Burkitt lymphoma risk shows geographic and temporal associations with Plasmodium falciparum infections in Uganda, Tanzania, and Kenya.

Endemic Burkitt lymphoma (eBL) is a pediatric cancer coendemic with malaria in sub-Saharan Africa, suggesting an etiological link between them. However, previous cross-sectional studies of limited geographic areas have not found a convincing association. We used spatially detailed data from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) study to assess this relationship. EMBLEM is a case-control study of eBL from 2010 through 2016 in six regions of Kenya, Uganda, and Tanzania. To measure the intensity of exposure to the malaria parasite, Plasmodium falciparum, among children in these regions, we used high-resolution spatial data from the Malaria Atlas Project to estimate the annual number of P. falciparum infections from 2000 through 2016 for each of 49 districts within the study region. Cumulative P. falciparum exposure, calculated as the sum of annual infections by birth cohort, varied widely, with a median of 47 estimated infections per child by age 10, ranging from 4 to 315 infections. eBL incidence increased 39% for each 100 additional lifetime P. falciparum infections (95% CI: 6.10 to 81.04%) with the risk peaking among children aged 5 to 11 and declining thereafter. Alternative models using estimated annual P. falciparum infections 0 to 10 y before eBL onset were inconclusive, suggesting that eBL risk is a function of cumulative rather than recent cross-sectional exposure. Our findings provide population-level evidence that eBL is a phenotype related to heavy lifetime exposure to P. falciparum malaria and support emphasizing the link between malaria and eBL.

Unraveling cervical cancer screening dilemmas: histopathological insights from VIA and LEEP at bugando medical centre, Mwanza.

BACKGROUND: The single-visit strategy, also known as the "screen-and-treat" approach, is widely used to screen for cervical cancer in low- and middle-income countries. The screen-and-treat approach leads to unnecessary or inadequate treatment. Thus, a study was conducted to determine the histopathological patterns of aceto-white lesions on visual inspection with acetic acid (VIA) in patients who underwent a Loop Electrosurgical Excision Procedure (LEEP) at Bugando Medical Centre between January 2016 and December 2020. METHOD: A 5-year retrospective cross-sectional case record review was conducted on 329 women who had LEEP at Bugando Medical Centre following a positive VIA cervical screening test. A standard data abstraction form was used to collect patient information. Missing client information records and LEEP without histopathological results were exclusion criteria. For statistical analysis, STATA version 15 was used; in descriptive statistics, frequency, mean, and standard deviation were used. The Chi2 and Fisher's exact tests were used to investigate the relationship between patient characteristics and histopathological patterns, and a P-value of 0.05 was considered statistically significant in multinomial models. RESULTS: This study looked at 329 patients who had LEEP following a VIA positive but were not eligible for cryotherapy. Our study participants had a mean age of 40 ± 8.2 SD. There were 203 (61.7%) patients with benign lesions, including 4 with schistosomiasis and 2 with cervical tuberculosis. The precancerous lesions were discovered in 100 cases (30.4%), and 26 (7.9%) already had invasive cervical cancer. Out of 100 patients with precancerous lesions, 58 (17.6%) and 42 (12.8%) have high- and low-grade squamous intraepithelial (HSIL and LSIL) lesions, respectively. The presence of a precancerous lesion was found to be associated with age 31-40 years (P-value 0.042) and HIV positivity (P-value 0.004). CONCLUSION: Most patients in this study had benign cervical lesions, which do not require LEEP treatment. Nonetheless, a considerable percentage of invasive cervical malignancies and rare benign diseases such as schistosomiasis and cervical tuberculosis were identified. A screen-and-treat approach within well-equipped tertiary hospitals like Bugando Medical Centre should explore alternative options instead of relying solely on straight LEEP.

Sickle cell allele HBB-rs334(T) is associated with decreased risk of childhood Burkitt lymphoma in East Africa.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.

Enhancing information on stage at diagnosis of cancer in Africa.

