In low- and middle-income settings, microbiologic evaluation of chemotherapy-associated febrile illness is limited by cost. Cost-effective diagnostic algorithms could streamline evaluation for chemotherapy-associated febrile illness where comprehensive testing is not possible, particularly in HIV- and tuberculosis (TB)-endemic settings. In this study, we created a decision analytic model to evaluate costs, diagnostic yield, and cost-effectiveness of diagnostic algorithms for adult inpatients with solid tumors who developed chemotherapy-associated febrile illness in Uganda. Given the high prevalence of HIV, TB, and malaria, diagnostics included serum cryptococcal antigen (CrAg) lateral flow assay, Alere TB urinary lipoarabinomannan (LAM), malaria rapid testing, and aerobic blood cultures. We considered the following testing algorithms: 1) a comprehensive approach where all tests were performed on all participants and 2) stepwise algorithms where tests were performed in series and stopped with the first positive result. Prevalence data and test performance were taken from the published literature. A comprehensive testing strategy yielded 32.2% correct diagnoses at a cost of $97.85 per correct diagnosis. Of the stepwise strategies, testing CrAg first yielded the cheapest strategy at a cost of $85.49 per correct diagnosis and the highest number of appropriate diagnoses (29.9%). The incremental cost-effectiveness ratio was $234 per additional correct diagnosis for the comprehensive strategy when compared with the sequential strategy. Although comprehensive diagnostic testing is optimal for patients who experience chemotherapy-associated febrile illness, if this strategy is unavailable, stepwise testing with CrAg first and then, TB LAM is optimal to maximize correct diagnosis and minimize costs.

Abstract Background Microbiology diagnostic tests are often prohibitively expensive in resource-limited settings. Cost-effective diagnostic algorithms could potentially guide diagnostic evaluation for chemotherapy-associated febrile illness in resource-limited settings where comprehensive testing is not possible. This is particularly true in sub-Saharan Africa, where the high prevalence of HIV and tuberculosis (TB) place patients at increased risk of developing opportunistic infections that do not frequently occur among patients receiving chemotherapy in the United States or Europe. Methods We created a decision analytic model to evaluate the costs, diagnostic yield, and cost-effectiveness of diagnostic algorithms for adult inpatients with solid tumors who developed fever within 30 days of receiving chemotherapy in Uganda. Since Uganda has a high prevalence of HIV and TB, diagnostics included serum cryptococcal antigen (CrAg) lateral flow assay, Alere TB urinary lipoarabinomannan (LAM), malaria rapid testing, and aerobic blood cultures. We considered the following testing algorithms: 1) a comprehensive approach where all tests were performed, and 2) various stepwise algorithms where tests were performed in series and stopped testing with the first positive result. We obtained prevalence data from a cohort of 100 patients with solid tumors who were admitted to the Uganda Cancer Institute (Kampala, Uganda) with fever. Test performance was taken from the published literature. Results A comprehensive diagnostic testing strategy yielded 64% of correct diagnoses at a cost of $97.85 per correct diagnosis. Of the stepwise strategies, testing CrAg first yielded the cheapest strategy, at a cost of $85.49 per correct diagnosis, and the highest number of appropriate diagnoses (59%). The incremental cost-effectiveness ratio was $234 per additional correct diagnosis for the comprehensive over this sequential strategy. Conclusion Comprehensive diagnostic testing is optimal for patients who experience post-chemotherapy febrile illness in resource-limited settings. If this strategy is not available, stepwise testing with CrAg then TB LAM is the optimal strategy to maximize correct diagnosis and minimize costs. Disclosures All Authors: No reported disclosures

