Department of Pathology

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A 10-year review of fatal community assault cases at a regional forensic pathology facility in Cape Town, South Africa
(Health and Medical Publishing Group, 2015) Herbst, Celeste Ingrid; Tiemensma, Marianne; Wadee, Shabir Ahmed
Background. An increase in autopsied community assault (CA) fatalities was observed at the Tygerberg Forensic Pathology Services (FPS), Cape Town, South Africa (SA). There is a paucity of information on the incidence and prevalence of these cases in SA. Objectives. To determine the patterns and trends of injuries sustained in so-called CA fatalities. Methods. A retrospective and descriptive study was conducted. Fatal CA cases admitted to the Tygerberg FPS over the 10-year period 1 January 2003 - 31 December 2012 were reviewed. Data were collected from autopsy/postmortem reports, contemporaneous notes, attached hospital records, the South African Police Services (SAPS) 180 form (completed by the SAPS representative) and other FPS documentation. Results. A total of 424 cases of fatal CA were seen during the study period, with an annual increase between 2003 and 2007 and a second peak in 2012. The cause of death in most cases was multiple injuries (42.0%), with blunt-force trauma being the basis of most injuries sustained. The area with the greatest burden of injury was the township of Mfuleni (73 CA deaths per 100 000 population). There was a predominance of males, with only one female fatality recorded. Conclusion. Adequate policing in prevalent areas is essential to address unnecessary loss of life and the burden imposed by these cases on the criminal justice system and healthcare services.
38 years after its discovery, Ebola virus spins out of control
(South African Centre for Epidemiological Modelling and Analysis (SACEMA), 2014-09) Preiser, Wolfgang
The evolutionary origin of Ebolaviruses is not very clear. The simple notion that these viruses have been circulating for many millennia in wildlife in tropical parts of Africa, occasionally spilling over into human populations, often brought on by human activities, may not be correct or at least incomplete. Over time a number of Ebola disease outbreaks reported and a pattern in the outbreak response seemed to have been established. A lot was also learnt about Ebola viruses, their epidemiology and ecology. However, the 2014 Ebola outbreak challenges our understanding in many respects.
An 8-year retrospective study of adult and paediatric Burkitt’s lymphoma at Tygerberg Hospital, South Africa
(AOSIS, 2020-04-30) Musekwa, Ernest; Chapanduka, Zivanai C.; Bassa, Fatima; Kruger, Mariana
Background: Burkitt lymphoma(BL) is a high grade non-Hodgkin lymphoma, which may be underdiagnosed in South Africa, due to a high burden of infectious diseases such as HIV and TB which may present with similar clinical features. Aim: To describe demographics and clinico-pathological characteristics of patients diagnosed with BL. Setting: Tygerberg Hospital (TBH), South Africa between 2007-2014. Methods: We performed a retrospective descriptive and survival analysis of patients diagnosed with BL at TBH between 01 January 2007 and 31 December 2014 with at least 24-month follow-up. Data was collected from the Tygerberg Lymphoma Study Group database and the South African Children Cancer Study Group Tumour Registry. Results: There were 73 patients with BL, of whom 68 were admitted to TBH and whose data was further analysed. The majority of patients were adults (74%). There was a female predominance in adults and a male predominance in children (p = 0.002). Various regimens were used in adults while a single treatment protocol was used in children. The proportion of patients with HIV and advanced BL was higher in adults than in children. The 2-year overall survival of the treatment group was 45%. The outcome of patients with BL in adults (34%) was poorer than that of children (69%) (p = 0.022). HIV negative patients had a non-significant survival advantage (57%) over HIV positive patients with 41% 2-year overall survival (p = 0.2876). Conclusion: This study demonstrates a better cure rate in children treated for BL compared to adults, with HIV-infection being a risk factor for poor outcome.
