Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Background: The assignment of radiation weighting factors to high energy neutron sources is important as there is reason to believe that neutron relative biological effectiveness (RBE) may be related to the inherent radiosensitivity of different individuals. A study was undertaken to quantify the inherent radiosensitivities of lymphocytes obtained from different donors to 60Co y-rays and p(66)/Be neutrons. For this a novel semi-automated image analysis process has been employed. In addition the responses of lymphocytes with different inherent radiosensitivities have also been tested using Auger electrons emitted by 123I. Methods: The RBE of neutrons was determined from dose-response curves for lymphocytes from different donors. Isolated T-lymphocytes irradiated in vitro were cultured to induce micronuclei in binucleated cells and micronuclei (MN) formations numerated using a semi-automated Metafer microscope system. The accuracy in obtaining dose response curves with this method has been tested by evaluating dispersion parameters of MN formations in the response to the different treatment modalities. Differences in the inherent radiosensitivities of cells from different donors were ascertained using 95 % confidence ellipses. [123I]Iododeoxyuridine was prepared in a formulation that allows incorporation of 123I into the DNA of lymphocytes. Micronucleus formations to this treatment were evaluated in lymphocytes with established differences in inherent radiosensitivities. Results: The image analysis system proved to be consistent in detecting micronuclei frequencies in binucleated lymphocytes. As a result, differences in the inherent radiosensitivities of different individuals were distinctive and could be stated at the 95% confidence level. The inter-individual radiosensitivity variations were considerably smaller for blood cells exposed to high energy neutrons compared to 60Co y-rays. Relative biological effectiveness (RBEM) values between 2 and 13 were determined that are highly correlated with the inherent radioresistance of lymphocytes obtained from different individuals. As such radiation weighting factors for high energy neutrons cannot be based on cytogenetic damage determined in lymphocytes from a single donor. Dispersion parameters for micronuclei formations proved to vary according to ionization density. The variation in RBE with neutron dose changed according to theoretical considerations and automated image analysis detection of MN is thus a suitable method to quantify radiation weighting factors. A clear reduction in the variation in radiosensitivity is noted for lymphocytes exposed to Auger electrons compared to 60Co y-rays. The effectiveness of Auger electrons from [123I]IUdR to induce biological damage is demonstrated as the number of disintegrations needed to yield micronuclei formations was found to be more than two orders of magnitude less than that of other compounds. An increase in the RBE of Auger electrons with radioresistance can be inferred from these findings and constitutes a basis for therapeutic gain in treating cells compared to using radioisotopes emitting low-LET radiation. / AFRIKAANSE OPSOMMING: Agtergrond: Die bepaling van straling gewigsfaktore vir hoë energie neutron bronne is belangrik, aangesien daar rede is om te glo dat die relatiewe biologiese effektiwiteit (RBE) kan verband hou met die inherente stralings sensitiwiteit van verskillende individue. Hierdie studie is onderneem om die inherente radiosensitiwiteit van limfosiete verkry vanaf verskillende skenkers te kwantifiseer na blootstelling aan 60Co y -strale en p(66)/Be neutrone. Vir hierdie doel is daar van 'n semi-outomatiese beeldontleding metode gebruik gemaak. Daarbenewens is die reaksie van limfosiete met vooraf bepaalde inherente radiosensitiwiteite ook getoets aan die hand van Auger elektrone wat uitgestraal word deur 123I. Metodiek: Die RBE van neutrone was bepaal uit dosis mikrokerne frekwensie verwantskappe verkry vir limfosiete. Geïsoleerde T-limfosiete was in vitro bestraal en gekweek om mikrokerne te vorm in dubbelkernige selle. Die mikrokerne was gekwantifiseer deur die gebruik van 'n semi-outomatiese Metafer mikroskoop stelsel. Die akkuraatheid in die verkryging van dosis-effek krommes met hierdie metode is getoets deur die ontleding van verspreidings parameters van MN vorming in reaksie op behandeling met die verskillende stralings modaliteite. Verskille