PURPOSE:Acute leukemias are associated with substantial morbidity and mortality, particularly in the adult population. Despite an increasing burden of acute leukemia in developing countries, there are limited data on clinical outcomes and prognostic factors in this setting. In this study, we aimed to describe the clinical characteristics, survival, and prognostic factors of adults with acute leukemia at the Uganda Cancer Institute (UCI).METHODS:A retrospective cohort study was conducted between January 2009 and December 2018, reviewing data of patients 18 years or older with a cytopathologic diagnosis of acute leukemia at UCI. Data were extracted on clinical and laboratory characteristics, response to treatment, and survival. Cox-proportional hazards regression and survival analysis were performed to determine survival rates and associated factors. P < .05 was considered statistically significant.RESULTS:In total, 233 participants were enrolled. Most (59.2%. n = 138) participants were male, with a median age of 32 years (IQR, 23-48 years), and 136 (58.4%) had AML. Overall, the 1-year survival was 16.5%, with a median survival time of 47 (IQR, 21-219) days. Predictors of mortality were being a female (adjusted hazard ratio [aHR], 2.8; 95% CI, 1.2 to 6.7; P = .022) and overweight (aHR, 4.2; 95% CI, 1.3 to 13.4; P = .015). Among the patients who had AML, the predictors were poor Eastern Cooperative Oncology Group (ECOG; aHR, 3.1; 95% CI, 1.6 to 6.2; P = .001) and HIV (aHR, 6.0; 95% CI, 1.7 to 20.5; P = .004). Among the patients who had ALL, the predictors were poor ECOG (aHR, 2.3; 95% CI, 1.3 to 4.1; P = .006).CONCLUSION:Patients with acute leukemia in Uganda have poor overall survival. Prospective studies are recommended to better understand causes of early mortality.

Abstract Background Little is known about the microbiology and outcomes of chemotherapy-associated febrile illness among patients in sub-Saharan Africa. Understanding the microbiology of febrile illness could improve antibiotic selection and infection-related outcomes. Methods From September 2019 through June 2022, we prospectively enrolled adult inpatients at the Uganda Cancer Institute who had solid tumors and developed fever within 30 days of receiving chemotherapy. Evaluation included blood cultures, malaria rapid diagnostic tests, and urinary lipoarabinomannan testing for tuberculosis. Serum cryptococcal antigen was evaluated in participants with human immunodeficiency virus (HIV). The primary outcome was the mortality rate 40 days after fever onset, which we estimated using Cox proportional hazards models. Results A total of 104 febrile episodes occurred among 99 participants. Thirty febrile episodes (29%) had ≥1 positive microbiologic result. The most frequently identified causes of infection were tuberculosis (19%) and bacteremia (12%). The prevalence of tuberculosis did not differ by HIV status. The 40-day case fatality ratio was 25%. There was no difference in all-cause mortality based on HIV serostatus, presence of neutropenia, or positive microbiologic results. A universal vital assessment score of >4 was associated with all-cause mortality (hazard ratio, 14.5 [95% confidence interval, 5–42.7]). Conclusions The 40-day mortality rate among Ugandan patients with solid tumors who developed chemotherapy-associated febrile illness was high, and few had an identified source of infection. Tuberculosis and bacterial bloodstream infections were the leading diagnoses associated with fever. Tuberculosis should be included in the differential diagnosis for patients who develop fever after receiving chemotherapy in tuberculosis-endemic settings, regardless of HIV serostatus.