BACKGROUND/PURPOSE: Stage at diagnosis is an important metric in treatment and prognosis of cancer, and also in planning and evaluation of cancer control. For the latter purposes, the data source is the population-based cancer registry (PBCR), but, although stage is usually among the variables collected by cancer registries, it is often missing, especially in low-income settings. Essential TNM has been introduced to facilitate abstraction of stage data by cancer registry personnel, but the accuracy with which they can do so is unknown. METHODS: 51 cancer registrars from 20 countries of sub-Saharan Africa (13 anglophone, 7 francophone) were tasked with abstracting stage at diagnosis, using Essential TNM, from scanned extracts of case. The panel comprised 28 records of each of 8 common cancer types, and the participants chose how many to attempt (between 48 and 128). Stage group (I-IV), derived from the eTNM elements that they assigned to each cancer, was compared with a gold standard, as decided by two expert clinicians. RESULTS: The registrars assigned the correct stage (I-IV) in between 60 and 80% of cases, with the lowest values for ovary, and the highest for oesophagus. The weighted kappa statistic suggested a moderate level of agreement between participant and expert (0.41-0.60) for 5 cancers, and substantial agreement (0.61-0.80) for three, with the best for cervix, large bowel, oesophagus and ovary, and the worst (weighted kappa 0.46) for non-Hodgkin lymphoma (NHL). For all except NHL, early stage (I/II) and late stage (III/IV) was correctly identified in 80% or more of the cases. CONCLUSIONS: A single training in staging using Essential TNM resulted in an accuracy that was not much inferior to what has been observed in clinical situations in high income settings. Nevertheless, some lessons were learned on how to improve both the guidelines for staging, and the training course.

The whole-genome landscape of Burkitt lymphoma subtypes.

Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry-based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.

Invasive breast Cancer treatment in Tanzania: landscape assessment to prepare for implementation of standardized treatment guidelines.

BACKGROUND: Incidence of breast cancer continues to rise in low- and middle-income countries, with data from the East African country of Tanzania predicting an 82% increase in breast cancer from 2017 to 2030. We aimed to characterize treatment pathways, receipt of therapies, and identify high-value interventions to increase concordance with international guidelines and avert unnecessary breast cancer deaths. METHODS: Primary data were extracted from medical charts of patients presenting to Bugando Medical Center, Tanzania, with breast concerns and suspected to have breast cancer. Clinicopathologic features were summarized with descriptive statistics. A Poisson model was utilized to estimate prevalence ratios for variables predicted to affect receipt of life-saving adjuvant therapies and completion of therapies. International and Tanzanian guidelines were compared to current care patterns in the domains of lymph node evaluation, metastases evaluation, histopathological diagnosis, and receptor testing to yield concordance scores and suggest future areas of focus. RESULTS: We identified 164 patients treated for suspected breast cancer from April 2015-January 2019. Women were predominantly post-menopausal (43%) and without documented insurance (70%). Those with a confirmed histopathology diagnosis (69%) were 3 times more likely to receive adjuvant therapy (PrR [95% CI]: 3.0 [1.7-5.4]) and those documented to have insurance were 1.8 times more likely to complete adjuvant therapy (1.8 [1.0-3.2]). Out of 164 patients, 4% (n = 7) received concordant care based on the four evaluated management domains. The first most common reason for non-concordance was lack of hormone receptor testing as 91% (n = 144) of cases did not undergo this testing. The next reason was lack of lymph node evaluation (44% without axillary staging) followed by absence of abdominopelvic imaging in those with symptoms (35%) and lack of histopathological confirmation (31%). CONCLUSIONS: Patient-specific clinical data from Tanzania show limitations of current breast cancer management including axillary staging, receipt of formal diagnosis, lack of predictive biomarker testing, and low rates of adjuvant therapy completion. These findings highlight the need to adapt and adopt interventions to increase concordance with guidelines including improving capacity for pathology, developing complete staging pathways, and ensuring completion of prescribed adjuvant therapies.

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.

Using digital health to facilitate compliance with standardized pediatric cancer treatment guidelines in Tanzania: protocol for an early-stage effectiveness-implementation hybrid study.

