Faculty of Medicine and Health Sciences

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The vision of the Faculty of Medicine and Health Sciences is to be a dynamic, people-centred and inclusive environment, internationally recognised for its excellence in research, education and clinical training in medicine and health sciences, and for the contribution it makes to improving health and health care in South Africa, the African continent and beyond.

This faculty was known as the Faculty of Health Sciences until 30 April 2012.

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Assessment of point-of-care testing for prediction of aromatase inhibitor-associated side effects in obese postmenopausal breast cancer patients screened for cardiovascular risk factors
(Stellenbosch : Stellenbosch University, 2021-12) Milambo, Jean Paul Muambangu; Akudugu, John M.; Nyasulu, Peter S.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Global Health. Epidemiology and Biostatistics.
ENGLISH SUMMARY : Background: Aromatase inhibitors (AIs) constitute a standard of care for post- and premenopausal patients with estrogen receptor-positive breast cancer (BC). Obesity and mediators of inflammation have been identified as the most important risk and predictive factors in postmenopausal breast cancer survivors (BCS) using AIs. However, data on the feasibility of point-of-care (POC) genotyping using high sensitivity C-reactive protein (hs-CRP) and body mass index (BMI) as predictors of drug toxicity among postmenopausal BCS in African clinical settings are lacking. Aim: The study was conducted to assess the impact of AIs on hs-CRP and BMI, which are used at POC for prediction of therapy-associated side effects among obese postmenopausal breast cancer patients in Africa. Methods: One hundred and twenty-six female BC patients with cancer stages ranging from 0-III were recruited at Tygerberg Hospital (TBH) in the Western Cape Province of South Africa, between August 2014 and February 2017, for the study. A Quasi-experimental study was conducted. Patients were initially subjected to AIs and subsequently followed up at months 4, 12, and 24. Baseline clinical and biomedical assessments were conducted at commencement of study to predict hs-CRP and BMI at months 12 and 24, using a multiple imputation model. A random effects model was used to monitor the changes over the time. Statistical analyses were performed using SPSS 18.0 software (SPSS Inc., Chicago, IL, USA) and STATA version 16. Analyses were two-tailed and a p-value < 0.05 was considered statistically significant. Results: The mean age of the participants was 61 years (SD = 7.11 years; 95% CI: 60-62 years). Linear regression revealed that hs-CRP was associated with waist circumference (OR: 7.5; p= 0. 0116; 95%CI: 1.45 to 39.61) and BMI (OR: 2.15; p=0.034, 95%CI: 1.02 to 4.56). Waist circumference was associated with hypertension (OR: 3, 83; p= 0.003, 95%CI: 1.56 to 9.39), and chemotherapy was associated with waist circumference by (p= 0. 016; 95%CI: 0.11 to 0. 79). hs-CRP levels were significantly correlated with BMI and total body fat (TBF) among postmenopausal using aromatase inhibitors. Random linear effects modelling revealed stronger statistical association between BMI and homocysteine (p=0.021, 95%CI: 0.0083 to 0.1029). Weight and TBF were strongly associated after 24 months of follow-up. In addition, hs-CRP was associated with BMI (p=0.0001) and other inflammatory markers such as calcium (p=0.021, 95%CI: 0.0083 to 0.1029), phosphate (p=0.039, 95%CI: 0.0083 to 0.1029), and ferritin (p=0.002, 95%CI: 0.0199 to 0.084). Multiple imputation modelling indicated that there were statistically significant variations in TBF, weight, homocysteine, ferritin, and calcium between baseline and after 24 months of follow-up. Mathematical modeling Comparison of genotyping from HyBeacon® probe technology to Sanger sequencing showed that yielded sensitivity of 99% (95% CI: 94.55 to 99.97%), specificity of 89.44% (95% CI: 87.25 to 91.38%), PPV of 51% (95%: 43.77 to 58.26%), and NPV of 99.88% (95% CI: 99.31 to 100.00%). Based on the mathematical model, the assumptions revealed that incremental cost-effective ratio (ICER) was R7 044.55. Conclusion: This study revealed that hs-CRP and BMI are predictors of CVD-related adverse events in obese postmenopausal patients. Calcium, phosphate, homocysteine, and ferritin should also be incorporated in POCT. There were statistically significant variations in TBF, weight, hs-CRP, BMI, homocysteine, ferritin, and calcium between baseline and after 24 months of follow-up. HyBeacon® probe technology at POC for AI-associated adverse events maybe cost-effective in Africa while adjunct to standard practice. The appropriate pathways for implementation of POC testing in postmenopausal breast cancer survivors need further investigation in different clinical settings with real data for external validation.