Abstract Background: Health related quality of life in patients with urinary bladder cancer is important to measure outcomes beyond morbidity and biological functioning. In 2020, Bladder cancer (BC) contributed to 3% of all cancer worldwide. Globocan 2018 estimated the prevalence of BC in Uganda at 0.8% with a mortality of 75.9%. BC affects the overall quality of life among patients with several factors influencing this outcome. Our aim was to determine the overall health related quality of life and associated factors among patients with BC in our setting in MNRH in Uganda. Methods: A sample of 111 patients, with histological diagnosis of BC, attending urology clinic or admitted to the urology ward in MNRH were recruited consecutively over a 4-month period. Data was collected by administering the EORTC -QLQ C-30 questionnaire which is a standard interviewer-administered, internationally accepted tool that is validated in Uganda in addition to an associated factors questionnaire. This tool assessed five domains, with symptoms scale and overall QOL. The mean and standard deviation of the overall quality of life were obtained to determine the mean HRQOL. Using simple linear regression, the factors associated with the mean HRQOL were assessed. Results A total of 111 participants were analyzed and their mean age was 56.6 (SD± 17.3). Most were males 73 (65.8%) and most had attained a primary level of education 55 (49.5%). Most had no comorbidities 65 (58.6%). The mean HRQOL among patients with BC in MNRH was found to be 36.2%(±13.5). The mean duration with symptoms was 13.5 months (SD± 15.3) Conclusion. Patients with bladder cancer in MNRH face a unique burden with their diagnosis and have been found to have a very low HRQOL which is significantly associated with increasing age and reduced duration of symptoms. This calls for timely interventions with holistic management and lifelong follow up of these patients.

Background. Neutropenic fever (NF) is associated with significant morbidity and mortality for patients receiving cancer treatment in sub-Saharan Africa (sSA). However, the antibiotic management of NF in sub-Saharan Africa has not been well described. We evaluated the timing and selection of antibiotics for patients with NF at the Uganda Cancer Institute (UCI). Methods. We conducted a retrospective chart review of adults with acute leukemia admitted to UCI from 1 January 2016 to 31 May 2017, who developed NF. For each NF event, we evaluated the association of clinical presentation and demographics with antibiotic selection as well as time to both initial and guideline-recommended antibiotics. We also evaluated the association between ordered antibiotics and the in-hospital case fatality ratio (CFR). Results. Forty-nine NF events occurred among 39 patients. The time to initial antibiotic order was <1 day. Guideline-recommended antibiotics were ordered for 37 (75%) NF events. The median time to guideline-recommended antibiotics was 3 days. Fever at admission, a documented physical examination, and abdominal abnormalities were associated with a shorter time to initial and guideline-recommended antibiotics. The in-hospital CFR was 43%. There was no difference in in-hospital mortality when guideline-recommended antibiotics were ordered as compared to when non-guideline or no antibiotics were ordered (hazard ratio, 0.51 [95% confidence interval {CI},.10-2.64] and 0.78 [95% CI,.20-2.96], respectively). Conclusions. Patients with acute leukemia and NF had delayed initiation of guideline-recommended antibiotics and a high CFR. Prospective studies are needed to determine optimal NF management in sub-Saharan Africa, including choice of antibiotics and timing of antibiotic initiation.

Background: The occurrence of venous thromboembolism (VTE) in patients with cancer leads to a reduced life expectancy. There is an increased incidence of cancer and its associated mortality in Uganda. We described the survival and characteristics of patients with cancer associated thrombosis (CAT) in a tertiary oncology centre in Uganda. Methods: We performed a retrospective study on patients with CAT at the Uganda Cancer Institute (UCI) using a homogenous purposive sampling method. Results: One hundred and eleven patients with documented VTE were included in the analysis. At entry, the mean age was 52.4 years, and 69 were female. Ninety eight had deep venous thrombosis, while 12 had pulmonary embolism. The most common cancer diagnoses were haematologic (30), gynaecologic (20) and prostate (17) cancers. Treatment regimens included anticoagulation with low-molecular weight heparin (LMWH) (72) and combined LMWH with warfarin (22). The median overall survival (OS) was 6.3 months, with a 1-year survival rate of 41.5%. Patients with significantly increased hazard of mortality were those with upper gastrointestinal (UGI) malignancies, colorectal and breast cancers. Patients with a body mass index of 25-29.9 kg/m(2) (overweight) had a slightly reduced hazard of mortality. Conclusion: The OS of patients with CAT at the UCI is short. Most patients with CAT presented with advanced stage cancers and at a relatively young age. Patients with UGI, colorectal and breast cancers had increased hazards of mortality, whereas those who were overweight had a slight reduction in the hazard of mortality.

