Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKÆ´ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Metabolic and cardiovascular disease risk for Zimbabwean men with prostate cancer receiving long-term androgen deprivation therapy.

Introduction: Prostate cancer is a leading cause of cancer-related mortality in the majority of sub-Saharan Africa region countries. Androgen deprivation therapy (ADT) is effective treatment, however ADT is associated with complications including metabolic syndrome and cardiovascular disease. Although cardiovascular disease is a leading cause of mortality among prostate cancer patients, there is limited information on ADT impact on metabolic syndrome and cardiovascular disease risk among Africans. An observational prospective cohort study was carried out in Harare, Zimbabwe. Prostate cancer patients due to be initiated on ADT (medical or surgical) were assessed for metabolic syndrome and a 10-year Atherosclerotic Cardiovascular Disease (ASCVD) 10-year risk probability score was done before ADT and followed up to 9 months. Results: 17 black Zimbabwean men were enrolled with a median age 72 years. Most participants (59%) had stage IV disease and 75% opted for surgical castration. At enrolment 23.5% had metabolic syndrome and this increased to 33% after 9 months of ADT. Baseline ASCVD risk was in the high risk category for 68.8% of participants and remained above 50% after 9 months of ADT. In this cohort, there is a 10% absolute increase in metabolic syndrome prevalence amongst African men with prostate cancer within 9 months of ADT initiation.

Clinical presentation and diagnosis of adult patients with non-Hodgkin lymphoma in Sub-Saharan Africa.

Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in Sub-Saharan Africa (SSA). Comprehensive diagnostics of NHL are essential for effective treatment. Our objective was to assess the frequency of NHL subtypes, disease stage and further diagnostic aspects. Eleven population-based cancer registries in 10 countries participated in our observational study. A random sample of 516 patients was included. Histological confirmation of NHL was available for 76.2% and cytological confirmation for another 17.3%. NHL subclassification was determined in 42.1%. Of these, diffuse large B cell lymphoma, chronic lymphocytic leukaemia and Burkitt lymphoma were the most common subtypes identified (48.8%, 18.4% and 6.0%, respectively). We traced 293 patients, for whom recorded data were amended using clinical records. For these, information on stage, human immunodeficiency virus (HIV) status and Eastern Cooperative Oncology Group Performance Status (ECOG PS) was available for 60.8%, 52.6% and 45.1%, respectively. Stage at diagnosis was advanced for 130 of 178 (73.0%) patients, HIV status was positive for 97 of 154 (63.0%) and ECOG PS was ≥2 for 81 of 132 (61.4%). Knowledge about NHL subclassification and baseline clinical characteristics is crucial for guideline-recommended treatment. Hence, regionally adapted investments in pathological capacity, as well as standardised clinical diagnostics, will significantly improve the therapeutic precision for NHL in SSA.

Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial.

BACKGROUND: Optimal treatment regimens for AIDS-associated Kaposi sarcoma, a frequent contributor to morbidity and mortality among people with HIV, have not been systematically evaluated in low-income and middle-income countries, where the disease is most common. In this study, we aimed to investigate optimal treatment strategies for advanced stage disease in areas of high prevalence and limited resources. METHODS: In this open-label, non-inferiority trial, we enrolled people with HIV and advanced stage AIDS-associated Kaposi sarcoma attending 11 AIDS Clinical Trials Group sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) with a centralised computer system to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with antiretroviral therapy (ART; combined efavirenz, tenofovir disoproxil fumarate, and emtricitabine). The primary outcome was progression-free survival (PFS) at week 48, using a 15% non-inferiority margin to compare the investigational groups against the active control group. Safety was assessed in all eligible treated study participants. The study was registered with ClinicalTrials.gov, NCT01435018. FINDINGS: 334 participants were enrolled between Oct 1, 2013, and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm, as per the recommendations of the Data and Safety Monitoring Board (DSMB). The etoposide plus ART arm also closed due to inferiority in March, 2016, following a DSMB recommendation. Week-48 PFS rates were higher in the paclitaxel plus ART arm than in both investigational arms. The absolute differences in PFS were -30% (95% CI -52 to -8) for the comparison of paclitaxel plus ART (week 48 PFS 50%, 32 to 67; n=59) and etoposide plus ART (20%, 6 to 33; n=59), and -20% (-33% to -7%) for the comparison of paclitaxel plus ART (64%, 55 to 73; n=138) and bleomycin and vincristine plus ART (44%, 35 to 53; n=132). Both CIs overlapped the non-inferiority margin. The most common adverse events, in 329 eligible participants who began treatment, were neutropenia (48 [15%]), low serum albumin (33 [10%]), weight loss (29 [9%]), and anaemia (28 [9%]), occurring at similar frequency across treatment arms. INTERPRETATION: Non-inferiority of either investigational intervention was not shown, with paclitaxel plus ART showing superiority to both oral etoposide plus ART and bleomycin and vincristine plus ART, supporting its use in treating advanced AIDS-associated Kaposi sarcoma in resource-limited settings. FUNDING: US National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health.

