Theses and Dissertations (Nuclear Medicine)
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Item Quantification of pulmonary tuberculosis characteristics from digital chest x-rays using radiomics(University of Pretoria, 2023) Sathekge, Mike Machaba; Rae, William I.D.; Martinson, Neil A.; tamarisk.duplessis@gmail.com; Du Plessis, TamariskPulmonary tuberculosis (PTB) is internationally one of the leading causes of death from a single infectious agent, and South Africa remains in the top 8 countries globally with the highest number of new infections. A chest x-ray (CXR) is still the most common radiological imaging procedure for PTB screening, diagnosis and monitoring, but it cannot be used as a standalone diagnostic tool due to the subjectivity associated with reporting. This can be addressed by quantifying digital CXR with tools such as radiomic feature extraction. In this thesis a unique sliding window segmentation method was developed to eliminate the difficult and time-consuming task of accurate PTB disease segmentation from planar images. It was applied as a secondary segmentation, superimposed on a primary automatic lung segmentation, that divided the entire lung region into uniform windows that overlapped while sliding over the CXR in both image dimensions. When radiomic features were extracted from each sliding window, it allowed the distribution of the features across the lung region to be evaluated. Three different outcomes were achieved when radiomic feature extraction was applied to chest x-rays using the sliding window segmentation. Firstly a model was developed that can automatically differentiate normal CXR from CXR with PTB cavities, which could improve the accuracy of CXR reporting currently regaining prominence as a high-volume screening tool. Secondly, signature parameter maps that showed a strong correlation to the lung pathology were constructed. This might be valuable as a quantitative supplementary indicator in the management of PTB disease and further increase the acceptance of CXR as a tool for assessing the TB response in medical research and clinical practice. Finally, a radiomics score was constructed that was able to quantify the change in the disease characteristics as seen from digital CXR of patients diagnosed with PTB. This radiomic score analysis of serial x-rays taken while patients receive TB therapy has the potential to be a quantitative monitoring tool of response to therapy. Radiomics was therefore successfully applied in this study to quantify the characteristics of PTB from chest x-rays.Item 18F-PSMA-1007 in recurrent prostate cancer, a new frontier in prostate cancer PET imaging(University of Pretoria, 2020) Sathekge, Mike Machaba; Vorster, M.; Lengana, ThaboProstate cancer remains a significant cause of cancer morbidity and mortality in men worldwide accounting for the second-highest incidence of all cancers in males. A disproportionate incidence, morbidity and mortality of prostate cancer have been reported in black males than their white counterparts however very little is known of their imaging differences when presenting with biochemical recurrence. The imaging modalities employed in cancer staging (computed tomography, magnetic resonance imaging, bone scan and positron emission tomography) have been under debate due to their varying sensitivities. The prostate bed is the most common site of early recurrence of prostate cancer. The currently used PSMA ligands (68Ga-PSMA and 99mTc-PSMA) undergo early urinary clearance resulting in interfering physiological activity within and surrounding the prostate. This can result in sites of cancer recurrence being obscured. 18F-PSMA-1007 has an advantage of delayed urinary clearance thus the prostate region is reviewed without any interfering physiological activity. There however is limited data on the diagnostic performance of 18F-PSMA-1007 in early biochemical recurrence. To our knowledge we were the first to describe the differences in 68Ga-PSMA imaging findings between black and white prostate cancer patients with biochemical recurrence. We found a significant correlation between PSA values and the diagnostic performance of 68Ga-PSMA imaging in both groups. However there was no significant difference in the detection rate, distribution pattern and the median number of lesions between the two racial groups suggesting that the tumour burden and growth rate of androgen dependent prostate cancer may be similar in both races. We also found 68Ga-PSMA to be superior to bone scan in the assessment of skeletal metastases in the initial staging of high-risk prostate cancer, demonstrating a higher detection rate and specificity, indentifying marrow and lytic skeletal metastases thath had been missed by bone scan. To our knowledge we were also the first to conduct a head to head comparison of 68Ga-PSMA and 18F-PSMA-1007 in this thesis. Though limited by a small number of patients, 18F-PSMA-1007 detected more recurrence sites than 68Ga-PSMA. 18F-PSMA-1007 demonstrated a sensitivity, specificity, positive and negative predictive value of 88.9%, 100%, 100%, and 92.3% respectively while 68Ga-PSMA-11 demonstrated sensitivity, specificity, positive and negative predictive value of 44.4%, 83.3%, 80%, and 66.6% respectively. In our thesis, 18F-PSMA-1007 performed equally to other reported PSMA PET agents when compared with a similar cohort of patients with biochemical recurrence and low PSA value. PSA doubling time proved significantly related to the detection rate of 18F-PSMA-1007 whilst no significant relationship was seen with PSA