Risk factors for Burkitt lymphoma in East African children and minors: A case-control study in malaria-endemic regions in Uganda, Tanzania and Kenya.

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in sub-Saharan African countries, however, few epidemiologic studies have been undertaken and none attempted enrolling cases from multiple countries. We therefore conducted a population-based case-control study of eBL in children aged 0-15 years old in six regions in Northern Uganda, Northern Tanzania and Western Kenya, enrolling 862 suspected cases and 2,934 population controls (response rates 98.5-100%), and processing ~40,000 vials of samples using standardized protocols. Risk factor questionnaires were administered, and malaria period prevalence was measured using rapid diagnostic tests (RDTs). A total of 80.9% of the recruited cases were diagnosed as eBL; 61.4% confirmed by histology. Associations with eBL risk were computed using logistic regression models adjusted for relevant confounders. Associations common in at least two countries were emphasized. eBL risk was decreased with higher maternal income and paternal education and elevated with history of inpatient malaria treatment >12 months before enrollment. Reporting malaria-attributed fever up to 6 months before enrollment and malaria-RDT positivity at enrollment were associated with decreased eBL risk. Conversely, reporting exposure to mass malaria suppression programs (e.g., indoor residual insecticide) was associated with elevated risk. HIV seropositivity was associated with elevated eBL risk, but the relative impact was small. The study shows that it is feasible to conduct networked, multisite population-based studies of eBL in Africa. eBL was inversely associated with socioeconomic status, positively associated with inpatient malaria treatment 12 months ago and with living in areas targeted for malaria suppression, which support a role of malaria in eBL.

Mean platelet counts are relatively decreased with malaria but relatively increased with endemic Burkitt Lymphoma in Uganda, Tanzania, and Kenya.

Platelet counts are decreased in Plasmodium falciparum malaria, which is aetiologically linked with endemic Burkitt lymphoma (eBL). However, the pattern of platelet counts in eBL cases is unknown. We studied platelet counts in 582 eBL cases and 2 248 controls enrolled in a case-control study in Uganda, Tanzania and Kenya (2010-2016). Mean platelet counts in controls or eBL cases with or without malaria-infection in controls versus eBLcases were compared using Student's t-test. Odds ratios (ORs) and two-sided 95% confidence intervals (95% CIs) were estimated using multiple logistic regression, controlling for age, sex, haemoglobin and white blood cell counts. Platelets were decreased with malaria infection in the controls [263 vs. 339 × 109 platelets/l, P < 0·0001; adjusted OR (aOR) = 3·42, 95% CI: 2·79-4·18] and eBL cases (314 vs. 367 × 109 platelets/l, P-value = 0·002; aOR = 2·36, 95% CI: 1·49-3·73). Unexpectedly, platelets were elevated in eBL cases versus  controls in overall analyses (mean: 353 vs. 307 × 109 platelets/l, P < 0·0001; aOR = 1·41; 95% CI: 1·12-1·77), and when restricted to malaria-positive (mean 314 vs. 263 × 109 platelets/l, P < 0·0001; OR = 2·26; 95% CI: 1·56-3·27) or malaria-negative (mean 367 vs. 339 × 109 platelets/l, P < 0·001; OR = 1·46; 95% CI: 1·17-1·83) subjects. Platelets were decreased with malaria infection in controls and eBL cases but elevated with eBL.

A spatiotemporal analysis of invasive cervical cancer incidence in the state of Maryland between 2003 and 2012.

PURPOSE: Invasive cervical cancer (ICC) rates have tremendously declined in the United States, yet new cases consistently occur in Maryland and throughout the United States. We hypothesized that although rates have generally declined, this decline is uneven across counties and over time. METHODS: Space-time cluster detection analysis was conducted to evaluate clusters of ICC incidence at the county level within Maryland between 2003 and 2012. RESULTS: The most likely cluster was a cluster of low incidence, which included 6 counties in eastern Maryland for the period 2009-2012. A secondary cluster of low rates, comprising 2 metropolitan counties in northern Maryland, was observed for the period 2009-2012. Two of the three clusters of high ICC rates occurred in 2009-2012 in the large metropolitan area of Baltimore City and another cluster in Frederick County, in rural western Maryland. The third cluster of high rates was observed 2005-2008, in western Maryland. CONCLUSION: In recent periods, some Maryland counties have experienced anomalously high or low ICC incidence. Clusters of high incidence are not explained by differences in screening rates and may be due to failures in follow-up care for cervical abnormalities that need to be investigated. Clusters of low incidence may represent areas of successful ICC control.