in die inherente stralingsensitiwiteite van die selle van verskillende skenkers was vasgestel deur die konstruksie van 95 % betroubaarheidsinterval ellipse. [123I]Iododeoxyuridine was ook berei om 123I in die DNA van limfosiete in te bou. Die mikrokerne vorming op die behandeling is beoordeel in limfosiete met gevestigde verskille in inherent radiosensitiwiteite. Resultate: Die beeld analise stelsel bewys om konsekwent te wees in die opsporing van mikrokerne wat vorm in dubbelkernige limfosiete. Verskille in die inherente radiosensitiwiteite van verskillende skenkers kon vasgestel word op die 95 % betroubaarheidsvlak. Die skommeling in inter-individuele stralings sensitiwiteite was kleiner vir bloed selle blootgestel aan hoë-energie neutrone in vergelyking met 60Co y-strale. Relatiewe biologiese effektiwiteit (RBEM) waardes tussen 2 en 13 is bepaal wat sterk verband hou met die inherente radioweerstandbiedendheid van limfosiete verkry vanaf verskillende persone. As sodanig kan straling gewigsfaktore vir hoë energie neutrone nie gebaseer word op sitogenetiese skade in limfosiete van 'n enkele skenker nie. Verspreidings parameters vir mikrokern vorming het gewissel as ‘n funksie van ionisasiedigtheid van die straling. Die verandering in RBE met neutron dosis verloop volgens teoretiese oorwegings en die semi-outomatiese beeldontledings metode om mikrokerne op te spoor is dus geskik om stralings gewigsfaktore te kwantifiseer. 'n Duidelike afname in die verandering in die stralingsensitiwiteite is waargeneem vir limfosiete blootgestel aan Auger elektrone in vergelyking met 60Co y-strale. Die hoë doeltreffendheid van Auger elektrone afkomstig van [123I]IUdR om biologiese skade te veroorsaak, word weerspieël deur die feit dat die getal disintegrasies wat nodig is om mikrokerne te vorm meer as twee ordes grootte minder is as dié van ander verbindings. 'n Toename in die RBE van Auger elektrone in selle wat radioweerstandbiedend is kan afgelei word uit hierdie bevindinge. Dit vorm 'n basis vir terapeutiese wins in die behandeling van selle in vergelyking met die gebruik van radio-isotope wat lae ionisasie digthede tot stand bring.

Thesis (MMed)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Background: Hybrid imaging using single photon emission computed tomography/low dose (x-ray) computed tomography (SPECT/LDCT) is of benefit in preoperative scintigraphy of primary hyperparathyroidism. The role of SPECT/LDCT in preoperative assessment of renal hyperparathyroidism has not yet been examined. The aim of the study was to determine whether SPECT/LDCT conferred any benefit over SPECT alone in terms of detection and/or localization of hyperfunctioning parathyroid tissue in this patient group. Methods: A retrospective study of patients with renal hyperparathyroidism and positive planar and SPECT scintigraphy was undertaken. All patients underwent planar scintigraphy using 99mTc-pertechnetate immediately followed by 99mTc-sestamibi as well as SPECT/LDCT 60 min after sestamibi injection and a delayed static image to assess for differential washout at 2-3 hours. Planar subtraction images were generated. For each patient, two nuclear physicians reported on planar+ SPECT images followed by planar + SPECT/LDCT images (assisted by a radiologist). Confidence for the presence of hyperfunctioning parathyroid tissue as well as confidence of location was scored on a Likert-type scale. Interpretation of planar + SPECT was compared with interpretation of planar + SPECT/LDCT. The impact of LDCT on equivocal lesions and number of ectopic lesions detected was also assessed. Results: Twenty patients (M:13; F:7) imaged between February 2008 and June 2011 were included [mean age: 40 years (24 – 55)]. Mean creatinine was 687 μmol/l (169-1213), mean corrected calcium: 2.55 mmol/l (1.95-3.33) and median PTH 167 pmol/l (2.4 - >201). Thirty-five lesions were detected on planar and SPECT and this was unchanged after assessment of the LDCT data. Confidence for the presence of parathyroid pathology changed in 5 patients (5 lesions) with the addition of LDCT. LDCT changed the mean confidence of parathyroid pathology from 3.17 to 3.29 (p=0.16). Addition of LDCT reduced the number of equivocal lesions from 18 (14 patients) to 14 (10 patients) (p=0.13). The addition of LDCT changed localization in 4 lesions (3 patients). Confidence in localization of pathology changed in 9 lesions (7 patients) and the mean localization confidence score was