Introduction: Breast carcinoma is the most common malignancy amongst women in South Africa. Triple assessment has been pivotal in the work up and management of breast carcinoma. Breast cytology has been used as a component of the triple assessment. Although core needle biopsy (CNB) is the gold standard and the preferred diagnostic modality, there is still a role for fine needle aspirate cytology (FNAC) in resource limited settings. The present study was conducted at Groote Schuur Hospital in Cape Town, South Africa. Aims: 1. To assess the utility of the International Academy of Cytology (IAC) Yokohama System for Reporting Breast FNAC five category stratifications in our institution. 2. To assess the respective risk of malignancy (ROM) for each category. 3. To assess the diagnostic yield of the breast FNAB at our institution by comparing it to the matched histopathology over a 12-month period. Methodology: A retrospective longitudinal descriptive study was done. A computerized search on TrakCare NHLS for the year 2019, identified 884 patients who had breast cytology and corresponding histology specimens. The cytology categories(C1-C5) were first reclassified according to the IAC Yokohama system. The new cytology category was then compared to the histological diagnosis for each patient. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and risk of malignancy (ROM) were calculated. Results: The sensitivity, specificity, PPV, and NPV were 83.10%, 93.01%, 88.86% and 89.13% respectively. The Cohen's kappa coefficient was 0.659 and percentage agreement was 80.85%. The ROM was calculated; insufficient (9.09%), benign (4.46%), atypia (45.28%), suspicious for malignancy (72.5%) and malignant (91,09%). Conclusion: Breast aspiration cytology performed at GSH has shown good correlation with histopathology as well a high sensitivity and specificity comparable to international standards. The ROM is comparable to previous similar studies. Overall, our results show that breast aspiration cytology is a rapid, accurate and cost-effective diagnostic procedure in our institution that is very useful in the diagnosis of benign and malignant breast lesions.

Includes bibliographical references (leaves 180-211).

Introduction: Juvenile pilocytic astrocytomas are one of the most frequent central nervous system tumours occurring in children. While they are classified as WHO Grade I tumours, their natural progression is difficult to predict with some patients suffering significant morbidity and mortality despite showing similar light microscopic features. Activation of the MAPK pathway of cell proliferation is a consistent finding in these tumours. Studies of these tumours are largely aimed at components of this pathway in an effort to establish reliable prognostic and predictive markers. Aims and objectives: Our study was aimed at reviewing the light microscopic features and also evaluating the BRAF, p16 and protein kinase ERK components of the MAPK pathway. The findings thereof were correlated with the clinical picture to establish if these markers have any prognostic or predictive value. Materials and methods: The total number of cases retrieved was 62. The light microscopic findings were evaluated. The cases were analysed for overexpression of BRAF by fluorescence in-situ hybridisation and p16 and pERK by immunohistochemistry. Our findings were considered statistically significant if P < 0.05. Results: There were no specific light microscopic findings present in those cases associated with disease progression and recurrence. BRAF overexpression was associated with better clinical outcomes (P=0.03). There was no statistically significant correlation between p16 and pERK expression and patient outcomes. Conclusion: Overexpression of BRAF in juvenile pilocytic astrocytomas is associated with better clinical outcomes. BRAF may still serve as a therapeutic target and reduce risks associated with surgery, especially in tumours that are not surgically accessible. Further evaluation of p16, pERK and other components of the MAPK pathway of cellular proliferation will undoubtedly be useful in identifying therapeutic targets for those patients who experience disease recurrence and progression.

