A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Masters of Science in Medicine (Pharmacology) Johannesburg, 2013 / Colon cancer is the third most common cancer worldwide and the second most common in the western world. More than 40 % of colon cancer sufferers develop metastases and chemotherapy is often used alone or in combination with radiotherapy as adjunctive therapy for the advanced disease. A major effort has been made in the past decade to develop anticancer agents through both empiric screening and rational design of new compounds. These attempts are made to improve the survival rate, reduce the severe adverse effects associated with existing cancer chemotherapeutic agents as well as to reduce the development of drug resistance. In the present study, two colon cancer cell lines were exposed to novel imidazo[1,2-a]pyridines and novel nucleoside analogues, aiming to investigate the cytotoxic efficacy on the cells, the mode of cell death, and to explore the pathways by which cell death was induced.

Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011 / Oesophageal squamous cell carcinoma (OSCC) has a high prevalence in the Asiatic belt and areas of Africa. In South Africa (SA), the incidence of this cancer in the Eastern Cape is one of the highest in the world. The molecular carcinogenesis of this disease remains unresolved. Single nucleotide polymorphism (SNP) array technology provides a high resolution technique to determine DNA copy number imbalances across the whole genome. DNA copy number changes can affect oncogenes and tumour suppressor genes, contributing to carcinogenesis. The aim of this study was to map common chromosomal break points previously identified in five SA OSCC cell lines by multi colour fluorescence in situ hybridisation (FISH) and to characterise copy number changes in these cell lines and OSCC patient’s specimens using SNP array technology. Genome wide copy number analysis was performed on the cell lines and 51 OSCC retrospective samples from the Eastern Cape region using Affymetrix® 500K SNP arrays. A number of genes were significantly affected by copy number changes across specimens. The copy number status of some of these candidate genes identified by arrays, were verified by (FISH) in a subset of the samples. Expression of the EPHA3, FGF3, FGF4, FGF19 and C-MYC candidate genes was assessed in the cell lines and four fresh samples. The common translocation break point previously detected in 5 cell lines involving chromosome 3p11.2 correlated with deletions affecting the EPHA3 gene in 4 of the 5 cell lines and was deleted in 74% of the OSCC cohort. EPHA3 is an ephrin A3 receptor tyrosine kinase that has been shown to have both oncogenic and tumour suppressor functionality. In addition, significant regions of amplification and deletion identified genes (CCND1, C-MYC, FHIT, SFRP1, SFRP2, FGF3, FGF4, FGF19, SMAD4, SMAD6 and FBXW7) involved in the Wnt, TGF-β and FGF. Deletion of the genes, WRN, ATM, RAD18 and XRCC4 involved in DNA repair pathways, may contribute to genetic instability that is characteristic of OSCC. This study has highlighted some molecular pathways that may contribute to better understanding carcinogenesis of OSCC in South Africa.

