Burkitt's lymphoma and emerging therapeutic strategies for EBV and Aids-associated lymphoproliferative diseases in East Africa
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In 1958, Denis Burkitt was the first to describe a reticulum cell sarcoma of the jaw in children at the Mulago Hospital and Makerere University Scbool of Medicine in Kampala, Uganda, which was later determined to be a malignant lymphoma by O'Conor and Davies (1,2). Since then, the epidemiological, clinicopathological, and molecular characterization and treatment of Burkitt's Lymphoma (BL) has been the subject of intense investigation. Lately association of HlV infection with a distinct subtype of Burkitt's lymphoma has renewed interest in the disease that has served as a model for understanding the possible role of viruses in cancer (Lyrnphomagenesis). Epstein Barr virus (EBV) has been associated with endemic BL as an aetiologic agent for a long time. This has been supported by important epidemiologic studies done in East Africa. The high frequency of EBV DNA in HIV¬associated BL suggests an important role for EBV in the pathogenesis of BL, other lyrnphoprolifcrative disorders, and Hodgkin's disease. Possible mechanisms through immune dysregulation, and cytogenetic alteration such as the c-myc translocation, point to common pathogenic pathways for the "BL-syndrome" occurring in three different subtypes of disease (e.g., endemic, sporadic, and AIDS-associated). The common pathogenetic mechanisms and the central role of EBV are instructive in the development of clinical approaches in the prevention and treatment of all EB V -associated lymphomas especially in the era of AIDS pandemic. A series of articles related to Burkitt's lymphoma, EBV-associated rumours such as Hodgkin s disease, and therapeutic strategies suitable for evaluation in a region of the world with scarce resources for the supportive care of patients undergoing myelotoxic therapy, and hardest hit by the AIDS pandemic are compiled for this special supplement to the East Africa Medical Journal. This work builds on an emerging scientific partnership amongst investigators at the Kenyatta National Hospital and University of Nairobi, College of Health Sciences in Kenya; the Uganda Cancer Institute and Makerere University School of Medicine ill Kampala; and investigators at the Case Western Reserve University (Case) School of Medicine in Cleveland, Ohio, University of Miami in Florida, and the Ohio State University in Columbus in the United States (3). It is important to highlight that investigators from among these four institutions will be leading an International Working Group as part of the re-organized National Cancer Institute sponsored AlDS Malignancy Consortium, that is taking shape with the competitive renewal of this research programme in the fall of 2005. One of the papers on the clinical characteristics of BL in Kenya considers from the vantage point that even within the spectrum of "BL-syndrome" there may be clinical features that can differentiate subtypes of endemic BL in Kenya. The treatment of Burkitt' lymphoma has been challenging throughout the world, especially in the setting of AIDS. One strategy in the pre-highly active antiretroviral therapy (HAART) era was to purse dose¬modification of chemotherapy, which resulted in comparable efficacy outcomes with lessened myelotoxicity (4). As the AIDS epidemic advances in the HAART era, it is apparent that the natural history of AIDS-related BL in the United States is further evolving and patients will benefit by returning to more aggressive cytotoxic chemotherapy regimens used in the treatment of sporadic BL (5), In Africa, the treatment of BL has evolved from single-agent cyclophosphamide to exploring more intense, but dose-adjusted multi-agent regimens, which are till associated with unacceptably high mortality rates following a recent report from Malawi (6,7). Confronted with the realities of myelotoxic therapy in Africa, the three other papers address therapeutic approaches suitable in this region of the world. Also presented is a conceptual framework with which to explore clinical strategies to overcome myelo suppression in East Africa. Furthermore there is emerging data as discussed also in this issue that is beginning to consider directly targeting EBV using agents that disrupt EBV latency, activate the lytic pathway of viral replication, and thereby render BL cells more highly sensitive to antiviral attack using zidovudine. Lastly, the pragmatism of using oral chemotherapy in this setting is captured in the final paper using an oral regimen for Hodgkin's diseases that is also being dose¬modified and tested in East Africa for the management of AIDS-related non-Hodgkin's lymphoma (8).