Cost of Operating Population-Based Cancer Registries: Results from 4 Sub-Saharan African Countries.

Large differences exist in the coverage and quality of cancer surveillance systems across the world, with limited data currently available from low-resource settings. Information on the resources required to register cancer cases are needed in order for global, national, regional, and local stakeholders to adequately support cancer registry operations. The objective of this study is to estimate the cost of cancer registration and report the cost per cancer incident case, the cost per inhabitant in the area covered by the registry, and cost allocated to specific registry activities. The International Registry Costing Tool (IntRegCosting Tool) of the Centers for Disease Control and Prevention was used to assess the costs and resources used by 4 registries in sub-Saharan Africa (Zimbabwe, Uganda, Kenya, and Seychelles). The cost of registering a cancer case ranged from $9 to $96, with lower costs in low- and middle-income countries than in the high-income country. The cost of cancer registration at the population level is very low, ranging from 1 to 17 cents per person. The detailed cost information provided in this manuscript can help registries in in sub-Saharan Africa understand the cost of their registry operations and identify approaches to improve efficiency to meet program priorities. Furthermore, it provides additional evidence to inform funding and resource allocation decisions to advance cancer registration in the region.

Medical Education Partnership Initiative (MEPI) in Zimbabwe: Outcomes and Challenges.

BACKGROUND: Sub-Saharan Africa has an inadequate number of health professionals, leading to a reduced capacity to respond to health challenges, including HIV/AIDS. From 2010 to 2015, the Medical Education Partnership Initiative (MEPI)-sponsored by the U.S. Presidents Emergency Plan for AIDS Relief (PEPFAR) and the National Institutes of Health (NIH)-was enthusiastically taken up by the University of Zimbabwe College of Health Sciences (UZCHS) and 12 other sub-Saharan African universities to develop models of training to improve medical education and research capacity. In this article, we describe the outcomes and challenges of MEPI in Zimbabwe. METHODS: UZCHS in partnership with the University of Colorado, Denver; Stanford University; University of Cape Town; University College London; and King's College London designed the Novel Education Clinical Trainees and Researchers (NECTAR) program and 2 linked awards addressing cardiovascular disease and mental health to pursue MEPI objectives. A range of medical education and research capacity-focused programs were implemented, including faculty development, research support, mentored scholars, visiting professors, community-based education, information and technology support, cross-cutting curricula, and collaboration with partner universities and the ministries of health and education. We analyzed quantitative and qualitative data from several data sources, including annual surveys of faculty, students, and other stakeholders; workshop exit surveys; and key informant interviews with NECTAR administrators and leaders and the UZCHS dean. FINDINGS: Improved Internet connectivity and electronic resource availability were early successes of NECTAR. Over the 5-year period, 69% (115 of 166) of faculty members attended at least 1 of 15 faculty development workshops. Forty-one faculty members underwent 1-year advanced faculty development training in medical education and leadership. Thirty-three mentored research scholars were trained under NECTAR, and 52 and 12 in cardiovascular and mental health programs, respectively. Twelve MEPI scholars had joined faculty by 2015. Full-time faculty grew by 36% (122 to 166), annual postgraduate and medical student enrollment increased by 61% (75 to 121) and 71% (123 to 210), respectively. To institutionalize and sustain MEPI innovations, the Research Support Center and the Department of Health Professions Education were established at UZCHS. CONCLUSION: MEPI has synergistically revitalized medical education, research capacity, and leadership at UZCHS. Investments in creating a new research center, health professions education department, and, programs have laid the foundation to help sustain faculty development and research capacity in the country.

