The management of women with mild and moderate dyskaryosis remains controversial. Any strategy must aim to be safe, efficient and cost effective. Two alternative strategies consist of immediate colposcopy for all women or a policy of cytological surveillance with colposcopy reserved for women with persistent dyskaryosis. Instead of a blanket policy for all women, selective approaches might be useful if accurate predictors of underlying high grade cervical intraepithelial neoplasia (CIN) were identified. Finally the effective treatment of women is important to prevent the development of invasive cancer. Large Loop Excision of the Transformation Zone or LLETZ is a relatively new treatment modality which has rapidly been established as the preferred treatment for women with CIN but it's efficacy has not been studied beyond a period of six months. The core of the thesis is description of a large prospective randomised study carried out in the University of Aberdeen. This was a four year project sponsored by the charity Birthright (now Well-being). Nine hundred and two women with a single smear showing mild or moderate dyskaryosis were recruited and allocated in a random fashion to either an immediate treatment group and one of three surveillance groups with periods of up to 24 months before treatment. Outcome measurements included the cytological and histological results. The cost effectiveness of two alternate management strategies for women with mild dyskaryosis is also described. The use of social factors and virological tests as secondary screening techniques is examined to determine if they might select women with high grade disease. Finally, the outcome of treatment of women including 400 women from the Birthright study using large loop excision of the transformation zone (LLETZ) is assessed.

Human papillomavirus (HPV), a major sexually-transmitted disease, causes cervical cancer, in addition to numerous other cancers in females and males. This thesis uses mathematical modeling, theory and simulations to study the transmission dynamics of HPV, and associated dysplasia, in a community. A new deterministic model is designed and used to assess the population-level impact of Pap cytology screening on the transmission dynamics of the disease in a community. The model is rigorously analyzed for its dynamical features, vis-a-vis determining the conditions for the effective control (or elimination) and persistence of the disease. Furthermore, the effect of uncertainties in the estimates of the parameter values used in the numerical simulations of the model is accounted for via uncertainty and sensitivity analysis. Simulations of the model show that Pap screening dramatically reduces the incidence of cervical cancer in the community.

No description available.

