Doctoral Degrees (Nuclear Medicine)

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Evaluation of small molecule inhibitors of HER2, PI3K, mTOR and Bcl-2 for their radiomodulatory effects in human breast cancer cell lines
(Stellenbosch : Stellenbosch University, 2016-12) Hamunyela, Roswita Hambeleleni; Akudugu, John M.; Serafin, Antonio Mendes; Stellenbosch University. Faculty of Medicine and Health Science. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : Breast cancer remains the most commonly diagnosed cancer in women. It is responsible for 32% of all cancers and 15% of all cancer-related deaths in females. Patients with triple-negative breast cancers (TNBC) constitute about one-fifth of all breast cancer patients. TNBC is an aggressive and heterogeneous disease entity in comparison with other types of breast cancer and, therefore, tends to be resistant to existing treatment regimens, such as, targeted and hormone therapies. Although cancer treatment has evolved from being invasive and highly toxic to being more specific with reduced normal tissue toxicity, intrinsic tumor resistance still limits the benefit of therapy with radiation, drugs, and antibodies. To address this important clinical challenge, attempts have been made to better understand the molecular determinants of treatment resistance. This resistance can be attributed to the heterogeneity in the distribution of potential target antigens in a given tumor cell population, which leads to the inability to effectively target all cells with toxic levels of a particular therapeutic agent. There is evidence to suggest that proliferative pathways of triple-negative tumors are still poorly understood, which could be the reason for the observed treatment resistance. Targeted treatment modalities that are singly effective for triple-negative breast cancer are lacking, partly due to paucity of relevant targets as they are devoid of the human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and oestrogen receptor (ER). Novel treatment approaches are, therefore, needed to overcome the challenges in the treatment of triple-negative breast cancers if treatment outcomes are to be improved. Concomitant targeting of cell signaling entities other than HER2, PR and ER may sensitize triple-negative tumors to radiotherapy. In this study, inhibition of HER2, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and the pro-survival gene (Bcl-2) with small molecule inhibitors, TAK-165 (against HER2), NVP-BEZ235 (against PI3K and mTOR), and ABT-263 (against Bcl-2), singly or as cocktails, resulted in significant radio sensitization of human breast cell lines with features similar to those of triple negative cancers. This radio sensitization was seen at 2 and 6 Gy, indicating that a therapeutic benefit could be derived in conventional as well as stereotactic radiotherapy. A moderate to strong synergism was also demonstrated for NVPBEZ235/TAK-165 and NVP-BEZ235/ABT-263 cocktails. The strongest synergy was seen in the latter cocktail. In conclusion, inhibition of PI3K, mTOR and Bcl-2 could potentially be effective in the treatment of triple-negative breast cancer. The therapeutic benefit can be improved, if the target inhibition is followed by radiotherapy.
Glomerular filtration rate measurement and estimation : improvement and validation of existing methods
(Stellenbosch : Stellenbosch University, 2019-12) Holness, Jennifer Lyn; Warwick, James Mathew; Davids, Mogamat Razeen; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : Glomerular filtration rate (GFR) is regarded as the best measure of kidney function. It can either be measured or estimated. This dissertation aims to provide a better understanding of GFR measurement in order to improve its performance and interpretation. It also aims to validate GFR estimation in local populations and to demonstrate the utility of simple adaptations of existing equations to improve estimation. On completion of a GFR measurement, various quality control (QC) checks are performed to ensure the accuracy of the result. However, this requires comparison with clearly defined reference ranges. In a study of healthy, potential kidney donors, reference data for two QC parameters were defined. In a study analysing the effect of measurement errors on GFR, the single-sample method was found to be the most robust technique overall, although for all methods measurement error was generally insignificant compared to expected biological variation in GFR. However, at low GFR values measurement errors were shown to affect all methods significantly. Errors in measurement of the doses were found to have the greatest impact on accuracy. Using nuclear medicine techniques 51Cr-ethylenediaminetetra-acetic acid (51Cr-EDTA) is the most commonly used and widely studied exogenous filtration marker. However, 99mTc-diethylenetriaminepenta-acetic acid (99mTc-DTPA) is gaining favour because of a few technical advantages it has over 51Cr-EDTA, its lower cost, and recent issues with the availability of 51Cr-EDTA. In response to a systematic review suggesting that GFR measurement from the plasma clearance of 99mTc-DTPA was inaccurate, a mini meta-analysis was performed that demonstrated excellent agreement between 51Cr-EDTA and 99mTc-DTPA clearance, thus supporting the use of 99mTc-DTPA as a reliable alternative. Where GFR cannot be routinely measured, it is frequently estimated using a creatinine-based equation. The use of any equation first requires validation in the population in which it will be used. In a study evaluating the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in non-cancer, mixed ancestry adults, both equations were found to perform well. However, in a study that evaluated equations in adults with cancer, the GFR estimates were found to be biased and imprecise. This study highlighted the limitations of using estimated GFR for guiding management decisions in cancer patients. A further study evaluated 11 estimating equations in non-cancer and cancer populations of South African children. The accuracy of all estimates was poor, particularly in the cancer group. Given the extensive use of GFR estimates in South Africa, these findings have profound implications for their use in the management of children and adults with cancer in this country. Developing new equations for a specific population requires large datasets and incurs costs that are impractical in most middle- or low-income countries. A simpler alternative is to adapt existing equations. This work demonstrates the application of a relatively simple approach to adapt existing equations, using modest amounts of data and a readily available Microsoft® Excel-based tool. While this approach is simple and likely to require further refinement, its utility was demonstrated in paediatric and adult cancer populations.