An 8-year retrospective study of adult and paediatric Burkitt’s lymphoma at Tygerberg Hospital, South Africa
(AOSIS, 2020-04-30) Musekwa, Ernest; Chapanduka, Zivanai C.; Bassa, Fatima; Kruger, Mariana
Background: Burkitt lymphoma(BL) is a high grade non-Hodgkin lymphoma, which may be underdiagnosed in South Africa, due to a high burden of infectious diseases such as HIV and TB which may present with similar clinical features. Aim: To describe demographics and clinico-pathological characteristics of patients diagnosed with BL. Setting: Tygerberg Hospital (TBH), South Africa between 2007-2014. Methods: We performed a retrospective descriptive and survival analysis of patients diagnosed with BL at TBH between 01 January 2007 and 31 December 2014 with at least 24-month follow-up. Data was collected from the Tygerberg Lymphoma Study Group database and the South African Children Cancer Study Group Tumour Registry. Results: There were 73 patients with BL, of whom 68 were admitted to TBH and whose data was further analysed. The majority of patients were adults (74%). There was a female predominance in adults and a male predominance in children (p = 0.002). Various regimens were used in adults while a single treatment protocol was used in children. The proportion of patients with HIV and advanced BL was higher in adults than in children. The 2-year overall survival of the treatment group was 45%. The outcome of patients with BL in adults (34%) was poorer than that of children (69%) (p = 0.022). HIV negative patients had a non-significant survival advantage (57%) over HIV positive patients with 41% 2-year overall survival (p = 0.2876). Conclusion: This study demonstrates a better cure rate in children treated for BL compared to adults, with HIV-infection being a risk factor for poor outcome.
Aberrant in vitro HLA-DR expression in patients with chronic fatigue
(Health and Medical Publishing Group (HMPG), 1990-08) Van Greune, C. H. J.; Bouic, P. J. D.
To the Editor: The chronic fatigue syndrome (CFS) is a clinical entity characterised by chronic fluctuating fatigue associated-with a multitude of related symptoms, which may vary between patients. It is of unknown causation, but usually follows a presumed acute viral infection.
Academic publishing in pandemic times
(ASSAf, 2020-09-21) Preiser, Wolfgang; Preiser, Rika
ENGLISH ABSTRACT: Even though it tends to feel like ages, it has not been that long since the final days of 2019, when cases of severe respiratory illness (now known as COVID-19), caused by a previously unknown coronavirus (since named SARSCoV- 2), were reported from China. The ongoing COVID-19 pandemic has brought unprecedented disruption to almost every area of our daily and professional lives. Science has not been spared, nor has scientific publishing. Most researchers have been unable to continue with their work, and many had to all but re-invent their teaching. Quite a few have re-invented themselves as coronavirus researchers.1 As biomedical researchers, we are astonished to see how much interest the public is taking in our findings. For no other disease do members of the public so fervently seek out reports in traditional and social media about the latest research findings. These reports often trigger controversial discussions, mostly on social media platforms, about rather complicated aspects of epidemiology, diagnostics, pathogenesis or therapy. Many of these issues are matters outside the realm of everyday life and normally left to experts to assess the evidence and translate it into practice.
Adenosine deaminase estimations in the differentiation of pleural effusions
(Health & Medical Publishing Group, 1982-10) Maritz, F. J.; Malan, C.; Le Roux, I.
Adenosine deaminase (ADA) estimations were performed on the pleural fluid from 368 effusions. The mean (±SD) ADA concentration in tuberculous effusions was 92.11 ± 37.05 U/l, and these values were found to be highly statistically different from the 23.3 ± 13.15 U/l in secondary malignant tumours of the pleura, the 34.86 ± 14.2 U/l in mesotheliomas, and the 23.81 ± 15.07 U/l in pulmonary embolism. The ADA values of 64.3 ± 44.95 UlI in lymphoproliferative disorders were less significantly different. No statistical difference could be found between values in the tuberculous group and the ADA levels of 97.57 ± 82 U/l found in para-infective effusions, but these could be distinguished from each other by microscopic examination of the pleural fluid. The importance of ADA estimations in the diagnosis and differentiation of tuberculous effusions is discussed and the role of microscopy is emphasized.
Adult T-cell leukaemia / lymphoma in an adolescent patient : expect the unexpected
(AOSIS, 2020-05-25) Abdullah, Ibtisam; Nell, Erica-Mari; Chapanduka, Zivanai C.