Introduction: Although cervical cancer can be prevented through known interventions it still remains a major cause of mortality in developing countries. Currently in South Africa there is little literature on cervical cancer radiotherapy treatment and its prognostic factors. Knowledge of prognostic factors helps in understanding the determinants of a disease better and optimize treatment strategies. The aim of this study was to determine overall survival rate and to investigate potential prognostic factors for cervical cancer in patients who underwent radiotherapy during the period of 1 January 2004 to 31 December 2006 at the Division of Radiation Oncology, Charlotte Maxeke Johannesburg Academic Hospital. Methods: This was a retrospective cohort study of 900 patients who were treated with radiotherapy between 1 January 2004 and 31 December 2006. Patient and treatment related data was obtained from the hospital treatment records. Follow-up was then censored as of 31st of December 2008. Subjects of this study had either mono-therapy or a combination of therapies: external beam radiotherapy, brachytherapy and chemotherapy. A Cox regression model was fitted to determine the prognostic and predictive factors of cervical cancer. Kaplan Meier methods were used to establish the effect of different socio-demographic and clinic-pathological factors on overall survival. The overall two year survival was also determined. Results: At 2 years post-treatment for each individual patient, 26 out of 900 patients had died, 281 were still alive and 593 lost to follow up leaving 307 patients available for analysis. The overall 2 year mortality rate was 45 per 1000 person years and highest in the period of 0-6 months. In the final model, completion of brachytherapy remained a significant predictor of survival (HR=0.04, 95% CI: 0.01-0.11, p<0.001) after adjusting for all other factors. Furthermore, HIV status was the only significant prognostic factor (HR=3.23, 95% CI: 1.04- 10, p=0.042). Patients who had brachytherapy treatment prescribed and completed the prescription were 96% less likely to die compared to those who didn’t complete it at any point in time, after adjusting for age and HIV status. Patients who were HIV positive were approximately three times more likely to die as compared to HIV negative patients at any point in time after adjusting for age and completed brachytherapy. The overall 2-year survival rate was 92% for this group of patients. Conclusion: Completion of the brachytherapy prescription was a significant predictor of treatment outcome, while the patient’s HIV status was also a significant prognostic factor for treatment. Patients who were HIV positive were three-times more likely to die compared to HIV negative patients. The overall 2-year survival rate was 92%, however, these results need to be interpreted with caution due to the large loss to follow-up in this patient population. Prospective clinical trials are recommended in the future to confirm the validity of the findings of this work in a representative patient population. In addition this work puts forward some suggestions to optimize treatment of cervical cancer patients in typical university teaching public health centres in South Africa.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in the field of Epidemiology and Biostatistics. Johannesburg, June 2017 / Cervical cancer (CC) is the leading cause of female cancer morbidity and mortality in South Africa, despite the introduction of preventive programs. However, there is a paucity of information on current CC rates and trends in South Africa. This study aimed to evaluate the national trends and determinants of CC over a 19 year period (1994-2012). We conducted temporal analyses of age-standardised incidence rates (ASIR) from 1994 to 2009 and age-standardised mortality rates (ASMR) from 2004 to 2012 using data from the National Cancer Registry and Statistics South Africa, respectively. We also evaluated a novel surrogate measure (complement of MR: IR ratio) to calculate five-year relative survival rates of CC (2004-2009). Temporal analyses were stratified by the province of residence, histological type, population- and age-groups, while linear regression models were fitted to determine the average annual percent change (AAPC) of the time trends. Spatial distribution was conducted by utilising the GIS coordinates of SA to map the provincial ASMR. Unconditional logistic regression analyses were carried out for three casecontrol studies using data from the hospital-based Johannesburg Cancer Case-Control Study (JCCCS) (1995-2010), to evaluate the effect of HIV infection; tobacco smoking and alcohol abuse and sexual and reproductive behaviours on the risk CC in Black South Africans. The cases were participants with CC while controls were other female cancer participants that had no known association with CC and its risk factors. There were 75,099 incident cases and 25,101 mortalities from CC in the periods studied with women below 50 years accounting for 43.1% of the cases and 35.7% deaths. The ASIR was 22.1/100,000 in 1994 and 23.3/100,000 in 2009 and there was an average annual decrease in incidence of 0.9% (AAPC=-0.9%, P-value<0.001). The ASMR decreased slightly from 13.9/100,000 in 2004 to 13.1/100,000 in 2012 (AAPC = -0.6%, P-value < 0.001). Based on current trends, the ASIR and ASMR were predicted to increase to 26.3/100,000 and 14.6/100,000 in 2030, respectively. From 2004 to 2012, five provinces had increased mortality rates (AAPC: 1.2 – 8.3, P-value<0.001) while four provinces had decreased mortality rates (AAPC: -16.6 - -1.0, P-value<0.001). In 2012, the ASMR in Black population group was 5.7-fold higher than in the White population group. The highest mortality was recorded in Mpumalanga Province (19.8/100,000) and the least in the Eastern Cape Province (8.9/100,000). From 2000 to 2009, the ASIR of adenocarcinoma of the cervix was relatively low (2.00 to 2.6 per 100,000 women) and stable, while the incidence of squamous cell carcinoma was high (17.0 to19.0 per 100,000 women) and the rate increased by 1.4% annually. The relative survival rates were higher in White and Indians/Asian women (60-80%) than in Blacks and Coloureds (40- 50%). The results of the JCCCS studies showed that the association between CC and HIV infection increased from two-fold (adjusted odds ratio, (adjOR) =1.98; 95% CI: 1.34-2.92) during the pre-anti-retroviral therapy (ART) era (1995-2003) to three-fold (adjOR=2.94 95%CI: 2.26- 3.83) in the ART era (2004-2010). Current tobacco smoking (adjOR=2.1, 95%CI: 1.10-4.01) and snuff use (adjOR=1.3, CI: 1.08-1.61) increased the likelihood of CC among Black women in South Africa. The risk of CC increased with prolonged use of hormonal contraceptives (P-value for trend = 0.003) and high parity (>6) (adjOR=4.5, 95%CI: 2.85- 7.25). The incidence and mortality of CC are probably underestimated due to underreporting of cancer in the country. South Africa had minimal changes in overall CC rates between 1994 and 2012, despite the initiation of a population-based CC screening program in 2000 and the nationwide roll out of ART in 2004. There was a marked disparity in CC rates by population group, age and province. HIV-infected women and those who use tobacco are more likely to develop CC, therefore targeted programs should be introduced to inform women about risk factors for CC. Maternal and child health initiatives should also involve CC control activities since a considerable number of women of the reproductive age (15 – 49 years) were affected. / MT2017