Cervical cancer is the fourth most common female malignancy worldwide and is substantively higher in low-income and middle-income countries. In South Africa, cervical cancer is a leading cause of mortality amongst women. The anti-cancer actions of the vitamin D and its numerous metabolites are an active field of research. The family of vitamin D metabolites regulate numerous cellular pathways which are implicated in tumorigenesis. Pre-clinical studies and clinical studies have yielded promising, although conflicting results in various cancers. Some healthy and cancerous tissue express an autocrine vitamin D metabolising system (VDMS) which is capable of tightly regulating intracellular metabolism and growth. The VDMS expresses activating and inactivating enzymes and a vitamin D receptor (VDR). At the cellular level, the VDMS can activate and inactivate vitamin D precursors and transduce signals to the nucleus to regulate various cell health genes, including cell growth, metabolism and survival. Healthy and cancerous cervical tissue express a VDMS. The anti-cancer actions of cholecalciferol, an early precursor of activated vitamin D, is poorly studied in cervical cancer. This study aimed to characterise cholecalciferol’s action on cell growth, cell death and the VDMS in a high-grade cervical cancer cell line, SiHa. SiHa cell cultures were treated with a range of cholecalciferol doses (26 nM, 104 nM, 260 nM and 2600 nM) for 72 hours. Cell count and viability were assessed by crystal violet and trypan blue assays, respectively. Cell proliferation was enumerated by Ki67 nuclear antigen and the cell cycle profile analysed by flow cytometry. Apoptotic cell death was investigated by measuring mitochondrial membrane potential (∆Ψm), phosphatidylserine (PS) externalisation, effector caspase activation and evaluation of DNA damage markers by flow cytometric analysis. The biochemical markers microtubule-associated proteins 1A/1B light chain 3B-II (LC3-II) and lactate dehydrogenase (LDH) were also measured by flow cytometry and spectrophotometric analysis to identify autophagic cell death and necrosis, respectively. In addition, brightfield microscopy and transmission electron microscopy (TEM) were respectively used to characterise morphological and ultrastructural features of apoptosis, autophagic cell death and necrosis. The VDMS in SiHa control and experimental cultures were characterised by the investigation of intracellular gene and protein expression of the cholecalciferol activating (CYP2R1 and CYP27A1) and inactivating (CYP24A1) enzymes, and the VDR. Qualitative microscopical analysis evaluated classical characteristics of cell death and semi-quantitative analysis of apoptosis was performed. Data were analysed using a one-way ANOVA and Bonferroni post-hoc test. p < 0.05 was considered statistically significant. A significant decrease in cell count and cell viability was identified in SiHa cell cultures treated with 2600 nM cholecalciferol. Furthermore, significant increase in biochemical markers of apoptosis were identified including, decreased ∆Ψm; PS exposure; terminal caspase activation; and nuclear damage at 2600 nM cholecalciferol treatment of SiHa cell cultures. Moreover, the biochemical findings were supported by brightfield microscopy and TEM, which observed classical apoptotic features viz. membrane blebbing, apoptotic bodies and nuclear fragmentation. Also, a significantly increased number of apoptotic cells were enumerated. There was no evidence of autophagic cell death and necrosis. Additionally, a significant increase in 25-hydroxylase (CYP2R1) gene and protein expression was identified in SiHa cells treated with 2600 nM cholecalciferol. Conversely, a significant decrease in 1α-hydroxylase (CYP27B1) gene and protein expression was identified in SiHa cells treated with 2600 nM cholecalciferol. Furthermore, significant increase in both 24-hydroxylase (CYP24A1) and VDR expression at gene and protein levels were observed in 2600 nM experimental SiHa cultures. In conclusion, cholecalciferol exerts growth inhibition and apoptosis in SiHa cells at 2600 nM. This is accompanied by CYP2R1 and VDR upregulation which suggests autocrine activation to calcidiol and intracellular nuclear signalling, respectively. It is therefore hypothesised that calcidiol synthesised de novo binds to VDR and induces apoptosis in SiHa cell line. / Dissertation (MSc (Chemical Pathology))--University of Pretoria, 2020. / Chemical Pathology / MSc (Chemical Pathology) / Restricted