ENGLISH ABSTRACT: This case study explores a clinicopathological presentation of Adult T-cell leukaemia/lymphoma (ATLL) at Tygerberg Hospital; a disease associated with adulthood noted in an adolescent patient. Adult T-cell leukaemia–lymphoma oncogenesis develops through a multistep process with an accumulation of mutations. Infection through human T-lymphotropic virus type 1 (HTLV-1) is the first step of a multistep process resulting in eventual clonal proliferation of mature T-cells. There is a long latency period of 20–50 years from the time of infection with HTLV-1 to the development of symptoms of ATLL; thus, ATLL is a malignancy associated with adulthood. The median age of diagnosis is 58, ranging from the third to ninth decade of life. This is an ideal learning case as it highlights the importance of recognising ATLL in children and young adults in our population.
African civil society initiatives to drive a biobanking, biosecurity and infrastructure development agenda in the wake of the West African Ebola outbreak
(African Field Epidemiology Network, 2016) Abayomi, Akin; Gevao, Sahr; Conton, Brian; Deblasio, Pasquale; Katz, Rebecca
This paper describes the formation of a civil society consortium, spurred to action by frustration over the Ebola crises, to facilitate the development of infrastructure and frameworks including policy development to support a harmonized, African approach to health crises on the continent. The Global Emerging Pathogens Treatment Consortium, or GET, is an important example of how African academics, scientists, clinicians and civil society have come together to initiate policy research, multilevel advocacy and implementation of initiatives aimed at building African capacity for timely and effective mitigations strategies against emerging infectious and neglected pathogens, with a focus on biobanking and biosecurity. The consortium has been able to establish it self as a leading voice, drawing attention to scientific infrastructure gaps, the importance of cultural sensitivities, and the power of community engagement. The GET consortium demonstrates how civil society can work together, encourage government engagement and strengthen national and regional efforts to build capacity.
Age and race distribution of patients who undergo haematological investigations at Tygerberg Hospital (Afrikaans)
(HMPG, 1977-11) Brink S.; Van Schalkwyk D.J.; Steytler J.G.
The race, age and sex of patients referred for peripheral blood investigations at the Tygerberg Hospital were analysed statistically. An IBM 370/158 computer was used. Two groups were compared. The first was a 'low Hb group' of 2065 patients who had at least once during the first 6 months of 1976 had a haemoglobin (Hb) value of 10 g/dl or lower. The second, a 'hospital group' of 600 patients, was selected with the aid of tables for generating random numbers and was representative of the general hospital population. Rank order correlation methods using the ratios between the observed and the population percentages (based on the census figures for the Cape Peninsula) for the different age groups, between the race-age combinations, were used, and significant differences were found. In the hospital group the higher percentage of women between 20 and 39 years and the higher percentage of men older than 60 years was striking. In the low Hb group 38.8% of the patients were below 4 years of age, and 61% in the microcytic group (mean corpuscular volume (MCV) below 75 fl) were under the age of 6 years. The largest number of cases of iron-deficient anaemias in the hospital was therefore found in children. The MCV and Hb values had a fairly normal distribution, but in the macrocytic subdivision (MCV higher than 95 fl) of the low Hb group, White men were significantly over-represented. In the hospital group Hb and MCV values were slightly lower than the values accepted in a normal population, the mean MCV of women being lower than that of men (P < 0.01), and the values of non-Whites being lower than those of Whites.
The agreement between fasting glucose and markers of chronic glycaemic exposure in individuals with and without chronic kidney disease : a cross-sectional study
(BMC (part of Springer Nature), 2020-01-30) George, Cindy; Matsha, Tandi E.; Korf, Marizna; Zemlin, Annalise E.; Erasmus, Rajiv T.; Kengne, Andre P.
