ETD Collection
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Item The role of geographical distance and referral patterns on stage at presentation in South Africa: a review of two South African breast units(2024) Pothas, CatharinaIntroduction: Historically breast cancer incidence has been low in Africa but now accounts for most cancer deaths in women in many sub-Saharan African countries. The purpose of this study is to examine the role of referral patterns and geographical distance on the stage at presentation. Methods: This retrospective cross-sectional study was undertaken at the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) and Chris Hani Baragwanath Academic Hospital (CHBAH) breast units from July 2015 to September 2017. The participants were grouped into both early (I and II) and advanced (III and IV) stage breast cancer. Demographic data (age, residential distance, referral pattern) and histological characteristics (immunohistochemistry and grade) were compared. Bivariate logistic regression models were applied on all variables with a subsequent multivariate analysis on all statistically significant variables. Results: Of the 1008 participants enrolled in the cohort, 55% presented with advanced stage disease. Referral pattern was statistically significant on bi- and multivariate analyses with a 50% increased risk of having advanced disease following indirect referral (from secondary hospital or specialist) regardless of other socio-demographic or histological characteristics (p<0.001, OR = 1.49, 95%CI 1.13-1.97). Geographical distance had no influence on stage at presentation (p=0.075, OR = 1.36, 95%CI 1.03-1.80). Conclusion: Referral patterns play an important role as a barrier to care in the South African public sector. Direct referral routes are needed with simple access to specialised breast unitsItem Recurrence rate in stage iv breast cancer patients: a retrospective cohort study(2024) Grobler, LeandaMetastatic breast cancer (mBC) remains incurable, with a median overall survival (OS) of approximately three years and a five-year survival rate of approximately 25%, irrespective of the economic classification of the country where treatment is received. Cyclin-dependent kinase (CDK) inhibitors increase overall survival in both first and second-line settings in the treatment of human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor (HR)-positive mBC. This retrospective cohort study investigated the progression-free survival in women with mBC receiving combination therapy with abemaciclib (CDK4/CDK6 inhibitor) and letrozole or fulvestrant as opposed to abemaciclib only. The study included all eligible women with stage IV breast cancer treated with abemaciclib at a private oncology facility in Johannesburg over the study period. Data was collected from medical records for the period 01 April 2019 to 31 March 2021. In women with stage IV mBC, analyses were performed to evaluate the overall survival rate, the likelihood of progression-free survival, and the safety of abemaciclib. The progression-free survival probability was 60% after a period of 17 months irrespective of treatment options. After 17 months, the OS of women on a combination of abemaciclib and letrozole was 80%, a combination of abemaciclib and fulvestrant was 80%, and abemaciclib monotherapy was 70%. The most noted adverse effects were diarrhoea (92.0%), fatigue (48.0%), hepatotoxicity (16.0%) and neutropenia (92.0%). Abemaciclib with endocrine therapy or an aromatase inhibitor (AI) provided an improvement in the OS compared to abemaciclib monotherapy. These findings are representative of the use of abemaciclib in a local population and are similar to those of larger studies carried out internationally.Item The roles of miRNA-128 and miRNA-223 in cholesterol-mediated drug resistance in breast cancer(2024) Palma, Gabriella Bianca HenriquesBreast cancer (BC) is the most prevalent cancer in women, with 70% of BC cases being hormone responsive (estrogen receptor positive (ER+)). This ER+ BC subtype relies on estrogen for enhanced cell proliferation and survival. The main therapeutic strategy to prevent hormone responsive BC recurrence is with the use of endocrine therapy such as Tamoxifen (TAM). Despite the success in reducing mortality rates of BC patients with the use of adjuvant TAM and chemotherapy, cancer drug resistance remains a significant challenge. A major contributor to this resistance is the dysregulation of cholesterol homeostasis in these cells. BC cells have elevated intracellular cholesterol levels, which is associated with cancer progression. In our previous research, we observed that the use of a cholesterol depleting agent, Acetyl Plumbagin (AP) in combination with TAM, led to the induction of cell death via cholesterol depletion. These results therefore warranted further investigation into the molecular mechanisms in which TAM + AP are involved in. MicroRNAs (miRNAs) regulate cholesterolrelated and cancer drug resistance pathways, and the aberrant expression of these miRNAs are often associated with increased cancer proliferation and resistance. It was therefore predicted that manipulating the expression of these target miRNAs could lead to a reduction in BC related drug resistance via cholesterol depletion. Thus, we aimed at investigating the roles of miRNA128 and miRNA-223 in cholesterol-mediated TAM resistance. Three BC cell lines (MCF-7 (estrogen-dependent), MDA-MB-231 (estrogen-independent), and Long-Term Estrogen Deprived (LTED)) were treated with a combination of 1 µM TAM and 10 µM AP following transfection with a miR-128 inhibitor or a miR-223 mimic. Cell viability and cholesterol levels were assessed following treatments. In addition, gene and protein expression levels involved in cancer