Introduction: Differentiating follicular adenoma (FA), follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC) remain a diagnostic challenge in some cases. This is as a result of the assessment of nuclear features being highly subjective, and the threshold for confirming cytomorphological features for papillary thyroid carcinoma varying greatly among pathologists which results in poor interobserver agreement. Diagnostic challenges may be encountered with some encapsulated follicular-patterned neoplasms of the thyroid due to uncertainty about the presence of capsular or vascular invasion. Immunohistochemistry may provide a better alternative to distinguishing these entities. Aims and objectives: To study the expression of biomarkers HBME-1, CD15, CK-19 and BRAF V600E in follicular adenoma, follicular carcinoma and follicular variant of papillary thyroid carcinoma. To ascertain the usefulness of these markers in differentiating these follicular-patterned thyroid neoplasms. Materials and methods: This is a ten-year retrospective study in which seventy-nine cases consisting of follicular adenoma (n=26), follicular thyroid carcinoma (n=25) and follicular variant of papillary thyroid carcinoma (n=28) were retrieved and reviewed. Four immunohistochemical stains (CD15, CK-19, HBME-1 and BRAF V600E) were performed and scored in tumour tissue. Data were analysed to determine if there was any correlation between the expression of the immunomarkers and the three follicular patterned thyroid neoplasms. Results: The patients' ages ranged from 13 to 74 years. There was a female bias with a female-to-male ratio of 4:1. HBME-1 expression showing varying intensity and proportion was seen in 7 (28%) FA, 15 (65%) FTC and 22 (79%) FVPTC. CK-19 expression showing varying intensity and proportion was seen in 5 (19%) FA, 3 (13%) FTC and 18 (72%) FVPTC. BRAF V600E expression showing varying intensities and proportions was seen in 3 (11%) of FVPTC. FA and FTC cases were all negative for BRAF V600E. CD15 expression showing varying intensity and proportion was seen in 2 (8%) FA, 6 (24%) FTC and 9 (33%) FVPTC. Statistical analysis detected a significant association between group and HBME-1 and CK-19 (H-score, proportion and intensity). The post-hoc comparison revealed that follicular adenoma was significantly more likely to have negative HBME-1 staining and a lower H-score when compared to follicular thyroid carcinoma and follicular variant of papillary thyroid carcinoma. The follicular variant of papillary thyroid carcinoma was significantly more likely to have an HBME-1 intensity of three and a higher H-score compared to follicular adenoma. Post-hoc comparison revealed that follicular adenoma was significantly more likely to have a negative CK-19 and a lower H-score when compared to follicular thyroid carcinoma and follicular variant of papillary thyroid carcinoma. Follicular variant of papillary thyroid carcinoma was significantly more likely to have a CK-19 intensity of three and a higher H-score compared to follicular thyroid carcinoma. HBME-1 had an overall specificity and sensitivity of 72% and 74% for distinguishing FA from FTC and FVPTC (benign from malignant). CK-19 had an overall specificity and sensitivity of 80.8% and 43.8% for distinguishing FA from FTC and FVPTC (benign from malignant). CK-19 had specificity of 87% and sensitivity of 72% for distinguishing FTC from FVPTC. Combining HBME-1 and CK-19 did not significantly increase the sensitivity and specificity of these markers. There was statistically no significant association between group and BRAF V600E and CD15 biomarkers. Conclusion: The study, within the small sample size power limitations, has shown that CK-19 may have a role in distinguishing follicular thyroid carcinoma from follicular variant of papillary thyroid carcinoma. In addition, HBME-1 and CK-19 may be used in differentiating benign follicular-patterned thyroid lesions from malignant follicular patterned thyroid lesions.

Background Tuberculosis (TB), especially extrapulmonary TB, is a difficult diagnosis to make in children due to the paucibacillary nature of paediatric disease and difficulty in obtaining sputum and tissue samples for microbiology confirmation. Lymphadenopathy in children with suspected cervicofacial TB are amenable to FNA or surgery for further cytological and histological assessment. It is therefore important to understand how well the morphologic features (from cytology and histology) correlate with defined reference standards (TB culture and molecular evidence of MTb) for the diagnosis of TB and the reliability of these features. Aim The aim of the study is to determine how well the cytology and histology-made TB diagnoses in children with suspected cervicofacial EPTB correlates with TB culture and MTb PCR results. Materials and methods This is a descriptive retrospective study that involved a re-appraisal of all patients with suspected cervicofacial EPTB who had histology and cytology performed at Red Cross Children's Hospital identified from the National Health Laboratory Service (NHLS) Trakcare system over a 5 year period (2012-2017). Following identification of histopathology accession numbers, histopathology reports and slides were retrieved from the archive of the Division of Anatomical Pathology/ National Health Laboratory Service, Red Cross Children's Hospital, Cape Town for evaluation. In addition, results for Genexpert testing and TB culture were identified using the National Health Laboratory Service (NHLS) Trakcare system. In patients that did not have either of the above, MTb PCR testing was performed. Results Data from the reports of 76 children with suspected cervicofacial TB were included in this study. More biopsies were submitted for histology (48) than for cytology (22). Six children had biopsies for both cytology and histology done. Most children had suspected and confirmed TB involvement of the cervical lymph nodes. On histology, the feature that correlated the best with proven TB was necrotising granulomatous inflammation (79.5% of cases had confirmed TB). On cytology, necrotising inflammation, necrotising granulomatous and non-necrotising granulomatous inflammation correlated well with proven TB. The sensitivity of cytology was 77.3% against TB culture and 81.8% against GXP for TB diagnosis. Whilst for histology the sensitivity was 82.5% against TB culture and 90.3% against GXP as reference standards for TB diagnosis. Conclusion FNA for cytology is a safer procedure with less complications than biopsy for histology. Also, the use of cytology together with a GXP renders a rapid and accurate diagnosis of TB and our findings are supportive for the combined use of these modalities as first line investigations. However, every attempt should still be made to obtain a sample for TB culture (as the WHO recommended gold standard for TB confirmation).