Evaluation of BCL-2 and PARP-1 as potential therapeutic targets to radiosensitise lung cancer
(Stellenbosch : Stellenbosch University, 2021-12) Guillaume, Muteba Mpolesha; Akudugu, John M.; Serafin, Antonio M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : Lung cancer remains the most incident malignancy worldwide, representing 13% of all cancers. It is also the leading cause of death in the world, accounting for 18 18.2% of global cancer-related deaths. The burden of lung cancer in Africa is increasing due to ag ageing an and population growth, increased prevalence of risks factors such as smoking, occupational exposure, infections, lifestyle changes, and environmental pollutants. The efficacy of many therapeutic strategies has been hindered by normal tissue toxicity and treatment resistance. For many cancer patients, radiotherapy has been the chosen therapeutic option to minimise cancer cell spread by shrinking the tumour while ensuring protection of normal tissue. There is evidence that small molecule inhibitor s can effectively target cell survival signa signalling pathways, but cancer cell cells manage to find molecular escape routes to either repair the damage or evade cell death. Combination therapy appears to be an appropriate approach to address these challenges. Therefore, targeting more than one component of the cell survival signa signalling pathways could potentially sensitise cancer cells to irradiation and improve the outcome of radiotherapy. The purpose of this study was to evaluate the role of targeting the anti-apoptotic (B-cell lymphoma 2 (Bcl -2)) pathway and the DNA repair (poly (ADP ADP-ribose) polymerase 1 (PARPPARP-1)) pathway with specific inhibitors in modulating the radiosensitivity of a lung cancer cell line ( and an apparently normal lung cell line ( For this, Bcl -2 and PARP PARP-1 were inhibited using ABT ABT-737 and ABT ABT-888, respectively. At a dose of 2 Gy, the typical fractional dose in conventional radiotherapy, combined inhibition of Bcl-2 and PARP-1 or inhibition of Bcl-2 alone resulted in significant radio-sensitisation in only the A549 cells. However, at a larger radiation dose of 6 Gy (a potentially useful fractional dose in hypo-fractionated radiotherapy), inhibition of Bcl-2 and PARP-1 markedly radio-sensitised the apparently normal (L132) and malignant (A549) cell lines, respectively. These findings suggest that use of Bcl-2 and PARP-1 inhibitors might be beneficial when combined with conventional radiotherapy, but not with hypo-fractionated radiotherapy when large fractional radiation doses are employed. However, validation of these results with a larger panel of cell lines is warranted.
Evaluation of small molecule inhibitors of HER2, PI3K, mTOR and Bcl-2 for their radiomodulatory effects in human breast cancer cell lines
(Stellenbosch : Stellenbosch University, 2016-12) Hamunyela, Roswita Hambeleleni; Akudugu, John M.; Serafin, Antonio Mendes; Stellenbosch University. Faculty of Medicine and Health Science. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : Breast cancer remains the most commonly diagnosed cancer in women. It is responsible for 32% of all cancers and 15% of all cancer-related deaths in females. Patients with triple-negative breast cancers (TNBC) constitute about one-fifth of all breast cancer patients. TNBC is an aggressive and heterogeneous disease entity in comparison with other types of breast cancer and, therefore, tends to be resistant to existing treatment regimens, such as, targeted and hormone therapies. Although cancer treatment has evolved from being invasive and highly toxic to being more specific with reduced normal tissue toxicity, intrinsic tumor resistance still limits the benefit of therapy with radiation, drugs, and antibodies. To address this important clinical challenge, attempts have been made to better understand the molecular determinants of treatment resistance. This resistance can be attributed to the heterogeneity in the distribution of potential target antigens in a given tumor cell population, which leads to the inability to effectively target all cells with toxic levels of a particular therapeutic agent. There is evidence to suggest that proliferative pathways of triple-negative tumors are still poorly understood, which could be the reason for the observed treatment resistance. Targeted treatment modalities that are singly effective for triple-negative breast cancer are lacking, partly due to paucity of relevant targets as they are devoid of the human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and oestrogen receptor (ER). Novel treatment approaches are, therefore, needed to overcome the challenges in the treatment of triple-negative breast cancers if treatment outcomes are to be improved. Concomitant targeting of cell signaling entities other than HER2, PR and ER may sensitize triple-negative tumors to radiotherapy. In this study, inhibition of HER2, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and the pro-survival gene (Bcl-2) with small molecule inhibitors, TAK-165 (against HER2), NVP-BEZ235 (against PI3K and mTOR), and ABT-263 (against Bcl-2), singly or as cocktails, resulted in significant radio sensitization of human breast cell lines with features similar to those of triple negative cancers. This radio sensitization was seen at 2 and 6 Gy, indicating that a therapeutic benefit could be derived in conventional as well as stereotactic radiotherapy. A moderate to strong synergism was also demonstrated for NVPBEZ235/TAK-165 and NVP-BEZ235/ABT-263 cocktails. The strongest synergy was seen in the latter cocktail. In conclusion, inhibition of PI3K, mTOR and Bcl-2 could potentially be effective in the treatment of triple-negative breast cancer. The therapeutic benefit can be improved, if the target inhibition is followed by radiotherapy.
