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Purpose:An unmet need in low-resource countries is an automated breast cancer detection assay to prioritize women who should undergo core breast biopsy and pathologic review. Therefore, we sought to identify and validate a panel of methylated DNA markers to discriminate between cancer and benign breast lesions using cells obtained by fine-needle aspiration (FNA).Experimental Design: Two case–control studies were conducted comparing cancer and benign breast tissue identified from clinical repositories in the United States, China, and South Africa for marker selection/training (N = 226) and testing (N = 246). Twenty-five methylated markers were assayed by Quantitative Multiplex-Methylation-Specific PCR (QM-MSP) to select and test a cancer-specific panel. Next, a pilot study was conducted on archival FNAs (49 benign, 24 invasive) from women with mammographically suspicious lesions using a newly developed, 5-hour, quantitative, automated cartridge system. We calculated sensitivity, specificity, and area under the receiver-operating characteristic curve (AUC) compared with histopathology for the marker panel.Results:In the discovery cohort, 10 of 25 markers were selected that were highly methylated in breast cancer compared with benign tissues by QM-MSP. In the independent test cohort, this panel yielded an AUC of 0.937 (95% CI = 0.900–0.970). In the FNA pilot, we achieved an AUC of 0.960 (95% CI = 0.883–1.0) using the automated cartridge system.Conclusions:We developed and piloted a fast and accurate methylation marker–based automated cartridge system to detect breast cancer in FNA samples. This quick ancillary test has the potential to prioritize cancer over benign tissues for expedited pathologic evaluation in poorly resourced countries.

Objectives To assess whether women with HIV who had low-grade squamous intraepithelial lesions (LSIL) on cytology had cervical disease. Methods The present retrospective cross-sectional study included data from women with LSIL who attended a tertiary hospital in South Africa between April 1, 2003, and December 31, 2013. Patient information was extracted from a colposcopy database. Results The study included 652 patients. The median age was 36 years (interquartile range [IQR] 31-42 years; range 18-66 years) and the median parity was three (IQR 2-5; range 0-10). In all, 266 (40.8%) women had a histology result of HPV or cervical intraepithelial neoplasia 1 (CIN1); 386 (59.2%) had a histology result of CIN2 or higher. The median cluster of differentiation 4 (CD4) count was 275.00 cells/mm3 (IQR 173.50-434.00 cells/mm3 ; range 2-1211 cells/mm3 ). A total of 312 (47.9%) women were using antiretroviral therapy. Use of antiretroviral therapy (unadjusted odds ratio 0.57; P=0.001) and a CD4 count of at least 200 cells/mm3 (unadjusted odds ratio 0.81; P=0.002) were associated with a histology result of HPV or CIN1. Conclusion Most of the women with a cytology report of LSIL had CIN2 or higher, suggesting that the practice of referral for colposcopy should continue.

Background: Despite the rampant human immunodeficiency (HIV) epidemic in Africa, there is a paucity of published data of HIV-related Epstein-Barr virus-associated smooth muscle tumours (EBV-SMT) from Africa.Methods: We embarked on retrospective documentation of the clinicopathological features of confirmed HIV-related EBV-SMT over a 5-year time frame at the largest hospital in Africa. All haematoxylin and eosin stained tissue sections, immunohistochemistry and EBV in situ hybridisation (ISH) investigations were reviewed in conjunction with clinical data.Results: Fourteen (n = 14) EBV-SMT were confirmed in 13 patients (age range: 10–53 years). Five paediatric patients and a predominance of females (70%) were evident in this series. All patients were HIV seropositive and CD4 counts ranged from 1 to 1331 cells/ul (median 355 cells/ul; mean 442 cells/ul). Tumour-associated pain was a common symptom in the paediatric age group, while neurological symptoms were frequent in the adults due to paraspinal c...