Kaposi Sarcoma Incidence, Burden, and Prevalence in United States People with HIV, 2000-2015.

BACKGROUND: The introduction of combination antiretroviral therapy (cART) has led to a significant reduction in Kaposi sarcoma (KS) incidence among people with HIV (PWH). However, it is unclear if incidence has declined similarly across key demographic and HIV transmission groups and the annual number of incident and prevalent KS cases remains unquantified. METHODS: Using population-based registry linkage data, we evaluated temporal trends in KS incidence using adjusted Poisson regression. Incidence and prevalence estimates were applied to CDC HIV surveillance data, to obtain the number of incident (2008-2015) and prevalent (2015) cases in the United States. RESULTS: Among PWH, KS rates were elevated 521-fold [95% confidence intervals (CI), 498-536] compared with the general population and declined from 109 per 100,000 person-years in 2000 to 47 per 100,000 person-years in 2015, at an annual percentage change of -6%. Rates declined substantially (P trend < 0.005) across all demographic and HIV transmission groups. Of the 5,306 new cases estimated between 2008 and 2015, 89% occurred among men who have sex with men. At the end of 2015, 1,904 PWH (0.20%) had been diagnosed with KS in the previous 5 years. CONCLUSIONS: A consistent gradual decline in KS incidence has occurred among PWH in the United States during the current cART era. This decrease is uniform across key demographic and HIV transmission groups, though rates remain elevated relative to the general population. IMPACT: Continued efforts to control HIV through early cART initiation and retention in care need to be maintained and possibly expanded to sustain declines.

Inverse association of falciparum positivity with endemic Burkitt lymphoma is robust in analyses adjusting for pre-enrollment malaria in the EMBLEM case-control study.

BACKGROUND: Falciparum and endemic Burkitt lymphoma (eBL) are co-endemic in Africa, but the malaria experience in eBL patients is unknown. A lower prevalence of falciparum has been reported in eBL patients, but those results are anecdotally attributed to pre-enrollment anti-malaria treatment. METHODS: We studied 677 eBL patients and 2920 community controls aged 0-15 years enrolled in six regions in Uganda, Tanzania, and Kenya during 2010-2016. Falciparum was diagnosed using thick blood film microscopy (TFM) and antigen-capture rapid diagnostic tests (RDTs). Guardians of the children answered a 40-item structured questionnaire about their child's pre-enrollment lifetime malaria history and treatment, demographics, socioeconomics, animal exposures, fevers, and hospitalizations. We utilized exploratory factor analysis to reduce the 40 questionnaire variables into six factors, including Inpatient malaria and Outpatient malaria factors that were surrogates of pre-enrollment anti-malaria treatment. The six factors accounted for 83-90% of the variance in the questionnaire data. We calculated odds ratios and 95% confidence intervals (OR 95% CI) of association of eBL with falciparum positivity, defined as positive both on TFM or RDTs, or only RDTs (indicative of recent infection) or TFM (indicative of current falciparum infection) versus no infection, using multivariable logistic regression, controlling for group of age (0-2, 3-5, 6-8, 9-11 and 12-15 years), sex, and study site and the afore-mentioned pre-enrollment factors. RESULTS: The prevalence of falciparum infection was 25.6% in the eBL cases and 45.7% in community controls (aOR = 0.43, 95% CI: 0.40, 0.47; P < 0.0001). The results were similar for recent falciparum infection (6.9% versus 13.5%, aOR = 0.44, 95% CI: 0.38, 0.50; P < 0.0001) and current falciparum infection (18.7% versus 32.1%, aOR = 0.47, 95% CI: 0.43, 0.51; P < 0.0001). These aORs for any, recent and current falciparum infection did not change when we adjusted for pre-enrollment factors (aORs = 0.46, =0.44, and = 0.51, respectively) were significantly lower in stratified analysis for any infection in children < 5 years (aOR = 0.46; 95% CI: 0.29, 0.75) or ≥ 10 years (aOR = 0.47; 95% CI: 0.32, 0.71). CONCLUSION: Our study results reduce support for pre-enrollment antimalaria treatment as a sole explanation for the observed lower falciparum prevalence in eBL cases and open a space to consider alternative immunology-based hypotheses.

Assessment of Mixed Plasmodium falciparum sera5 Infection in Endemic Burkitt Lymphoma: A Case-Control Study in Malawi.

