Saudi Cultural Missions Theses & Dissertations
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Item Restricted Advanced diffusion-weighted MRI of breast cancer: response to neoadjuvant chemotherapy and correlation with dynamic contrast-enhanced MRI(University of Leeds, 2025) Almutlaq, Zyad; Buckley, David; Wilson, DanielBackground: Previous studies showed promising applications of intravoxel incoherent motion (IVIM) and stretched-exponential (SEM) models of diffusion-weighted imaging (DWI) in breast imaging; however, their ability to predict early breast cancer response to neoadjuvant chemotherapy (NACT) was minimally investigated. Aims: To evaluate accuracy, bias, precision, and in-vivo repeatability of IVIM parameters estimated using different curve-fitting methods and determine the optimum for analysing the acquired clinical breast DWI data. To investigate the value of conventional monoexponential versus advanced (IVIM and SEM) DWI models parameters estimated from whole-tumour, tumour diffusion cold-spot, and perfusion hot-spot regions to assess early breast cancer response to NACT. To explore relationships between IVIM and dynamic contrast-enhanced (DCE)-MRI perfusion-related parameters, and between DWI diffusion coefficients and DCE-MRI cellularity-related measures in the same three tumour regions. Materials: MRI dataset of primary breast cancer patients acquired at pretreatment and after one and three NACT cycles. Simulated data represent IVIM parameter ranges observed in these patients. Results: Constrained oversegmented-fitting was the optimum IVIM curve-fitting method, producing parameter estimates with the smallest errors, highest precision, and best repeatability. Tumour volume was significantly larger in non-responders across all time-points and demonstrated reasonable predictive performance (AUC=0.84-0.88; p<0.05). The monoexponential model was unable to predict response (p>0.05), while IVIM and SEM models differentiated response groups at pretreatment tumour hot-spot regions and after one NACT cycle in three tumour regions, displaying reasonable predictive performance (AUC=0.71-0.79 at pretreatment, 0.71-0.83 after one cycle; p<0.05). IVIM and DCE-MRI perfusion-related parameters were uncorrelated (p>0.5), but statistically significant, moderate between-subject (r=0.405-0.461; p<0.05) and within-subject (rrm=0.514-0.619; p<0.05) correlations between diffusion coefficients and DCE-MRI cellularity-related measures were observed in the whole-tumour regions. Conclusion: IVIM and SEM models demonstrated better predictive capabilities for response than the monoexponential model. While IVIM and DCE-MRI perfusion-related parameters were uncorrelated, diffusion coefficients and DCE-MRI cellularity-related measures correlated.28 0Item Open Access Application and Development of Contrast-Enhanced Ultrasound for Perfusion Quantification in Kidney Disease(2023-02-18) Almushayt, Shatha Jamal Abdullah; Selby, NicholasChanges in microvascular perfusion play a critical role in the pathophysiology of kidney disease and its sequelae. This thesis describes research work that aimed to optimise and use an ultrasound imaging method to quantify tissue perfusion in patients with kidney disease, specifically Contrast Enhanced Ultrasound (CEUS) applied in the kidneys and in skeletal muscle. This work systematically reviewed prior evidence about the acute changes that haemodialysis exerts on skeletal muscle perfusion, metabolism and function. In a clinical study, changes in skeletal muscle microvascular perfusion during haemodialysis are then explored, as a potential factor that could contribute to skeletal muscle wasting in this population. Findings are then corroborated by an analysis of pre-existing data looking at the associations between hand-grip strength, dialysis related parameters (e.g. blood pressure and ultrafiltration volume) and nutritional measures. In the second half of the thesis, CEUS is used to assess renal perfusion, optimising the protocol for CEUS in healthy volunteers. Then, intra-subject repeatability of the different CEUS perfusion parameters was determined in healthy volunteers studied twice, as well as inter-operator repeatability of image analysis. Finally, a pilot study was undertaken in patients with AKI applying CEUS in this setting and generating preliminary clinical data.11 0Item Restricted Melanin Nanoparticles as a Potential Iron Chelation Therapy for Women with Beta Thalassemia during Pregnancy(2022-12-09) Bakhamis, Nahla; Townley, HelenThe main challenges in developing medications that are safe to use during pregnancy is to minimize foetal exposure to the drug, which has become increasingly challenging with the increased prevalence of chronic conditions among young women. In beta thalassemia, patients can now survive beyond puberty and achieve pregnancy. β-TM pregnancies, however, are at high risk of maternal morbidity due to the complication of iron overload. Current chelation medications are withheld during pregnancy as they can cross the placenta causing potential risk to the foetus. This thesis addressed this complicated challenge in which a chelation agent needs to be retained in the maternal circulation and not cross the placenta. Previous experiments in iron-overloaded mice have shown that melanin nanoparticles can effectively chelate iron. Since the interaction between nanoparticles and cells/tissues is determined by particle characteristics and functionalization that can manipulated at synthesis, it was hypothesized that a melanin nanoparticulates with appropriate characteristics could be restricted from movement across the placenta, and safely used to treat the mother. A library of melanin nanoparticles of different sizes was established, and functionalized. This was followed by particle characterization and imaging. Functional analysis confirmed that particles were able to chelate iron more effectively than the iron chelator desferroxamine at the same concentration. Haemocompatibility testing found that the particles did not cause red cell haemolysis or blood clots. Moreover, it was determined that a cut off size of 200 nm can be restricted from passing across the placental barrier in an in vitro model using a human choriocarcinoma cell line and ex vivo human placental perfusion. Finally, physiological changes during pregnancy such as the decrease in plasma albumin concentrations can alter the volume of distribution as well as the transport of drugs. Proteomics analysis was used to identify nanoparticle binding proteins in the serum from pregnant women, non-pregnant women, and women with beta thalassemia. 43 significantly different proteins between the three serum groups were identified, followed by the gene ontology analysis of cellular components that revealed the mediation of biological identity of the bio-inspired melanin in the biological system.23 0