BACKGROUND: Molecular analysis has shown that breast carcinomas can be classified into several intrinsic subtypes, with implications for management and prognosis. In the majority of pathology laboratories molecular analysis of each case is not possible and immunohistochemistry is used for subtyping. This includes analysis of hormone receptors as well as HER-2-neu and Ki67. The methodology for the interpretation of the proliferation index using Ki67 remains an area of uncertainty. We investigated the degree of agreement between different methods of Ki67 interpretation. MATERIALS AND METHODS: We analysed 204 breast core biopsies diagnostic of breast carcinoma using visual estimation/eyeballing (EB), Immunoratio©(IR), and counting by two pathologists (CP1 and CP2). The correlation between the different methods and the inter-observer agreement between the two pathologists was assessed. Specific analysis was also done with respect to classification of cases into low Ki67 groups (using Ki67 values less than 14% and less than 20%) since this is critical in classifying tumours into Luminal A and Luminal B subtypes. RESULTS: Correlation between the different methods was best achieved comparing IR and CP1, and worst comparing CP1 and EB. Correlation was better when considering inter-observer variability (CP1 vs CP2). Comparing the number of cases classified as low Ki67 (less than 14% and less than 20%) the Cohen’s Kappa statistic varied from κ = 0.267 to κ = 0.814 with different methods. When limiting the analysis to cases with a Ki67 of 10–25% according to any method, there was greater disagreement. CONCLUSION: At the higher and lower Ki67 levels, the correlation between the methods of assessment was acceptable, however, at levels close to the cut-off values for Lumial A versus Luminal B, several patients would be differently classified by the different methods and therefore potentially receive suboptimal management.

INTRODUCTION Despite widespread access to antiretroviral therapy (ART), the burden of advanced HIV disease in South Africa is high. This translates into an increased risk of AIDS-related opportunistic infections, including invasive mycoses. METHODS Using a limited number of non-culture-based diagnostic assays, we aimed to determine the prevalence of invasive mycoses and tuberculosis among hospitalised adults with very advanced HIV (CD4 counts

Hepatosplenic T-cell lymphoma (HSTCL) is a rare type of Non-Hodgkin Lymphoma (NHL), grouped under the mature or peripheral T-cell lymphomas. It is characterised by extranodal infiltration and proliferation of malignant T-cells within the sinusoids of the liver, sinuses and red pulp of the spleen, and the bone marrow. The tumour cells express CD2 and CD3, but are CD4, CD5 and CD8 negative and express a clonally restricted gamma–delta (or less commonly alpha–beta) T-cell receptor. The disease has an aggressive clinical course associated with a poor prognosis. We highlight and report three patients from South Africa with HSTCL, all of whom had hepatosplenomegaly and cytopaenias, and despite being HIV seronegative and immunocompetent, had a poor outcome, with a mean survival of 7.5 months in the two evaluable patients. This rare entity has not previously been reported from South Africa and as yet needs to be adequately characterised in a population where lymphoma is the most common haematological malignancy in adults, and where approximately two thirds of the adult lymphoma population are HIV seropositive. Keywords: Hepatosplenic T-cell lymphoma, Hepatosplenomegaly, Cytopaenias, Aggressive course, Poor prognosis, South Africa

In the low-income HIV-endemic regions of sub-Saharan Africa, malignancies related to HIV have long been recognized as a major public health problem. However, epithelial malignancies associated with older age, such as breast cancer, are also rising dramatically in those regions. We compared consecutive HIV-positive and -negative black women diagnosed with breast cancer at a large public hospital in Soweto, South Africa, on age, year of diagnosis, stage, grade, and receptor status, and grouped HIV-positive patients by CD4 cell counts. We computed prevalence ratios of the associations of HIV status and CD4 category with stage, grade, receptor status, and among the HIV-positive patients, receipt of ART, controlling for age and year of diagnosis. Of 1,092 patients, 765 were tested for HIV; 151 (19.7 %) tested positive, a prevalence similar to that in the source population. Although, HIV-positive patients were younger than HIV-negative patients (p

