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 Medicine in Diagnostic Radiology Johannesburg, 2019 / INTRODUCTION Breast cancer is one of the leading causes of cancer deaths worldwide. Triple negative breast Cancer (TNBC) is an aggressive subtype, commonly described as presenting at a younger age, in women of African descent and in low socioeconomic groups. Commonly it demonstrates benign imaging features making diagnosis a challenge. Early detection and treatment is imperative. AIM To determine the common imaging features of TNBC in South Africa. METHOD A retrospective study was conducted at a tertiary institution in South Africa. the study population included all biopsy proven TNBC patients presenting between 01/01/2012 – 30/06/2016. All the initial mammograms were re-read by three independent radiologists using a data collection sheet. Illegible or incomplete reports were excluded from the study. RESULTS In our population, TNBC commonly presented in African women with an average age of 54.2 and range 25-95 years, with 47% being pre-menopausal. Typical mammographic features were an oval (27%) or irregular (27%) shaped mass with well circumscribed margins (33%). Our lesions were much larger than those reported in the literature (1). Global asymmetry and architectural distortion were commonly associated features. On ultrasound, the lesions were mostly irregularly shaped (56%) with spiculated borders (29%) and hypoechoic (80%) with axillary adenopathy (81%). CONCLUSION The majority of our patient population presented with a clinically palpable mass, that was larger and had more aggressive features than usually described in the literature. This can be attributed to delayed presentation, due to numerous factors. In order to improving the detection rate and reduce mortality, education and screening programs play a major role. / E.K. 2019

Inflammatory Breast Cancer (IBC) is a rare, lethal, and understudied form of breast cancer. Although affecting 1-2% of the population, the remission rate is half that of the spectrum of other breast cancers, and most cases present in the advanced stages due to rapid undetectable development. Of the diagnosed cases, systemic chemotherapeutics are relatively ineffective in comparison to non-IBC breast cancer cases, indicating other unique mechanisms driving IBC progression. Historically, the specific sensitivities of a particular tumor type or subtype have been linked to genetic alterations that represent addiction hubs, such as hyperactivation of oncogenes due to mutation. Although some efforts have been made to characterize the molecular fingerprint of inflammatory breast cancers (IBCs), unfortunately, no clinical application has emerged from these studies. Thus, we decided to utilize a different strategy to identify the Achilles' heel of IBC cells. Using shRNA libraries, we performed an unbiased genome-wide loss-of-function screen comparing the gene functions required for survival of IBC and non-IBC cells. Histone deacetylase 6 (HDAC6) emerged as one of the top genes required for IBC cell survival and was further validated. HDAC6 is vital in the cell's unfolded protein response (UPR) to clear misfolded or toxic protein, and IBC cells proved to be preferentially sensitive to this aspect of HDAC6 inhibition, displaying increased protein accumulation, ER stress indicators, and subsequent apoptosis upon failure to clear or refold accumulated proteins. These data indicate HDAC6 is a crucial gene required for IBC cell line survival, in part due to its function in IBC cell UPR. Furthermore, emerging orally bioavailable agents for HDAC6 inhibition make it a promising candidate towards tailored therapeutic implementation in IBC patient trials.

published_or_final_version / Public Health / Master / Master of Public Health

published_or_final_version / Pathology / Master / Master of Philosophy

M. Tech. / AIM: To determine the efficacy of Astragalus membranaceous tincture at maintaining the circulating white blood cell count (WBC) and absolute neutrophil count (ANC) of breast cancer patients receiving chemotherapy. METHODS: This is an open-label study with an active control group. Both the study and control group consisted of fifteen participants. The participants in the study group each received ten millilitres of Astragalus membranaceous 1:2 tincture daily for the duration of their course of chemotherapy. RESULTS: The overall decrease in the WBC and ANC in the control was 4.9 and 3.13 parts per billion per litre, respectively. The study group showed an overall decrease of 2.7 and 1.9 parts per billion per litre, respectively. The average overall reduction in chemotherapy dose was 4.79 percent in the study group and 20.21 percent in the control. In all of the analyses p > 0.05. The small sample size, poor patient compliance and skewed distribution of the variables hindered the reliability of the results. CONCLUSION: The positive effects observed in the study group cannot be extrapolated to the entire population, however further research is strongly motivated.