Wits School of Public Health May 2015 / Background and objectives: Cervical cancer is a major cause of cancer-related deaths in many developing countries yet it is a preventable and treatable in early disease. Recent research has seen increasing morbidity and mortality due to cancer of the cervix attributed to the advent of the human immunodeficiency virus (HIV) epidemic worldwide. Papanicolaou smears (Pap smears) to detect cervical abnormalities are currently the best known form of early detection and prevention of invasive cervical cancer (ICC). Knowledge and awareness about cervical cancer and associated risk factors, and cervical screening is very important in determining appropriate health seeking behaviours with the aim to reduce morbidity and mortality. This study examines awareness, perceived risk and practices related to cervical cancer screening among HIV-positive women in an urban HIV clinic in Johannesburg, South Africa. This will be useful in making recommendations with regards to designing and planning of screening programmes, and addressing cervical cancer education and awareness. Materials and methods: This study analysed secondary data collected from an ongoing cervical cancer study undertaken by Right to Care in partnership with the Clinical HIV Research Unit (CHRU) among HIV-positive adult (18 years and older), female patients enrolled in the Themba Lethu Clinic HIV care and treatment programme in Johannesburg, South Africa from November 2009 to December 2012. Clinical data for all respondents was extracted from TherapyEdge-HIVTM, the electronic medical database system used for patient management at the facility. Descriptive statistics were used to summarise baseline characteristics. Models using logistic regression were developed to estimate odds ratios (OR) to further identify baseline sociodemographic factors and clinical characteristics associated with behaviours studied (awareness, perceived risk and practice related to cervical cancer and Pap smear testing) and to identify the association between these factors and the prevalence and severity of cervical disease. Awareness of the Pap smear test and the human papillomavirus (HPV) was assessed based on whether the women report knowing what a Pap smear test is, and whether they have ever heard about HPV. Perceived risk about getting cervical cancer was assessed based on how worried the study participants were about getting cervical cancer. Previous Pap screening practice was assessed using reported screening history of the study participants. In addition to this, a subanalysis was conducted to see how these responses compare to 1) the recommended practice according to the South African national cervical cancer screening guidelines based on the age of participants, and 2) the latest HIV treatment guidelines based on year of HIV diagnosis. Analysis of attrition of study participants at 12 months of study participation was conducted using different time to event analysis techniques including Kaplan Meier, Log-rank test and Cox proportional hazards model. Cox proportional hazards models were fitted to investigate associations between baseline covariate and attrition. A sub-analysis was also carried out using descriptive statistics and chi-square tests to compare the cohort of patients that were included in the study (the VICAR1 cohort) and the rest of the larger Themba Lethu Clinic (TLC) population that was not included in the study to see if there were any significant differences noted between the two groups. In addition, a sensitivity analysis of the of 12 month follow up study visit was conducted using descriptive statistics and chi-square tests to determine if there were any significant differences between study participants that came for their 12 month study visit and those that did not come for their 12 month study visit. Results: Eight hundred and fifty seven (71.30%) participants reported to be aware of Pap smear screening, with only 18.15% reporting to be aware of HPV. Of the 1192 participant who had data to ascertain perceived risk regarding cervical cancer disease, 662 (55.54%) of the women were very worried, 250 (20.97%) were somewhat worried, 280 (23.49%) were not worried about getting cervical cancer. A total of 381 (36.46%) women had adequate practice according to the national cervical cancer screening guidelines. While 304 (28.57%) had adequate practice according to the national HIV treatment guidelines. Factors associated with Pap smear screening awareness were being in the 50+ age group (aOR=4.70, 95% CI 1.63-13.55) as compared to the 18-29 age group, being of non-South African nationality (aOR=0.41, 95% CI 0.20-0.83), having a grade 10 to matric level education (aOR=2.12, 95%CI 1.28-3.52), and a tertiary level education (aOR=2.62, 95%CI 1.07-6.41) as compared to having a less than a grade 10 level education. None of the factors assessed were found to be significantly associated with awareness regarding HPV. Factors associated with perceived risk regarding cervical cancer disease were having a tertiary education (aOR=3.74, 95%CI 1.13-12.38) as compared to having less than a grade 10 level, taking snuff (aOR=0.55, 95%CI 0.33-0.92) and drinking alcohol (aOR=2.53, 95% CI 1.24- 5.17). Being in the 30-39 age group (aOR=12.23, 95%CI 4.00-37.35) as compared to being in 18-29 age group, cohabiting with a partner (aOR=0.36, 95%CI 0.17-0.75) as compared to being single, being self-employed (aOR=2.95, 95%CI 0.82-10.66) as compared to those in full time employment, and being initiated on highly active antiretroviral therapy (aOR=0.17, 95%CI 0.06-0.55) were associated with Pap smear screening practices according to the national cervical cancer guidelines. None of the factors proved to be significantly associated with the practice according to the national HIV treatment guidelines, this is mainly because the HIV treatment guidelines have stricter screening requirements for HIV positive women. Those that had a moderate to severe baseline study Pap smear at enrolment into the study were 92% less likely to have disease progression at their 12 month Pap smear screening (aOR=0.08, 95%CI 0.05-0.13) compared to those that had a negative baseline Pap smear at study enrolment. This is mostly because they would have had a treatment intervention based on their baseline study Pap screening result therefore they would mostly likely not have disease progression at a follow up screening. Only seven women enrolled in the study died of non-cervical cancer related causes during the study period. In the analysis on all-cause attrition (deceased or lost to follow up) those that are initiated on highly active antiretroviral therapy were 92% less likely to be deceased or lost to follow up than those that were not initiated on highly active antiretroviral therapy (aOR=0.08, 95% CI 0.05-0.13). The global test for the overall model showed that the proportional hazard assumption had not been violated, p=0.684. Conclusions: Results for our study showed high levels of Pap smear screening awareness amongst the study participants. However, low levels of Pap screening uptake was observed for study participants. These results and results shown in previous studies show that awareness is only the first hurdle in the challenges related to cervical cancer prevention and treatment. Adequate practice is the factor that will have the most positive influence on the disease morbidity and mortality. Rates of screening practices have been found to be worse in populations with less than 70% Pap smear screening awareness. Findings from this study and similar findings from other studies highlight that more research needs to be done into effective health education programmes to address the gaps in adequate screening practice. These efforts should not only target the clients but also the health providers as they also have an important role to play in improving awareness, knowledge and practices related to cervical cancer and Pap smear screening amongst their clients.