Introduction: Breast cancer is well known as the stereotypical women's cancer, and prostate cancer represents the well-known stereotypical male counterpart. While prostate cancer carries the potential to metastasize to the breast, the synchronous or metachronous co-occurrence of primary breast and primary prostate cancers is quite unusual. Prostate cancer in men of African descent may have its own behaviour with regards to its relationship with male breast cancer. Case presentation: Case 1: A 64 year old male presented to Chris Hani Baragwanath Hospital (CHBAH) with a 2 years history of a painless left breast lump. A core biopsy was done and confirmed breast carcinoma. Tamoxifen was started but, due to disease progression, he underwent left modified radical mastectomy followed by chemotherapy. Prostate biopsy was done for raised Prostate Specific Antigen (PSA) and suspicious prostate on digital rectal examination. A prostatic adenocarcinoma was subsequently diagnosed with bone metastases on bone scan. He was started on Androgen deprivation therapy and followed up every 3 months. Case 2: A 68 year old male presented to CHBAH with a 1 year history of a painless right breast lump. A core biopsy confirmed breast cancer. Tamoxifen was started, followed by right modified radical mastectomy and chemotherapy for disease progression. A raised PSA and suspicious prostate on digital rectal examination prompted a prostate biopsy revealing a prostatic adenocarcinoma. Bone scan was negative for metastasis. He is currently on 3 monthly Androgen deprivation therapy and awaiting radiation. Conclusion: This clinical practice article not only presents this exceptionally rare duality but highlights that both cancers can coexist either as sporadic conditions, or as a result of genetic mutations. Thus, we suggest that men with prostate cancer be screened clinically, biochemically and genetically for breast cancer and vice versa.

Introduction: Breast cancer incidence is rapidly increasing globally with 1.7 million new cases and 600,000 deaths due to the disease annually. Death due to breast cancer is four to six times more frequent in the developing world compared to the USA due to lack of early detection, definitive diagnosis, and limited access to treatment. Ultrasound imaging for early detection and ultrasound guided fine needle aspiration (FNA) of suspicious lesions followed by an automated, cartridge-based analysis of methylated genes could triage malignancies for faster pathology assessment and treatment, thus enabling better use of scarce resources. Experimental Procedures: To identify a panel of methylated DNA markers to enable sensitive and specific detection of malignant breast lesions, we screened 24 methylated genes (known to be frequently methylated in malignant breast tissue and unmethylated in normal breast tissue) by Quantitative Multiplex Methylation-Specific PCR (QM-MSP) analysis. Formalin-fixed paraffin-embedded (FFPE) sections of biopsies of both benign and malignant breast lesions from the USA, China and South Africa were analyzed. Samples were divided into Training and Test sets. The Training set consisted of 206 tissues [66 invasive ductal carcinoma (IDC), 30 ductal carcinoma in situ (DCIS), 99 benign breast disease (BBD) and 11 normal breast (NB)]. The gene panel selected in the Training set was examined in an independent Test set of tissues (n=204) [65 IDC, 29 DCIS, 99 BBD and 11 NB]. Further, we optimized the technical performance of an automated, prototype breast cancer detection cartridge system for quantitative assessment of gene methylation and tested it in pilot study using FNA samples from breast cancers. Results: Analysis of the tissues in the Training set (n=206) led to the selection of a panel of 10 genes highly methylated in malignant lesions with little or no methylation in benign lesions. For the 10-gene panel to achieve a sensitivity greater than 90%, a laboratory cutoff of 14.5 cumulative methylation (CM) units (out of a possible 10,000 units) was set. In the Training set, the 10-gene panel achieved a sensitivity of 90% and a specificity of 85% with receiver operating characteristic (ROC) statistics: ROC, AUC= 0.947. In a blinded Test set of tissue samples (n=204), with a laboratory cutoff of 14.5 CM units, the 10-gene panel achieved a sensitivity of 87% and a specificity of 89%, with ROC statistics: p Conclusions: QM-MSP of breast lesions led to the selection of a panel of 10 genes methylated for detection of breast cancer. We have validated the technical performance of an automated, prototype cartridge system. The study reveals the potential of methylation markers to provide fast, accurate and automated cancer detection at a low cost in developing regions globally. Research Use Only. Not for diagnostic tests. A sponsored research agreement from Cepheid to Dr. Sukumar's Lab at Johns Hopkins University. Citation Format: Bradley M. Downs, Mary Jo Fackler, Claudia Mercado-Rodriguez, Ashley Cimino-Mathews, Chuang Chen, Jing-Ping Yuan, Eunice van den Berg, Leslie M. Cope, Susan C. Harvey, Syed Z. Ali, Suzana Tulac, Kriszten J. Kocmond, Edwin W. Lai, Brian Rhees, Mike Bates, Saraswati Sukumar. An automated breast cancer detection assay for screening in the developing world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-220.