>Magister Scientiae - MSc / Breast cancer is responsible for a large portion of cancer-related deaths. Worldwide, incidence is increasing. Routinely-used treatments for breast cancer are invasive and are associated with a range of side-effects which may affect quality of life. Fucoidan, a marine bioactive compound, found primarily in brown seaweed, has various medicinal qualities. Among its bioactivities studied, it has potent anticancer activity. Despite numerous studies, the mechanism of action of fucoidan on cancer cells remains unclear. This project aims to shed light on the mechanism of action of fucoidan by studying its effect on the MCF7 breast cancer cell proteome. The IC50 obtained for fucoidan treated MCF7 cells was 0.2 mg/ml. Decrease in expression of XIAP and phosphorylation of ERK1/2 was observed, indicating a decrease in inhibition of apoptosis and increased sensitivity to apoptosis, respectively. Literature reports activation of several caspases, including caspase-3, in various cell lines after to fucoidan treatment. Taken together, with data from the current study it can be said that fucoidan treatment led to cell death by apoptosis. SILAC analysis identified over 2000 proteins with more than 1700 at 95% confidence. STRING analysis of enriched proteins revealed 19 cell death related proteins. However, SILAC results were ambiguous with regards to differential protein regulation and should be repeated with lower electrospray ionization flow rates, pairwise and single sample runs, and validation with Western blot analysis of various apoptosis related proteins and biochemical assays. / National Research Foundation

Breast cancer is one of the leading causes of death, with mortality rate estimates of 465 000 deaths per annum. It is estimated that 1.3 million women are diagnosed with the disease each year especially in the developing countries. Current chemotherapy relies on the use of high doses of non-specific toxic agents that possess adverse side effects and compromise patient’s compliance and adherence to treatment. Paclitaxel, one of the common drugs used in breast cancer chemotherapy results in sensory and motor neuropathy, whilst hormonal therapy e.g. Herceptin causes severe cardiovascular, gastrointestinal and cutaneous side effects. There has been a demand in developing newer cancer agents that demonstrate selective cytoxicity with minimal effect on normal body tissue. Numerous studies have shown that marine organisms produce a wide range of halogenated compounds that possess cytotoxic properties, and hence can be a source of new drug hits or leads for cancer therapy. Halomon, a polyhalogenated monoterpene from Portieria hornemannii, displayed interesting activity against brain, renal and lung cancer tumours with selective/differential cytotoxicity. This inspired us to focus our project on halogenated monoterpenes isolated from the same Rhodophyta class as P. hornemannii but with particular attention to Plocamium species. Several metabolites have been isolated from P. cornutum, P. corallorhiza and P. suhrii that possess interesting cytotoxicities against a breast cancer cell line (MCF7) and an oesophageal cancer line (WHCO1). The aim of the project was therefore centred at isolating target compounds for preliminary structure-activity studies against a breast cancer cell line, and use this information to synthesize a series of analogues that are more stable than the natural products and yet as active using a fragment-based type approach to map out pharmacophoric elements. Five metabolites were isolated from P. cornutum and five from P. corallorhiza. Cell-based assays were conducted using an MTT assay kit against MCF7 and MDA-MB-231 breast cancer cell lines and (1E,3E,5S,6R)-1,5,6-trichloro-2-(dichloromethyl)-6-methylocta-1,3,7-triene, isolated from P. cornutum was the most active with IC50 values of 3.0 μM and 6.15 μM respectively. Introduction of a terminal aromatic ring to enhance stability, together with varying substituents (H, CH3, CF3, Br, CN, CHO, CHCl2) on position 7 of the molecule, gave rise to a series of cinnamate ester derivatives inspired by (1E,3E,5S,6R)-1,5,6-trichloro-2-(dichloromethyl)-6-methylocta-1,3,7-triene. The analogues were synthesized from their benzaldehyde precursors via Aldol condensation, esterification and Wittig reactions. Their carboxylic acid counterparts were synthesized by hydrolysis of the parent esters in an attempt to promote water solubilities of the analogues. Biological activity assays were then conducted with the cinnamate analogues against the MDA-MB-231 breast cancer cell line using an MTT assay kit. Ester derivatives with -CHO and -CHCl2 functionalities had IC50 values of 43.45 μM and 100.01 μM respectively whilst the other ester derivatives were inactive. It was concluded that either an aldehyde (-CHO) or gem-dichlorides (-CHCl2) is specifically required for cytotoxic activity to be observed. None of the carboxylic acids were active which could have been due to failure of the compounds to enter the breast cancer cells and reach the target site because of their polar nature. Compounds with -CHO and -CHCl2 functionalities were therefore selected for future SARs studies.