BACKGROUND: Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in Africa and is linked to Plasmodium falciparum (Pf) malaria infection, one of the most common and deadly childhood infections in Africa; however, the role of Pf genetic diversity is unclear. A potential role of Pf genetic diversity in eBL has been suggested by a correlation of age-specific patterns of eBL with the complexity of Pf infection in Ghana, Uganda, and Tanzania, as well as a finding of significantly higher Pf genetic diversity, based on a sensitive molecular barcode assay, in eBL cases than matched controls in Malawi. We examined this hypothesis by measuring diversity in Pf-serine repeat antigen-5 (Pfsera5), an antigenic target of blood-stage immunity to malaria, among 200 eBL cases and 140 controls, all Pf polymerase chain reaction (PCR)-positive, in Malawi. METHODS: We performed Pfsera5 PCR and sequencing (~3.3 kb over exons II-IV) to determine single or mixed PfSERA5 infection status. The patterns of Pfsera5 PCR positivity, mixed infection, sequence variants, and haplotypes among eBL cases, controls, and combined/pooled were analyzed using frequency tables. The association of mixed Pfsera5 infection with eBL was evaluated using logistic regression, controlling for age, sex, and previously measured Pf genetic diversity. RESULTS: Pfsera5 PCR was positive in 108 eBL cases and 70 controls. Mixed PfSERA5 infection was detected in 41.7% of eBL cases versus 24.3% of controls; the odds ratio (OR) was 2.18, and the 95% confidence interval (CI) was 1.12-4.26, which remained significant in adjusted results (adjusted odds ratio [aOR] of 2.40, 95% CI of 1.11-5.17). A total of 29 nucleotide variations and 96 haplotypes were identified, but these were unrelated to eBL. CONCLUSIONS: Our results increase the evidence supporting the hypothesis that infection with mixed Pf infection is increased with eBL and suggest that measuring Pf genetic diversity may provide new insights into the role of Pf infection in eBL.

Cancer risk following lymphoid malignancies among HIV-infected people.

OBJECTIVE(S): HIV-infected people have increased cancer risk. Lymphoma survivors have an increased risk of certain second primary cancers in the general population, but second cancer risk among HIV-infected people is poorly understood. Herein, we characterized the risk of cancers following lymphoid malignancies among HIV-infected people. DESIGN: Population-based linkage of HIV and cancer registries. METHODS: We used data from the US HIV/AIDS Cancer Match Study (1996-2015) and evaluated the risk of first nonlymphoid malignancy in Cox regression models, with first lymphoid malignancy diagnosis as a time-dependent variable. RESULTS: Among 531 460 HIV-infected people included in our study, 6513 first lymphoid and 18 944 first nonlymphoid malignancies were diagnosed. Risk of nonlymphoid cancer following a lymphoid malignancy was increased overall [adjusted hazard ratio (aHR) = 2.7; 95% confidence interval (CI) = 2.3--3.2], and specifically for cancers of the oral cavity (aHR = 2.6; 95% CI = 1.2-5.5), colon (2.4; 1.1-5.0), rectum (3.6; 1.9-6.7), anus (3.6; 2.5-5.1), liver (2.0; 1.2-3.5), lung (1.6; 1.1-2.4), vagina/vulva (6.1; 2.3-16.3), and central nervous system (5.0; 1.6-15.6), Kaposi sarcoma (4.6; 3.4-6.2), and myeloid malignancies (9.7; 6.1-15.4). After additional adjustment for prior AIDS diagnosis and time since HIV diagnosis, aHRs were attenuated overall (aHR = 1.7; 95% CI = 1.5-2.0) and remained significant for cancers of the rectum, anus, and vagina/vulva, Kaposi sarcoma, and myeloid malignancies. CONCLUSION: HIV-infected people with lymphoid malignancies have an increased risk of subsequent non-lymphoid cancers. As risks remained significant after adjustment for time since HIV diagnosis and prior AIDS diagnosis, it suggests that immunosuppression may explain some, but not all, of these risks.

Prevalence of Cervical Dysplasia in HIV-Positive and HIV-Negative Women at the Sihanouk Hospital Center of HOPE, Phnom Penh , Cambodia

