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

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 75-81).

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 119-148).

Li Chun-bong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 147-169). / Abstracts in English and Chinese. / Abstract --- p.i / Declaration --- p.vi / Acknowledgments --- p.vii / Table of Contents --- p.xi / List of Figures --- p.xii / List of Tables --- p.xvi / Abbreviations --- p.xvii / Chapter CHAPTER 1 --- INTRODUCTION AND LITERATURE REVIEWS / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.2 --- Carcinoma of the cervix --- p.6 / Chapter 1.2.1 --- Squamous carcinoma --- p.6 / Chapter 1.2.2 --- Adenosquamous carcinoma --- p.7 / Chapter 1.2.3 --- Adenocarcinoma --- p.8 / Chapter 1.3 --- Molecular biology of Human papillomavirus --- p.9 / Chapter 1.3.1 --- Genome structure and organization of HPV --- p.9 / Chapter 1.3.2 --- Expression of papillomavirus genes --- p.11 / Chapter 1.3.3 --- Taxonomy of HPV --- p.20 / Chapter 1.4 --- Diagnostic techniques in HPV detection --- p.23 / Chapter 1.4.1 --- Southern blot analysis --- p.23 / Chapter 1.4.2 --- Dot blot analysis --- p.25 / Chapter 1.4.3 --- In situ hybridization --- p.26 / Chapter 1.4.4 --- Hybird Capture System --- p.28 / Chapter 1.4.5 --- Polymerase Chain Reaction --- p.30 / Chapter 1.5 --- Human papillomavirus in cervical carcinoma --- p.33 / Chapter 1.5.1 --- Prevalence --- p.33 / Chapter 1.5.2 --- Transmission --- p.37 / Chapter 1.5.3 --- Risk Factors --- p.39 / Chapter CHAPTER2 --- MATERIALS AND METHODS / Chapter 2.1 --- Materials --- p.44 / Chapter 2.1.1 --- Chemicals and regents --- p.44 / Chapter 2.1.2 --- Specimens collection --- p.48 / Chapter 2.2 --- Methods --- p.49 / Chapter 2.2.1 --- Summary of methodology --- p.50 / Chapter 2.2.2 --- DNA extraction from fresh and paraffin embedded tissues --- p.51 / Chapter 2.2.3 --- Polymerase Chain Reaction using HPV Consensus Primer MY09/11 --- p.55 / Chapter 2.2.3.1 --- Template for PCR --- p.55 / Chapter 2.2.3.2 --- PCR amplification --- p.55 / Chapter 2.2.3.3 --- PCR product analysis --- p.56 / Chapter 2.2.4 --- DNA sequencing --- p.57 / Chapter 2.2.4.1 --- DNA sequencing reaction for ALFexpress DNA automatic sequencing --- p.57 / Chapter 2.2.4.2 --- ABI comparative PCR sequencing --- p.59 / Chapter 2.2.4.3 --- DNA sequence analysis --- p.60 / Chapter 2.2.5 --- Restriction Fragment Length Polymorphism --- p.61 / Chapter 2.2.5.1 --- Template preparation --- p.61 / Chapter 2.2.5.2 --- Restriction enzyme digestion --- p.62 / Chapter 2.2.5.3 --- Agarose gel electrophoresis analysis --- p.62 / Chapter 2.2.6 --- HPV Type Specific PCR --- p.63 / Chapter 2.2.6.1 --- Preparation of positive control DNA --- p.63 / Chapter 2.2.6.2 --- Preparation of HPV 52 and HPV 58 type specific PCR --- p.63 / Chapter 2.2.6.3 --- PCR primer design --- p.66 / Chapter 2.2.6.4 --- PCR amplification --- p.68 / Chapter 2.2.7 --- Polymerase Chain Reaction using HPV Consensus Primer GP5+/6+ --- p.71 / Chapter 2.2.7.1 --- Template for PCR --- p.71 / Chapter 2.2.7.2 --- PCR amplification --- p.71 / Chapter 2.2.7.3 --- PCR product analysis --- p.72 / Chapter 2.2.8 --- Statistical analysis --- p.72 / Chapter CHAPTER3 --- RESULTS / Chapter 3.1 --- Histology review of tumor specimens --- p.73 / Chapter 3.2 --- Polymerase chain reaction of HPV consensus primer MY09/11 --- p.76 / Chapter 3.3 --- DNA sequencing reaction --- p.81 / Chapter 3.4 --- Restriction fragment length polymorphism --- p.86 / Chapter 3.5 --- HPV type specific polymerase chain reaction --- p.90 / Chapter 3.6 --- Polymerase chain reaction of HPV consensus primer GP5+/6+ --- p.109 / Chapter 3.7 --- "Correlations of HPV prevalence, geographical variation, histology and age of the cervical cancer patients" --- p.112 / Chapter CHAPTER4 --- DISCUSSION / Chapter 4.1 --- Prevalence of HPV infection in cervical cancer in China --- p.118 / Chapter 4.2 --- DNA extraction and detection methods --- p.131 / Chapter 4.3 --- Intratype variation of HPV --- p.141 / Chapter CHAPTER5 --- CONCLUSION AND FUTURE PERSPECTIVE --- p.143 / REFERENCES --- p.147 / RELEVANT PUBLICATIONS --- p.170

