Treatment delays in children and young adults with lymphoma: report from an East Africa Lymphoma Cohort Study

Background: Affordable treatments for lymphoma from the WHO's essential medicine list are available in low-income settings. However, precise diagnosis is often lacking and prolonged time to diagnosis and treatment results in poor treatment outcomes. So far, a detailed analysis of the root causes of the treatment delay is lacking. Methods: This prospective cohort study was conducted at three tertiary cancer hospitals in Tanzania and one cancer centre, St. Mary's Hospital-Lacor Hospital, in Northern Uganda. The study included patients with a confirmed diagnosis of lymphoma. The primary outcome was the median total treatment delay and its components. Total treatment delay was defined as the time taken from the onset of symptoms to receiving definitive cancer treatment. Results: The median age of patients was 12 years (IQR 9-18), and 100 (68%) were males. The median Total Treatment Delay for the entire cohort was 124 days (95% CI 107 - 136). Not started treatment probability for the entire cohort was 64% (95% CI 56-72) at 90 days and 30% (24 - 39) at 180 days. The median Total Treatment Delay for Burkitt lymphoma was 91 days (95% CI 80 - 115), while for DLBCL and Hodgkin lymphoma, it was 114 days (95% CI 84 - 148) and 232 days (95% CI 179 - 305), respectively. Conclusion: Significant treatment delay for lymphoma patients emanates from healthcare system-related factors. Due to delays in referrals from primary care and lack of capacity of pathology in secondary care, initial treatment decisions are still often based on clinical suspicion and urgency

IFNL4 Genotypes and Risk of Childhood Burkitt Lymphoma in East Africa.

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be expressed only by carriers of the genetic variant rs368234815-dG within the first exon of the IFNL4 gene. Genetic inability to produce IFN-λ4 (in carriers of the rs368234815-TT/TT genotype) has been associated with improved clearance of hepatitis C virus (HCV) infection. The IFN-λ4-expressing rs368234815-dG allele (IFNL4-dG) is most common (up to 78%) in West sub-Saharan Africa (SSA), compared to 35% of Europeans and 5% of individuals from East Asia. The negative selection of IFNL4-dG outside Africa suggests that its retention in African populations could provide survival benefits, most likely in children. To explore this hypothesis, we conducted a comprehensive association analysis between IFNL4 genotypes and the risk of childhood Burkitt lymphoma (BL), a lethal infection-associated cancer most common in SSA. We used genetic, epidemiologic, and clinical data for 4,038 children from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) and the Malawi Infections and Childhood Cancer case-control studies. Generalized linear mixed models fit with the logit link controlling for age, sex, country, P. falciparum infection status, population stratification, and relatedness found no significant association between BL risk and 3 coding genetic variants within IFNL4 (rs368234815, rs117648444, and rs142981501) and their combinations. Because BL occurs in children 6-9 years of age who survived early childhood infections, our results suggest that additional studies should explore the associations of IFNL4-dG allele in younger children. This comprehensive study represents an important baseline in defining the health effects of IFN-λ4 in African populations

Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10-6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control

Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa

In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10-11 and 3.74×10-2, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research

Age and geographic patterns of Plasmodium falciparum malaria infection in a representative sample of children living in Burkitt lymphoma-endemic areas of northern Uganda