Evaluation of the effect of low and intermediate frequency electromagnetic waves on radiosensitivity
(Stellenbosch : Stellenbosch University, 2016-12) Chinhengo, Angela; Akudugu, John M.; Serafin, Antonio M.; Stellenbosch University. Faculty of Medicine and Health Science. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : The incidence of epidemic Kaposi’s sarcoma in HIV/AIDS patients is high due to their compromised immune system. HIV-positive individuals presenting with cancer tend to be more sensitive to ionizing radiation and are at a higher risk of developing severe side effects during radiotherapy, and there is a need to develop non-invasive methods to preferentially sensitize cancer cells and reduce therapeutic doses. Here, the effects of 100 and 1000 Hz electromagnetic fields (EMF) broadcast via an argon plasma ray tube at 50 W on the radio sensitivity of apparently normal Chinese hamster lung fibroblasts (V79) and human malignant melanoma cells (MeWo) were evaluated using the colony forming assay. Pre-exposure of the fibroblasts to both fields had no effect on their radio sensitivity, if X-ray irradiation followed within 2 h or at 6 h. Significant radio sensitization was observed when X-rays were administered 4 h after EMF exposure. For the MeWo cells, pre-exposure to 100 Hz resulted in a significant radioprotection when irradiation followed within 6 h. However, treatment of these cells with a 1000 Hz field significantly potentiated the effect of X-rays. When cells were irradiated prior to EMF exposure, the V79 cells were marginally protected by the 100 Hz field and sensitized by the 1000 Hz field. In contrast, the melanoma cells were slightly protected by the 1000 Hz field and sensitized by the 100 Hz field. The survival rate of the normal fibroblasts when treated with 2 Gy, in two fractions of 1 Gy 6 h apart, was similar to those obtained when cells received an acute dose of 2 Gy 6 h prior to or after exposure to both EMF frequencies. On the other hand, the melanoma cells were significantly sensitized when they were either treated with a combination of X-rays and then 100 Hz EMF 6 h later or with a combination of either of the EMF frequencies and then X-rays 6 h later. These data suggest that use of electromagnetic fields may sensitize tumours to radiation therapy and reduce normal tissue toxicity. Informed and well-designed combinations of low-medium frequency electromagnetic fields and radiation therapy might be beneficial in the management of cancers, especially epidemic Kaposi’s sarcoma.
Novel treatment strategies for breast, lung and cervical cancer
(Stellenbosch : Stellenbosch University, 2019-12) Hamid, Mogammad Baahith; Akudugu, John M.; Serafin, Antonio M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Radiobiology.