Introduction: There is a high burden of cervical cancer in Cambodia, yet published data on the prevalence of cervical dysplasia and the risk factors contributing to the development of pre-cancerous lesions in Cambodian women is very limited. In addition, as it is well known that HIV positivity increases cervical cancer risk, it is important to quantify the prevalence of cervical dysplasia and carcinoma among Cambodian women living with HIV disease. Methods: A cross-sectional study was conducted with a sample of 499 HIV+ and 501 HIV- Cambodian women at the Sihanouk Hospital Center of HOPE. Visual inspection with 5% acetic acid was the method of screening. Colposcopy was performed on all VIA+ patients, and subsequent treatment followed WHO guidelines. Logistic regression models, stratified by both HIV+ and HIV- groups, were used to assess significant factors associated with having dysplasia. Results: VIA+ results were prevalent in both the HIV+ and HIV- arms of the study. The HIV+ patients were more likely to have a lower age at coitarche, lower weight, 2 or more lifetime sexual partners, two or greater pregnancies, or be unmarried. The estimated prevalence of VIA detected cervical dysplasia was 11% for the entire study sample, 13.4% in the HIV positive (HIV+) group and 8.6% in the HIV negative (HIV-) group (OR: 1.65; 95% CI: 1.10, 2.48; p=0.01). For the HIV+ group, having a history of 4 or more full-term pregnancies (OR: 3.42; 95% CI: 1.01-11.64; p=0.049) was found to be significantly associated with having an increased risk of developing cervical dysplasia in the multivariate model. Conclusion: Cervical dysplasia is prevalent in both HIV positive and negative Cambodian women and a VIA based national screening programs need to be developed and expanded to provide access to affordable and effective treatment for cervical dysplasia and cancers.

A Cross-Sectional Population Study of Geographic, Age-Specific, and Household Risk Factors for Asymptomatic Plasmodium falciparum Malaria Infection in Western Kenya.

The burden of Plasmodium falciparum (Pf) malaria in Kenya is decreasing; however, it is still one of the top 10 causes of morbidity, particularly in regions of western Kenya. Between April 2015 and June 2016, we enrolled 965 apparently healthy children aged 0-15 years in former Nyanza and Western Provinces in Kenya to characterize the demographic, geographic, and household risk factors of asymptomatic malaria as part of an epidemiologic study to investigate the risk factors for endemic Burkitt lymphoma. The children were sampled using a stratified, multistage cluster sampling survey design. Malaria was assessed by rapid diagnostic test (RDT) and thick-film microscopy (TFM). Primary analyses of Pf malaria prevalence (pfPR) are based on RDT. Associations between weighted pfPR and potential risk factors were evaluated using logistic regression, accounting for the survey design. Plasmodium falciparum malaria prevalence was 36.0% (27.5%, 44.5%) by RDT and 22.3% (16.0%, 28.6%) by TFM. Plasmodium falciparum malaria prevalence was positively associated with living in the lake-endemic area (adjusted odds ratio [aOR] 3.46; 95% confidence interval [95% CI] 1.63, 7.37), paternal occupation as peasant farmer (aOR 1.87; 1.08, 3.26) or manual laborer (aOR 1.83; 1.00, 3.37), and keeping dogs (aOR 1.62; 0.98-2.69) or cows (aOR 1.52; 0.96-2.40) inside or near the household. Plasmodium falciparum malaria prevalence was inversely associated with indoor residual insecticide spraying (IRS) (aOR 0.44; 0.19, 1.01), having a household connected to electricity (aOR 0.47; 0.22, 0.98), and a household with two (aOR 0.45; 0.22, 0.93) or ≥ three rooms (aOR 0.41; 0.18, 0.93). We report high but geographically heterogeneous pfPR in children in western Kenya and significant associations with IRS and household-level socioeconomic factors.

Utilization of Pap testing among women living with HIV enrolled in primary care in Baltimore, Maryland: A 10-year longitudinal study, 2005-2014.

Frequent Pap testing is recommended among women living with HIV (WLWH) due to their elevated risk for cervical cancer. However, there are few recent longitudinal evaluations of utilization and determinants of Pap testing among WLWH. Medical and pathology records of WLWH seen at Johns Hopkins Hospital between 2005 and 2014 were assessed using Prentice, Williams, Peterson models. Of 554 WLWH in care for ≥ 18 months, 79% received Pap testing, however only 11% consistently received Pap testing at the recommended interval. Some women (5%) were consistently under-screened (tested at longer intervals) and 21% did not receive any Pap testing at during follow-up. WLWH with decreased likelihood of screening included older women, injection drug users, whites and those who had lived for longer with HIV. In contrast, only women with a prior abnormal Pap result were more likely to receive Pap testing. CD4 cell count and health insurance were not significant determinants. Although many WLWH in care received Pap testing, some WLWH were unscreened or underscreened. Determinants of Pap testing for WLWH include socio-demographic factors and a prior abnormal result; these present potential targets in an urban HIV care setting for closer monitoring and directed interventions to improve utilization among WLWH.