Thesis (MSc)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: Planar bone scintigraphy is highly sensitive but it may not be sensitive enough to detect subtle lesions in complex bony structures such as the spine. The accurate anatomic localisation of lesions in regions such as this is also limited using planar images. Single Photon Emission Computed Tomography (SPECT) results in a higher lesion contrast resulting in an improved sensitivity for the detection of subtle lesions. SPECT also enables improved lesion localisation, often valuable in distinguishing benign from malignant disease in the spine. A number of previous studies have demonstrated that the addition of SPECT of the spine significantly enhances the value of bone scintigraphy for the detection of bone metastases compared to planar imaging alone. These studies were however not done in the African context where patients typically present with more advanced disease. In a retrospective study of 576 patients with known primary tumors sent to our institution for bone scintigraphy for the diagnosis of bone metastases, we evaluated 119 patients in whom both planar imaging and SPECT were obtained. The studies were graded for the probability of metastatic disease, and the number of spinal lesions was determined with and without SPECT. The influence of adding SPECT on the interpretation of the study was determined in terms of the reported probability of metastatic disease, the exclusion and confirmation of metastatic disease, the decisiveness of interpretation, and the number of spinal lesions. The addition of SPEeT resulted in a statistically significant change in the interpretation of studies, although the actual numbers of patients affected were relatively small. SPEeT resulted in a more decisive interpretation of bone scintigraphy. There was a significant increase in the number of spinal lesions detected after the addition of SPEeT. It was concluded that although the use of SPEeT is ideal, acceptable results could be achieved using planar imaging alone in this patient population. This is particularly relevant in the African context, where SPEeT is often unavailable or scarce and in great demand. / AFRIKAANSE OPSOMMING: Planare beenflikkergrafie is hoogs sensitief, maar moontlik nie sensitief genoeg om subtiele letsels in ingewikkelde beenstrukture soos die werwelkolom aan te toon nie. Akkurate anatomiese lokalisasie van letsels in die genoemde strukture is beperk wanneer slegs planare beelde gebruik word. Enkelfoton-uitstraling Rekenaartomografie (EFERT) lewer 'n hoër letsel kontras, wat 'n verbeterde sensitiwiteit vir die opsporing van subtiele letsels tot gevolg het. EFERT lei ook tot verbeterde letsel lokalisasie, wat dikwels van waarde is om onderskeid tussen benigne en maligne siekte in die werwelkolom te tref. Reeds met 'n aantal vorige studies is aangetoon dat die toevoeging van EFERT van die werwelkolom die waarde van beenflikkergrafie in die opsporing van beenmetastases beduidend verhoog bo dié van planare beelding alleenlik. Hierdie studies is egter nie in omstandighede eie aan Afrika gedoen nie, waar pasiënte kenmerkend met gevorderde siekte voordoen. In In terugskouende studie van 576 pasiënte met bekende primêre tumore, wat na ons instelling verwys is vir beenflikkergrafie om beenmetastases op te spoor, het ons 119 pasiënte, wat beide planare beelding en EFERT ondergaan het, ge-evalueer. Die studies is gegradeer volgens die waarskynlikheid vir metastatiese siekte, en die hoeveelheid werwelkolom letsels, met en sonder EFERT, is bepaal. Die invloed van EFERT op die vertolking van die studie is bepaal in terme van die waarskynlikheid van metastatiese siekte, die bevestiging en uitskakeling daarvan, die beslistheid van vertolking, en die hoeveelheid werwelkolom letsels. Die toevoeging van EFERT het tot 'n statisties beduidende verandering in die vertolking van studies gelei, alhoewel die werklike getal pasiënte wat hierdeur geraak is, relatief min was. EFERT het 'n meer besliste vertolking van beenflikkergrafie tot gevolg gehad. Daar was 'n beduidende toename in die hoeveelheid werwelkolom letsels wat opgespoor is na die toevoeging van EFERT. Daar is tot die slotsom gekom dat, alhoewel die gebruik van EFERT wenslik is, aanvaarbare resultate met slegs die gebruik van planare beelding in hierdie pasiënt bevolkingsgroep verkry kan word. Dit is veral van belang in Afrikaomstandighede, waar EFERT dikwels onbeskikbaar of skaars is, en ook in groot aanvraag is.