BACKGROUND: In high-income countries (HICs), increased rates of survival among pediatric cancer patients are achieved through the use of protocol-driven treatment. Compared to HICs, differences in infrastructure, supportive care, and human resources, make compliance with protocol-driven treatment challenging in low- and middle-income countries (LMICs). For successful implementation of protocol-driven treatment, treatment protocols must be resource-adapted for the LMIC context, and additional supportive tools must be developed to promote protocol compliance. In Tanzania, an LMIC where resource-adapted treatment protocols are available, digital health applications could promote protocol compliance through incorporation of systematic decision support algorithms, reminders and alerts related to patient visits, and up-to-date data for care coordination. However, evidence on the use of digital health applications in improving compliance with protocol-driven treatment for pediatric cancer is limited. This study protocol describes the development and evaluation of a digital health application, called mNavigator, to facilitate compliance with protocol-driven treatment for pediatric cancer in Tanzania. METHODS: mNavigator is a digital case management system that incorporates nationally-approved and resource-adapted treatment protocols for two pediatric cancers in Tanzania, Burkitt lymphoma and retinoblastoma. mNavigator is developed from an open-source digital health platform, called CommCare, and guided by the Consolidated Framework for Implementation Research. From July 2019-July 2020 at Bugando Medical Centre in Mwanza, Tanzania, all new pediatric cancer patients will be registered and managed using mNavigator as the new standard of care for patient intake and outcome assessment. Pediatric cancer patients with a clinical diagnosis of Burkitt lymphoma or retinoblastoma will be approached for participation in the study evaluating mNavigator. mNavigator users will document pre-treatment and treatment details for study participants using digital forms and checklists that facilitate compliance with protocol-driven treatment. Compliance with treatment protocols using mNavigator will be compared to historical compliance rates as the primary outcome. Throughout the implementation period, we will document factors that facilitate or inhibit mNavigator implementation. DISCUSSION: Study findings will inform implementation and scale up of mNavigator in tertiary pediatric cancer facilities in Tanzania, with the goal of facilitating protocol-driven treatment. TRIAL REGISTRATION: The study protocol was registered in ClinicalTrials.gov (NCT03677128) on September 19, 2018.

Endemic Burkitt lymphoma: a complication of asymptomatic malaria in sub-Saharan Africa based on published literature and primary data from Uganda, Tanzania, and Kenya.

BACKGROUND: Endemic Burkitt lymphoma (eBL) is an aggressive B cell non-Hodgkin lymphoma associated with antigenic stimulation from Plasmodium falciparum malaria. Whether eBL risk is related to malaria parasite density is unknown. To address this issue, children with eBL, asymptomatic and clinical malaria, as a surrogate of malaria parasite density, were assessed. METHODS: Malaria-related laboratory results (parasite density, haemoglobin, platelet count, and white cell count [WBC]) count) were compiled for 4019 eBL cases and 80,532 subjects evaluated for asymptomatic malaria or clinical malaria (severe malaria anaemia, hyperparasitaemia, cerebral malaria, malaria prostration, moderate malaria, and mild malaria) in 21 representative studies published in Africa (mostly East Africa) and 850 eBL cases and 2878 controls with primary data from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) case-control study in Uganda, Tanzania, and Kenya. The average values of malaria-related laboratory results were computed by condition and trends across single-year age groups were assessed using regression and spline models. RESULTS: Overall, malaria infection or malaria was diagnosed in 37,089 of children compiled from the literature. Children with eBL and asymptomatic parasitaemia/antigenaemia, but not those with clinical malaria, were closest in their mean age (age 7.1-7.2 vs. 7.4-9.8 years), haemoglobin level (10.0-10.4 vs. 11.7-12.3 g/dL), malaria parasite density (2800 vs. 1827-7780 parasites/µL), platelet count (347,000-353,000 vs. 244,000-306,000 platelets/µL), and WBC count (8180-8890 vs. 7100-7410 cells/µL). Parasite density in these two groups peaked between four to five years, then decreased steadily thereafter; conversely, haemoglobin showed a corresponding increase with age. Children with clinical malaria were markedly different: all had an average age below 5 years, had dramatically elevated parasite density (13,905-869,000 parasites/µL) and dramatically decreased platelet count (< 159,000 platelets/µL) and haemoglobin (< 7 g/dL). CONCLUSIONS: eBL and asymptomatic parasitaemia/antigenaemia, but not clinical malaria, were the most similar conditions with respect to mean age and malaria-related laboratory results. These results suggest that children with asymptomatic parasitaemia/antigenaemia may be the population at risk of eBL.

Understanding women's perspectives on breast cancer is essential for cancer control: knowledge, risk awareness, and care-seeking in Mwanza, Tanzania.