Yeung Sze-wan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references. / Abstracts in English and Chinese. / ACKNOWLEDGEMENT --- p.i / ABSTRACT --- p.ii / ABBREVIATIONS --- p.vii / TABLE OF CONTENTS --- p.ix / Chapter CHAPTER 1 --- INTRODUCTION --- p.1-1 / Chapter 1.1 --- Anatomy of the Cervix --- p.1-1 / Chapter 1.2 --- Histology --- p.1-1 / Chapter 1.2.1 --- Squamous Epithelium --- p.1-1 / Chapter 1.2.2 --- The Endocervical Epithelium --- p.1-3 / Chapter 1.2.3 --- The Squamo-columnar Junction --- p.1-4 / Chapter 1.2.3.1 --- The Embryology --- p.1-4 / Chapter 1.2.3.2 --- Definition --- p.1-4 / Chapter 1.3 --- Human Papillomaviruses (HPVs) --- p.1-6 / Chapter 1.3.1 --- Structure of the Viruses --- p.1-6 / Chapter 1.3.2 --- The Nomenclature --- p.1-7 / Chapter 1.3.3 --- HPVs Genomic Structure and Properties of Gene Products --- p.1-7 / Chapter 1.3.4 --- Target Tissues --- p.1-8 / Chapter 1.3.5 --- Role of HPVs in the Carcinogenesis of Lesions --- p.1-9 / Chapter 1.3.6 --- Risk Groups of HPVs --- p.1-10 / Chapter 1.4 --- Pathology --- p.1-11 / Chapter 1.4.1 --- Macroscopic Features --- p.1-11 / Chapter 1.4.2 --- Symptoms and Diagnosis --- p.1-12 / Chapter 1.4.3 --- Histopathology --- p.1-13 / Chapter 1.4.3.1 --- Histopathological Grading of Cervical Intraepithelial Neoplasia --- p.1-19 / Chapter 1.4.3.2 --- Staging of Cervical Cancer --- p.1-24 / Chapter 1.5 --- Epidemiology of Cervical Intraepithelial Neoplasia and Cervical Cancer --- p.1-27 / Chapter 1.5.1 --- Descriptive Epidemiology --- p.1-28 / Chapter 1.5.2 --- Risk Factors --- p.1-30 / Chapter 1.6 --- Human Papillomavirus Type 16 --- p.1-42 / Chapter 1.6.1 --- Role of HPV16 in CIN and Cervical Carcinoma --- p.1-42 / Chapter 1.6.2 --- Viral Load of HPV 16 in CIN --- p.1-43 / Chapter 1.6.3 --- HPV 16 Viral Load as a Screening Tool --- p.1-46 / Chapter 1.7 --- Quantitation of HPV 16 --- p.1-48 / Chapter 1.7.1 --- Methods in Viral Quantification --- p.1-48 / Chapter 1.7.2 --- Selection of Methodology --- p.1-51 / Chapter 1.7.3 --- Correlation of HPV 16 Viral Loading with Severity of Cervical Lesions --- p.1-54 / Chapter CHAPTER 2 --- AIMS OF STUDY --- p.2-1 / Chapter CHAPTER 3 --- MATERIALS AND METHODS --- p.3-1 / Chapter 3.1 --- Materials --- p.3-1 / Chapter 3.1.1 --- Patients and Specimens --- p.3-1 / Chapter 3.2 --- Methods --- p.3-3 / Chapter 3.2.1 --- DNA Extraction --- p.3-3 / Chapter 3.2.2 --- Polymerase Chain Reaction --- p.3-7 / Chapter 3.2.3 --- Gel Electrophoresis --- p.3-8 / Chapter 3.2.4 --- Real-time Quantitation Polymerase Chain Reaction --- p.3-11 / Chapter 3.2.5 --- Statistical Analysis --- p.3-15 / Chapter CHAPTER 4 --- RESULTS --- p.4-1 / Chapter 4.1 --- Grading of Cervical Smears --- p.4-1 / Chapter 4.2 --- Incidence of HPV 16 Detected in Cervical Smears --- p.4-2 / Chapter 4.2.1 --- Detection of HPV 16 in Women for Routine Pap Smear --- p.4-2 / Chapter 4.2.2 --- Detection of HPV 16 in Women for Colposcopic Examination --- p.4-5 / Chapter 4.3 --- Quantification of HPV 16 by Real-time PCR --- p.4-5 / Chapter 4.3.1 --- Range of Detection --- p.4-10 / Chapter 4.3.2 --- Standard Curve --- p.4-12 / Chapter 4.3.3 --- Reproducibility of Quantitative Real-time PCR --- p.4-17 / Chapter 4.3.4 --- Sensitivity of Quantitative Real-time PCR --- p.4-17 / Chapter 4.3.5 --- Detection and Quantification of HPV 16 E6/7 Genes in HPV16 Positive Cervical Scrapes --- p.4-21 / Chapter 4.4 --- Comparison of HPV 16 Copy Number Detected among Three Lesion Groups --- p.4-22 / Chapter 4.5 --- Clinical Analysis --- p.4-27 / Chapter 4.6 --- HPV 16 DNA Copy Number in Lesion Groups --- p.4-28 / Chapter CHAPTER 5 --- DISCUSSION --- p.5-1 / Chapter 5.1 --- Selection of Material (Scrapes) --- p.5-1 / Chapter 5.2 --- Detection of HPV 16 in Cervical Scrapes --- p.5-3 / Chapter 5.2.1 --- Selection of HPV Type --- p.5-3 / Chapter 5.2.2 --- Techniques in Detecting HPV Viral Load --- p.5-3 / Chapter 5.2.2.1 --- Advantages of Quantitative Real-time PCR --- p.5-6 / Chapter 5.2.2.2 --- Parameters Affecting the Performance of Real-time PCR --- p.5-8 / Chapter 5.2.3 --- Selection of Detection Sites --- p.5-9 / Chapter 5.2.4 --- Standard Curve Establishment --- p.5-10 / Chapter 5.3 --- Comparison between Real-time PCR and Traditional PCR --- p.5-12 / Chapter 5.4 --- Role of HPV Viral Load in Cervical Neoplasm --- p.5-13 / Chapter 5.5 --- HPV Infection in Hong Kong Chinese Women --- p.5-17 / Chapter 5.6 --- Clinical Significance of HPV 16 Viral Load Detected in Cervical Neoplasm --- p.5-18 / Chapter 5.7 --- Future Prospect --- p.5-20 / Chapter CHAPTER 6 --- CONCLUSION --- p.6-1 / REFERENCES --- p.R-I