<p>Targeted radiotherapy (TRT) of cancer is a promising approach that enables selective treatment of tumour cells, while sparing normal tissue. The humanized monoclonal antibody A33 (huA33) is a potential targeting agent for TRT of colorectal cancer, since its antigen is expressed in more than 95 % of all colorectal carcinomas. The aim of this thesis was to evaluate the therapeutic potential of the two huA33-based TRT-conjugates, ¹⁷⁷Lu-huA33, and ²¹¹At-huA33.</p><p>The conjugates ¹⁷⁷Lu-huA33, and ²¹¹At-huA33, bound specifically to colorectal cancer cells, both <i>in vitro</i> and <i>in vivo</i>. A dose dependent cytotoxic effect of ²¹¹At-huA33 was also demonstrated <i>in vitro</i>. From a therapeutic perspective, both conjugates had a favourable biodistribution in tumour-bearing nude mice, with high tumour uptake and a low uptake in normal organs (with the exception of an expected thyroid uptake of ²¹¹At). After injection of ²¹¹At-huA33, the blood absorbed a slightly higher dose than the tumour, but for ¹⁷⁷Lu-huA33, the tumour received a 12 times higher dose than blood. Two days after intravenous injection of ¹⁷⁷Lu-huA33 in tumour-bearing mice, the tumours could be clearly visualised by gamma camera imaging, with very low interference from normal tissue radioactivity. In an experimental therapy study, also performed in tumour-bearing mice, there was an excellent therapeutic effect of ¹⁷⁷Lu-huA33. About 50 % of the treated animals were tumour free 140 days after injection of ¹⁷⁷Lu-huA33, while none of the non-radioactive controls survived beyond 20 days after injection of treatment substances.</p><p>In conclusion, this thesis demonstrates that the therapeutic conjugates ¹⁷⁷Lu-huA33, and ²¹¹At-huA33, are promising targeting agents that might help improve therapy of colorectal cancer.</p>

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Global sea levels are expected to rise as a result of climate change, which will lead to the inundation and erosion of low lying coastal areas and accelerate the intrusion of seawater into sub-surface sediments. Many of the UK’s legacy nuclear facilities are located in close proximity to the shore, raising questions regarding the potential mobilisation of radionuclides during sea level rise. Here batch and column experiments were used to simulate and investigate the effect of these processes on the mobilisation of key radionuclides Tc, 90Sr and U from oxic and reduced sediments under sea level rise scenarios. Strontium-90 was rapidly mobilised from exchangeable surface sites from oxic sediments during inundation and erosion scenarios with seawater (≈ 60%). Strontium release was driven by ion exchange between Sr90 and Mg2+ cations present in high concentrations in seawater. Uranium release from oxic and reduced sediments was kinetically controlled, characterised by slow release from a range of binding sites, promoted by the formation of U-carbonate complexes. Uranium mobilisation was slower from reduced sediments compared with oxic sediments under seawater flow conditions; therefore reduced sediments would act as a longer term source of U to marine environments. Release was more extensive from initially nitrate reducing sediments (53%) compared with extensively iron reducing sediments (38%), with the difference in release explained by the longer contact period of U(VI) with the iron reducing sediment relative to the nitrate reducing sediment which would lead to slower desorption. Additionally, U(IV) species would be released more slowly than U(VI) species sorbed to the sediments. The release of Tc was dependent on sediment re-oxidation coupled with the oxidation of Tc(IV) to Tc(VII). Batch experiments showed that only a small proportion of Tc was rapidly (within 5 days) released from the sediments into seawater and groundwater which suggests that the majority of any Tc(IV) contamination will be released slowly as the seawater plume migrates through the sediments. Technetium release was slowest, and ultimately limited to the greatest extent (17%), in initially Fe-reducing sediments, when they were re-oxidised in seawater. Thus the cycling of iron and the impact of the water chemistry on iron mineralogy were important for hindering Tc release. Column experiments showed that iron minerals were less effective at retarding Tc release under flow-through conditions. Kinetically controlled and solubility limited Fe dissolution led to on-going Tc release from the sediments, i.e. the retarding effect of iron phases was temporary and significantly more Tc was mobilised (79-93%) compared with the batch experiments (17-45%). This study has shown for the first time that radionuclides will be released from reduced and oxic sediments as a result of future sea level rise. Contaminated sediments have the potential to act as a secondary source of radionuclide contamination entering the marine environment from coastal nuclear sites. This information is essential when siting new nuclear facilities and when developing effective remediation, decommissioning and management strategies for legacy coastal sites.

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