Purpose: Data on multiple myeloma (MM) in sub-Sahara Africa is scarce. In Uganda, there is a progressively increasing incidence of MM over the years. Methods: We performed a retrospective study on 217 patients with MM at the UCI using purposive sampling method. The objectives of the study were to determine the clinical characteristics, treatment outcomes, 5 year overall survival and predic-tors of survival of patients with MM at the UCI from 01 January 2008 to 31 December 2012. Results: There were 119 (54.8%) males; the mean(SD) age of the study population at presentation was 59(12.8) years; 183(84.3%) patients presented with bone pain, and 135 (61.9%) had skeletal pathology; 186(85.3%) were HIV negative, and 152(70%) had Durie-Salmon stage III. The median overall survival was 2.5 years, (95% CI, 0.393-0.595); factors significantly associated with worse survival were Durie-Salmon stage III disease, HR=5.9, 95% CI (1.61 - 21.74; P=0.007) and LDH >225 U/L HR=3.3, 95% CI (0.57 - 5.92; P=0.029). Conclusion: Most patients with multiple myeloma at the UCI were diagnosed at a relatively young age, presented with late stage disease and bone pain, and had a shorter survival time. Factors associated with worse survival were Durie-Salmon stage III and LDH >225 U/L.

Haematological malignancies account for almost 10% of all cancers diagnosed in sub-Saharan Africa, although the exact incidences and treatment outcomes are difficult to discern because population-based cancer registries in the region are still underdeveloped. More research on haematological malignancies in sub-Saharan Africa is required to establish whether these cancers have a natural history similar to those diagnosed in high-income countries, about which more is known. Several factors negatively affect the outcome of haematological malignancies in sub-Saharan Africa, showcasing a need for improved understanding of the clinicobiological profile of these cancers to facilitate prevention, early detection, diagnosis, and appropriate treatment through increased capacity building, infrastructure, community awareness, coordinated resource mobilisation, and collaboration across the world. The east African governments have pooled resources for common investments to tackle non-communicable diseases, developing the East Africa's Centres of Excellence for Skills and Tertiary Education project funded by the African Development Bank, an initiative that could be replicated for the care of haematological malignancies in other countries in sub-Saharan Africa. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

The purpose of this article is to describe lessons from the first lymphoma clinical trial conducted by the AIDS Malignancy Consortium (AMC) in sub-Saharan Africa (SSA). AMC-068 was a randomized phase II comparison of intravenous versus oral chemotherapy for HIV-positive diffuse large B-cell lymphoma. Opening in 2016, AMC-068 planned to enroll 90 patients (45 per arm) in Kenya, Malawi, Uganda, and Zimbabwe over 24 months and follow patients for 24 months to assess overall survival. In 2018, the study closed after screening 42 patients but enrolling only 7. Challenges occurred during protocol development, pre-activation, and postactivation. During protocol development (2011-2012), major obstacles were limited baseline data to inform study design; lack of consensus among investigators and approving bodies regarding appropriateness of the oral regimen and need for randomized comparison with cyclophosphamide, doxorubicin, vincristine, and prednisone; and heterogeneity across sites in local standards for diagnosis, staging, and treatment. During pre-activation (2012-2016), challenges included unexpected length and layers of regulatory approval across multiple countries, need to upgrade pathology capacity at sites, need to augment existing chemotherapy infusion capacity at sites, and procurement issues for drugs and supplies. Finally, during postactivation (2016-2018), challenges included long delays between symptom onset and screening entry for many patients, leading to compromised performance status and organ function; other patient characteristics that frequently led to exclusion, including high tumor proliferative index or other pathologic features that were disallowed; and costs of routine diagnostic procedures often being borne by patients, which also contributed to pre-enrollment delays. Lessons from AMC-068 are being applied to the design and conduct of new AMC lymphoma trials in SSA, and the study has contributed to a strong operational foundation that will support innovative clinical trials in the future.