No description available.

BACKGROUND: Recently, it is found that T-helper (Th) 22 cells are involved in different types of autoimmune and tumor diseases. But, till now, no study has been carried out to understand the involvement of these cells in cervical cancer (CC). METHODS: Flow cytometry was used to determine the expression of interferon gamma (IFN-gamma), Interleukin-22 (IL-22), IL-17 in the peripheral blood of healthy controls (HC), CIN and cervical cancer patients. From peripheral blood mononuclear cells (PBMCs), mRNA expression levels of Aryl hydrocarbon receptor (AHR), RAR-related orphan receptor C (RORC), TNF-alpha and IL-6 were respectively determined. Using the method of ELISA, plasma concentrations of IL-22, IL-17 and TNF-alpha were examined. RESULTS: Th22 and Th17 cells were elevated in CC and CIN patients. Th1 cells and the plasma concentrations of IL-22 in CC patients were significantly increased compared with HC. In CC patients, an increased prevalence of Th22 cells was associated with lymph node metastases. There was a positive correlation between Th22 and Th17 cells, but an approximately negative correlation between Th22 and Th1 cells in CC patients. The mRNA expression of RORC, TNF-alpha and IL-6 was significantly high in CC patients. CONCLUSIONS: Our results indicate that there is a higher circulatory frequency of Th22, Th17 and Th1 cells in CC which may conjointly participate in the pathogenesis and growth of CC.

No description available.

No description available.

M.Med., Faculty of Health Sciences, University of the Witwatersrand, 2009 / Objectives Cancer of the cervix is one of the commonest cancers in South African females. Up to 30% of patients are HIV positive. The addition of chemotherapy to radiotherapy has been shown to significantly improve local control and survival and concurrent chemoradiation is the standard treatment for locally advanced cancer of the cervix. There is very limited literature available concerning the tolerance and efficacy of this treatment in HIV positive patients. This study aims to assess the acute toxicity of combined modality treatment in these patients. This study is part of a multicenter International Atomic Energy Agency sponsored study. Materials and methods Patients with FIGO stage IB2 to IIIB (without hydronephrosis) cervical cancer and who are HIV positive, were randomized to receive radiotherapy alone or chemo-radiation. All patients received 46 Gy in 23 fractions external beam radiation and high-dose-ratei brachytherapy 8 Gy x 3 fractions. Chemotherapy consisted of bolus Cisplatin 30mg/m2 weekly given concurrently with the radiotherapy. Acute treatment toxicity was documented weekly during treatment. Results 64 patients were recruited to the study. 31 patients were randomized to the chemoradiation arm and 33 patients to the radiation alone arm. Of the 64 patients recruited to the study, 6 in the chemoradiation arm and 5 in the radiation only arm did not receive any treatment and were therefore not evaluated. Stage IIB was the most common stage. The mean CD4 count was 410 in the chemoradiation arm vs. 358.4 in the radiation only arm at randomization. Only 6 patients were on antiretroviral therapy at start of treatment, 3 in each arm. The number of chemotherapy cycles received by patients in the chemoradiation arm ranged between 0 and 5 cycles. A total of 96 chemotherapy cycles were administered, with a median of 4 cycles per patient. Overall, at least 76% of patients received at least 4 cycles of chemotherapy. The full five intended courses of cisplatin were administered in 10 (40%) patients. Chemotherapy was not administered most commonly due to toxicity (renal, leucopaenia), other reasons being logistical and non compliance. The principle major adverse effects observed were leucopaenia and cutaneous reactions.