How efficient is Technitium -99m labelling of erythrocytes in patients with malaria?
(2011) Ekoume, F. P.; Rubow, S. M.
ENGLISH ABSTRACT: With the expansion of Nuclear Medicine techniques in developing countries, it is essential to ensure a quality imaging procedure. In the case of red cell labelling, any factor which interferes with the labelling can lead to sub-optimal studies. With regard to the high incidence of malaria in sub-Saharan African countries in general and in Cameroon particularly, a high percentage of patients referred to Nuclear Medicine departments also have malaria. The question arose whether the presence of Plasmodium in erythrocytes or anti-malarial medication could affect the labelling of erythrocytes with technetium-99m. The aim of this study was to investigate the impact of Plasmodium and anti-malarial medication on Tc-99m red cell labelling efficiency with in vitro kits in a population with a high prevalence of malaria infection. Approval for this study was obtained from ethics committees of both institutions. Three groups of 30 patients were enrolled in the study after giving informed consent: 1. Smear-negative patients in an area where malaria is endemic (control group M-). 2. Patients with malaria as determined by a positive malaria smear test (group M+). 3. Patients with malaria and on anti- malaria medication (group Mm). From each patient, a 5 ml blood sample was drawn in a heparinised blood collection tube. The red blood cells of each sample were labelled in vitro with Tc-99m, using an in vitro red blood cell kit. Labelling efficiency of the 3 groups was compared. The average labelling efficiency was 98.2% ± 2.3% in malaria-free individuals, 98.6% ± 2.6% in patients with malaria but not on treatment, and 98.6% ± 1.1% in patients with proven malaria on quinine treatment. Non parametric data analysis using the Kruskal-Wallis ANOVA test for the percentage of labelling efficiencies showed a P-value of 0.2117 which was a confirmation that there was no significant difference between the labelling efficiencies for the three groups. Radioactively labelled red blood cells are used in various nuclear medicine studies. Various drug therapies, including antibiotics, are known to either inflict direct or indirect damage to RBCs or their precursors or to impact influx or efflux of Tc-99m-pertechnetate into or out of RBCs, thereby decreasing labelling efficiency to such an extent that poor and inaccurate diagnostic information is obtained. The results of this study indicate that malaria parasites and anti-malarial treatment with quinine do not affect in vitro erythrocyte labelling with Tc-99m, and should thus not interfere with nuclear medicine investigations.
Implementation of guidelines on hospital radiopharmacy in low-income settings
(Stellenbosch : Stellenbosch University, 2020-12) Ekoume, Fany Pricile; Rubow, Sietske Margarete; Boersma, Hendrikus H.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : Although radiopharmacy is more than 50 years old, it is still in a stage of rapid development. This dissertation focuses on quality issues in radiopharmacies in developing countries. Guidelines for radiopharmacy practice in many countries prescribe complex facilities, especially air handling units, and extensive quality assurance and documentation requirements. In developing countries, these guidelines are currently not always met. In numerous countries in Africa, enforcement of the international guidelines would lead to closure of radiopharmacies, and consequently, loss of Nuclear Medicine services. The question arises what the consequences of not meeting the requirements of the guidelines are, and if practice can be improved without major expenditure. This study considered certain aspects of Good Radiopharmacy Practice (GRP) recommendations and collected information from both a relatively well-equipped facility at Tygerberg Hospital (TBH) in South Africa, and a more basic radiopharmacy facility at Yaoundé General Hospital in Cameroon (YGH) to investigate the conditions that will ensure safe and effective products. Factors assessed include efficacy and microbial safety of the radiopharmaceuticals, with some comparison to a state-of-the-art Good Manufacturing Practice (GMP) compliant radiopharmacy at the University Medical Centre Groningen (UMCG) in the Netherlands. An adapted version of the Quality Management Audits in Nuclear Medicine (QUANUM) tool, tailored for the radiopharmacy context, was used to determine the status of practice in the two African radiopharmacies. Once the current situation and product quality in these radiopharmacies was determined, basic, low-cost interventions to minimise deficiencies were implemented at YGH and the effects of the interventions were assessed. Where the necessary level of safety and efficacy could not be met with currently available systems despite interventions, this was reported. The efficacy of radiopharmaceuticals depends on their radiochemical purity. As lack of validation of analytical methods was one of the shortcomings noted in the YGH audit, experimentally validating a cost-effective radiochromatography method to be used at YGH was the first step of corrective actions implemented. As the provision of clean air and maintenance of air handling systems and equipment require a large budget, special emphasis was placed in three further chapters of the dissertation on assessment of microbial contamination of products, and measures to ensure sterility of products. At YGH, we reached better control of microbiological air quality. This was achieved by the implementation of simple microbiological air sampling methods, and subsequent introduction of hygienic and procedural improvements. Sterility testing of SPECT radiopharmaceuticals showed a low contamination rate at both TBH and YGH. Nevertheless, preparing radiopharmaceuticals in a well-maintained laminar air flow cabinet is recommended in order to reduce the risk of contamination of products by airborne microorganisms. The serious consequences that could arise from not meeting GRP requirements, include transmission of microbial infection to patients or administering radiochemically impure products. This dissertation presents the first work evaluating an affordable approach of the implementation of GRP in sub-Saharan Africa. It is highly recommended to all radiopharmacies in the developing world to adapt GRP in their context and to implement an optimised quality assurance programme, striving for continuous improvement.