improved from 4.2 to 4.46 (p=0.002) with LDCT. The number of lesions classified as ectopic increased from 5 (on planar+SPECT) to 8 (with addition of LDCT) (p=0.25). Conclusion: In renal hyperparathyroidism SPECT/LDCT altered localization of lesions detected on planar and SPECT alone and improved reader confidence of localization accuracy. SPECT/LDCT conferred no additional benefit over SPECT in terms of detection, confidence of parathyroid pathology or ability to distinguish equivocal from non-equivocal parathyroid lesions. The addition of LDCT did not detect significantly more ectopic lesions. Whereas the minor improvement in reader confidence of localization (with addition of LDCT) was of questionable clinical significance, we speculate that the changed and presumably improved localization of lesions on SPECT/LDCT had potential clinical impact in a significant proportion of patients. On this basis we recommend the use of hybrid SPECT/LDCT in imaging of renal hyperparathyroidism when surgery is considered. / AFRIKAANSE OPSOMMING: Agtergrond: Hibriedbeelding met enkelfoton emissie rekenaartomografie / lae dosis rekenaartomografie (EFERT/LDRT) is voordelig in pre-operatiewe beelding van primêre hiperparatiroïedisme. Die rol van EFERT/RT in pre-operatiewe evaluering van renale hiperparatiroïedisme is nog nie ondersoek nie. Die doel van hierdie studie was om in hierdie pasiëntgroep te bepaal of EFERT/RT 'n voordeel bo EFERT alleen verleen. Metode: 'n Retrospektiewe studie van pasiënte met renale hiperparatiroïedisme en positiewe planare en EFERT flikkergrafie is onderneem. Na die toediening van 99mTc-pertegnetaat is planare beelding op alle pasiënte gedoen, onmiddellik gevolg deur 99mTc-sestamibi sowel as EFERT/RT beelding 60 min na sestamibi inspuiting en 'n laat statiese beeld vir differensiële uitwas op 2-3 uur. Planare subtraksiebeelde is verkry. Twee kerngeneeskundiges het die planare + EFERT beelde van elke pasiënt gerapporteer, waarna die planare + EFERT/RT beelde met die hulp van 'n radioloog gerapporteer is. Sekerheid oor die teenwoordigheid van hiperfunksionerende paratiroïedweefsel sowel as die sekerheid oor die lokalisering daarvan, is op 'n Likert-tipe skaal verkry. Interpretasie van planare + EFERT is vergelyk met die interpretasie van planare + EFERT/RT. Die impak van LDRT op twyfelagtige letsels en die aantal ektopiese letsels waargeneem, is ook bepaal. Resultate: Twintig pasiënte (M:13; F:7) met beelding tussen Februarie 2008 en Junie 2011 is ingesluit [gemiddelde ouderdom: 40 jaar (24-55)] . Die gemiddelde kreatinien was 687 μmol/l (169-1213), gemiddelde gekorrigeerde kalsium 2.55 mmol/l (1.95-3.33) en mediaan PTH 167 pmol/l (2.4->201). Vyf en dertig letsels is op planare en EFERT beelde waargeneem en was onveranderd na assessering van die LDRT-data. Sekerheid oor die teenwoordigheid van paratiroïedpatologie het verander in 5 pasiënte (5 letsels) met die toevoeging van LDRT. LDRT het die gemiddelde sekerheid van paratiroïedpatologie van 3.17 tot 3.29 verander (p = 0.16). Toevoeging van LDRT het die aantal twyfelagtige letsels van 18 (14 pasiënte) tot 14 (10 pasiënte) verminder (p = 0.13). Die byvoeging van LDRT het die lokalisering in 4 letsels (3 pasiënte) verander. Sekerheid oor die lokalisering van patologie is in 9 letsels (7 pasiënte) verander en die gemiddelde lokalisering betroubaarheidswaarde is verbeter van 4.2 tot 4.46 (p = 0.002) met LDRT. Met die byvoeging van LDRT het die aantal letsels geklassifiseer as ektopies van 5 tot 8 (p = 0.25) toegeneem. Gevolgtrekking: In renale hiperparatiroïedisme het EFERT/RT die lokalisering van letsels wat op planare + EFERT beelding alleen waargeneem is, verander en die leser se vertroue om akkuraat te lokaliseer verbeter. EFERT/LDRT het geen bykomende voordeel bo EFERT in terme van die opsporing, sekerheid van paratiroïedpatologie of onderskeidingsvermoë tussen twyfelagtige teenoor nie-twyfelagtige paratiroïedletsels verleen nie. Met die byvoeging van LDRT is nie beduidend meer ektopiese letsels gevind nie. Terwyl die geringe verbetering in die sekerheid van lokalisering (met die byvoeging van LDRT) van twyfelagtige kliniese betekenis was, spekuleer ons dat die verandering en vermoedelik verbeterde lokalisering van letsels op EFERT/LDRT ʼn potensiële kliniese impak het in 'n beduidende aantal pasiënte. Die gebruik van EFERT/LDRT in die beelding van renale hiperparatiroïedisme wanneer chirurgie oorweeg word, word dus vir bogenoemde rede aanbeveel.