Background: To assess whether the agreement between fasting glucose and glycated proteins is affected by chronic kidney disease (CKD) in a community-based sample of 1621 mixed-ancestry South Africans. Methods: CKD was defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m2. Fasting plasma glucose and haemoglobin A1c (HbA1c) concentrations were measured by enzymatic hexokinase method and highperformance liquid chromatography, respectively, with fructosamine and glycated albumin measured by immunoturbidimetry and enzymatic method, respectively. Results: Of those with CKD (n = 96), 79, 16 and 5% where in stages 3, 4 and 5, respectively. Those with CKD had higher levels of HbA1c (6.2 vs. 5.7%; p < 0.0001), glycated albumin (15.0 vs. 13.0%; p < 0.0001) and fructosamine levels (269.7 vs. 236.4 μmol/l; p < 0.0001), compared to those without CKD. Higher fasting glucose levels were associated with higher HbA1c, glycated albumin and fructosamine, independent of age, gender, and CKD. However, the association with HbA1c and glycated albumin differed by CKD status, at the upper concentrations of the respective markers (interaction term for both: p ≤ 0.095). Conclusion: Our results suggest that although HbA1c and glycated albumin perform acceptably under conditions of normoglycaemia, these markers correlate less well with blood glucose levels in people with CKD who are not on dialysis.
Aircraft fatality investigation as a function of a comprehensive health service
(Health & Medical Publishing Group, 1977-07-20) Schwar, T. G.
[No abstract available]
Alfal-Fetoproteien in neonatale geelsug
(HMPG, 1978-08) Malan Christina; Donald, P. R.; Odendaal , H. J.; Shanley , B. C.
The relationship between the concentration of alphal-fetoprotein (AFP) in cord blood and neonatal jaundice has been examined in 259 neonates. Cord blood AFP varies inversely with gestational age, as does the incidence of severe jaundice. Among babies born at term a higher mean AFP concentration in cord blood was found in the group which subsequently developed marked hyperbilirubinaemia. On average, the full-term babies with a cord blood AFP level above 130 mg/l developed more pronounced jaundice than the rest. We conclude that cord blood AFP concentrations reflect the maturity of the liver in both premature and full-term infants. It is a better criterion than the estimation of gestational period by physical examination of the baby.
Analyses of HIV-1 integrase sequences prior to South African national HIV-treatment program and availability of integrase inhibitors in Cape Town, South Africa
(Nature Publishing Group, 2018) Brado, Dominik; Obasa, Adetayo Emmanuel; Ikomey, George Mondinde; Cloete, Ruben; Singh, Kamalendra; Engelbrecht, Susan; Neogi, Ujjwal; Jacobs, Graeme Brendon
ENGLISH ABSTRACT: HIV-Integrase (IN) has proven to be a viable target for highly specific HIV-1 therapy. We aimed to characterize the HIV-1 IN gene in a South African context and identify resistance-associated mutations (RAMs) against available first and second generation Integrase strand-transfer inhibitors (InSTIs). We performed genetic analyses on 91 treatment-naïve HIV-1 infected patients, as well as 314 treatment-naive South African HIV-1 IN-sequences, downloaded from Los Alamos HIV Sequence Database. Genotypic analyses revealed the absence of major RAMs in the cohort collected before the broad availability of combination antiretroviral therapy (cART) and INSTI in South Africa, however, occurred at a rate of 2.85% (9/314) in database derived sequences. RAMs were present at IN-positions 66, 92, 143, 147 and 148, all of which may confer resistance to Raltegravir (RAL) and Elvitegravir (EVG), but are unlikely to affect second-generation Dolutegravir (DTG), except mutations in the Q148 pathway. Furthermore, protein modeling showed, naturally occurring polymorphisms impact the stability of the intasome-complex and therefore may contribute to an overall potency against InSTIs. Our data suggest the prevalence of InSTI RAMs, against InSTIs, is low in South Africa, but natural polymorphisms and subtype-specific differences may influence the effect of individual treatment regimens.
Analysis of hereditary haemochromatosis and clinical correlations in the elderly
(Stellenbosch : Stellenbosch University, 2000-12) Bouwens, C. S. H.; Kotze, Maritha J.; Maritz, F. J.; De Villiers, J. N. P.; Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Pathology.