Investigation into various aspects of radiolabelling somatostatin peptide derivatives with 68Ga eluted from a SnO2-based 68Ge/68Ga generator
(Stellenbosch : Stellenbosch University, 2018-03) Prince, Deidre Mabel; Rubow, Sietske Margarete; Rossouw, Daniel Dutoit; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : 68Ge/68Ga generators ensure the supply of 68Ga for positron emission tomography (PET), for instance for somatostatin receptor imaging with 68Ga-DOTA-labelled somatostatin analogues. There are various generators available and their eluates are processed differently for radiolabelling of peptides. The objectives of this study were to investigate various aspects of the elution characteristics of the generator, to optimize labelling conditions using different eluate processing techniques such as fractionation and cation exchange chromatography and to develop user-friendly kit formulations. This study was approved by the Stellenbosch University Health Research Ethics Committee and permission was granted for the experimental work to be conducted at iThemba LABS. Elution efficiencies were determined using different HCl concentrations (0.2 M – 1.0 M). Metal analysis and 68Ge breakthrough determination were performed on eluates. Radiolabelling parameters were optimized, using fractionated eluates and different DOTA-peptide masses (15 to 50 μg) at pH 3.5 – 4.0 in sodium acetate buffer. Different heating times and heating methods and the influence of various periods of non-elution of the generator on radiolabelling results were investigated. Cationic resins were investigated for eluate processing. Radiolabelling parameters, using cationic resin-processed eluates, were optimized. Labelling was conducted at various pH values, using different quantities of buffer. DOTA-peptide kits for both fractionated and resin-processed eluates were developed and tested for sterility, endotoxin content and stability. Radiochemical yields, radiolabelling efficiency and radiochemical purity of 68Ga-DOTA-peptides were determined. The elution efficiency of the generator increased with an increase in the concentration of HCl eluent. The 68Ge breakthrough increased dramatically at 0.8 M HCl. Most metal contaminants were lowest when eluting with 0.2 M HCl and the Zn content increased with the increase in HCl concentration. The eluent of choice for the SnO2-based generator was confirmed to be 0.6 M HCl. For radiolabelling, 35 μg DOTA-peptide (9.2 – 9.4 μM) was the most favourable. Extended heating times and heating method did not significantly impact on the radiolabelling. The radiolabelling efficiencies were consistently above 90 % even after 3 weeks of non-elution of the generator, but radiochemical yields dropped after 7 days. DOTA-peptide kits for fractionated eluates were successfully developed and the radiolabelling quality was found to be superior over peptide stock solutions. A radiolabelling method using a cationic exchange resin was successfully adapted for the SnO2 generator. 68Ga was efficiently adsorbed on a Bond Elut SCX (100 mg) cartridge and desorbed by acidified solutions of NaCl. The SCX resin effectively removed about 98 % of deliberately “spiked” metals from the 68Ga eluate. An optimized labelling method based on the use of SCX-purified eluates was developed, producing radiochemical yields of almost 85 % and lead to the successful formulation of DOTATATE kits. The quality was found to be suitable over a 3-month period. In conclusion, a kit type labelling procedure, using cationic resin purified 68Ga eluates, provides the most practical method to produce 68Ga-labelled DOTA-peptides.