Thesis (MScMedSc)--Stellenbosch University, 2010. / ENGLISH ABSTRACT: Radiolabelled compounds have been widely used as investigative tools for psychiatric disorders using positron emission tomography (PET) or single photon emission tomography (SPECT) of the brain. In particular 123I-5-IR91150, a serotonin (5-HT) 2a antagonist, has been used for imaging the serotonergic system. The current study developed optimal radiolabelling and purification methods in our laboratory with the objective that it can provide 123I- 5-I-R91150 in sufficient quantity and of acceptable pharmaceutical quality for human use. Unlabelled R91150 was obtained from Janssen Pharmaceutica (Beerse, Belgium). Carrier free [123I]Iodine was produced by iThemba LABS, South Africa, via the 127I(p,5n)123Xe-123I reaction, providing Na[123I] in 0.05 N sodium hydroxide with a specific activity of 4000-6000 MBq/ml. A direct electrophilic radioiodination method of labelling was used in this study for labelling 123-I-5-IR91150 in glacial acetic acid. After radiolabelling, the product was purified using two different methods, namely a high performance liquid chromatography (HPLC) purification method and a solid phase extraction (SPE) method. The analyses of the purified product for both methods were done using HPLC. Methods were tested to reduce the volume of the purified product using C8 or C18 solid phase extraction cartridges. The average labelling efficiencies for SPE and HPLC purification methods were 76% ± 13.6% and 52% ± 11.2% respectively. The yields of 123I-5-I-R91150 were about 80%. Sep-Pak C8 and C18 were both unable to concentrate the HPLC purified product. Products from both purification methods were sterile and pyrogen free. Both SPE and HPLC purification methods have been shown to provide products meeting most criteria set for this study. However, both methods have advantages and disadvantages. The SPE purification method provided higher labelling efficiency and a much lower product volume. The stability of this product is however of concern as some free iodide was detected. If this purification method is used, the product should therefore be administered as soon as possible after completion of analysis. After HPLC purification, the undiluted product remained stable up to 4.15 hours after production but the product volume was relatively high, and purification time-consuming. In order to obtain a useful patient dose, labelling would have to start with at least 740 MBq 123I and the labelled product should be collected in fractions of 5 ml or less in order to obtain a fraction of sufficiently high specific activity. It was concluded that radiolabeling R91150 is possible at our institution, but that an improved HPLC system would be of value for routine production of a pure and safe product. / AFRIKAANSE OPSOMMING: Radioaktief gemerkte verbindings word baie gebruik as ondersoekmiddel vir psigiatriese afwykings met behulp van positron emissive tomografie (PET) of enkelfoton emissie tomografie (SPECT) van die brein. Die verbinding 123I-5-IR91150, ‘n serotonien (5-HT) 2a antagonis, is beskryf vir beelding van die serotonerge sisteem. Die huidige studie het ondersoek ingestel na optimale metodes vir radioaktiewe merking en suiwering vir ons laboratorium met die doel om 123I-5-I-R91150 in genoegsame hoeveelhed en van aanvaarbare farmaseutiese gehalte geskik vir menslike gebruik te verskaf. R91150 is van Janssen Pharmaceutica (Beerse, België) verkry. Draervry [123I]jodium is deur iThemba LABS, Suid-Afrika, via die 127I(p,5n)123Xe-123I reaksie geproduseer, om Na[123I] in 0.05 N natriumhidroksied met spesifieke aktiwiteit van 4000-6000 MBq/ml te lewer. ‘n Direkte elektrofiliese radioiodineringsmetode is in hierdie studie gebruik om 123-I-5-I-R91150 in ysasynsuur te merk. Na radioaktiewe merking is die radioaktiewe