Background: The optimal chemotherapy regimen for treating HIV associated NHL in low resource settings is unknown. We conducted a retrospective study to describe survival rates, treatment response rates and adverse events in patients with HIV associated NHL treated with CHOP and dose adjusted-EPOCH regimens at the Uganda Cancer Institute. Methods: A retrospective study of patients diagnosed with HIV and lymphoma and treated at the Uganda Cancer Institute from 2016 – 2018 was done. Results: One hundred eight patients treated with CHOP and 12 patients treated with DA-EPOCH were analysed. Patients completing 6 or more cycles of chemotherapy were 51 (47%) in the CHOP group and 8 (67%) in the DA-EPOCH group. One year overall survival (OS) rate in patients treated with CHOP was 54.5% (95% CI, 42.8 – 64.8) and 80.2% (95% CI, 40.3 – 94.8) in those treated with DA-EPOCH. Factors associated with favourable survival were BMI 18.5-24.9 kg/m 2 , (p=0.03) and completion of 6 or more cycles of chemotherapy, (p<0.001). The overall response rate was 40% in the CHOP group and 59% in the DA-EPOCH group. Severe adverse events occurred in 19 (18%) patients in the CHOP group and 3 (25%) in the DA-EPOCH group; these were neutropenia (CHOP=13, 12%; DA-EPOCH=2, 17%), anaemia (CHOP=12, 12%; DA-EPOCH=1, 8%), thrombocytopenia (CHOP=7, 6%; DA-EPOCH=0), sepsis (CHOP=1), treatment related death (DA-EPOCH=1) and hepatic encephalopathy (CHOP=1). Conclusion: Treatment of HIV associated NHL with curative intent using CHOP and infusional DA-EPOCH is feasible in low resource settings and associated with >50% one year survival.

Purpose "Endemic" Burkitt lymphoma (BL) is a common childhood cancer in Africa. Social and treatment factors may contribute to poor survival. With the aim of improving BL outcomes in Uganda, we undertook a comprehensive project (BL Project) that provided diagnostic support, access to standard chemotherapy, nutritional evaluations, and case management. We evaluated survival of children with BL in the context of the project. Patients and methods Patients followed by the BL Project who consented to research were enrolled in this study. Children with a pathology diagnosis consistent with BL were eligible. Data were collected prospectively. First-line chemotherapy generally consisted of six cycles of cyclophosphamide, vincristine, low-dose methotrexate (COM). We used Kaplan-Meier and Cox regression analyses to evaluate factors associated with overall survival (OS). Results Between July 2012 and June 2017, 341 patients with suspected BL presented to the BL Project. One hundred eighty patients with a pathology-based diagnosis were included in this study. The median age was seven years (interquartile range, 5-9), 74% lived >= 100 km from the Uganda Cancer Institute, 61% had late-stage disease, 84% had ECOG performance status < 3, 63% reported B-symptoms, and 22% showed neurologic symptoms. Fewer than 10% abandoned therapy. The four-year OS rate was 44% (95% CI, 36%-53%). In a multivariate model, ECOG status was significantly associated with mortality. Conclusion The BL Project reduced effects of lacking supportive care and oncology resources, and allowed patients from Uganda to receive curative intent therapy with minimal loss to follow-up. Nonetheless, OS remains unacceptably low. Improved therapeutic approaches to endemic BL are urgently needed in Africa.