To determine the effect of the time interval between cervical cytology screening and histology at treatment on grade of cervical disease.In a retrospective cross-sectional study at a colposcopy clinic in Soweto, Johannesburg, South Africa, data were compared from women with cytologic abnormalities referred for colposcopy between April 2003 and June 2010 to determine whether early (≤ 180 days) or late (180 days) referral had an impact on dysplasia grade.In the early and late referral groups, there were 213 (13.43%) and 201 (14.63%) women, respectively, with upgrading of cervical dysplasia (P=0.35), and 1373 (86.57%) and 1173 (85.37%) women, respectively, with downgrading or no change (P=0.35). Risk factors for upgrading were HIV infection (odds ratio [OR], 1.63; P0.001) and condom use (OR, 1.30; P=0.02). Four cases (0.68%) of invasion among women with low-grade squamous intraepithelial lesion (LSIL) and 50 cases (2.11%) among women with high-grade SIL (HSIL) were not detected by cytology. Risk factors for invasive disease on histology were age (OR, 1.09 per year; P0.001), parity (OR, 1.32 per pregnancy; P0.001), and HSIL on cytology (OR, 3.17; P=0.03).There was no difference in the up- or downgrading of cervical dysplasia between the 2 referral groups.

INTRODUCTION: Estimates of the proportion of estrogen receptor negative (ERN) and triple-negative (TRN) breast cancer from sub-Saharan Africa are variable and include high values. Large studies of receptor status conducted on non-archival tissue are lacking from this region. METHODS: We identified 1218 consecutive women (91% black) diagnosed with invasive breast cancer from 2006–2012 at a public hospital in Soweto, South Africa. Immunohistochemistry based ER, progesterone receptor (PR) and human epidermal factor 2 (HER2) receptors were assessed at diagnosis on pre-treatment biopsy specimens. Mutually adjusted associations of receptor status with stage, age, and race were examined using risk ratios (RRs). ER status was compared with age-stratified US Surveillance Epidemiology and End Results program (SEER) data. RESULTS: 35% (95% confidence interval (CI): 32-38) of tumors were ERN, 47% (45-52) PRN, 26% (23-29) HER2P and 21% (18-23) TRN. Later stage tumors were more likely to be ERN and PRN (RRs 1.9 (1.1-2.9) and 2.0 (1.3-3.1) for stage III vs. I) but were not strongly associated with HER2 status. Age was not strongly associated with ER or PR status, but older women were less likely to have HER2P tumors (RR, 0.95 (0.92-0.99) per 5 years). During the study, stage III + IV tumors decreased from 66% to 46%. In black women the percentage of ERN (37% (34-40)) and PRN tumors (48% (45-52)) was higher than in non-black patients (22% (14-31) and 34% (25-44), respectively, P = 0.004 and P = 0.02), which remained after age and stage adjustment. Age-specific ERN proportions in black South African women were similar to those of US black women, especially for women diagnosed over age 50. CONCLUSION: Although a greater proportion of black than non-black South African women had ER-negative or TRN breast cancer, in all racial groups in this study breast cancer was predominantly ER-positive and was being diagnosed at earlier stages over time. These observations provide initial indications that late-stage aggressive breast cancers may not be an inherent feature of the breast cancer burden across Africa.