ENGLISH ABSTRACT: Hereditary haemochromatosis (HH) is an autosomal recessive iron storage disease where the accumulation of iron in parenchymal organs may lead to diabetes, heart failure, liver cirrhosis, arthropathy, weakness and a variety of other ailments if preventive measures are not taken. HH is often not considered as a cause of these conditions, particularly not in the elderly where the background frequencies of type II diabetes, osteoarthritis and heart failure are generally high. Heterozygosity for C282Y, the HFE-mutation causing HH in approximately 80% of affected individuals worldwide, has been linked to a raised incidence of malignancies of the colon and rectum, stomach and the haematological system. One of the highest carrier-frequencies (116) in the world for this mutation has been reported in the South-African Afrikaner population, resulting in C282Y-homozygosity in approximately 1 in every 115 people in this group. A sample of 197 elderly Afrikaner volunteers was recruited for genotype/phenotype association studies. Their clinical presentation was denoted, biochemical iron-status determined and HFE genotyping performed. Either an increase or decrease in survival, or both, were proposed, depending on possible gender effects. HH has been positively associated with various cancer types, but may also protect against iron-deficiency anaemia which is by far the most frequent cause of anaemia in the older person. This study has led to the following findings: 1. The carrier frequency of mutation C282Y was found to be 1/8 in the elderly population (similar in males and females), which is slightly lower than the 1/6 reported in younger adults from the same population. Only one C282Y homozygote and two C282YIH63D compound heterozygotes were detected, all of them female. 2. The prevalence of diabetes, heart disease, arthropathy or a combination of these conditions did not differ significantly in C282Y heterozygotes and the mutationnegative group. 3. Among 24 C282Y heterozygotes only one individual with rectal carcmoma was detected compared with two cases with rectal- and seven with colonic malignancies in 153 mutation-negative individuals. The single female C282Y homozygote identified suffered from both rectal and colon carcinoma and died approximately 6 months ago as a consequence of her colon malignancy. 4. Serum ferritin appears to be a highly unreliable parameter of iron status, particularly in the elderly where a variety of factors that may influence the levels are often present in elderly individuals. This may be due to ageing alone or as a result of multiple comorbidities. 5. Serum ferritin levels were lower than expected in elderly subjects with mutation C282Y and compound heterozygotes with both C282Y and H63D, which may be related to a variable penetrance of the HFE gene mutations. It is possible that variation in other genes exist that confer protection against iron-loading by gene-gene interaction. The probability that environmental factors (e.g. a low iron diet) are more important in this respect cannot be excluded, although this is considered less likely in the light of the fact that the same trend was observed in all mutation-positive elderly individuals. It is therefore highly likely that C282Y -positive subjects with significant iron loading have died before reaching their seventies, particularly since none of the males included in this study were homozygous or compound heterozygous for the mutations analysed. In conclusion, possession of a mutant HFE gene does not appear to confer a survival advantage in old age, neither does it seem that mutation carriers with significant ironloading are overlooked by the medical fraternity. Further investigations are warranted to shed more light on the contributions of gene-gene and gene-environment interaction in the clinical manifestation of Hll, and how these processes can be manipulated to prevent the symptoms of this largely underdiagnosed disease.
Analysis of HIV-1 diversity and inflammatory markers in HIV-associated neurocognitive disorders (HAND).
(Stellenbosch : Stellenbosch University, 2022-04) Ruhanya, Vurayai; Engelbrecht, Susan; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology.