ENGLISH SUMMARY : Cancer continues to be a global health burden, especially in the economically developing regions. The complex nature of this cancer contributes to a range of clinical challenges. Breast, lung and cervical cancer are known to have the highest incidence and mortality rates globally. Although many therapeutic options are available to treat cancer, the efficacy of most therapies is hindered due to normal tissue toxicity and tumour resistance. Novel treatment strategies are thus warranted to address clinical challenges and significantly improve patient outcomes. More than 50% of cancer patients receive radiotherapy throughout their illness. DNA damage resulting in cell death, as a consequence of ionising radiation exposure, has assisted in clinical tumour management. However, inherent and acquired resistance as well as the manipulation of essential pathways, like cell metabolism, have aided cancer cells to evade the toxic effects of radiotherapy. Increasing the therapeutic window of this treatment modality may benefit a large number of patients. There is evidence to suggest that ionising radiation may activate cell survival signalling pathways. Targeting the components of these pathways may modify cell metabolism and significantly radiosensitise cancer cells. Therefore, combining targeted therapy and ionising radiation may be a viable therapeutic strategy. The objective of this study was to inhibit molecular targets of key pathways which regulate cell survival, and expose breast, lung, cervical cancer and normal cell lines to doses of radiation, so as to establish potential therapeutic targets that may be amenable to combined modality therapy, and formulate a cocktail of inhibitors to evaluate its radiosensitising capability and effect on cellular metabolic activity. In this study, clonogenic assays were performed to determine the relative sensitivity of 6 cell lines (cancer: MDA-MB-231 (breast), MCF-7 (breast), HeLa (cervix) and A549 (lung); apparently normal: L132 (lung) and MCF-12A (breast)) to ionising radiation and inhibitor therapy. Mathematic modelling was used to determine the mode of interaction between EGFR, PI3K/mTOR, and BcL-2 inhibitors, as well as, the modifying effects of inhibitors on the radiosensitivity and metabolic activity of the cell lines. This study found that potential therapeutic benefit might be obtained by treating MDA-MB-231, MCF-7, HeLa and A549 cells with X-rays. The MCF-7 cell line showed the highest potential of therapeutic benefit with a greater than 2-fold higher radiosensitivity, relative to the normal MCF-12A cells. The A549 cell line showed the lowest potential for therapeutic benefit, when compared with the L132 cell line. Inhibition of PI3K and mTOR with NVP-BEZ235 resulted in a significant therapeutic benefit for the lung and cervical cancer cell lines, minor therapeutic benefit in the MCF-7 cell line, and no benefit for the MDA-MB-231 cell line. Bcl-2 inhibition with ABT-263 had either no effect on the MDA-MB-231 and A549 cell lines or resulted in potential therapeutic benefits for MCF-7 and HeLa cell lines. Pre-treatment of breast (MDA-MB-231 and MCF-7) and lung (A549) cancer cell lines with a cocktail of an EGFR (AG-1478), PI3K/mTOR (NVP-BEZ235), or Bcl-2 (ABT-263) inhibitors had an enhancing effect on radiosensitivity and cellular metabolic activity. The same treatment provided radioprotection, and reduced the metabolic activity of the cervical cancer cell line, HeLa. These findings suggest that concurrent inhibition of EGFR, PI3K, mTOR, and Bcl-2 during radiotherapy might improve the treatment response of breast and lung cancer in patients. Future studies validating these findings for lower inhibitor concentrations might be more relevant in the clinical setting, as systemic toxicity is a major concern. A study exposing cells to fractionated radiotherapy, after inhibitor pre-treatment, may further reveal the therapeutic potential of the inhibitors used in this study. Evaluating the effect of inhibitor pre-treatment and radiofrequency field, which have been shown to exhibit radiomodulatory effects on cancer and normal cell lines, may provide insight into the development of a novel therapeutic strategy.
Radiosensitisation of low HER-2 expressing human breast cancer cell lines
(Stellenbosch : Stellenbosch University, 2015-04) Hamid, Mogammad Baahith; Akudugu, John M.; Serafin, Antonio M.; Stellenbosch University. Faculty of Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH ABSTRACT: Breast Cancer remains one of the world’s leading causes of cancer related deaths amongst women. Its treatment has evolved from invasive, highly toxic therapies to treatments that possess a higher specificity and a lower toxicity. Despite improvements in overall survival, many patients do not benefit from these agents because of acquired and/or inherent tumour resistance, which could hinder treatment efficacy. Novel treatment strategies are, therefore, warranted to address these challenges and to significantly improve patient responses. Inhibiting components of the HER-2 signalling pathway can significantly sensitise breast cancer cells to low doses of ionising radiation. The objective of this study was to inhibit key molecular targets of the human epidermal growth factor receptor 2 (HER-2) signalling pathway and expose breast cancer cell lines to doses of radiation, so as to establish potential therapeutic targets that may be amenable to combined modality therapy, and formulate a cocktail of inhibitors to evaluate its radiosensitising capability. This study found that pre-treatment of two breast cancer cell lines (MDA-MB-231 and MCF-7) with a HER-2 inhibitor (TAK-165) had little or no effect on radiosensitivity. However, a radiation enhancement was observed when these cells were pre-treated either with BEZ235, a dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target for rapamycin (mTOR), or a cocktail of TAK-165 and BEZ235. These findings suggest that concurrent inhibition of HER-2, PI3K and mTOR during radiotherapy might improve treatment response of breast cancer patients.
A retrospective analysis of toxicity and outcomes following chemotherapy for the older population at a single institution
(Stellenbosch : Stellenbosch University, 2018-03) Pupwe, George; Fourie, Anna Elizabeth; Akudugu, John M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Radiation Oncology.
