Sir Michael Anthony Epstein (1921-2024).

Codiscoverer of the Epstein-Barr virus.

Denis Burkitt: A legacy of global health.

When first described in 1958, Burkitt lymphoma was considered by many to be an African curiosity. However, over the next few decades, over 10,000 publications on Burkitt lymphoma would influence many facets of oncology research including immunology, molecular genetics, chemotherapy, and viral oncology. At the time of discovery, its distribution in equatorial Africa was unique; it was where a child was born and lived, and not what race they were, that conveyed the greatest incidence risk. Its association with Epstein-Barr virus brought attention to the possibility that oncogenesis may be influenced by viruses. The influence that Burkitt lymphoma had on furthering oncology is far-reaching, and it is fitting that the physician credited with bringing attention to this disease was himself broad in his influence. Denis Burkitt was a humanitarian surgeon whose work was not limited to Burkitt lymphoma: he instigated a plan to rid an entire Ugandan district of yaws, he designed and created affordable orthopaedic equipment that could be locally produced in Kampala, and he was an early advocate of a high fiber diet. The following article will examine the biography of Denis Burkitt, with a focus on how he was able to further oncology and global health.

Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study.

Discovering how to improve survival and establishing clinical reference points for children diagnosed with endemic Burkitt lymphoma (eBL) in resource-constrained settings has recaptured international attention. Using multivariate analyses, we evaluated 428 children with eBL in Kenya for age, gender, tumor stage, nutritional status, hemoglobin, lactate dehydrogenase (LDH), Epstein-Barr virus (EBV) and Plasmodium falciparum prior to induction of chemotherapy (cyclophosphamide, vincristine, methotrexate and doxorubicin) to identify predictive and prognostic biomarkers of survival. During this 10 year prospective study period, 22% died in-hospital and 78% completed six-courses of chemotherapy. Of those, 16% relapsed or died later; 31% achieved event-free-survival; and 31% were lost to follow-up; the overall one-year survival was 45%. After adjusting for covariates, low hemoglobin (<8 g/dL) and high LDH (>400 mU/ml) were associated with increased risk of death (adjusted Hazard Ratio (aHR) = 1.57 [0.97-2.41]) and aHR = 1.84, [0.91-3.69], respectively). Anemic children with malaria were 3.55 times more likely to die [1.10-11.44] compared to patients without anemia or malarial infection. EBV load did not differ by tumor stage nor was it associated with survival. System-level factors can also contribute to poor outcomes. Children were more likely to die when inadvertently overdosed by more than 115% of the correct dose of cyclophosphamide (a HR = 1.43 [0.84-2.43]) or doxorubicin (a HR = 1.25, [0.66-2.35]), compared with those receiving accurate doses of the respective agent in this setting. This study codifies risk factors associated with poor outcomes for eBL patients in Africa and provides a benchmark by which to assess improvements in survival for new chemotherapeutic approaches.

Burkitt's Lymphoma.

Endemic Burkitt's lymphoma (BL) remains the most prevalent pediatric cancer in sub-Saharan Africa even though it was the first human cancer with a viral etiology described over 50 years ago. Epstein-Barr virus (EBV) was discovered in a BL tumor in 1964 and has since been implicated in other malignancies. The etiology of endemic BL has been linked to EBV and Plasmodium falciparum malaria co-infection. While epidemiologic studies have yielded insight into EBV infection and the etiology of endemic BL, the modulation of viral persistence in children by malaria and deficits in EBV immunosurveillance has more recently been reified. Renewed efforts to design prophylactic and therapeutic EBV vaccines provide hope of preventing EBV-associated BL as well as increasing the ability to cure this cancer.

Mapping the methodologies of Burkitt lymphoma.

While recent accounts have emphasised the planned, large-scale and systematic character of cancer virus research in the mid-C20, I argue here that a distinctive kind of small-scale scientific research existed, and made a distinctive contribution to the development of the field as a whole. Using the case of the research carried out to understand the causes of Burkitt lymphoma in Africa during the 1960s, I highlight two distinctive practices--geographical mapping and the re-purposing of existing disease infrastructure--that played a central role in this episode. My intention here is threefold: first, I will argue that this research is unlike the research practices usually identified as typical 'big science' research concerning cancer viruses, particularly in the United States. Second, I will argue that this kind of research is also clearly distinct from the kind of research that Derek Price (Price, 1963) characterised as 'little science'. Thirdly, I will sketch a positive characterisation of this kind of research as 'small science'. I conclude by suggesting that this characterisation may be applied to other kinds of historical biomedical research, and that so doing may offer the pluralist a useful alternative way of understanding medical research in the twentieth century.