velocity. We found the optimal PSA cut-off value of 1.26ng/ml to identify biochemical recurrence.Item Determining the diagnostic accuracy of 68Ga citrate-PET/CT in distinguishing benign from malignant lesions in the lung(University of Pretoria, 2014) Sathekge, Mike Machaba; Maganga, Ann; Van de Wiele, C.; marizavorster@gmail.com; Vorster, MarizaNo abstractItem Substance P radiolabeled with 68Ga as a novel-imaging agent for increased Neurokinin-1 Receptor availability in chronic pain disorders(University of Pretoria, 2019-12) Sathekge, Mike Machaba; Zeevaart, Jan Rijn; Ebenhan, Thomas; Janine.Suthiram@necsa.co.za; Suthiram, JanineThe World Health Organization estimates that up to 33% of the world’s population suffers from chronic pain originating from an underlying musculoskeletal disorder. The prevalence of this class of diseases is on the rise with a high estimated economic impact world-wide, also in South Africa. The clinical challenge associated with chronic pain is a lack of understanding of the core pathology of the disease mechanisms involved coupled with mostly non-specific diagnostic tools and ineffective chronic pain treatment. The emerging neuropeptide Substance P (SP) targets the neurokinin-1 receptor (NK1R) and is intimately involved in the processes of inflammation and chronic pain. This is evident from histology reports of elevated levels of SP and NK1R in chronically painful tendon tissue. Molecular imaging modalities such as Positron Emission Tomography/Computed Tomography (PET/CT) have the ability to visualise and provide a quantitative measurement in vivo of the function of cellular and biological processes. Visualisation of the normal NK1R expression in vivo as well as its pathological expression on non-neural cells and tissue cells could improve understanding of the behaviour of the receptor. In this study the tracer biodistribution, pharmacokinetic and targeted in vivo PET/CT imaging of [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP was evaluated for the assessment of NK1R expression in healthy dogs and in dogs with suspected osteoarthritic conditions. The radiolabelling approach used 68Ga-activity from a tin-dioxide-based 68Ge/68Ga generator, supporting optimal radiosynthesis of [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP by way of varying parameters such as 68Ga-peptide acidity (pH) of radiolabelling solution, peptide concentration, reaction time, the benefit of a heated step, purification and the introduction of freeze dried aliquots of the peptide. Formulation was carried out to ensure physiological pH, sterility, low salt and reduced ethanol content. The potential to adapt the radiosynthesis proposed for [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP to its therapeutic counterpart [213Bi]Bi-DOTA-[Thi8,Met(O2)11]SP was determined. The modification of the peptide sequence warranted in vitro assessment of the SP analogue testing DOTA-[Thi8,Met(O2)11]SP mode of action towards the tachykinin receptor family and its dose dependent agonist/antagonist behaviour at NK1R in particular. Healthy and diseased (suspected osteoarthritis) outbreed dogs were the animal of choice because their physiology is known to be closer to humans. Furthermore, a larger animal model is a more suitable fit to a clinical PET/CT camera. Ethical approval was obtained from the Animal Ethics Committee at the University of Pretoria. Animals that met the inclusion criteria were injected with the radiotracer and each animal was allowed three static whole-body PET/CT scans at 30, 60 and 120 min post injection. Blood samples were obtained at certain time points and the bladder of the animal voided prior to each image. Time-activity curves facilitated the calculation of the pharmacological half-life and urinary elimination rate of the radiopharmaceutical. Radiosynthesis, optimisation, and a safe for administration formulation of [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP (0.05 mg/28 nmol, pH 6.5, <5% ethanol) was achieved by way of a robust, repeatable method (95 ºC, 15 min, C18 purification) that used freeze-dried aliquots of the peptide. The optimised parameters were improved when compared with other 68Ga-peptide preparations suitable for pre-clinical or clinical application. Reliably high radiolabelling efficiencies were achieved (>90%) with colloids <6% and uncomplexed 68Ga <3% (n > 3). Excellent radiochemical purity >99% could be achieved following C18-based solid phase extraction. [68Ga]Ga DOTA-[Thi8,Met(O2)11]SP was prepared with high specific activity (13.5 ± 3.9 MBq/nmol) providing sufficient yields to serve multiple doses for pre-clinical imaging studies. [213Bi]Bi-DOTA-[Thi8,Met(O2)11]SP was prepared using a simple, robust radiolabelling method similar to that employed for [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP. The theranostic pair of [68Ga]Ga-/[213Bi]Bi-DOTA-[Thi8,Met(O2)11]SP may not have application in chronic pain disorders, however the safe to administer formulation may be of benefit for other applications. The optimised radiosynthesis of [213Bi]Bi DOTA-[Thi8,Met(O2)11]SP achieved a RCP of 65.7%, 91.2% and 97.5% (using 0.05 mg, 222-259 MBq, n = 3) after 5, 10 and 15 min incubation, respectively. A simpler radiolabelling method applicable to [68Ga]Ga-/[213Bi]Bi-DOTA-[Thi8,Met(O2)11]SP was successfully established. [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP was found to have similar efficacy and potency as native SP but greater selectivity for the NK1R in vitro. The DOTA conjugated peptide functions as an agonist at the receptor with no