ENGLISH SUMMARY: HIV-associated neurocognitive disorders (HAND), which involve impairment or disruption of neurocognitive functioning have become one of the most frequent complications in adult HIV-1 infections with global estimates ranging from 42% to 45%. The screening and diagnosis for HAND relies on multiple clinical and neuro-psychometric methods. However, these methods have a low reliability because they are not precise as most of possess inadequate psychometric properties and diagnostic accuracy. Therefore, this study aimed to describe and characterise viral and immunological determinants of HAND and evaluated their relationship with specific clinical, neuromedical and neuropsychological data to identify putative easy-to-measure biological markers for diagnosis of the condition. This study demonstrated that higher peripheral blood lymphocyte-derived HIV-1 proviral DNA is a predictor of global and domain-specific neurocognitive impairment among individuals infected with HIV-1 subtype C. The study also determined proviral load cut-off /threshold value for neurocognitive impairment and associated diagnostic accuracy. It also identified IP-10 and RANTES as a plasma chemokine bio-signature for HIV-associated neurocognitive impairment with diagnostic accuracy comparable to standard psychometric tests used to screen and describe severity of HAND. In addition, the study identified 3 viral genetic signatures for cognitive impairment, namely Lysine at codon 24, (24K) and Arginine at codon 29 (29R) on Tat protein and Tyrosine (Y) at position 45 (45Y) of Vpr. These three signature amino acids were related to classical markers for monitoring HIV infection. Finally, we identified 4 conserved fragment sequences, PEDQGPQREPYNEWTLE (5 to 21), LGQYIY (42 to 47), TYGDTW (49 to 54), PEDQGPQREPYNEW (5 to 18) on viral protein R, that were associated with higher plasma viral load and proviral load. The study has identified novel cytokine/chemokine and viral biomarker signatures for HIV associated neurocognitive impairment with low to moderate diagnostic accuracy. The findings demonstrated a need for interdisciplinary approach to elucidate possible molecular interactions between the peripheral blood immune markers, viral signatures and the CNS that are linked to observed clinical outcomes of neurodegradation in HIV infection. The identified biomarkers can be further investigated for use as screening tools and treatment endpoints for HAND.
Analysis of single nucleotide polymorphisms with opposite effects on serum iron parameters in South African patients with multiple sclerosis
(Stellenbosch : Stellenbosch University, 2014-04) Moremi, Kelebogile Elizabeth; Van Rensburg, S. J.; Kotze, Maritha J.; Geiger, D.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology, Chemical Pathology.
ENGLISH ABSTRACT: There is growing interest in how genetic and environmental risk factors interact to confer risk for dysregulated iron homeostasis, which is considered a possible pathogenic mechanism in multiple sclerosis (MS). While iron deficiency has been associated with greater disability and disease progression, cerebral accumulation and overload of insoluble iron has also been reported in MS patients. Variation in the matriptase-2 (TMPRSS6) gene has recently been described that may lead to reduced iron levels, which raised the question of whether it may be involved in dysfunctional iron regulation as a pathogenic mechanism in MS. The aims of the study were as follows: 1)) comparison of the allele frequencies and genotype distribution for TMPRSS6 A736V (rs855791, c.2207C>T) and HFE C282Y (rs1800562, c.845G>A) between patients diagnosed with MS and unaffected controls; 2) determination of the effects of clinical characteristics, relevant lifestyle factors and genotype on serum iron parameters in MS patients compared to population matched controls; and 3) determination of clinical outcome in relation to age of onset and degree of disability in MS patients. The study population included 121 Caucasian MS patients and 286 population-matched controls. Serum iron, transferrin, ferritin and transferrin saturation levels were available from previous studies and lifestyle factors were subsequently documented in a subgroup of 68 MS patients and 143 controls using the study questionnaire. Genotyping of TMPRSS6 A736V and HFE C282Y were performed using allele-specific TaqMan technology. The genotype distribution and allele frequencies of TMPRSS6 A736V and HFE C282Y did not differ between MS patients and controls. MS patients homozygous for the iron-lowering minor T-allele of TMPRSS6 A736V had significantly lower serum iron levels (p=0.03) and transferrin saturation levels (p=0.03) compared to CC homozygotes. In MS patients the iron-loading minor A-allele of HFE C282Y was also associated with a paradoxical decrease in serum ferritin (p<0.01) compared to GG homozygotes. When considering the combined effect of the minor alleles of TMPRSS6 A736V and HFE C282Y with opposite effects on iron levels, we found a significant reduction in serum ferritin levels (p<0.05), independent of age, sex, body mass index (BMI) or dietary red meat intake in MS patients. A similar effect was not observed in the population- and age-matched controls. Higher dietary red meat intake correlated significantly with increased ferritin only in controls (p=0.01 vs. 0.21 for MS patients). In the presence of the minor allele of HFE C282Y, the TMPRSS6 A736V CT and TT genotypes were associated with a significantly earlier age of onset of MS when the post hoc test was applied (p=0.04). All the study aims were successfully accomplished. Our results support the possibility of an epistatic effect between TMPRSS6 A736V and HFE C282Y associated with reduced ferritin levels in MS patients. Pathology-supported genetic testing (PSGT) applied in this study as a new concept for analysis of complex diseases with a genetic component, is well placed to optimise clinical management in patients with MS.