11000 Background: Development of cancer services in low and middle income countries (LMIC) is a challenge. The Medical Education, Training and Fellowship (METAF) program aims to improve early detection, research and treatment of cancer in East Africa (EA). Through clinical training courses, participating physicians will be better equipped to diagnose, triage and manage cancer within local hospitals. Methods: The EADB, which is responsible for the development of infrastructure in EA, through the British Council, appointed the RCP as the technical partner in this 4-year project. During Year 1, a needs assessment was carried out in Kampala with oncologists from Kenya, Tanzania, Uganda and Rwanda. Course conveners were recruited, curricula developed and two intensive “training of trainers” (TOT) courses delivered with RCP volunteers teaching alongside local faculty. In Year 2, 5 training courses were delivered, including the first round of ‘cascaded’ courses, facilitated by trainers who participated in the previous TOT workshops, supported by a member of local faculty and an RCP volunteer. Quantitative feedback to evaluate learning was gathered using multiple choice tests at the beginning and end of training. Qualitative feedback was gathered from written evaluations at the end of each course. Course content is continually amended based on country specific needs and participant and faculty feedback. Results: Since the launch of the program in 2016, 7 clinical training activities have been delivered; 3 oncology ToT workshops and 4 oncology cascaded training courses. During Years 1 and 2 the total number of doctors trained across East Africa as part of the METAF programme was 137. Participant feedback suggests that over 935 clinical staff will benefit from the knowledge gained on the clinical courses through mentoring by course participants at home facilities. Conclusions: The TOT solution to the need for a rapid cascade of knowledge has been well received and demonstrated to be effective within this multinational program. The methodology may be applicable to similar needs in LMIC settings. Lessons learned to date will be implemented during Years 3 & 4.

### Mentored research ### Clinical training ### Investment in human capacity and infrastructure ![Figure 1.][1] Figure 1. ![Figure 2.][1] Figure 2. ![Figure 3.][1] Figure 3. Map of Uganda indicating Kampala, the location of the UCI-Fred Hutch Cancer Centre. The UCI-

Background: Endemic Burkitt Lymphoma (eBL) is the most common childhood cancer in many countries of sub-Saharan Africa (SSA). Reported overall survival (OS) rates in SSA are low at 30-50%, especially compared to survival of children with sporadic Burkitt Lymphoma treated in high-resource settings (OS 85-95%)(Patte, Auperin et al. 2007, Buckle, Maranda et al. 2016, Stanley, Westmoreland et al. 2016). The Burkitt Lymphoma (BL) project in Uganda was initiated as a collaboration between the Fred Hutchinson Cancer Research Center and Uganda Cancer Institute (UCI) in July 2012. The project provided resources for timely pathologic diagnosis, chemotherapy during stock-outs, case management to improve adherence, transportation, and standardized recording of care and clinical outcomes. We sought to determine OS and response to treatment in this patient population with eBL who received enhanced care through this demonstration project. Methods:Every child presenting to the UCI with suspected BL and enrolled in the BL project between July 2012 and December 2014 underwent diagnostic evaluation with a core needle biopsy of the tumor, abdominal ultrasound, and chest radiography. Patients with confirmed BL at enrollment, as determined by pathology review and physician assessment, were staged based on physical exam according to Ziegler. Most received first-line therapy consisting of cyclophosphamide, vincristine and methotrexate (COM) every two weeks for six planned cycles. Treatment response was evaluated ≤ 3 months from starting the 6th cycle of COM. Following completion of therapy, patients were followed monthly for three months, then every three months for up to a year. Follow-up data through March 26, 2015 was included. Kaplan-Meier methodology was used to estimate 1-year OS. Results:A total of 202 patients with suspected BL were followed by the BL project during this time period. Of these, 142 (70%) were confirmed to have BL. The remainder had other cancers or benign diseases (24%) or had inadequate diagnostic data (6%). The median age of patients with BL was 7 years and the majority were male (63%). Approximately half of patients had late-stage disease (49% Ziegler stages C, D or AR) and had a high LDH at presentation (54%). Of the 142 with BL, 78% initiated COM, 6% other chemotherapy, and 16% were not treated with chemotherapy (18 died in the first 40 days and 5 were exited). Among 110 patients who initiated COM, the treatment response after 6 cycles was complete response (CR) for 46%, partial response (PR) for 7%, stable (SD) or progressive disease (PD) for 2%, relapsed disease (RD) for 1%, but there was no response assessment within 3 months of the 6th cycle for 10%. The remaining patients who did not complete 6 cycles either switched to second line therapy (7%), abandoned treatment (9%), died (9%), exited the program (3%), or were censored (6%) within 6 months of starting treatment. Among the subset of 73 patients who completed six cycles of treatment, the responses after 6 cycles were as follows: CR 70%, PR 11%, SD or PD 3%, RD 1%, unknown 15%. At 1 year, OS for the entire cohort with confirmed eBL was 53% (95% CI 43%, 62%; Figure 1). Among the patients who initiated COM, survival at 1 year post treatment initiation was 60% (95% CI 49%, 70%; Figure 2). These data represent preliminary results of our ongoing analysis. An updated analysis, along with associations of baseline factors, including CNS status, anemia, thrombocytopenia, B symptoms, tumor lysis syndrome and HIV status, as well as other infections (malaria, Hepatitis B), with clinical outcomes will be presented. Conclusion:Survival ofpatients with eBL treated in a low-resource setting remains inferior compared to children treated for sporadic BL in higher resource settings. The BL project was able to provide pathologic diagnoses, assure access to chemotherapy, enhance supportive care, and reduce abandonment to less than 10%, but still only slightly more than half of patients with a confirmed diagnosis survived one year. Ongoing obstacles to improving outcomes are inaccurate diagnosis and lacking supportive care to allow more intensive therapies. Improved diagnostic capacity as well as the ability to provide more potent and potentially less toxic treatment modalities may help to address the poor survival of children with a disease that is so successfully treated in higher resource settings. Disclosures Casper:Up to Date: Patents & Royalties; TempTime: Consultancy, Other: Travel, Accommodation, Expenses; Janssen: Consultancy, Research Funding; GSK: Other: Travel, Accommodation, Expenses; Roche: Consultancy, Other: Travel, Accommodation, Expenses.

