Into and out of Africa--taking over from Denis Burkitt.

Denis Burkitt's description of the eponymous lymphoma in 1958 in Uganda, opened up a vast and important field of enquiry in haematology and oncology. His pioneering experiments with chemotherapy demonstrated the possibility of cure, often with a single dose. His geographical explorations showed the tumour to be delimited by climate, suggesting an infectious cause vectored by mosquitoes. His clinical observations furthered the field of cancer immunotherapy. And his collegial, inquisitive nature facilitated the development of an enduring cancer research centre in Kampala. Burkitt's legacy in Uganda has wide-reaching effects that endure not only in Uganda but also throughout the haematology-oncology community to this day.

Lack of germ-line promoter methylation in BRCA1-negative families with familial breast cancer.

Hereditary breast cancer accounts for about 10% of breast cancer in the United States, but high-penetrance, germ-line mutations in BRCA1 and BRCA2 are responsible for less than half of these high-risk families. Epigenetic modification of DNA by promoter methylation can result in a potentially heritable epimutation that silences the gene. Using a highly sensitive technique, we assayed the BRCA1 gene for promoter methylation among 41 BRCA1- and BRCA2-negative women whose personal and family histories indicated a high risk of BRCA mutations (median prior likelihood = 60%) using the BRCAPro model. DNA from 19 women who were "true negatives" for BRCA mutations served as controls. We found no evidence for promoter methylation among the high-risk women who tested negative for germ-line BRCA mutations. Thus, epimutation is an unlikely explanation for hereditary breast cancer in women who test negative for BRCA mutations.

A New Master's Degree in Global Health: Reflections on a 5-year Experience.

BACKGROUND: The University of California-San Francisco's (UCSF) Master of Science (MS) degree in global health sciences, a 1-year degree program started in 2008, is the first accredited master's degree in global health in the country. OBJECTIVE: The aim of this study was to review the genesis and structure of the MS degree program, and describe its progress over its first 5 years. METHODS: We reviewed the program's teaching methods, academic curriculum, course evaluations, and backgrounds and outcomes of the first 127 graduates. Student opinions were gathered from anonymous course evaluations. Student outcome data and graduates' perspectives were gathered through a voluntary, anonymous, online survey. We reflect on student demand, program strengths and weaknesses, and future academic directions. FINDINGS: The program's structure arose from three learning objectives identified by the Curriculum Committee: a multidisciplinary approach to the foundations of global health, an emphasis on research design and methods, and an application of theory to international fieldwork. The resulting broad curriculum has attracted students of diverse backgrounds, which has enriched classroom discussions. Over the first 5 years, the program revised its fieldwork project criteria to allow more flexibility in design, leading to a higher rate of publication and enabling students to graduate with an academic portfolio. Students have reported that the high faculty-to-student ratio has fostered strong mentorship relationships; this is vital as 66% of graduates work in academics. Graduates have reflected that group work in the program appropriately prepared them for their work environment. The program's experience has guided its response to: pressure to focus on medical aspects of global health; students' needs for career skill-building; financial challenges; and trends toward online didactics. CONCLUSIONS: The recent surge in interest in global health careers has created demand for academic programs. UCSF has designed the MS degree program to balance breadth and depth of learning in a multidisciplinary curriculum, and combine career preparation and theoretical learning in a one-year academic degree. The challenges of balancing breadth and depth of learning in a multidisciplinary program, and combining career preparation and theoretical learning in a one-year academic degree, have informed UCSF's MS program design.

A case-control study of Burkitt lymphoma in East Africa: are local health facilities an appropriate source of representative controls?

BACKGROUND: We investigated the feasibility and appropriateness of enrolling controls for Burkitt lymphoma (BL) from local health facilities in two regions in Uganda. METHODS: BL case data were compiled from two local hospitals with capacity to diagnose and treat BL in North-west and North-central regions of Uganda during 1997 to 2009. Local health facility data were compiled from children attending four representative local health facilities in the two regions over a two week period in May/June 2010. Age and sex patterns of BL cases and children at local facilities were compared and contrasted using frequency tables. RESULTS: There were 999 BL cases diagnosed in the study area (92% of all BL cases treated at the hospitals): 64% were from North-central and 36% from North-west region. The mean age of BL cases was 7.0 years (standard deviation [SD] 3.0). Boys were younger than girls (6.6 years versus 7.2 years, P = 0.004) and cases from North-central region were younger than cases from North-west region (6.8 years versus 7.3 years, P = 0.014). There were 1012 children recorded at the four local health facilities: 91% at facilities in North-central region and 9% from facilities in North-west region. Daily attendance varied between 1 to 75 children per day. The mean age of children at health facilities was 2.2 years (SD 2.8); it did not differ by sex. Children at North-central region facilities were younger than children at North-west region facilities (1.8 years versus 6.6 years, P < 0.001). CONCLUSIONS: While many children attend local health facilities, confirming feasibility of obtaining controls, their mean age is much lower than BL cases. Health facilities may be suitable for obtaining young, but not older, controls.

