3) To determine the feasibility of obtaining and processing skin biopsies and blood samples in the PACER-TRANS molecular sub-study. 4) To assess the value of dynamic PET imaging as a predictive factor in patients with pancreatic cancer. 5) To assess current practice in the management of cholangiocarcinoma (CCA) at The Christie NHS Foundation Trust. 6) To develop a clinical trial for patients with locally advanced CCA (LACCA). Materials and methods: 1) To date ten patients have been recruited to the PACER study. 2) The QA strategy for PACER was developed. 3) Five patients consented to give blood and skin biopsies. RNA was extracted from the skin samples using the Trizol method. Blood was centrifuged and plasma aliquots were frozen for further proteomics studies. 4) C50]H20 scans of two pancreatic cancer patients were used to calculate perfusion parameters. 5) Case notes of 132 CCA patients registered at The Christie between 2000-2004 were reviewed. 6) A protocol for a phase 1/11 trial for patients with LACCA was written with the help of experts in molecular biology and pharmacology. Findings: 1) Cetuximab and RT was generally we" tolerated (one episode of grade 3 hypomagnesaemia). At 6-month follow up, one patient had a partial response, two stable disease and six progression; one patient died before the 6-month follow-up. At the time of analysis, five patients survived. The 6-month survival was 75% (Kaplan-Meier method). 2) A QA strategy was implemented involving treatment and patient questionnaires and dummy runs. 3) High quality RNA for further downstream analysis has been successfully extracted from skin samples. 4) It is feasible to calculate perfusion parameters (blood flow and Vd) in patients with pancreatic cancer using [150]H20 PET. 5) The CCA review showed that patients generally had advanced disease, CHT was the predominant treatment and median survival was poor regardless of treatment type. 6) The protocol for BRACE, a phase 1/11 clinical trial of capecitabine, erlotinib and RT in patients with LACCA, was completed and it is hoped to set up the trial in early 2010. Conclusion: Novel RT treatment approaches appear promising