produk deur twee verskillende metodes gesuiwer, naamlik ‘n HPLC metode en ‘n soliede fase ekstraksie (SPE) metode. Vir beide metodes is die produk deur middel van HPLC analiseer. Metodes is getoets om die volume van die gemerkte produk met C8 of C18 SPE kolommetjies te verminder. Die gemiddelde bindingsdoeltreffendheid vir die SPE en HPLC suiweringsmetodes was 76% ± 13.6% en 52% ± 11.2% onderskeidelik. Die opbrengs van 123I-5-I-R91150 was ongeveer 80%. Sep-Pak C8 en C18 kon beide nie gebruik word om die HPLC gesuiwerde produk te konsentreer nie. Produkte van beide suiweringsmetodes was steriel en pirogeenvry. Daar is getoon dat beide suiweringsmetodes produkte lewer wat aan die meeste kriteria wat in hierdie studie gestel is, voldoen. Beide metodes het egter voor- en nadele. Die SPE suiweringsmetdode het tot hoër bindingsdoeltreffendheid gelei, asook ‘n baie laer produkvolume. Daar is egter ‘n mate van kommer oor die stabiliteit van die produk aangesien vry radiojodied waargeneem is. Indien hierdie suiweringsmetode gebruik word, moet die produk dus so gou as moontlik na voltooiing van analise toegedien word. Na HPLC suiwering was die onverdunde produk tot 4.15 uur na produksie stabiel maar die produkvolume was relatief hoog en suiwering tydrowend. Om ‘n bruikbare pasiëntdosis te verkry moet merking met ten minste 740 MBq 123I begin en die gemerkte produk moet na suiwering in fraksies van 5 ml of minder versamel word om ‘n fraksie met geskikte spesifieke aktiwiteit te verkry. Die gevolgtrekking is gemaak dat radioaktiewe merking van R91150 by ons instelling moontlik is, maar dat ‘n verbeterde HPLC sisteem vir roetineproduksie van ‘n suiwer en veilige produk van waarde sou wees.

Thesis (MSc (Medical Imaging and Clinical Oncology. Nuclear Medicine))--University of Stellenbosch, 2010. / ENGLISH SUMMARY: Introduction: Bone scintigraphy is used extensively in evaluating metastatic disease. There are currently no clear recommendations for the use of SPECT/CT in metastatic bone disease. Existing procedural guidelines from the Society of Nuclear Medicine (SNM) for SPECT/CT do not provide specific indications for use of SPECT/CT in bone scintigraphy, and there are currently no other guidelines for the use of SPECT/CT in bone scintigraphy that the author is aware of. The aim of this study was to investigate the additional value of SPECT/CT, and to identify the clinical indications for which SPECT/CT is most useful in patients with suspected bone metastases. Subjects and Methods: Forty-two patients with equivocal lesions on planar scintigraphy were prospectively recruited and planar imaging, SPECT, and SPECT/CT done on all patients. On reading of SPECT and then SPECT/CT, patients and individual lesions were classified as malignant, benign or equivocal. Radiological studies and available clinical information were also used during reading of scans. Review of clinical information, radiological studies and/or follow-up bone scans were used as gold standard. The results of the SPECT and SPECT/CT were compared in terms of proportion of equivocal findings and accuracy. Results: Forty-two patients with 189 skeletal lesions were examined. There was a diverse variety of primary tumours, although the majority had breast (n=22) or prostate cancer (n=8). Overall, SPECT/CT resulted in a significant reduction in the proportion of equivocal findings on both a patient-wise (p=0.0015) and lesion-wise basis (p<0.0001). The overall accuracy of SPECT/CT was significantly higher than that of SPECT on both a patient-wise (p=0.0026) and lesion-wise basis (p<0.0001). Generally SPECT/CT decreased the proportion of equivocal findings and increased the accuracy independent of the presence of bone pain, type of primary tumour, or skeletal region involved. SPECT/CT did not significantly improve the diagnostic