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.

Burkitt lymphoma in Uganda, the legacy of Denis Burkitt and an update on the disease status.

Burkitt lymphoma (BL) was first described in Uganda in 1958 as a sarcoma of the jaw but later confirmed to be a distinct form of Non Hodgkin lymphoma (NHL). This discovery was the defining moment of cancer research in Uganda, which eventually led to the establishment of a dedicated cancer research institute, the Uganda Cancer Institute (UCI) in 1967. The centre was dedicated to Denis Burkitt in recognition of his contribution to cancer research in East Africa. BL is still the commonest NHL in childhood in Uganda. Its incidence has significantly increased recently due to yet unknown factors. Although the human immunodeficiency virus (HIV) was considered a possible reason for the increase, there is no evidence that it has substantially impacted on the epidemiology of the disease. However, for those patients with BL who are co infected with HIV there is a clear impact of the disease on clinical presentation and outcome. HIV-infected patients commonly present with extra facial sites and tend to have poor overall survival (median survival of 11·79 months). In summary, BL, as a disease entity in Uganda, has maintained the same clinical characteristics since its discovery, despite the emergence of HIV during the intervening period.

Denis Parsons Burkitt CMG, MD, DSc, FRS, FRCS, FTCD (1911-93) Irish by birth, Trinity by the grace of God.

Denis Parsons Burkitt, surgeon and research scientist, is a household name in the medical profession. Denis received his BA in 1933 and graduated as a physician in 1935 from Trinity College, Dublin. After serving as a surgeon in the Royal Army Medicine Corps during World War II, he worked as a surgeon and lecturer in Africa. It was in Africa that he developed exceptional observational and analytical skills, which led him to identify and formally develop a successful treatment for a childhood cancer that is now called Burkitt Lymphoma. The influence of Christianity in his life was huge. Throughout his life he remained extremely modest, attributing much of what he had achieved to the work of others. Denis's contributions to haemato-oncology remain salient today, and his discoveries continue to generate new research. Throughout his career he received some of the highest scientific honours from many different countries across the globe.

Burkitt lymphoma and the discovery of Epstein-Barr virus.

The chance germinal encounter with the first lecture outside Africa on Burkitt lymphoma is described together with the hypothesis of a viral cause. Repeated virological investigations on lymphoma biopsies proved negative, leading to the idea that a latent virus might be activated if lymphoma cells could be cultured, although no human lymphoid cell had at that time ever been maintained in vitro. A chance event reminding of the need for suspension culture with mouse lymphomas led to success. The cultured cells carried a morphologically unequivocal, strangely inert, herpesvirus shown later to be immunologically, biologically and biochemically unique. How this new agent acquired its name, Epstein-Barr virus, is explained.

[Nasopharyngeal carcinoma in sub-Saharan Africa: a tribute to Mr. Peter Clifford].

Poorly differentiated nasopharyngeal carcinoma (NPC) is a major malignancy in certain areas of Asia. It exists also in Africa, notably among largely Arab populations in North Africa, and in "hotspots" in East Africa among "native" Africans. This article deals with the latter, as studied and defined in depth during the 1960s and 70s by the Irish-born surgeon, Peter Clifford. Through his published works, he has influenced and helped define the field of head and neck cancer as it exists in Kenya. He also did pioneering work on the African childhood malignancy, Burkitt's lymphoma (BL). Both BL and NPC have been ultimately shown to be associated with the human herpes Epstein-Barr virus (EBV). This article is written as a tribute to Peter Clifford, focusing on his work on NPC, where he first defined the disease "hotspots" in the Kenyan Highlands, studied how best to treat the malignancy in the absence of radiotherapy, looked at possible NPC predisposing factors in the Kenyan setting, and ultimately addressed how the cancer cells interact with EBV. Peter Clifford's pioneering work was cut short by accident. Although outside East Africa he remains largely an 'unsung hero' in the field, his influence has been great. It begs to be re-addressed and reconsidered.

The curious case of the tumour virus: 50 years of Burkitt's lymphoma.

Burkitt's lymphoma (BL) was first described 50 years ago, and the first human tumour virus Epstein-Barr virus (EBV) was discovered in BL tumours soon after. Since then, the role of EBV in the development of BL has become more and more enigmatic. Only recently have we finally begun to understand, at the cellular and molecular levels, the complex and interesting interaction of EBV with B cells that creates a predisposition for the development of BL. Here, we discuss the intertwined histories of EBV and BL and their relationship to the cofactors in BL pathogenesis: malaria and the MYC translocation.