M.A. / The aim of this study was to ascertain the coping methods of women in long term follow-up of breast cancer treatment. Furthermore, personality traits that deal with the spectrum of positive affectivity were introduced to determine whether these impact on women's appraisal of their situation and their subsequent choice of coping mechanism. Thus, a process approach to exploring coping strategies and a goal-attainment conceptualization of hope were used to determine whether hope is associated with coping appraisal in the long term follow-up of breast cancer treatment. Furthermore, high hope women were expected to use more problem focused coping methods and low hope women were expected to use more emotion focused coping skills. Women in cancer remission who attend yearly or six-monthly check-ups at the Johannesburg hospital were approached to complete the questionnaire and brief interview. Although the study did not confirm that low hope and high hope women use different kinds of coping strategies, the predicted relationship between hope and challenge appraisals was supported by significant correlations. However, it was found that hope may be analogous to positive affect, thus indicating the need for further validation of the Hope Scale. Finally, it was concluded that breast cancer need not be seen as a devitalising disease and that there are a variety of coping strategies which can be utilized to enhance patient's positive emotional state. The women in this study use the emotion focused coping skill of positive reappraisal which concentrates on the possibilities for mastery and growth that inhere in their long term follow-up treatment. Moreover, women are extremely positive and hopeful in their daily outlook and while this personality trait seems to suggest that denial is at play, it is more likely that women in long term remission have a strong belief in their own personal qualities and future. Women in this study choose to distance themselves from the implicit trauma of the threat of recurrence in favour of an active belief in their personal resilience to overcome any stressful event or outcome.

A simple method to verify the total treatment time generated by the treatment planning system (TPS) when the CONTURA MLB or the SAVI applicator are used for APBI treatments has been developed. The method compares the time generated by the TPS to a predicted time, calculated by inserting parameters obtained from the TPS in equations generated in this Thesis. The equations were generated by linearly fitting data from clinical cases that had been treated using the Contura MLB or the SAVI applicator at the Lynn Cancer Institute of the Boca Raton Regional Hospital. The parameters used were the PTV coverage, Air Kerma Strength, Balloon Volume (Contura data fit) and Evaluation PTV (SAVI data fit). As an outcome of this research, it is recommended that the plan should be reevaluated when the percent difference between the generated and the predicted times exceeds 5% for the Contura MLB, or 10% for the SAVI. / by Andreas Kyriacou. / Thesis (M.S.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

Accelerated Partial Breast Irradiation (APBI) is a common treatment of breast cancer with many modalities including 3D Conformal Radiation Therapy (3D-CRT), Intensity Modulated Radiation Therapy (IMRT), and High Dose Rate Brachytherapy (HDR). In this research, a retrospective analysis of patient’s data was performed to analyze the NTCP/TCP (Normal Tissue Complication Probability/Tumor Control Probability) and Dose Volume Histogram (DVH) parameters for HDR with SAVI, 3D, and IMRT and compare them focusing on critical organs such as the heart, ipsilateral lung, chest wall, ribs, and skin. TCP was 90.275%, 55.948%, and 53.369% for HDR, 3D, and IMRT respectively. The ribs were the most sensitive critical organ for all 3 modalities with a mean NTCP of 8%, 15%, and 8% for HDR, 3D, and IMRT respectively. DVH analysis showed HDR spares critical organs more than EBRT except for 2 patients receiving high doses to the ribs and chest wall. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2019. / FAU Electronic Theses and Dissertations Collection