ENGLISH SUMMARY: Introduction: Surgical treatment of colorectal cancer (CRC) in elderly patients has improved, but data on adjuvant and palliative chemotherapy tolerability and benefits in this growing population remains scarce. The elderly population is mostly underrepresented in clinical trials and results for this group of patients are seldom reported separately. Patients and method: Using a retrospective study, we analyzed demographics, compared toxicities in the age groups < 70 years and ≥ 70 years in colorectal cancer patients at Tygerberg Hospital (South Africa). We assessed tumor related mortality, progression free survival (PFS) and overall survival (OS) including predictive factors of OS. Results: A total of 50 patients received either adjuvant or palliative chemotherapy. Different chemotherapy regimens were used. There was no difference in overall or severe (Common Toxicity Criteria Grades 3-4) toxicity in both age groups. Out of the 50 patients, 8 (16%) had Grade 3-4 toxicity. Of these 4 (15%) were < 70years, 4 (17%) were ≥ 70 years. The progression free survival (PFS) and overall survival (OS) were measured using Kaplan-Meier curves. The mean follow-up time was 47.5 months (range: 14.4-80.8 months, 95% CI 41.5-53.5 months). The 5-year overall survival rate for Stage II&III patients <70 years and ≥70 years were 80.9% and69.5%, respectively, and not significantly different; P=0.5156; HR=0.65 (95% CI: 0.17-2.41). Also, no statistically significant difference emerged between the 5-year progression free survival rates of 70.7% and 58.8%; P=0.4920; HR=0.68 (95% CI: 0.23-2.04). For Stage IV patients, there were no significant differences in survival in both groups. There were no survivors beyond 40 months. Median survival rates were similar at 16.3 months (for < 70 years) and 15.9 months (for ≥ 70 years); P=0.8105; HR=1.14(95% CI: 0.35-3.81). There were also no progression free survivors beyond 23 months. Median PF survival rates were 11.1 months (for < 70 years) and 13.5 months (for ≥ 70 years), and were not significantly different; P=0.1743; HR=1.99 (95% CI: 0.66-9.67). Weight loss and performance status (PS) were evaluated as potential predictive factors of OS. For Stage II&III patients of <70 and ≥70 years of age, 68 and 84% of patients presented with a weight loss of <5%, respectively. The corresponding proportions of Stage IV patients were 75 and 100%. Also, 84 and 100% of Stage II&III patients <70 and ≥70 years, respectively, had a PS of 1. All Stage IV patients had a PS of 1. Conclusion: “Fit” elderly patients benefit, at least to the same extent, from adjuvant and palliative chemotherapy as younger patients in this cohort. Therefore, standardized adjuvant and palliative chemotherapy could be offered to elderly patients and they should not be excluded from clinical trials.
Treatment of advanced salivary gland tumours with neutron radiotherapy
(Stellenbosch : Stellenbosch University, 2016-12) Lombe, Dorothy Chilambe; Simonds, Hannah; Akudugu, John M.; Stellenbosch University. Faculty of Medicine and Health Science. Dept. of Medical Imaging and Clinical Oncology. Radiation Oncology.
ENGLISH SUMMARY : Background: Success rates in the treatment of salivary gland malignancies are associated with completeness of surgical resection with or without postoperative radiotherapy. For patients with unresectable tumours, radiotherapy is an option to attempt to gain local control and improve survival. Different modalities of radiotherapy are available and fast neutrons represent a form of radiotherapy effective in controlling locally advanced salivary gland malignancies. We report on 22 patients treated for locally advanced parotid gland malignancies at iThemba Laboratory for Accelerator Based Sciences via a tertiary institution in Cape Town, South Africa. Methods: Records of patients with unresectable parotid gland malignancies treated with neutron radiotherapy at a tertiary institution between January 1991 and December 2012 were reviewed retrospectively. Twenty-two patients were eligible for statistical analysis. Results: Complete, partial and no response rates were 64%, 14% and 22%, respectively. Of the 14 patients with a complete response, 3 recurred with the earliest recurrence being at 18 months. Locoregional control was 80% and 69% at 2 and 5 years respectively. Twelve out of the 22 patients died post treatment. Overall survival at 2 years was 40% and at 5 years 35%. Seven cases of CTCAE grade 3 and above late toxicities were observed. These included bone necrosis, eardrum perforation and skin ulceration. Conclusions: Treatment modality of this group of patients depends on availability. Response rates of parotid gland malignancy to neutron radiotherapy in this small cohort are comparable to historical controls.

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