BACKGROUND: Breast Cancer is the most common cancer in women worldwide. Since 2008, Mwanza, Tanzania, has worked to provide comprehensive cancer services through its Zonal consultant hospital. New national guidelines focused on clinical breast exam requires that women be aware of and seek care for breast concerns. Therefore, this study aims to understand breast cancer awareness in Mwanza and describe women-level barriers, care-seeking behavior, and perspectives on breast cancer. METHODS: A community-based survey was administered to conveniently sampled women aged 30 and older to assess women's perspectives on breast cancer and care-seeking behavior. RESULTS: Among 1129 women with a median age of 37 (IQR: 31-44) years, 73% have heard of cancer and 10% have received breast health education. Women self-evaluated their knowledge of breast cancer (from 1-none to 10-extremely knowledgeable) with a median response of 3 (IQR: 1-4). Only 14% felt they knew any signs or symptoms of breast cancer. Encouragingly, 56% of women were fairly-to-very confident they would notice changes in their breasts, with 24% of women practicing self-breast examination and 21% reporting they had received a past breast exam. Overall, 74% said they would be somewhat-to-very likely to seek care if they noticed breast changes, with 96% noting severity of symptoms as a motivator. However, fear of losing a breast (40%) and fear of a poor diagnosis (38%) were most frequent barriers to care seeking. In assessing knowledge of risk factors, about 50% of women did not know any risk factors for breast cancer whereas 42% of women believed long term contraceptive use a risk factor. However, 37% and 35% of women did not think that family history or being older were risk factors, respectively. CONCLUSIONS: The success of efforts to improve early diagnosis in a setting without population-based screening depends on women being aware of breast cancer signs and symptoms, risks, and ultimately seeking care for breast concerns. Fortunately, most women said they would seek care if they noticed a change in their breasts, but the low levels of cancer knowledge, symptoms, and common risk factors highlight the need for targeted community education and awareness campaigns.

Ten-year surgical experiences with penile cancer at a tertiary care hospital in northwestern Tanzania: a retrospective study of 236 patients.

BACKGROUND: Penile cancer is an uncommon malignancy in developed countries, but the incidence is as high as 10% to 20% of all male cancers in some developing countries. There is a paucity of published data on this subject in our setting. This study describes the clinicopathological presentation and treatment outcome of this condition in our environment, and highlights challenges associated with the care of these patients and proffers solutions for improved outcome. METHODS: This was a retrospective study of histologically confirmed cases of penile cancer seen at Bugando Medical Centre between January 2004 and December 2013. RESULTS: There were 236 penile cancer patients representing 2.2% of all male malignancies during the study period. The median age was 47 years with a modal age group of 41 to 50 years. Of the 236 patients, 147 (62.3%) had severe phimosis. The majority of patients (89.8%) were uncircumcised. A history of human papilloma virus (HPV) was reported in 12 (5.1%) cases. One hundred eighty-two (77.1%) patients reported history of cigarette smoking. Seven (6.7%) patients were human immunodeficiency virus (HIV) positive. The majority of the patients (68.6%) presented with Jackson's stages III and IV. Squamous cell carcinoma was the most common histopathological type (99.2%). Lymph node metastasis was recorded in 65.3% of cases, and it was significantly associated with the tumor size, histopathological subtype, histopathological grade, lympho-vascular invasion, positive resection margins, and urethral involvement (P < 0.001). Distant metastasis accounted for 4.2% of cases. The majority of patients (63.1%) underwent partial penectomy. Chemotherapy and radiotherapy were given in 14 (5.9%) and 12 (5.1%) patients, respectively. Complication and mortality rates were 22.0% and 4.2%, respectively. HIV positivity, histopathological stage and grade of the tumor, and presence of metastases at the time of diagnosis were the main predictors of death (P < 0.001). The median length of hospitalization was 14 days. Local recurrence was reported in 12 (5.3%) patients. Data on long-term survivals were not available as the majority of patients were lost to follow-up. CONCLUSIONS: Penile cancer is not rare in our environment. The majority of patients present late with advanced stage of the disease. Early detection of primary cancer at an early stage may improve the prognosis.

Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting.