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009.

Cervical cancer is the third most commonly diagnosed cancer globally and it has also been identified as one of three AIDS defining malignancies. Highly active antiretroviral therapy (HAART) is a combination of three or more antiretroviral drugs which are classified as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). HAART has been shown to play a significant role in reducing the incidence of some AIDS defining malignancies, although its effect on cervical cancer is still unclear. It is hypothesized that HAART might reduce cancer risk by interacting with different signalling molecules and pathways that are involved in cancer in order to induce cell death and thus inhibit cell proliferation. The broader aim of this study was to understand the relationship between cervical cancer and HAART. This was achieved by studying the expression of key signalling molecules in cancer; MUC1 and NFkB (P65) and morphological features using scanning electron microscopy following 24 hour treatment of a cervical cancer cell line, HCS-2 with drugs which are commonly used as part of HAART; Emtricitabine (FTC), Tenofovir disoproxil fumarate (TDF), Efavirenz (EFV), Atripla combination (ATP) and Kaletra combination (LPV/r) at their clinical plasma concentrations. Quantitative real time polymerase chain reaction (qPCR) was used in order to study the gene expression of MUC1 and P65 and the data was analysed using the 2-ΔΔCT method to calculate fold change. The statistical analysis was conducted using JMP 11 software. MUC1 and P65 gene expression was reduced following drug treatment. Protein expression was studied by means of Immunofluorescence and MUC1 and P65 protein expression was reduced following drug treatment. Scanning electron microscopy revealed characteristic features of apoptotic cell death such as loss of cell contacts, reduced density and size of microvilli, increase in surface blebbing and budding and degradation of apoptotic bodies following treatment with all the drugs. In conclusion, the drugs used in this study