BACKGROUND: Falciparum malaria is an important risk factor for African Burkitt lymphoma (BL), but few studies have evaluated malaria patterns in healthy BL-age children in populations where both diseases are endemic. To obtain accurate current data, patterns of asymptomatic malaria were investigated in northern Uganda, where BL is endemic. METHODS: Between 2011 and 2015, 1150 apparently healthy children under 15 years old were sampled from 100 villages in northern Uganda using a stratified, multi-stage, cluster survey design. Falciparum malaria prevalence (pfPR) was assessed by questionnaire, rapid diagnostic test (RDT) and thick film microscopy (TFM). Weighted pfPR and unadjusted and adjusted associations of prevalence with covariates were calculated using logistic models and survey methods. RESULTS: Based on 1143 children successfully tested, weighted pfPR was 54.8% by RDT and 43.4% by TFM. RDT sensitivity and specificity were 97.5 and 77.8%, respectively, as compared to TFM, because RDT detect malaria antigens, which persist in peripheral blood after clinical malaria, thus results based on RDT are reported. Weighted pfPR increased from 40% in children aged under 2 years to 61.8% in children aged 6–8 years (odds ratio 2.42, 95% confidence interval (CI) 1.26–4.65), then fell slightly to 49% in those aged 12–15 years. Geometric mean parasite density was 1805.5 parasites/µL (95% CI 1344.6–2424.3) among TFM-positive participants, and it was higher in children aged <5 years at 5092.9/µL (95% CI 2892.7–8966.8) and lower in those aged ≥10 years at 983.8/µL (95% CI 472.7–2047.4; P = 0.001). Weighted pfPR was lower in children residing in sub-regions employing indoor residual spraying (IRS) than in those residing in non-IRS sub-regions (32.8 versus 65.7%; OR 0.26, 95% CI 0.14, 0.46). However, pfPR varied both within IRS (3.2–55.3%) and non-IRS sub-regions (29.8–75.8%; Pheterogeneity <0.001). pfPR was inversely correlated with a child’s mother’s income (P = 0.011) and positively correlated with being enrolled in the wet season (P = 0.076), but sex was irrelevant. CONCLUSIONS: The study observed high but geographically and demographically heterogenous patterns of asymptomatic malaria prevalence among children living in northern Uganda. These results provide important baseline data that will enable precise evaluation of associations between malaria and BL. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12936-017-1778-z) contains supplementary material, which is available to authorized users

MOESM1 of A cross-sectional study of asymptomatic Plasmodium falciparum infection burden and risk factors in general population children in 12 villages in northern Uganda

Additional file 1: Table S1. Weighted distribution of characteristics of apparently healthy children aged 0–15 years enrolled between October 2011 and February 2014 in 12 villages in northern Uganda

Associations between IgG reactivity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens and Burkitt lymphoma in Ghana and Uganda case-control studiesResearch in context

Background: Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma linked to Plasmodium falciparum (Pf) malaria in sub-Saharan Africa. We investigated antibody reactivity to several human receptor-binding domains of the Pf erythrocyte membrane protein 1 (PfEMP1) that play a key role in malaria pathogenesis and are targets of acquired immunity to malaria. Methods: Serum/plasma IgG antibody reactivity was measured to 22 Pf antigens, including 18 to PfEMP1 CIDR domains between cases and controls from two populations (149 eBL cases and 150 controls from Ghana and 194 eBL cases and 600 controls from Uganda). Adjusted odds ratios (aORs) for case-control associations were estimated by logistic regression. Findings: There was stronger reactivity to the severe malaria associated CIDRα1 domains than other CIDR domains both in cases and controls. eBL cases reacted to fewer antigens than controls (Ghana: p = 0·001; Uganda: p = 0·03), with statistically significant lower ORs associated with reactivity to 13+ antigens in Ghana (aOR 0·39, 95% CI 0·24–0·63; pheterogeneity = 0·00011) and Uganda (aOR 0·60, 95% CI 0.41–0·88; pheterogeneity = 0·008). eBL was inversely associated with reactivity, coded as quartiles, to group A variant CIDRδ1 (ptrend = 0·035) in Ghana and group B CD36-binding variants CIDRα2·2 (ptrend = 0·006) and CIDRα2·4 (ptrend = 0·033) in Uganda, and positively associated with reactivity to SERA5 in Ghana (ptrend = 0·017) and Uganda (ptrend = 0·007) and group A CIDRα1·5 variant in Uganda only (ptrend = 0·034). Interpretation: eBL cases reacted to fewer antigens than controls using samples from two populations, Ghana and Uganda. Attenuated humoral immunity to Pf EMP1 may contribute to susceptibility to low-grade malaria and eBL risk. Funding: Intramural Research Program, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. Keywords: Non-Hodgkin lymphoma, Plasmodium falciparum malaria, PfEMP1, Epstein-Barr virus, Burkitt lymphoma, Afric