Thesis (PhD (Pathology. Anatgomical Pathology))--University of Stellenbosch, 2005. / The formation of granulomas at the site of antigen presentation in both tuberculosis and sarcoidosis is an essential component of host immunity for controlling inflammation. Granuloma formation is a complex process that also requires recruitment and activation of lymphocytes and macrophages to the site of infection and arrangement into a granuloma. It is dependant on the activation of especially IFNγ secreting CD4+ T cells, resulting in a Th1 profile. However, it is suggested that a persistently high IFNγ is responsible for the damage caused by granulomatous disease and that moderating cytokines, resulting in a Th0 profile, are necessary to down-regulate the IFNγ response to more appropriate levels later in the disease process, after the antigen has been effectively contained. I propose that: “Cytokine profiles determine clinical and histopathological phenotypes of disease. This thesis tests the hypothesis that it will be reflected by cytokine expression profiles in granulomas in different forms of tuberculosis and in sarcoidosis.” To examine this, biopsy tissue was obtained from patients with pulmonary cavitary tuberculosis, pleural tuberculosis in HIV sero-negative and sero-positive patients, and sarcoidosis. The diagnosis of tuberculosis or sarcoidosis was confirmed, granulomas were characterised as necrotic or non-necrotic, sarcoidosis cases were graded histologically and in situ hybridisation was performed for IL-12-, IFNγ-, TNFα- and IL-4-mRNA. In all patients with pleural tuberculosis, a Th0 profile was noted, while necrotic granulomas were more evident in HIV positive than HIV negative patients. There was a clear association between TNFα and necrosis in tuberculous granulomas that may be ascribed to the increased apoptotic activity of TNFα. An increase in IFNγ correlated with an increase in necrosis, supporting the theory that high IFNγ levels later in disease is detrimental. This effect may be enhanced by a strong presence of TNFα positive cells. An increase in both Th1 and Th2 cytokine mRNA in HIV positive patients supports the theory that an overproduction of cytokines may be a mechanism to compensate for the failure of another immune effector mechanism. Findings in pulmonary tuberculosis were similar to those in pleural tuberculosis. In all sarcoidosis cases the presence of a very strong Th1 and TNFα, but no Th0 response was confirmed. None of the differences in either the histological grading, or the clinical outcome of patients were reflected in the cytokine profile. It is possible that this profile does not reflect the histological grade of disease or that it may reflect various stages of disease. These findings support the theory that a strong Th1 presence later in disease, in conjunction with TNFα may induce fibrosis, as most of these cases showed signs of at least focal fibrosis. Numerous aspects, including a T helper response are involved in granulomatous inflammation. The earlier dogma of good, beneficial (Th1) versus evil, detrimental (Th2), is an oversimplification of a very complex process. It is clear that the effect of a cytokine depends at least partially on the stage of disease. The balance between the various cytokines, and the levels of these cytokines contribute to their role in resolution or disease progression. An early, pure Th1 response may be beneficial if effectively clearing the granuloma-inducing antigen. At this stage, a Th2 presence will be harmful as clearing of the antigen will not be as effective. In chronic disease where failure to remove the antigen results in progression of granulomas with subsequent necrosis and/or fibrosis, a proinflammatory Th1 response may be detrimental and minimising of this effect is needed. An overly strong presence of the various cytokines may also be detrimental, while lower levels will be beneficial.