Leung Chun-on, Paul. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 149-167). / Content Page / Acknowledgments --- p.7 / Chapter / Chapter Chapter1 --- Introduction --- p.8 / Chapter Chapter2 --- Literature Review --- p.13 / Chapter 2.1 --- Anatomy of the cervix --- p.13 / Chapter 2.2 --- Classification --- p.14 / Chapter 2.2.1 --- Cervical intraepithelial neoplasia (CIN) --- p.14 / Chapter 2.2.2 --- Cervical cancer --- p.17 / Chapter 2.2.3 --- Incidence and screening --- p.21 / Chapter 2.2.4 --- Etiology / Chapter 2.2.4.1 --- Sexual and reproductive factors --- p.23 / Chapter 2.2.4.2 --- Smoking as a risk factor --- p.23 / Chapter 2.2.4.3 --- Male partner contribution --- p.24 / Chapter 2.2.4.4 --- Human papillomaviruses and cervical cancer --- p.24 / Chapter 2.2.4.5 --- Oral contraceptive pills --- p.27 / Chapter 2.2.4.6 --- Oncogenes and tumour suppresser genes --- p.28 / Chapter 2.2.4.7 --- Oncogenes and cervical cancer --- p.35 / Chapter 2.3 --- Immunohistochemical technique in cancer study / Chapter 2.3.1 --- Principle of immunostaining --- p.39 / Chapter 2.3.2 --- Fixation --- p.40 / Chapter 2.3.3 --- Section preparation --- p.41 / Chapter 2.3.4 --- The choice of antibodies --- p.41 / Chapter 2.3.5 --- Enzyme labels --- p.42 / Chapter 2.3.6 --- Blocking endogenous enzymes --- p.43 / Chapter 2.3.7 --- Blocking background staining --- p.43 / Chapter 2.3.8 --- Dilution preparation --- p.44 / Chapter 2.3.9 --- The Avidin-Biotin technique --- p.44 / Chapter 2.3.10 --- Control --- p.47 / Chapter 2.3.11 --- Antigen retrieval --- p.47 / Chapter 2.3.12 --- Cell counting and scoring --- p.49 / Chapter 2.4 --- The application of Polymerase Chain Reaction Single-Strand Conformation Polymorphism(PCR-SSCP) in cancer study --- p.52 / Chapter Chapter3 --- Materials and Methods --- p.56 / Chapter 3.1 --- Materials --- p.56 / Chapter 3.2 --- Methods --- p.61 / Chapter 3.2.1 --- Specimens collection --- p.61 / Chapter 3.2.2 --- Antibodies preparation --- p.63 / Chapter 3.2.3 --- Immunohistochemical staining and antigen retrieval procedures --- p.63 / Chapter 3.2.4 --- Cell counting and scoring --- p.68 / Chapter 3.2.5 --- PCR-SSCP analysis for myc gene mutation --- p.70 / Chapter 3.2.5.1 --- DNA extraction --- p.70 / Chapter 3.2.5.2 --- PCR --- p.72 / Chapter 3.2.5.3 --- Preparing the single strand DNA --- p.73 / Chapter 3.2.5.4 --- Electrophoresis --- p.73 / Chapter 3.2.5.5 --- Gel drying and scanning --- p.77 / Chapter 3.2.6 --- Statistical analysis --- p.77 / Chapter Chapter 4 --- Result --- p.78 / Chapter Chapter 5 --- Discussion --- p.126 / Chapter Chapter 6 --- Conclusions --- p.144 / Reference --- p.148