Evaluating the Causal Link Between Malaria Infection and Endemic Burkitt Lymphoma in Northern Uganda: A Mendelian Randomization Study

Submitted by Nuzia Santos ([email protected]) on 2018-03-14T17:44:37Z No. of bitstreams: 1 Evaluating the Causal Link Between Malaria.pdf: 271793 bytes, checksum: 2844c8378094216bfb4d102d6677dd91 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2018-03-14T18:01:40Z (GMT) No. of bitstreams: 1 Evaluating the Causal Link Between Malaria.pdf: 271793 bytes, checksum: 2844c8378094216bfb4d102d6677dd91 (MD5)Made available in DSpace on 2018-03-14T18:01:40Z (GMT). No. of bitstreams: 1 Evaluating the Causal Link Between Malaria.pdf: 271793 bytes, checksum: 2844c8378094216bfb4d102d6677dd91 (MD5) Previous issue date: 2017African Field Epidemiology Network. EMBLEM Study. Kampala, UgandaNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USAFundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, BrazilMakerere University. College of Health Sciences. Department of Medical Microbiology. Kampala, UgandaAfrican Field Epidemiology Network. EMBLEM Study. Kampala, UgandaNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USAAfrican Field Epidemiology Network. EMBLEM Study. Kampala, UgandaAfrican Field Epidemiology Network. EMBLEM Study. Kampala, UgandaNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USAAfrican Field Epidemiology Network. EMBLEM Study. Kampala, Uganda/ University of Maryland School of Medicine. Institute of Human Virology Benjamin Emmanuel. Baltimore, MD, USAAfrican Field Epidemiology Network. EMBLEM Study. Kampala, UgandaWorld Health Organization. Regional Office for Africa. Brazzaville, CongoNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USAOhio State University. Department of Pathology. Columbus, OH, USANational Institutes of Health. National Institute of Allergy and Infectious Diseases. Division of Intramural Research. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USASt. Mary's Hospital. EMBLEM Study. Lacor, Gulu, UgandaNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USABackground: Plasmodium falciparum (Pf) malaria infection is suspected to cause endemic Burkitt Lymphoma (eBL), but the evidence remains unsettled. An inverse relationship between sickle cell trait (SCT) and eBL, which supports that between malaria and eBL, has been reported before, but in small studies with low power. We investigated this hypothesis in children in a population-based study in northern Uganda using Mendelian Randomization. Methods: Malaria-related polymorphisms (SCT, IL10, IL1A, CD36, SEMA3C, and IFNAR1) were genotyped in 202 eBL cases and 624 controls enrolled during 2010–2015. We modeled associations between genotypes and eBL or malaria using logistic regression. Findings: SCT was associated with decreased risk of eBL (adjusted odds ratio [OR] 0•37, 95% CI 0•21–0•66; p = 0•0003). Decreased risk of eBL was associated with IL10 rs1800896-CT (OR 0•73, 95% CI 0•50–1•07) and -CC genotypes (OR 0•53, 95% CI 0•29–0•95, ptrend = 0•019); IL1A rs2856838-AG (OR 0•56, 95% CI 0•39–0•81) and -AA genotype (OR 0•50, 95% CI 0•28–1•01, ptrend = 0•0016); and SEMA3C rs4461841-CT or -CC genotypes (OR 0•57, 95% CI 0•35–0•93, p = 0•0193). SCT and IL10 rs1800896, IL1A rs2856838, but not SEMA3C rs4461841, polymorphisms were associated with decreased risk of malaria in the controls. Interpretation: Our results support a causal effect of malaria infection on eB