The main purpose of this study was to assess the value of the autopsy in clinical medicine today. This has been achieved by analysing several variables. Clinical diagnostic accuracy was determined by assessing the concordance/discrepancy of clinical and autopsy diagnoses. In addition, several variables were assessed, namely whether or not the size of the hospital, type of ward, autopsy rate, age of the patient, and degree of confidence with which the clinical diagnosis was made had any bearing on the accuracy of the diagnosis. The impact of the newer diagnostic tests on clinical diagnosis was also assessed to confirm or refute the widely held opinion amongst clinicians that diagnostic advances have indeed reduced the need for autopsies. The attitudes of pathology registrars and consultants towards the autopsy were analysed, using a questionnaire proposed by Stubbs et al.

Thesis (MSc)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: Pre-eclampsia is a condition unique to pregnancy and primarily affects the maternal and placental vascular endothelium. It has significant morbidity and mortality consequences for both mother and infant. Despite global research into the aetiology of the condition, the cause for this condition remains unknown. Several factors, including a strong family history of hypertension in pregnancy point to a familial or genetic component in the pathophysiology of this complication. The purpose of this research project was to investigate candidate genes implicated in endothelial damage. Common methylene-tetra-hydrofolate reductase (MTHFR) gene mutations C677T and A1298C, factor V Leiden mutation R506Q and prothrombin mutation A20210G were investigated in 50 patients with an uncomplicated pregnancy outcome (controls) and 350 patients with various clinical manifestations of preeclampsia, including severe, early onset forms and abruptio placentae. Fasting homocystein levels were determined biochemically on all participants. In addition, 126 consecutive pregnant patients were recruited at booking, fasting lipograms were performed on them as well as mutation screening of 7 common mutations in the low-density lipoprotein receptor gene. This was correlated with eventual pregnancy outcome, and those with an uncomplicated outcome were selected as an additional control group. A significant association between hyperhomocysteinaemia and early onset severe pre-eclampsia could be demonstrated. Mutant allele T of the C677T mutation could be associated with hyperhomocysteinaemia but not with pre-eclampsia whilst mutant allele C of mutation A1298C demonstrated a significant correlation with diastolic blood pressure. In addition, combined heterozygosity for these mutations may serve as a marker for abruptio placentae. / ENGLISH ABSTRACT: Pre-eklampsie is 'n hipertensiewe toestand uniek aan menslike swangerskap en dit affekteer hoofsaaklik die vaskulêre endoteel. Die toestand hou ernstige morbiditeit en mortaliteit vir beide ma en baba in en na jare se navorsing is die oorsaak van hierdie toestand steeds onbekend. Epidemiologiese studies toon 'n duidelike familiële verband aan wat die vermoede laat ontstaan dat daar 'n onderliggende genetiese aspek tot die ontwikkeling van die siektetoestand is. Die doel van hierdie navorsingsprojek was om gene te ondersoek wat geïmpliseer word in endoteel skade. Twee algemene mutasies, C677T en A1298C in die MTHFR geen asook faktor V Leiden R506Q en protrombien A20210G mutasies is ontleed in 50 pasiënte met 'n ongekompliseerde swangerskapsverloop en in 350 pasiënte met 'n swangerskap gekompliseer deur verskillende kliniese manifestasies van die siekteproses, insluitende vroeë aankoms erge pre-eklampsie en abruptio placentae. Op alle pasiënte is ook 'n vastende homosistiën vlak biochemies bepaal. 'n Verdere 126 opeenvolgende pasiënte is gewerf tydens hulle eerste besoek aan die voorgeboortekliniek en vastende lipogramme is op almal uitgevoer. Mutasie sifting vir 7 algemene mutasies in die lae-digtheids lipoproteïen reseptor geen is op hierdie groep gedoen en die resultaat is met die uiteindelike swangerskapsuitkoms gekorreleer. Pasiënte met 'n uitkoms ongekompliseer deur hipertensie is gekies om deel te wees van 'n verdere kontrolegroep. Daar was 'n betekenisvolle verband tussen hiperhomositiënemie en erge, vroeë aankoms pre-eklampsie. Die T alleel van die C677T mutasie is geassosieer met hiperhomosistiënemie maar nie met pre-eklampsie nie. Die C alleel van die A 1298C mutasie toon 'n betekenisvolle verband met diastoliese bloeddruk. Gekombineerde heterosigositeit vir beide MTHFR mutasies kan 'n moontlike merker vir abruptio placentae wees.

