Investigating Tissue Heterogeneity using MRI in Prostate Cancer

Multi-parametric MRI, a promising new technique for grading prostate cancer using MRI, classifies a high number of regions as indeterminate. This is a symptom of the wider problem that clinical usage of MRI in prostate cancer only includes basic techniques and does not directly categorise tissue microstructure. This work provides insight into the microstructure of the prostate using a combination of new tissue models and acquisition schemes. Each is tested with the aim of producing a method that is better at detecting and grading prostate cancer. The first section utilises microstructural diffusion models to better quantify tissue heterogeneity in the prostate. The two models investigated provided more information about the heterogeneous nature of the prostate that ADC and showed significant difference between lesions and normal tissue. The next section looks into combining multi-echo T2 (ME-T2) sequences with quantitative tissue modelling called Luminal Water Imaging (LWI). This work produced an optimal LWI fitting technique and acquisition. Then the ability of LWI to detect the PI-RADS v2.0 score of regions of interest was examined, showing that it was able to differentiate between scores better than ADC. This work also showed that LWI can differentiate between tumour and normal tissue with an AUC of 0.81 (p<0.05) when compared to ADC with an AUC of 0.75 (p<0.05) in this dataset. The next section further improves the acquisitions using larger datasets. It showed that correcting for imperfect pulse refocusing could improve on the performance of LWI in detecting PCa. This work also showed that fewer echoes could be used in the acquisition. Neural networks were then used to detect and grade prostate cancer using the data points from both multiple b-value diffusion and ME-T2 decay curves. The neural network’s ability to distinguish between different PIRADS scores was shown to have an AUC of 0.87 (p<0.05) using 32-echo data

Characterization of the dystrophic muscle by 23Na NMR and 1H NMR T2 spectrum

The aim of the thesis is to investigate the sensitivity of novel NMR outcome measures (OM) aiming to quantify pathological changes in the dystrophic muscle. Muscular dystrophy (MD) refers to a heterogeneous group of diseases with progressive muscle wasting and associated weakness characterized by variable degrees of necrosis, regeneration, ionic homeostasis disturbances, chronic inflamma-tion, and, ultimately, resulting in the replacement of muscles by fibro-fatty tissue. My focus was on the evaluation of 23Na NMR and advanced 1H transverse relaxation time (T2) techniques as early, sensitive OM. 23Na NMR measures the tightly controlled sodium concentrations and distribution in skeletal muscle tissue. This biophysical information can be used to assess ion homeostasis and cell integrity. However, 23Na NMR suffers from a low sensitivity and in vivo concentration compared to 1H. Alterations in the muscle 1H T2, commonly interpreted as an indicator of disease activity, are linked to a variety of non-specific events like oedema, inflammation, or necrosis that precede the actual muscle replacement by fat. Protocols including different 23Na NMR and 1H T2 methods were implemented to evaluate healthy and dystrophic skeletal muscle tissues of animal models and patients. This work provides evidence that 23Na NMR could offer a sensitive outcome measure able to monitor specific alteration of the dystrophic muscle at a very early stage

State of the Art and New Advances: Cardiac MRI

Cardiac Magnetic Resonance Imaging (CMR) is an advanced imaging modality for better assessment of cardiac structure, function and tissue characterization. This is an essential imaging modality when indicated for assessment of a variety of cardiomyopathies, cardiac ischemia, myocardial viability, arrhythmias, cardiac masses, congenital heart disease, shunts, acute and constrictive pericardial diseases among others. CMR is sometimes referred to as the non-invasive biopsy given the significant information it provides. This chapter discusses the current state of the art of CMR with discussion about the indications, common sequences used, and the role of CMR in evaluation of ischemic and non-ischemic cardiac disease. This chapter also discusses new advances and the future of the field of CMR

Ontogeny of rat CYP2E1 and CYP1A2 : a characterization and a pharmacokinetic model

Infantile exposure to xenobiotics, e.g. from breastfeeding, poses a serious toxicity risk. Since the toxicokinetic mechanisms that principally determine exposure outcomes undergo a significant developmental maturation, infants may respond to exposures in a different way than adults. Hence, suitable model systems are required to provide risk relevant information in pediatric populations. This dissertation’s primary goal was to provide a critical evaluation of two such model systems; first, a pharmacokinetic model that may predict an infant’s capacity to eliminate toxicants by cytochrome P-450 (CYP) mechanisms and second, the developing rat as a model of human CYP2E1 and CYP1A2 ontogeny.The first objective was to evaluate underlying assumptions of a pharmacokinetic model that describes the ontogeny of hepatic CYP activity using the rat. The study recognized some discrepancies with the stated assumptions. The impact of these discrepancies on the potential applicability of the model is discussed. As proof-of-concept, the observed data were fit to a model describing rat CYP2E1 and CYP1A2 ontogeny. A reasonable correlation (r = 0.75) was observed between observed and predicted oral clearance values of a CYP2E1 substrate indicating the potential applicability of such a model in risk assessment. The second objective was to conduct an extensive characterization of rat hepatic CYP2E1 and CYP1A2 ontogeny at mRNA, protein, activity and intrahepatic expression levels. The results were compared to available human data to determine the appropriateness of the rat for assessment of toxicokinetic mechanisms underlying age-dependent differences in susceptibility to toxicity. Similarities in age-dependent changes in mRNA, activity and zonal hepatic expression patterns were noted between the rat and human prior to weaning. Unlike human data, rats show good correlation between changes in CYP2E1 and CYP1A2 activity and transcript levels, but not with the immunoquantifiable protein. Recognizing such similarities and differences between rats and human regarding onset, rate and pattern of CYP ontogeny will improve the accuracy of rat-to-human extrapolation of developmental toxicokinetic data. Overall, the dissertation research provides mounting and supportive evidence for the use of such model systems in providing risk-relevant information in pediatric populations and to identify toxicokinetic mechanisms underlying age-dependent differences in susceptibility to toxicity