Esophageal cancer male to female incidence ratios in Africa: A systematic review and meta-analysis of geographic, time and age trends.

Esophageal squamous cell carcinoma (ESCC) remains the predominant histological subtype of esophageal cancer (EC) in many transitioning countries, with an enigmatic and geographically distinct etiology, and consistently elevated incidence rates in many Eastern and Southern African countries. To gain epidemiological insights into ESCC patterns across the continent, we conducted a systematic review and meta-analysis of male-to-female (M:F) sex ratios of EC age-standardised (world) incidence rates in Africa according to geography, time and age at diagnosis. Data from 197 populations in 36 countries were included in the analysis, based on data from cancer registries included in IARC's Cancer Incidence in Five Continents, Cancer in Africa and Cancer in Sub-Saharan Africa reports, alongside a systematic search of peer-reviewed literature. A consistent male excess in incidence rates overall (1.7; 95% CI: 1.4, 2.0), and in the high-risk Eastern (1.6; 95% CI: 1.4, 1.8) and Southern (1.8; 95% CI: 1.5, 2.0) African regions was observed. Within the latter two regions, there was a male excess evident in 30-39 year olds that was not observed in low-risk regions. Despite possible referral biases affecting the interpretability of the M:F ratios in place and time, the high degree of heterogeneity in ESCC incidence implies a large fraction of the disease is preventable, and directs research enquiries to elucidate early-age exposures among young men in Africa.

Feasibility and sustainability of an interactive team-based learning method for medical education during a severe faculty shortage in Zimbabwe.

BACKGROUND: In 2010, in the midst of the human immunodeficiency virus (HIV) epidemic in Zimbabwe, 69% of faculty positions in the Department of Medicine of the University of Zimbabwe College of Health Sciences (UZ-CHS) were vacant. To address the ongoing need to train highly skilled HIV clinicians with only a limited number of faculty, we developed and implemented a course for final-year medical students focused on HIV care using team-based learning (TBL) methods. METHODS: A competency-based HIV curriculum was developed and delivered to final-year medical students in 10 TBL sessions as part of a 12 week clinical medicine attachment. A questionnaire was administered to the students after completion of the course to assess their perception of TBL and self-perceived knowledge gained in HIV care. Two cohorts of students completed the survey in separate academic years, 2011 and 2012. Descriptive analysis of survey results was performed. RESULTS: Ninety-six of 120 students (80%) completed surveys. One hundred percent of respondents agreed that TBL was an effective way to learn about HIV and 66% strongly agreed. The majority of respondents agreed that TBL was more stimulating than a lecture course (94%), fostered enthusiasm for the course material (91%), and improved teamwork (96%). Students perceived improvements in knowledge gained across all of the HIV subjects covered, especially in challenging applied clinical topics, such as management of HIV antiretroviral failure (88% with at least a "large improvement") and HIV-tuberculosis co-infection (80% with at least a "large improvement"). CONCLUSIONS: TBL is feasible as part of medical education in an African setting. TBL is a promising way to teach challenging clinical topics in a stimulating and interactive learning environment in a low-income country setting with a high ratio of students to teachers.

Presence of Betapapillomavirus in Kaposi sarcoma lesions.

Human herpes virus 8 (HHV 8) is recognized as the necessary cause of Kaposi sarcoma (KS) and in the recent past the human papillomavirus (HPV) has been linked to the development of cutaneous basal cell and squamous cell carcinomas. In a cross sectional study investigating Beta-HPV infections in skin lesions, an unexpected occurrence of HPV DNA was found in KS lesions of HIV infected individuals. Of the 18 KS cases included in the study 16 (89%) had HPV DNA detected. The most common Betapapillomavirus types were HPV14 [15 cases (83.3%)], HPV12 [8 cases (44.4%)], and HPV24 [7 cases (39%)]. Multiple Beta-HPV types were detected in 10 (62.5%) of the participants with HPV DNA positive lesions; of these 7 had a CD4+ count below 350 cells/µl and 3 had CD4+ counts above 350 cells/µl. The presence of Beta-HPV DNA in KS lesions is a newly described phenomenon. Further studies to elucidate the role of Beta-HPV in KS need to be conducted as it is possible that HHV 8 may not be the solitary viral carcinogen in KS tumorigenesis.

Setting the research agenda in a resource-limited setting--viewpoint.