Thesis (PhD (Med))--Stellenbosch University, 2011. / ENGLISH ABSTRACT: Background and Objective: The most common cause of severe proteinuria/nephrotic syndrome (NS) in children worldwide is minimal change disease (MCD). This is also the pattern observed in white and Indian children in South Africa (SA). By contrast, black and mixed race/coloured children of Southern Africa in the 1960s to 1990s were shown to have a different pattern of NS. One of the main differences was the frequency of hepatitis B virus (HBV) associated glomerulonephritis, usually membranous glomerulonephritis (MGN). The objective of this project was a clinicopathological study of this subgroup of nephrotic children to document the disease further and in particular to seek correlations between pathological and clinical features including prognosis. A central focus was to document the detailed ultrastructural examination of the renal biopsies of these children and to correlate the spectrum of pathological features with demographic, clinical, laboratory and prognostic features. The hypothesis was that the clinicopathological features of HBV MGN in children differed substantially from idiopathic MGN in general (children and adults) and also from HBV MGN in adults and that HBV MGN in children should be viewed as a distinct disease. Patients and methods: The childhood (12 years and younger) patient cohort was 309 children with severe proteinuria/nephrotic syndrome who presented at Tygerberg Hospital (TBH) over a 21 year period from 1974-1995, including 67 children from Namibia. The study group was 71 children with HBV MGN who were followed up to 2005. The comparative adult group was 45 adults with MGN of whom 12 had HBV MGN and 33 idiopathic MGN. (A comparison could not be made with idiopathic MGN in childhood as this centre only had 2 such patients during the study period.) Demographic, clinical, laboratory and renal pathology data were collected, compared and correlated. Results: HBV associated MGN was the most frequent cause of NS in the Namibian subgroup, 25/67 (37%) and the third most frequent, 71/309 (23%) in the childhood cohort as a whole. The MGN group was 86% (71/83) of the total HBV childhood nephrotic cohort, by far the dominant subgroup. The average age of the 71 children with HBV MGN was 6.0 years (range 2-12 years) at presentation and boys comprised 80% of the group. Hepatitis B envelope antigen (HBeAg) was identified in the serum of 87% of children tested. Laboratory features different from idiopathic MGN included more prominent haematuria, mildly raised serum transaminases and more frequently lowered serum C3 and C4 levels. Light microscopic examination of renal biopsies showed mesangial proliferation in all patients but with minimal glomerular sclerosis and interstitial disease. On ultrastructural examination mesangial and subendothelial deposits were common and prominent as was mesangial interposition. The MGN of HBV in children therefore frequently showed mesangiocapillary glomerulonephritis (MCGN) features in addition to the subepithelial deposits of MGN. The subgroup of 23 whose renal biopsies displayed severe mesangial interposition in addition to the subepithelial deposits of MGN were termed the mixed HBV MGN-mesangiocapillary GN group. Virus like bodies and tubuloreticular inclusion bodies were both found in more than 80% of biopsies of childhood HBV MGN. HBeAg was identified in the subepithelial deposits in the glomeruli. This was the first time this feature was demonstrated in Africa. The 46 South African children with HBV MGN showed a cumulative remission rate of 25% at 2 years and 52% at 4 years. Seven of the children (10%) of the total cohort developed chronic renal failure (CRF). Age of 6 years and above at presentation and severe mesangial deposits on biopsy correlated with fewer remissions and poorer outcome. In 3 patients the interval between the diagnosis of HBV MGN and the onset of CRF was more than 19 years with the longest being 23 years. The 358 cases of childhood HBV MGN from Southern Africa constitute 37% of the reported childhood patients. Comparative data A comparison was made between the 71 children with HBV MGN, 12 adults with HBV MGN and 33 adults with idiopathic MGN. The main differences were that both HBV MGN groups included only coloured and black patients and were more predominantly male while the idiopathic MGN group included all races. In the HBV patients, haematuria was more frequent and severe, liver enzymes were frequently raised and C3 more frequently reduced than in the idiopathic cohort. Both groups of adult MGN patients had normal C4 levels while the childhood HBV MGN