Optimization of production methods for gallium-68 PET radiopharmaceuticals in a hospital radiopharmacy
(Stellenbosch : Stellenbosch University, 2020-12) Le Roux, Johannes Stephanus; Rubow, Sietske Margarete
ENGLISH SUMMARY : Production of radiopharmaceuticals intended for human use and research purposes is generally performed in well-equipped commercial or research facilities that usually have access to advanced equipment for the synthesis and quality control of radiopharmaceuticals. Nuclear Medicine departments are in most cases situated in hospitals. Radiopharmacies in these departments usually have limited space and equipment which necessitates careful consideration of suitable production methods. Optimization may include methods to simplify quality control procedures through the use of less sophisticated equipment and procedures. The purpose of this study was to demonstrate how to optimize production methods in an environment with limited resources using ubiquicidin labelled with gallium-68 as an example. The peptide ubiquicidin is currently investigated for localization of infections in patients using positron emission tomography (PET). Until recently, labelling ubiquicidin with gallium-68 was limited to a manual labelling method. Manual labelling methods are not recommended for the routine production of radiopharmaceuticals because of difficulty to comply with Good Manufacturing Practice (GMP). Manual labelling methods can also result in high radiation exposure to personnel. These disadvantages can be addressed by automation of production methods. The research conducted in this study shortly entails the following aspects: •Automation of a manual labelling method of ubiquicidin with gallium-68 •Optimization of the synthesis methods using radical scavengers •In-depth comparison of the labelling characteristics of the manual method to that of theautomated methods •Conducting a literature search into the toxicity of HEPES in humans and animals in order toclarify its use as a buffering agent in the labelling of radiopharmaceuticals • Investigating thin-layer chromatography as method to determine the radiochemical purity of gallium-68 ubiquicidin Two different automated synthesis methods were developed in this study. Optimization of the labelling methods was achieved by adding free-radical scavengers to reduce the formation of impurities. A comparison of the labelling characteristics of the manual labelling method with the automated methods showed that the results obtained with automated methods were more robust and repeatable. The literature search into the toxicity of HEPES showed that its toxicity in humans and animals may be overestimated by pharmacopoeias. The current limits applied by pharmacopoeias may be too strict. An evaluation of several thin-layer chromatography methods indicated that the method currently described in the literature may underestimate the presence of colloidal impurities in the final product. None of the other methods investigated in this study could distinguish the colloidal impurity from the labelled product. This aspect highlights the need for a final purification step to reduce the presence of colloidal impurities in the final product. The work presented in this study creates an important basis for optimization of production methods in a clinical environment. The study can further serve as a guideline to other nuclear medicine departments for optimization of radiopharmaceutical production methods.
Social anxiety disorder : Functional neuroimaging and social cognitive features
(Stellenbosch : Stellenbosch University, 2018-03) Doruyter, Alexander Govert George; Warwick, James Matthew; Lochner, Christine; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : Neuroimaging has enabled important progress in understanding the neurobiology of social anxiety disorder (SAD). Functional neuroimaging experiments in SAD have mostly focused on regional neural activity in response to anxiety provocation or processing of emotional faces, and have found hyper-activations in limbic and paralimbic circuitry. Relatively little however, is known about resting-state conditions in SAD and how these are affected by pharmacotherapy. What is known is almost entirely based on functional magnetic resonance imaging (fMRI) techniques which, while powerful, have some important limitations. Similarly, there has been only limited work investigating the resting neural correlates of social cognitive biases in SAD; how reward processing is disrupted in the condition; and how these respective features are affected by therapy. This thesis presents the first work on SAD investigating resting functional connectivity (RFC) based on nuclear neuroimaging methods. In an experiment that analysed RFC based on single photon emission computed tomography with technetium-99m hexamethyl propylene amine oxime, it was found that RFC differences in SAD were largely consistent with a contemporary network model based on fMRI, as well as implicating disrupted connectivity of the cerebellum. Another novel finding was how pharmacotherapy in SAD increased RFC of the anterior cingulate cortex. Using graph theory and resting-state fMRI, the first evidence of reduced global efficiency and increased clustering coefficients within the theory-of-mind network in SAD as well as independent evidence of social attribution bias in the same sample were reported. In an experiment that investigated regional resting metabolism in the disorder, there was evidence of abnormality in SAD compared to controls, as well as evidence of pharmacotherapy effects, in several biologically relevant regions. These results merit further investigation. Finally, in an fMRI-based experiment on reward processing in SAD, initial results identified no evidence of disrupted processing on a monetary reward task. The findings here support a neurobiological model of SAD in which alterations in resting regional metabolism may underlie disruptions in resting brain networks that have been implicated as being important in social cognitive processing. The results also suggest that pharmacotherapy may affect resting-state conditions through compensatory effects. Finally, the provisional findings are consistent with the theory that reward deficits in SAD may be limited to the processing of social reward, and may not extend to the processing of other reward types. Future SAD research should focus on collaborative work, using pooled datasets, and place greater emphasis on molecular disruptions in neurotransmitter systems involved in the disorder.

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