Welcome to Annals of Global Health,Annals of Global Health is a peer-reviewed, fully open access, online journal dedicated to publishing high quality articles dedicated to all aspects of global health. The journal's mission is to advance global health, promote research, and foster the prevention and treatment of disease worldwide. Its goals are to improve the health and well-being of all people, advance health equity, and promote wise stewardship of the earth's environment. The latest journal impact factor is 3.64.Annals of Global Health is supported by the Program for Global Public Health and the Common Good at Boston College. It was founded in 1934 by the Icahn School of Medicine at Mount Sinai as the Mount Sinai Journal of Medicine. It is a partner journal of the Consortium of Universities for Global Health. Authors of articles accepted for publication in Annals of Global Health will be asked to pay an Article Publication Charge (APC) to cover publication costs. This charge can normally be sourced from your funder or institution. We are committed to supporting authors from all countries to publish their work in Annals of Global Health regardless of national income level, and to achieve this goal, we waive the Article Publication Charge for manuscripts where all authors are from low-income or lower-middle-income countries (as defined by the World Bank). From time to time, Annals of Global Health publishes Special Collections, a series of articles organized around a common theme in global health. Recent Special Collections have included “Strengthening Women’s Leadership in Global Health”, “Decolonizing Global Health Education”, and “Capacity Building for Global Health Leadership Training”. Global health workers interested in developing a Special Collection are strongly encouraged to contact the Managing Editor in advance to discuss the project.