confidence of readers in equivocal lumbar lesions although accuracy was significantly improved in this region. Conclusion: SPECT/CT performs significantly better than SPECT alone for the interpretation of equivocal planar lesions. There is no evidence that the benefit of SPECT/CT is dependent on the type of primary tumour or the presence of bone pain. Where resources are limited, SPECT/CT is indicated only in those patients in whom correct classification of the lesions in question is expected to alter the patient’s management. SPECT/CT images should be interpreted with the aid of a diagnostic radiologist or nuclear medicine physicians should acquire sufficient experience in Computed Tomographic image interpretation in order to optimise diagnostic benefit from SPECT/CT. / AFRIKAANSE OPSOMMING: Inleiding: Beenflikkergrafie word wyd vir die evaluering van metastatiese siekte gebruik. Daar bestaan tans geen duidelike aanbevelings vir die gebruik van Enkelfotonemissie rekenaartomografie gekombineer met rekenaartomografie (EFERT/RT, Engels SPECT/CT) in metastatiese beensiekte nie. Bestaande riglyne van die Amerikaanse Society of Nuclear Medicine (SNM) vir EFERT/RT gee nie spesifieke indikasies vir die gebruik van EFERT/RT in beenflikkergrafie nie, en daar is tans geen ander riglyne waarvan die outeur bewus is nie. Die doel van hierdie studie was om die bykomende waarde van EFERT/RT te ondersoek, en om dié kliniese indikasies waar EFERT/RT in pasiënte met vermoedelike beenmetastases mees nuttig sal wees, te identifiseer. Pasiënte en Metodes: Twee en veertig pasiënte met twyfelagtige letsels op planare skeletflikkergrafie is prospektief geselekteer en planare beelding, EFERT en EFERT/RT is op alle pasiënte gedoen. Tydens beoordeling van EFERT en daarna EFERT/RT beelde is pasiënte en individuele letsels as maligne, benigne of twyfelagtig geklassifiseer. Radiologiese studies en beskikbare kliniese inligting is ook tydens interpretasie van flikkergramme gebruik. Kliniese inligting, radiologiese studies en/of opvolg beenflikkergramme is as goue standaard gebruik. Die resultate van EFERT en EFERT/RT is ten opsigte van die aantal twyfelagtige bevindings en akkuraatheid vergelyk. Resultate: Twee en veertig pasiënte met 189 skeletale letsels is ondersoek. Daar was ‘n verskeidenheid van primêre tumore, maar die meerderheid van pasiënte het borsvi (n=22) of prostaatkanker (n=8) gehad. Die gebruik van EFERT/RT het gelei tot ‘n betekenisvolle afname in die aantal twyfelagtige bevindings, beide op ‘n pasiënt- en ‘n letselbasis (p=0.0015 en p<0.0001 onderskeidelik). Die algehele akkuraatheid van EFERT/RT was betekenisvol hoër as die van EFERT alleen, beide op pasiënt- en op letselbasis (p=0.0026 en p<0.0001 onderskeidelik). Oor die algemeen het EFERT/RT die aantal twyfelagtige letsels verminder en die akkuraatheid verhoog, ongeag die teenwoordigheid van beenpyn, die tipe primêre tumor of die area van die skelet wat betrokke was. In twyfelagtige lumbale letsels het EFERT/RT nie die diagnostiese vertroue van beoordelaars van flikkergramme verhoog nie, alhoewel die akkuraatheid vir hierdie gebied wel betekenisvol toegeneem het. Gevolgtrekking: EFERT/RT vaar betekenisvol beter as EFERT in die beoordeling van twyfelagtige letsels op planare beenflikkergramme. Daar is geen bewys dat die voordeel van EFERT/RT afhanklik is van die tipe primêre tumor of die teenwoordigheid van beenpyn nie. Waar hulpbronne beperk is, is EFERT/RT slegs aangedui in dié pasiënte waar verwag word dat korrekte klassifikasie van die betrokke letsel behandeling sal beïnvloed. EFERT/RT beelde behoort met die hulp van ‘n diagnostiese radioloog beoordeel te word, of kerngeneeskundiges moet genoegsame ondervinding in die interpretasie van rekenaartomografiebeelde hê om die diagnostiese voordeel van EFERT/RT optimaal te kan benut.