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the branch of Paediatrics Johannesburg, 2014. / Background: To describe the relative frequency and distribution of neonatal tumours; to determine the age at presentation to the oncology unit and to determine the extent of the delay in referral. To describe any associated syndromes in individual malignancies. Material and methods: A retrospective case series was performed covering 24 years. Demographics, means of diagnosis, treatment and outcome details were reviewed. Results: There were a total of 2626 patients that presented to the oncology department with suspected malignancies. Out of that, 2308 patients were diagnosed with a malignancy and 318 patients had benign tumours. Over the 24 year period 117 tumours were diagnosed in neonates (4,4%). Due to incomplete data 29 patients were excluded. Of the remaining patients, 61 were diagnosed with benign tumours and 27 with malignant tumours. The male to female ratio was 1: 1,5. The mean age at presentation was 16 days. The mean age at diagnosis was 36 days. Histology and radiology were diagnostic in 40,9% and 19,3% respectively. A combination of histology and radiology was used to make a diagnosis in 21,6% of patients, 11,4% of diagnoses were based on clinical examination and 6,8% on biochemistry and haematology. Malignant soft tissue tumours were the most common malignancy (25,9%) followed by renal tumours (18,5%), leukaemia (14,8%), neuroblastomas (11,1%) and retinoblastomas (11,1%). Teratomas (45,9%) and benign vascular tumours (44,3%) were the most common benign tumours. Chemotherapy was used to treat 22 neonates, while 50 underwent surgical removal of the tumour. Half (51,9%) of the patients diagnosed with a malignant tumour died, while 11,1% of patients were iv lost to follow up. Just under 10% (8,2%) of the patients diagnosed with a benign tumour died, while 44,3% of patients were lost to follow up. The overall mortality amongst patients diagnosed with benign or malignant tumours was 21,6%. Conclusion: There is a much higher incidence of benign tumours diagnosed in neonates (69,3%) compared to older children (12,1%). Only 1,2% of all childhood malignancies in our unit occurred in the neonatal period, which is slightly lower than the reported 2%. Two of the major issues that need to be addressed in the future management of neonatal tumours are prompt referral for prompt diagnoses and better follow up.

Immunohistochemistry has been used as an aid in the histological diagnosis of salivary gland neoplasms as they often show overlapping histomorphological growth patterns.