The phenomenon of disproportionately large allocations of global health research resources to relatively limited components of the global health burden is widely acknowledged. Factors contributing to this are explored. The development of a national or regional research agenda is a critical step toward attempting to redress this imbalance. Key areas to be considered are a broad vision, dialogue, and commitment from those stakeholders comprising the "health research triangle": national policy makers and decision makers, key personnel in both health research and health care, and community representatives. The interdependent roles of human, material, and community resources are further examined.

AIDS-associated Kaposi sarcoma: outcomes after initiation of antiretroviral therapy at a university-affiliated hospital in urban Zimbabwe.

OBJECTIVE: To retrospectively investigate the outcomes of patients with AIDS-associated Kaposi sarcoma (AIDS-KS) after initiation of antiretroviral therapy (ART), under routine practice conditions, at a university-affiliated hospital in urban Zimbabwe. BACKGROUND: While studies from developed nations have demonstrated excellent outcomes for AIDS-KS patients treated with ART, few studies have examined the outcomes of African AIDS-KS patients after starting therapy. METHODS: A retrospective cohort of 124 AIDS patients initiating ART under routine practice conditions was studied. Thirty-one patients with AIDS-KS were matched 1:3 to 93 AIDS patients without KS (non-KS). The primary outcome was loss-to-care after initiation of therapy. Multivariate analysis was performed to identify significant predictors of loss-to-care. The percent change in weight at 6 months after starting ART was a secondary outcome. A sub-group analysis evaluated differences in pre-treatment variables between AIDS-KS patients retained-in-care compared to those lost-to-care. RESULTS: AIDS-KS patients had significantly greater 2-year proportional loss-to-care than matched non-KS AIDS patients (26.4% vs. 9.5%; p = 0.01) after initiation of ART. In multivariate analysis, the presence of KS (p = 0.02) was the only significant predictor of loss-to-care. AIDS-KS patients had significantly less weight gain after starting ART than non-KS AIDS patients (+3.4% vs. +6.4%; p = 0.03). AIDS-KS patients retained-in-care had significantly higher pre-treatment CD4+ lymphocyte counts than AIDS-KS patients lost-to-care (223 vs. 110 cells/mm(3); p = 0.04). CONCLUSIONS: In this retrospective study, AIDS-KS patients experienced significantly worse outcomes than matched non-KS AIDS patients after initiation of ART. AIDS-KS patients with higher pre-treatment CD4+ lymphocyte counts were more likely to be retained in care.

Cancer survival in a southern African urban population.

This paper provides the first comprehensive population based cancer survival estimates from the African continent. Five-year absolute and relative survival estimates are presented for black and white Zimbabwean patients diagnosed with cancer in Harare, Zimbabwe between the years 1993 and 1997. The survival of black Zimbabwean cancer patients are among the lowest ever reported from population based cancer registries. For most cancer sites, white Zimbabwean patients have much higher survival than black Zimbabweans, except for lung and colorectal cancer, for which the estimates are similarly poor. Race specific comparisons to cancer patients in the United States show that Zimbabwean patients have much lower survival than American cancer patients and that the gap between black Zimbabwean patients and black American patients is broader than between white Zimbabwean and white American patients. Access to and the ability to pay for medical care may be a very important barrier to better survival for the majority of black Zimbabwean patients and the most important cause for the very low cancer survival in this population.

Survival of cervix cancer patients in Harare, Zimbabwe, 1995-1997.

The survival experience of 284 patients with cancer of the cervix uteri registered by the population-based Zimbabwe National Cancer Registry in 1995-1997 is described. The vital status of these subjects was established by linkage with death registration and by retrieval of patient files from medical records departments. Untraced patients were contacted at home. Of the 284, 177 (62.3%) were dead and 76 (26.8%) were alive at the closing date of the study (31 December 1999), with only 31 cases (10.9%) lost to follow-up. Overall observed and relative survival at 3 years were 44.2% and 45.2%, respectively. Half of the cases (139) had been referred and treated in the radiotherapy department. Survival was significantly greater in the first 3 years for patients who received radiotherapy treatment compared to those that had not, but this difference had disappeared by the fourth year of follow-up. Many cases presented late (distant metastasis), and extent of disease was an important determinant of survival; cases with metastases had a risk of death some 3 times that of patients with localized disease. The results demonstrate the importance of earlier diagnosis and availability of effective treatment in the African context.