Analysis of the clinical utility of gene expression profiling in relation to conventional prognostic markers in South African patients with breast carcinoma
(Stellenbosch : Stellenbosch University, 2014-12) Grant, Kathleen Ann; Kotze, Maritha J.; Wright, Colleen A.; Apffelstaedt, Justus P.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Anatomical Pathology.
ENGLISH ABSTRACT: Breast cancer is a heterogeneous disease characterised by marked inter-individual variability in presentation, prognosis and clinical outcome. The recognition that morphological assessment has limited utility in stratifying patients into prognostic subgroups led to clinico-pathological classification of tumour biology, based on receptor expression using immunohistochemical (IHC) techniques. This standard is currently complemented by the development of gene expression profiling methodology that led to the identification of intrinsic molecular subtypes, reflecting tumour genetics as the true driver of biological activity in breast cancer. The study was based on the hypothesis that molecular classification of breast carcinomas integrated with established clinico-pathological risk factors will improve current diagnostic and risk management algorithms used in clinical decision-making. A pathology-supported genetic testing strategy was used to evaluate microarray-based gene profiling against diagnostic pathology techniques as the current standard. Clinico-pathological factors including age, number of positive axillary nodes, tumour size, grade, proliferation index and hormone receptor status was documented for 141 breast cancer patients (143 tumours) referred for microarray-based gene expression profiling between 2007 and 2014. Subsets of patients were selected from the database based on the inclusion criteria defined for three phases in which the study was performed, in order to determine 1) the percentage of patients stratified as having a low as opposed to high risk of distant recurrence using the 70-gene MammaPrint profile within the inclusion criteria, 2) correlation of HER2 status as determined by IHC and fluorescence in situ hybridisation (FISH) with microarray-based mRNA readout (TargetPrint), and 3) the relationship between hormone receptor determination as reported by standard IHC and molecular subtyping using the 80-gene BluePrint profile. Similar distribution patterns for MammaPrint low- and high-risk profiles were obtained irrespective of whether fresh tumour biopsies or formalin-fixed paraffin embedded (FFPE) tissue was used. During the first phase of the study, 60% of the 106 tumour specimens analysed with MammaPrint were classified as low-risk and 40% as high-risk using a newly-developed MammaPrint pre-screen algorithm (MPA) aimed at cost-saving. In the second phase of the study, performed in 102 breast tumours, discordant or equivocal HER2 results were found in four cases. Reflex testing confirmed the TargetPrint results in discordant cases, achieving 100% concordance regardless of whether fresh tumour or FFPE tissue was used for microarray analysis. For the third phase of the study 74 HER2-negative tumour samples were selected for comparative analysis. Statistically significant positive correlations were found between protein expression (IHC score) and mRNA (TargetPrint) levels for estrogen receptor (ER) (R=0.53, p<0.0001) as well as progesterone receptor (PR) (R=0.62, p<0.0001), while combined ER/PR tumour status was reported concordantly in 82.4% of these tumours. BluePrint was essential for interpretation of these results used in treatment decision-making. The MPA developed in South Africa in 2009 was validated in this study as an appropriate strategy to prevent chemotherapy overtreatment in patients with early-stage breast cancer. The use of microarray-based analysis proved to be a reliable ancillary method of assessing HER2 status in breast cancer patients. Risk reclassification based on the TargetPrint results helped to avoid unnecessary high treatment costs in false-positive cases, in addition to providing potentially life-saving treatment to those for whom it was indicated. While neither IHC nor TargetPrint estimation of intrinsic subtype correlated independently with the molecular subtype as indicated by BluePrint profiling, the ability to distinguish between basal-like and luminal tumours was enhanced when the combined protein and mRNA values was considered. Genomic profiling provided information over and above that obtained from routine clinico-pathological assessments. This finding supports the relevance of a pathology-supported genetic testing approach to breast cancer management, whereby advanced genomic testing is combined with existing clinico-pathological risk stratification methods for improved patient management.