Ng Ho Keung. / Thesis (M.D.)--Chinese University of Hong Kong, 1992. / Includes bibliographical references (leaves 241-276). / Declaration of originality --- p.4 / Acknowledgement --- p.5 / Publication of study materials --- p.6 / Summary of thesis --- p.8 / Chapter Chapter1 --- Meningiomas and arachnoid cells - an introduction --- p.15 / Chapter Chapter2 --- Mesenchymal and epithelial differen- tiation in meningiomas --- p.25 / Chapter Chapter3 --- The extracellular matrix proteins - their properties and significance in tumor biology --- p.55 / Chapter Chapter4 --- Objectives and methodology of present study --- p.73 / Chapter Chapter5 --- Comparative immunohistology of meningiomas with paraffin and cryostat sections --- p.79 / Chapter Chapter6 --- Immunoelectron microscopy of meningiomas for cytokeratin filaments --- p.93 / Chapter Chapter7 --- Cryostat section immunohistochemistry of meningiomas --- p.102 / Chapter Chapter8 --- Immunohistochemistry of meningiomas on cytologic smear preparations --- p.180 / Chapter Chapter9 --- In vitro immunohistochemical analysis of meningioma cultures --- p.194 / Chapter Chapter10 --- Overall discussion and conclusion List of tables --- p.240 / References --- p.241

by Ho King Wah Stephen. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 251-304). / Title Page --- p.1 / Table of Contents --- p.2 / Summary --- p.3 / Glossary of abbreviations used in the thesis --- p.10 / List of Figures --- p.12 / List of Tables --- p.20 / Acknowledgments --- p.24 / Chapter Chapter 1 --- Hepatic Cancer - Review of the Medical Literature --- p.25 / Chapter Chapter 2 --- Selective Internal Radiation Therapy - Review of the Medical Literature --- p.47 / Chapter Chapter 3 --- The Background In Physics --- p.76 / Chapter Chapter 4 --- Hypothesis and Testing the Hypothesis --- p.88 / Chapter Chapter 5 --- Parameters Required in the Partition Model --- p.98 / Chapter Chapter 6 --- Prediction of Radiation Dose and Verification of the Partition Model --- p.143 / Chapter Chapter 7 --- Clinical Evaluation of the Partition Model --- p.181 / Chapter Chapter 8 --- Conclusions and Future Development --- p.248 / References --- p.251

Lin Kwok Yin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 116-124). / Abstracts in English and Chinese. / ACKNOWLEDGMENT --- p.i / ABSTRACT --- p.ii / LIST OF CONTENTS --- p.vii / LIST OF APPENDIX --- p.x / LIST OF TABLES --- p.xi / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter CHAPTER 2 --- LITERATURE REVIEW --- p.3 / Introduction --- p.3 / Impact of childhood cancer on the family in general --- p.4 / Impact of childhood cancer on children with the disease --- p.10 / Impact of childhood cancer on the well siblings --- p.16 / Impact of childhood cancer on parents --- p.21 / Impact on families with terminally ill children --- p.25 / Impact of the disease on families who have lost children with cancer --- p.29 / Summary of literature review --- p.32 / Chapter CHAPTER 3 --- OBJECTIVES AND METHODOLOGY --- p.35 / Aim and objectives --- p.35 / Methodology and research design --- p.35 / Subjects for study --- p.36 / Data collection method --- p.38 / Data collection procedure --- p.42 / Data analysis --- p.45 / Validity --- p.47 / Reliability --- p.48 / Pilot study --- p.50 / Ethics --- p.51 / Chapter CHAPTER 4 --- FINDINGS AND DISCUSSION --- p.54 / Introduction --- p.54 / Parents --- p.55 / Summary of the findings obtained from parents' data --- p.75 / Children with cancer --- p.76 / Summary of the findings obtained from children's data --- p.85 / Siblings --- p.86 / Summary of the findings obtained from siblings' data --- p.98 / A comparison of the findings obtained from parents' and children's data --- p.99 / Chapter CHAPTER 5 --- CONCLUSION --- p.104 / Limitations --- p.104 / Implications for nursing practice --- p.107 / Recommendations for nursing practice and further research --- p.112 / Conclusion --- p.114 / REFERENCES --- p.116 / APPENDIX --- p.125

by Peter Man-Lung Teo. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.