BACKGROUND: Hepatocellular carcinoma is one of the most common cancers worldwide and its incidence is reported to be increasing in resource-limited countries. There is a paucity of published data regarding hepatocellular carcinoma in Tanzania, and the study area in particular. This study describes the clinicopathological profile of hepatocellular carcinoma in our local setting and highlights the challenging problems in the management of this disease. METHODS: This was a retrospective study of histopathologically confirmed cases of hepatocellular carcinoma seen at Bugando Medical Center between March 2009 and February 2013. RESULTS: A total of 142 patients (M: F = 2.2: 1) were studied representing 4.6% of all malignancies. The median age of patients was 45 years. Hepatitis B virus infection (66.2%) and heavy alcohol consumption (60.6%) were the most frequently identified risk factors for hepatocellular carcinoma. The majority of patients (88.0%) presented late with advanced stages. HBsAg was positive in 66.2% of the patients and Hepatitis C Virus antibody in 16.9%. Thirteen (9.2%) patients tested positive for HIV infection. Most patients (52.8%) had both right and left lobe involvement. The trabecular pattern (47.9%) was the most frequent histopathological type. None of patients had curative therapy because of the advanced nature of the disease. Coagulopathy (45.7%) was the most common complications. The overall mortality rate was 46.5% and it was significantly associated with comorbidity, HIV positivity, CD4+ count <200 cells/µl, high histological grade, advanced stage of the tumor, presence of distant metastases at the time of diagnosis, and associated complications (P < 0.001). The overall median duration of hospital stay was 14 days. The majority of patients (71.1%) were lost to follow-up at the end of the follow-up period. CONCLUSIONS: Hepatocellular carcinoma patients in this region are relatively young at diagnosis and the majority of them present late with an advanced stage and high rate of distant metastasis. Lack of awareness of the disease, poor accessibility to healthcare facilities, and lack of screening programs in this region may contribute to advanced disease at the time of diagnosis. There is a need for early detection, adequate treatment, and proper follow-up to improve treatment outcome.

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.

Relationship between non-Hodgkin's lymphoma and blood levels of Epstein-Barr virus in children in north-western Tanzania: a case control study.

BACKGROUND: Non-Hodgkin's Lymphomas (NHL) are common in African children, with endemic Burkitt's lymphoma (BL) being the most common subtype. While the role of Epstein-Barr Virus (EBV) in endemic BL is known, no data are available about clinical presentations of NHL subtypes and their relationship to Human Immunodeficiency Virus (HIV) infection and Epstein Barr Virus (EBV) load in peripheral blood of children in north-western, Tanzania. METHODS: A matched case control study of NHL subtypes was performed in children under 15 years of age and their respective controls admitted to Bugando Medical Centre, Sengerema and Shirati district designated hospitals in north-western, Tanzania, between September 2010 and April 2011. Peripheral blood samples were collected on Whatman 903 filter papers and EBV DNA levels were estimated by multiplex real-time PCR. Clinical and laboratory data were collected using a structured data collection tool and analysed using chi-square, Fisher and Wilcoxon rank sum tests where appropriate. The association between NHL and detection of EBV in peripheral blood was assessed using conditional logistic regression model and presented as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: A total of 35 NHL cases and 70 controls matched for age and sex were enrolled. Of NHLs, 32 had BL with equal distribution between jaw and abdominal tumour, 2 had large B cell lymphoma (DLBCL) and 1 had NHL-not otherwise specified (NHL-NOS). Central nervous system (CNS) presentation occurred only in 1 BL patient; 19 NHLs had stage I and II of disease. Only 1 NHL was found to be HIV-seropositive. Twenty-one of 35 (60%) NHL and 21 of 70 (30%) controls had detectable EBV in peripheral blood (OR = 4.77, 95% CI 1.71 - 13.33, p = 0.003). In addition, levels of EBV in blood were significantly higher in NHL cases than in controls (p = 0.024). CONCLUSIONS: BL is the most common childhood NHL subtype in north-western Tanzania. NHLs are not associated with HIV infection, but are strongly associated with EBV load in peripheral blood. The findings suggest that high levels of EBV in blood might have diagnostic and prognostic relevance in African children.

Clinicopathological patterns and challenges of management of colorectal cancer in a resource-limited setting: a Tanzanian experience.