drug resistance and cholesterol homeostasis were also assessed. It was found that the combination treatment with altered miRNA expression led to reduced cell viability and proliferation due to a reduction in free cholesterol, cholesteryl esters, and lipid rafts in all three BC cell lines. Moreover, miR-128 inhibition lowered the expression of genes involved in cholesterol synthesis and transport (HMGCR, HMGCS1, SREBF1/2, CETP, LCAT, and LDLR), drug resistance (ABCC5 and UGCG), and cell signalling (ESR1, EGFR, and IGF1R) in MCF7 cells. Whereas overexpression of miR-223 led to decreased expression in EGFR, ESR1, ABCC5, CETP, LCAT, LDLR, HMGCR, SREBF1, and SREBF2, with increased expression in ABCG1, PTEN, and TP53 in MDA-MB-231 cells. Therefore, the current study demonstrated that miR-128 and miR-223 could be potential targets in reducing TAM resistance through the depletion of excess cholesterol.Item The effect of imidazo [1,2-a] pyridine amines on MCF-7 and MDA-MB-231 breast cancer cells(2015) Kurebwa, Taurai, Flloyd.Breast cancer, is the most frequently diagnosed cancer in women and is associated with high mortality rates in South Africa. There is a high prevalence of metastatic breast cancer and triple negative tumours, which are associated with poor prognosis. In this study, the response of two breast cancer cell lines, MCF-7 and MDA-MB-231, were evaluated when treated with novel imidazo[1 ,2-a]pyridine amines. The compounds were synthesized by the School of Chemistry of the University of the Witwatersrand using the Groebke-Blackburn-Bienayme multicomponent reaction and tested for purity by elemental analysis. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay was used to determine the cytotoxic effects of test compounds on breast cancer cells and the toxic effect of compounds on non-tumorigenic unstimulated peripheral leukocytes. IC50 values of test compounds were calculated from sigmoidal dose response curves. The morphology of cells exposed to test compounds was assessed by fluorescent microscopy using Hoechst 33342, acridine orange and ethidium bromide. The ability of test compounds to induce apoptosis was measured by a colorimetric caspase-3 assay and a fluorometric Annexin-V-FITC assay. Monodansylcadaverine was used to determine if autophagic vacuoles were formed after exposure to test compounds. Three imidazo[1,2-a]pyridine amines, JD88, JD253 and JD256, were more cytotoxic to MCF-7 than to MDA-MB-231 cells. MCF-7 cells showed morphological features associated with apoptosis, and proteolysis by caspase-3/7 was observed after MCF-7 cells were exposed to JD88 for two hours. Vacuole formation induced by these compounds was not autophagic in since they did not co-localize with MDC florescent clusters. This together with the exposure of phosphatidylserine to the outer surface of MCF-7 cells suggests that apoptosis is induced in these cells. There was no evidence of cytochrome c translocation to the cytoplasm, which indicates that the intrinsic pathway of apoptosis is not activated. MDA-MB-231 cells treated with JD88, JD253 and JD256 were large with multiple nuclei and decondensed chromatin, morphological features associated with mitotic catastrophe. The cells also showed morphological features associated with necrosis and apoptosis, which include loss of cell membrane integrity and cell membrane blebbing respectively. MDA-MB-231 cells exposed to JD88 showed marked exposure of phosphatidylserine and this was observed to a minor extent in cells exposed to JD253 and JD256. Proteolysis by caspase-3/7 was activated in MDA-MB-231 cells exposed to JD88 as early as 2 hours after exposure. In conclusion three compounds; JD88, JD253 and JD256 were able to induce apoptosis in MCF-7 cells. These compounds were selectively toxic against MCF-7 cells compared to MDA-MB-231 cells and JD256 in particular was less toxic to leukocytes, which may translate to fewer serious adverse effects. Addition of a copper dioxygen complex to these compounds increases activity against both breast cancer cells. JD88 in particular has shown effective induction of apoptosis and this merits further investigation into its potential as a lead compound in breast cancer therapy.Item "We're living in an era of facebook and blogs. It's a familiar and comfortable space" : exploring the use of virtual support groups by women diagnosed with breast cance.(2012-07-02) Kgatitswe, Lesego BerthaThis research project explores the use of virtual support groups by women diagnosed with breast cancer in South Africa. Through a content analysis of the online forums and eight in-depth interviews with women of various backgrounds (age, race and socio-economic status) it becomes evident that women use these virtual spaces for information exchange, sense of belonging, search for meaning and most significantly support. Various factors within the illness experience of breast cancer influence the initial use, continuation, breaks and withdrawal from of these online forums. The analysis of online forums is framed around concepts of lay consultation, gender, adaptation theory and social capital to conceptualise and make sense of these virtual interactions. The virtual groups allow women to read and write on breast cancer according to their perceptions and experiences, thereby lessening the dominant medical power to create space for their personal voices. The interactions on the forums foster a sense of empowerment, social support and social engagement critical to their wellbeing and adaptation to the condition. This study also brings attention to the lack of studies about virtual groups within the South African context which is increasingly becoming significant as more and more individuals use virtual groups as part of health lay interaction and consultation.