group had reduced C4 levels. The immune complex pattern in both of the HBV MGN adult and childhood groups on biopsy was similar with more mesangial and subendothelial deposits as well as mesangial interposition than the idiopathic group. Despite this similarity between the two HBV groups, both adult groups showed more glomerular sclerosis and interstitial disease than the childhood group. The clinical outcome of the children’s cohort was better than the other 2 groups with remission (52%) more frequent at 4 years (p< 0.01) and better renal and patient survival. Including the 83 cases from this series, at least 1243 renal biopsy proven cases of HBV MGN have been reported in the English literature; children (80%) and adults (20%). The male gender predominance in both age groups for HBV MGN is similar (children 79%; adults 84%) and significantly greater than for idiopathic MGN. Conclusions: The findings confirm that HBV MGN in children is a distinct form of GN which broadens the classical morphologic description of MGN by often including a number of mesangiocapillary GN features. The subgroup of renal biopsies with the most severe mesangiocapillary GN features was classified as the mixed HBV MGNmesangiocapillary GN group. The MGN spectrum as a whole comprised 86% of the HBV positive childhood group. HBV MGN was the most frequent association with NS/severe proteinuria in the Namibian subgroup (37%) and the third largest group (19%) in the SA children. It showed a relatively high spontaneous remission rate but at least 10% of the children developed renal failure. Age of 6 years and above at presentation and severe mesangial deposits on biopsy correlated with fewer remissions and poorer outcome. Extended follow up (more than 15 years) was required to demonstrate renal failure in some patients in the poor outcome group. Urbanisation, associated with lower HBV carrier rates, and HBV vaccination (initiated routinely in 1995 in SA), have already lead to a sharply decreasing incidence of this disease in SA. HBV MGN has been a valuable and possibly unique model of human GN and MGN in particular in that the HBeAg has been identified in both the serum and glomeruli enabling confirmation of the aetiological role of HBeAg. / AFRIKAANSE OPSOMMING: Agtergrond en Doelwit: Die algemeenste oorsaak van erge proteïenurie/nefrotiese sindroom (NS) in kinders wêreldwyd is minimale veranderingsiekte. Hierdie patroon kom ook voor in blanke- en Indiër kinders in Suid-Afrika. In teenstelling hiermee is aangetoon dat swart en kleurling/gemengde ras kinders in Suider Afrika tussen die jare 1960s tot 1990s ’n ander patroon van nefrotiese sindroom gehad het. Een van die hoof verskille was die algemene voorkoms van hepatitis B virus (HBV) geassosieerde glomerulonefritis, gewoonlik membraneuse glomerulonefritis (MGN). Die doelwit van hierdie projek was ’n klinies-patologiese studie van hierdie subgroep van nefrotiese kinders ten einde die siekte verder te beskryf en veral om korrelasies te tref tussen patologiese en kliniese kenmerke insluitende prognose. Die gedetaileerde ultrastrukturele ondersoek van die kinders se nierbiopsies en die korrelasie van die spektrum patologiese kenmerke met demografiese, kliniese, laboratorium en prognostiese kenmerke was ‘n sentrale fokusarea. Die hipotese was dat die klinies-patologiese kenmerke van HBV MGN in kinders wesenlik van idiopatiese MGN in die algemeen verskil (in kinders en volwassenes) en ook van HBV MGN in volwassenes, en dat die beeld in kinders as ’n afsonderlike siekte beskou behoort te word. Pasiënte en metodes: Die kinder kohort (12 jaar en jonger) was 309 kinders met erge proteïenurie/nefrotiese sindroom wie in Tygerberg Hospitaal (TBH) behandel was oor ‘n 21 jarige periode vanaf 1974 tot 1995, insluitende 67 kinders van Namibië. Die studiegroep was 71 kinders met HBV MGN wie waar moontlik tot 2005 opgevolg was. Die vergelykende volwasse groep was 45 volwassenes met MGN van wie 12 HBV MGN gehad het en 33 idiopatiese MGN. (’n Vergelyking met idiopatiese MGN in kinders kon nie gedoen word nie omdat hierdie sentrum net twee sulke pasiënte tydens die studietyd behandel het.) Demografiese, kliniese, laboratorium en nierpatologie inligting is versamel, vergelyk en gekorreleer. Resultate: HBV geassosieerde MGN was die algemeenste oorsaak van NS in die Namibiese subgroep, 25/67 (37%) en die derde mees algemeen, 71/309 (23%) in die kinder kohort as geheel. Die MGN groep was 86% (71/83) van die totale HBV kinder nefrotiese kohort en verreweg die oorheersende subgroep. Die gemiddelde ouderdom van die 71 kinders met HBV MGN by presentering was 6.0 jaar (reikwydte 2-12 jaar) en seuns het 