antagonistic behavior. Activation of NK1R may result in undesired pharmacological effects which must be carefully considered when attempting translation into the clinical setting. The radiotracer was unable to elicit significant activation of any of the other tachykinin receptors at high concentrations and also did not have any antagonistic behaviour at these receptors. Favourable pharmacokinetics and biodistribution was determined in outbreed dogs for [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP which was deemed suitable for imaging of osteoarthritic pain. The pharmacological half-life was determined to be around 15 min. Excretion was predominantly renal with acceptable, transient liver uptake. Areas synonymous with osteoarthritis including the legs, paws, hips and shoulders presented with unilateral uptake of the tracer. This was observed in bone and soft tissue. Elevated and persistent uptake in characteristic NK1R-dense tissues such as the gut mucosa could be visualised. [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP-PET/CT imaging may be a powerful tool to detect NK1R-mediated tissue pain. However further investigations should focus on correlating the NK1R expression in non-neuronal tissues with the accumulation of [68Ga]Ga-DOTA-[Thi8,Met(O2)11]SP in vivo.Item Comparison of filtered back projection and Osem in reducing bladder artifacts in pelvic spect imaging(University of Pretoria, 2011-07-14) Sathekge, Mike Machaba; s2763625@tuks.co.za; Katua, Agatha MaryBladder artifacts during bone single photon emission computed tomography (SPECT) is a common source of errors. The extent and severity of bladder artifacts have been described for filtered back projection (FBP) reconstruction. OSEM may help to address this poor record of bladder artifacts, which render up to 20% of the images unreadable. Aims and objectives To evaluate the relationship of the bladder to acetabulum ratio in guiding the choice of the number of iterations and subsets used for OSEM reconstruction, for reducing bladder artifacts found on FBP reconstruction. Materials and Methods 105 patients with various indications for bone scans were selected and planar and SPECT images were acquired. The SPECT images were reconstructed with both filtered back projection and OSEM using four different combinations of iterations and subsets. The images were given to three well experienced Nuclear Physicians who were blinded to the diagnosis and type of reconstruction used. They then labelled images from the best to the worst after which the data was analysed. The bladder to acetabulum ratio for each image was determined which was then correlated with the different iterations and subsets used. Results The study demonstrated that reconstruction using OSEM led to better lesion detectability compared to filtered back projection in 87.62% of cases. It further demonstrated that the iterations and subsets used for reconstruction of an image correlates to the bladder to acetabulum ratio. Four iterations and 8 subsets yielded the best results in 48.5% of the images whilst two iterations and 8 subsets yielded the best results in 33.8%. The number of reconstructed images which yielded the best results with 2 iterations and 8 subsets were the same as or more than those with 4 iterations and 8 subsets when the bladder/acetabulum ratio was between 0.2-0.39. A ratio below 0.2 or above 0.39 supports the usage of 4 iterations and 8 subsets over 2 iterations and 8 subsets. Conclusion Bladder to acetabulum ratio can be used to select the optimum number of iterations and subsets for reconstruction of bone SPECT for accurate characterization of lesions. This study also confirms that reconstruction with OSEM (vs FBP) leads to better lesion detectability and characterisation.Item A study of the application of reduction gas analysis in determining the relationship between carboxyhaemoglobin and tissue co levels in brain, heart and skeletal muscle after extreme exposure to co poisoning in rats(University of Pretoria, 2007-03-29) Le Roux, C.G.J.; Vermaak, William J.H.; Vreman, H.J.; Piantadosi, C.A.; Cronje, Frans JohannesLittle is known of tissue carbon monoxide (CO) changes after acute exposure because tissue levels are in the order of picomoles per milligram and the technology to measure such low concentrations has only become available relatively recently. This study tested three hypotheses: That tissue CO levels (1) vary among tissues after acute poisoning; (2) change over time; but (3) cannot be predicted by measuring carboxyhaemoglobin (COHb) levels. Twenty four healthy male Sprague-Dawley rats were exposed to 2500 ppm CO in air for 45 min. This non-lethal exposure achieved reproducible COHb values of 66 to 72%. Animals were allowed to recover breathing air and were sacrificed at 30 minute intervals for 150 minutes. An additional nine male animals served as unexposed controls. Accurate measurements of tissue CO levels were made in blood, brain, heart, and skeletal muscle samples. All samples were prepared using the validated technique described by Vreman et al., and Reduction Gas Analysis was used to determine the pmol CO per wet weight tissue. Co-oximetry and gas chromatography were performed on all blood samples. Predictably, blood CO content dropped following exposure, but tissue CO content did not follow the same trend in all tissues. This study supports the hypothesis of (1) tissue and (2) time-related variability of CO concentration in three body tissues after exposure and (3) documents lack of utility of COHb for predicting tissue CO tissue values.