Analysis of viral diversity in relation to the recency of HIV-1C infection in Botswana
(Public Library of Science, 2016) Moyo, Sikhulile; Vandormael, Alain; Wilkinson, Eduan; Engelbrecht, Susan; Gaseitsiwe, Simani; Kotokwe, Kenanao P.; Musonda, Rosemary; Tanser, Frank; Essex, Max; Novitsk, Vladimir; De Oliveira, Tulio
Background: Cross-sectional, biomarker methods to determine HIV infection recency present a promising and cost-effective alternative to the repeated testing of uninfected individuals. We evaluate a viral-based assay that uses a measure of pairwise distances (PwD) to identify HIV infection recency, and compare its performance with two serologic incidence assays, BED and LAg. In addition, we assess whether combination BED plus PwD or LAg plus PwD screening can improve predictive accuracy by reducing the likelihood of a false-recent result. Methods: The data comes from 854 time-points and 42 participants enrolled in a primary HIV-1C infection study in Botswana. Time points after treatment initiation or with evidence of multiplicity of infection were excluded from the final analysis. PwD was calculated from quasispecies generated using single genome amplification and sequencing. We evaluated the ability of PwD to correctly classify HIV infection recency within <130, <180 and <360 days post-seroconversion using Receiver Operator Characteristics (ROC) methods. Following a secondary PwD screening, we quantified the reduction in the relative false-recency rate (rFRR) of the BED and LAg assays while maintaining a sensitivity of either 75, 80, 85 or 90%. Results: The final analytic sample consisted of 758 time-points from 40 participants. The PwD assay was more accurate in classifying infection recency for the 130 and 180-day cut-offs when compared with the recommended LAg and BED thresholds. A higher AUC statistic confirmed the superior predictive performance of the PwD assay for the three cut-offs. When used for combination screening, the PwD assay reduced the rFRR of the LAg assay by 52% and the BED assay by 57.8% while maintaining a 90% sensitivity for the 130 and 180-day cut-offs respectively. Conclusion: PwD can accurately determine HIV infection recency. A secondary PwD screening reduces misclassification and increases the accuracy of serologic-based assays.
Anti-HIV-1 activity of salivary MUC5B and MUC7 mucins from HIV patients with different CD4 counts
(BioMed Central, 2010-10) Habte, Habtom H.; De Beer, Corena; Lotz, Zoe E.; Roux, Paul; Mall, Anwar S.
Background: We have previously shown that MUC5B and MUC7 mucins from saliva of HIV negative individuals inhibit HIV-1 activity by 100% in an in vitro assay. The purpose of this subsequent study was to investigate whether MUC5B and MUC7 from saliva of HIV patients or with full blown AIDS had a similar inhibitory activity against the virus. Methods Salivary MUC5B and MUC7 from HIV patients with different CD4 counts (< 200, 200-400 and > 400) were incubated with HIV-1 prior to infection of the human T lymphoblastoid cell line (CEM SS cells). Cells were then cultured and viral replication was measured by a qualitative p24 antigen assay. The size, charge and immunoreactivity of mucins from HIV negative and positive individuals was also analysed by SDS-PAGE, Western blot and ELISA respectively. Results: It was shown that irrespective of their CD4 counts both MUC5B and MUC7 from HIV patients, unlike the MUC5B and MUC7 from HIV negative individuals, did not inhibit HIV-1 activity. Size, charge and immunoreactivity differences between the mucins from HIV negative and positive individuals and among the mucins from HIV patients of different CD4 count was observed by SDS-PAGE, Western blot and ELISA. Conclusions: Purified salivary mucins from HIV positive patients do not inhibit the AIDS virus in an in vitro assay. Although the reason for the inability of mucins from infected individuals to inhibit the virus is not known, it is likely that there is an alteration of the glycosylation pattern, and therefore of charge of mucin, in HIV positive patients. The ability to inhibit the virus by aggregation by sugar chains is thus diminished.

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