80% van die groep behels. Hepatitis B omhullingsantigeen (envelope antigen- HBeAg) is aangetoon in die serum van 87% van die kinders wie daarvoor getoets is. Laboratoriumkenmerke wat van idiopatiese MGN verskil het, het ingesluit meer prominente hematurie, gering verhoogde serum transaminases en meer dikwels verlaagde serum C3 en C4 vlakke. Ligmikroskopiese ondersoek van die nierbiopsies het mesangiale proliferasie in elke pasiënt getoon, maar met minimale glomerulêre sklerose en interstisiële siekte. Met ultrastrukturele ondersoek was mesangiale en subendoteliële neerslae asook mesangiale interposisie algemeen. Die MGN van HBV in kinders het dus dikwels kenmerke van mesangiokapillêre glomerulonefritis getoon bo en behalwe die subepiteliële neerslae van MGN. Die ondergroep van 23 van wie die nierbiopsies erge mesangiale interposisie aangetoon het asook die subepiteliale neerslae van MGN is die gemengde HBV MGN-mesangiokapillêre GN groep genoem. Virustipe liggaampies en tubuloretikulêre insluitingsliggaampies is in meer as 80% van die biopsies bevestig. HBeAg was in die subepiteliële neerslae identifiseer. Dit was die eerste keer dat hierdie kenmerk in Afrika identifiseer is. Die 46 Suid-Afrikaanse kinders het ’n kumulatiewe remissie koers van 25% teen 2 jaar en van 52% teen 4 jaar getoon. Sewe van die kinders (10%) van die hele kohort het kroniese nierversaking (KNV) ontwikkel. Ouderdom van 6 jaar en meer by presentasie en erge mesangiale neerslae in ‘n biopsie het met minder remissies en ’n swakker uitkoms gekorreleer. Drie pasiënte het meer as 19 jaar na aanvanklike voordoening ooglopende KNV ontwikkel, waarvan 23 jaar die langste interval was. Die 358 gevalle van kinderjare HBV MGN van Suidelike-Afrika maak 37% uit van die gerapporteerde kinder pasiënte. Vergelykende data ’n Vergelyking is getref tussen die 71 kinders met HBV MGN, 12 volwassenes met HBV MGN en 33 volwassenes met idiopatiese MGN. Die hoof verskille was dat beide HBV groepe net kleurling en swart pasiënte ingesluit het en meer oorwegend manlik was, terwyl die idiopatiese groep alle rasse ingesluit het. In die HBV pasiënte was hematurie meer algemeen en erg, lewer ensieme meer dikwels verhoog en C3 meer dikwels verlaag as in die idiopatiese kohort. Beide groepe van volwasse MGN pasiënte het normale C4 vlakke getoon terwyl die kindergroep met HBV MGN verlaagde C4 vlakke bewys het. Die immuunkompleks patroon in biopsies van die HBV MGN volwasse en kindergroepe was soortgelyk met meer mesangiale en subendoteliële neerslae asook meer mesangiale interposisie as in die idiopatiese groep. Ten spyte van hierdie ooreenkoms tussen die twee HBV groepe, het die twee volwasse groepe meer glomerulêre sklerose en interstisiële siekte as die kindergroep vertoon. Die kliniese uitkoms van die kinderkohort was beter as die ander twee groepe met remissie (52%) wat meer algemeen was teen 4 jaar (p< 0.01) en met beter nier- en pasïent oorlewing. Ingeslote die 83 gevalle van hierdie reeks, is ten minste 1243 nierbiopsie bewysde gevalle van HBV MGN in kinders (80%) en volwassenes (20%) in die Engelse literatuur gerapporteer. Die manlike oorheersing in beide ouderdomsgroepe van HBV MGN is soortgelyk (kinders 79%; volwassenes 84%) en betekenisvol meer as vir idiopatiese MGN. Gevolgtrekkings: Die bevindinge bevestig dat HBV MGN in kinders ’n afsonderlike vorm van GN is wat die klassieke beskrywing van MGN verbreed deur die algemene insluiting van ’n aantal mesangiokapillêre GN kenmerke. Die ondergroep van nier biopsies met erge mesangiokapillêre GN kenmerke is as die gemengde HBV MGNmesangiokapillêre GN groep geklassifiseer. Die MGN spektrum in geheel het 86% van die HBV positiewe kindergroep behels. HBV MGN was die mees algemene assosiasie met NS/erge proteïenurie in die Namibiese subgroep (37%) en die derde grootse groep (19%) onder die SA kinders. Die siekte het ’n relatiewe hoë spontane remissiekoers getoon, maar ten minste 10% van die kinders het nierversaking ontwikkel. Ouderdom van 6 jaar en meer by presentasie en erge mesangiale neerslae in ‘n nierbiopsie het met minder remissies en ’n slegter uitkoms gekorreleer. Uitgebreide opvolg (meer as 15 jaar) was nodig om nierversaking in sommige van die swak uitkomsgroep aan te toon. Verstedeliking is geassosieerd met laer HBV draersyfers en hierdie faktor saam met algemene HBV inenting in die kinderjare (wat in 1995 in SA begin was), het ’n skerp daling in die voorkoms van hierdie siekte in SA teweeg gebring. HBV MGN is ’n waardevolle en moontlik unieke model van menslike GN en MGN, veral omdat die HBeAg in beide die serum en glomeruli identifiseer kon word om die etiologiese rol van HBeAg te bevestig.