Infectious agents and human malignancies.

Cancer has periodically been proposed as transmissible disease in animals and humans, and specific pathogens have long been searched for. Several biomolecular studies, fundamental in understanding cancer pathogenesis, have identified mechanisms directly/indirectly involved in pathogens-related cancer, including 1) oncogene transduction, with introduction of exogenous oncogenic genes; 2) activation of endogenous oncogenes, comprising those from endogenous retroviruses; 3) inactivation of constitutive suppressor genes, with enhanced susceptibility to exogenous oncogenic agents. Further pathogens' indirect role is associated to cancer promotion through inflammation and angiogenesis. The global burden of cancer associated with infectious agents approaches 20% of all malignancies. Most of the common "infectious" cancers occur in developing countries and their "attributable risk" (i.e. the proportion of cancers that would not occur if the agent were removed) is considerable. Although the cancer role of often ubiquitous pathogens, and the molecular mechanisms involved in the infrequent progression of chronic infections to cancers are still often unknown, the identity of the agents and efforts to mitigate their effects can lead to effective cancer prevention and substantive public health benefit.

Ductal carcinoma in situ in BRCA mutation carriers.

PURPOSE: The current literature suggests that ductal carcinoma in situ (DCIS) of the breast is infrequently diagnosed in patients with BRCA germline mutations. We studied women at high risk of hereditary breast cancer syndromes who underwent testing for BRCA1 and BRCA2 to estimate DCIS prevalence and incidence in known BRCA-positive women compared with high-risk women who were mutation negative. METHODS: We analyzed breast event outcomes in a retrospective cohort of 129 BRCA-positive and 269 BRCA-negative women undergoing genetic testing for a BRCA mutation between September 1996 and December 2003 at University of California, San Francisco. We estimated the frequency of DCIS and invasive cancer and time to breast events from birth using a Cox proportional hazard model for competing risks. Histologic grade of DCIS was also compared between groups. RESULTS: Among BRCA carriers, 48 (37%) had DCIS (with or without invasive cancer) compared with 92 noncarriers (34%). Univariate analysis showed that both DCIS and invasive cancer had an earlier onset in mutation carriers than in noncarriers, although on a per-woman basis, this difference was not statistically significant. High-grade DCIS was more common in BRCA1 mutation carriers than in patients without a mutation (P = .02). CONCLUSION: DCIS is equally as prevalent in patients who carry deleterious BRCA mutations as in high familial-risk women who are noncarriers, but occurs at an earlier age. Our results argue for the consideration of DCIS as a criterion for BRCA risk assessments with appropriate weighting in prediction models such as BRCAPRO.

Helicobacter pylori and cancer among adults in Uganda.

Data from Africa on infection with Helicobacter pylori (H. pylori) are sparse. Therefore, as part of an epidemiological study of cancer in Uganda, we investigated the prevalence and determinants of antibodies against H. pylori among 854 people with different cancer types and benign tumours. Patients were recruited from hospitals in Kampala, Uganda, interviewed about various demographic and lifestyle factors and tested for antibodies against H. pylori. In all patients combined, excluding those with stomach cancer (which has been associated with H. pylori infection), the prevalence of antibodies was 87% (723/833) overall, but declined with increasing age (p = 0.02) and was lower among people who were HIV seropositive compared to seronegative (p < 0.001). Otherwise, there were few consistent epidemiological associations. Among those with stomach cancer, 18/21 (86%) had anti-H. pylori antibodies (odds ratio 0.8, 95% confidence intervals 0.2-2.9, p = 0.7; estimated using all other patients as controls, with adjustment for age, sex and HIV serostatus). No other cancer site or type was significantly associated with anti-H. pylori antibodies. The prevalence of H. pylori reported here is broadly in accord with results from other developing countries, although the determinants of infection and its' role in the aetiology of gastric cancer in Uganda remain unclear.

Clinical Trial of Malaria Prophylaxis in Tropical Splenomegaly Syndrome

A controlled; randomised; double-blinde trial of malaria prophylaxis in tropical splenomegaly syndrome showed a significant reduction in spleen size and an improvement of anemia and symptoms in patients treated with antimalarials compared with control subjects receiving placebo. this study confirms the observations from West Africa and provides further indirect evidence for a malarial aetiology of tropical splenomegaly syndrome