The endemic form of Burkitt lymphoma (eBL), the most common pediatric cancer in sub-Saharan Africa, is the prototypic infection-related malignancy. Virtually 100% of eBL tumor cells carry Epstein-Barr virus (EBV) DNA, and eBL is closely ecologically associated with holoendemic P. falciparum malaria. The cell that undergoes transformation in eBL is an antigen-experienced B lymphocyte that has reached the germinal center and initiated the process of somatic hypermutation (SHM). The tumor cells in eBL express functional B-cell antigen receptors (BCRs), most commonly of the IgM isotype. The rearranged immunoglobulin heavy ( IGH) and light ( IGκ/λ ) chain genes that encode Burkitt BCRs show evidence of SHM, demonstrating that eBL cells have uncoupled the processes of class switch recombination and SHM. Several lines of evidence suggest that BCR signaling pathways are active in eBL cells and that BCR signaling may contribute to the pathogenesis and maintenance of the disease. The uniquely rearranged BCR genes in eBL also represent a tumor-specific molecular signature that can be used to detect and quantitate eBL tumor cells in different tissue compartments. Therefore, Burkitt-associated BCRs have potential as both a disease biomarker and a therapeutic target. We utilized next-generation sequencing (NGS) to identify BCR gene rearrangements in eBL tumor cells obtained at the time of diagnosis from 22 patients, ages 4 to 12 (median: 7 years), with histologically confirmed Burkitt lymphoma who presented to the Uganda Cancer Institute in Kampala, Uganda. Thirteen of the patients were male and 9 were female; 3 patients were HIV-positive. Genomic DNA was isolated from cryopreserved tumor biopsies, and NGS of the IGH and IGκ/λ loci was performed to identify dominant BCR rearrangements in the eBL tumor cells. Sequence reads spanned a 130-nucleotide interval from the middle of framework region 3 (FR3) in the V gene segment to the 5’ region of the J gene segment. The reads captured the entirety of the CDR3 region. A single dominant IGH V-D-J rearrangement comprising >35% of all sequence reads was identified in 16 of the 22 samples. A single dominant IGκ or IGλ rearrangement was likewise seen in most cases with a single dominant IGH rearrangement. Two dominant but independent light chain rearrangements were seen in three eBL cases with a single dominant IGH rearrangement; whether both productive light chains are expressed at the RNA level is under active investigation. The utilization of IGH V- and J-gene segments in Burkitt-associated BCRs from this cohort of 22 patients was highly non-uniform, with utilization of IGHJ04-01 observed in 10 of the 16 cases with a single dominant IGH rearrangement. Analysis of BCR SHM patterns has revealed enrichment in CDRs as compared to FRs, suggesting antigen selection in eBL tumor cells, as well as a higher than expected rate of somatic mutations that create potential N-linked glycosylation sites. Deep sequencing of DNA extracted from peripheral blood mononuclear cells (PBMC) obtained at the time of diagnosis from 13 of the 22 patients identified sequences that were identical to the dominant IGH sequences observed in each patient’s tumor in 9 cases (69%). 5 of the 9 patients had early stage (Ziegler A) disease, demonstrating that Burkitt lymphoma cells commonly circulate in the blood. Current studies include sequencing of rearranged IGH genes present in PBMC after completion of primary therapy to determine if response is correlated with disappearance of the putative tumor-associated BCR sequences. Each eBL tumor sample is undergoing RNA analysis to confirm expression of the established dominant IGH and IGκ/λ rearrangements, as well as to determine the dominant BCR isotype. The complete light and heavy chain variable region sequences of the tumor-associated BCRs are being cloned by PCR with V gene leader peptide- and CDR3-specific primers to enable comprehensive assessment of SHM and BCR stereotypy. Identification of complete variable region sequences will also lay the foundation for synthesis of recombinant full-length membrane-associated and soluble forms of Burkitt BCRs. Reconstitution of Burkitt BCRs in vitro will allow evaluation of their antigenic specificity and signaling properties. Disclosures No relevant conflicts of interest to declare.

There is much commonality between chronic noncommunicable and communicable diseases which is best exemplified by cancers of infectious origin. It provides the perfect opportunity for harnessing the advances that have been made in the control of communicable diseases to attempt the control of noncommunicable diseases. There are possibilities at various levels of intervention, at primary, secondary and tertiary levels, which fit well within a well-planned national cancer control strategy. Prevention should proceed through steps of disruption of transmission, improvement in disease recognition and diagnosis, as well as through prompt effective treatment. This principle should work for both infection and the resultant cancer. Research is very important in understanding how best to use the available knowledge and how best to sequentially implement strategies. Finally, policies that acknowledge infection-related cancers as a major problem in the region should be in place.