The development and progression of carcinogenesis is a major area of interest to many scientists. Numerous factors, including both environmental and genetic have been implicated in the causation of cancer. It is clear that both these factors and others contribute to neoplastic development and progression. Microsatellites are short tandem repeat sequences which are located in the intron segments of the genome. These noncoding sequences range from 2 to 6 base pairs. An increase or decrease in the number of repeat sequences is referred to as microsatellite instability, also referred to as genetic instability. It is thought that microsatellite instability arises as a result of defects in DNA repair process. During DNA synthesis, the DNA repair genes ensure that the correct nucleotide is incorporated into the newly synthesised DNA strand, so when a mismatch base is incorporated, this is promptly removed and replaced with the correct base. However, if the repair system is defective this would give rise to numerous genetic aberrations along that region of the genome. Recently, microsatellite instability and allelic imbalance/loss of heterozygosity have been shown to play an important role in the development of many cancers, especially colorectal cancer (CRC) associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. This study was undertaken to investigate microsatellite instability and allelic imbalance in colorectal and oesophageal carcinomas in the KwaZulu Natal region of South Africa. The molecular analysis was correlated with clinicopathological data to establish a baseline level on which further studies could be performed. In addition, this study represents the first fluorescent based microsatellite analysis of these two common cancers in South Africa. Normal and tumour DNA was isolated from formalin fIxed paraffin embedded tissue. Fluorescent-based DNA technology using an automated DNA sequencer (Alf Express Automated DNA Sequencer) was employed. CY5 labelled primers for microsatellite markers (DCC, D18S34, D18S58, D3S659, D2S123 and D3S1255) were used. The data was captured and analysed using the Fragment Manager Software. The informativity of the microsatellite markers used in this study ranged from 50% to 71.8%. LOH/AI in the region of the DCC gene in the under 35 years of age CRC was 39.1%, while MSI in this region occurred in 31.25% of cases. The DNA repair gene status in these young patients was as follows: LOH/AI: 31.3% and MSI: 40.4%. In the over 50 years of age CRC, LOH/AI in the 18q region was 28% and MSI was 38%. The DNA repair genes (hMSH2 and hMLH1) in this cohort showed LOH/AI in 24% and MSI also in 24%. As regards oesophageal cancer, LOH/AI in the 18q region was 20.5% and MSI 7.7%. The repair genes showed LOH/AI in 17.9% and MSI in 10.25% of cases. When the molecular events were correlated with clinicopathological features, no statistically significant pattern emerged. However, it must be remembered that relatively small numbers of cases (39) were analysed.In conclusion: • No statistical correlation was found between clinicopathological characteristics and the molecular analysis in either CRC and oesophageal cancer. • LOH/AI and MSI was higher in the under 35 age group. • LOH/AI and MSI in 18q, 2p and 3p in sporadic CRC were similar to other fluorescent-based studies in patients over 50 years of age. • LOH/AI and MSI in 18q, 2p and 3p in oesophageal cancer was similar to studies from other geographical areas. • Finally, fluorescent-based microsatellite PCR and analysis was found to be an objective and efficient technique. / Thesis (Ph.D.)-University of Natal, 1998.