BACKGROUND: Colorectal cancer is one of the most common cancers worldwide and its incidence is reported to be increasing in resource-limited countries, probably due to the acquisition of a western lifestyle. However, information regarding colorectal cancer in Tanzania and the study area in particular is limited. This study was conducted in our local setting to describe the clinicopathological pattern of colorectal cancer and highlight the challenging problem in the management of this disease. METHODS: This was a retrospective study of histologically confirmed cases of colorectal cancer seen at Bugando Medical Center between July 2006 and June 2011. Data were retrieved from patients' files and analyzed using SPSS computer software version 17.0. RESULTS: A total of 332 colorectal cancer patients were enrolled in the study, representing 4.7% of all malignancies. Males outnumbered females by a ratio of 1.6:1. The median age of patients at presentation was 46 years. The majority of patients (96.7%) presented late with advanced stages. Lymph node and distant metastasis at the time of diagnosis was recorded in 30.4% and 24.7% of cases, respectively. The rectosigmoid region was the most frequent anatomical site (54.8%) involved and adenocarcinoma (98.8%) was the most common histopathological type. The majority of adenocarcinomas (56.4%) were moderately differentiated. Mucinous and signet ring carcinomas accounted for 38 (11.6%)and 15 (4.6%) patients, respectively. Three hundred and twenty-six (98.2%) patients underwent surgical procedures for colorectal cancer. Only 54 out of 321 (16.8%) patients received adjuvant treatment. Postoperative complication and mortality rates were 26.2% and 10.5%, respectively. The overall median duration of hospital stay was 12 days. Only nine out of 297 survivors (3.0%) were available for follow-up at the end of 5 years. Cancer recurrence was reported in 56 of 297 survivors (18.9%). Data on long-term survival were not available as the majority of patients were lost to follow-up. CONCLUSIONS: Colorectal cancer is not uncommon in our environment and shows a trend towards a relative young age at diagnosis and the majority of patients present late with advanced stage. There is a need for screening of high-risk populations, early diagnosis and effective cost-effective treatment and follow-up to improve outcome of these patients.

Cascade Analysis for Women Presenting With Breast Concerns to a Zonal Hospital in Mwanza, Tanzania.

PURPOSE: In Tanzania, high breast cancer mortality can be attributed to delays in diagnosis and treatment initiation. We adapted the cascade analysis method to depict sequential steps along the breast cancer care pathway in a tertiary hospital in Mwanza, to identify where correction of loss to attrition would have the biggest impact on improving outcomes. METHODS: This prospective cohort included adult women presenting with breast concerns between February 2020 and January 2022. Five cascade steps beginning with patients' initial clinical breast assessment (CBA) through cancer treatment were identified: (1) CBA, (2) ordering diagnostic test(s), (3) completion of diagnostic test(s), (4) receipt of final diagnosis, and (5) initiating cancer treatment. RESULTS: Overall, 721 eligible women with a median age of 42.8 years (IQR, 32.5-55.0) were included. Median time from presentation to treatment initiation was 35 days (IQR, 20-63). For step 1, 39.1% (n = 282) of patients were diagnosed with a benign concern and removed from the cascade. Completion rates for steps 2-4 were 95.0%, 90.2%, and 91.0, respectively. There were 156 (45.6%) patients diagnosed with breast cancer, and for step 5, 71.2% of patients initiated cancer treatment. In steps 2, 3, 4, and 5, there was a loss of 22, 41, 34, and 45 patients, respectively. If loss was eliminated at steps 2, 3, 4, or 5, an additional 6, 12, 11, or 45 patients, respectively, would have completed the pathway. CONCLUSION: Initiating cancer treatment was identified as the step with the biggest loss and, if remedied, would have the biggest impact on improving breast cancer outcomes at Bugando Medical Centre. These results will inform future programs focused on reducing overall loss in the system and supporting patients with breast cancer.

Analysis of Cancer Research Projects in Sub-Saharan Africa: A Quantitative Perspective on Unmet Needs and Opportunities.

PURPOSE: To evaluate the scope and types of cancer research projects in sub-Saharan Africa (SSA) to identify research gaps and inform future efforts. METHODS: This retrospective observational study summarized information on cancer research projects in SSA from the International Cancer Research Partnership (ICRP) between 2015 and 2020, alongside 2020 cancer incidence and mortality data from the Global Cancer Observatory. SSA cancer research projects were identified as led by investigators in SSA countries, or by investigators in non-SSA countries with collaborators in SSA, or in database keyword searches. Projects from the Coalition for Implementation Research in Global Oncology (CIRGO) were also summarized. RESULTS: A total of 1,846 projects were identified from the ICRP database, funded by 34 organizations in seven countries (only one, Cancer Association of South Africa, based in SSA); only 156 (8%) were led by SSA-based investigators. Most projects focused on virally induced cancers (57%). Across all cancer types, projects were most frequently related to cervical cancer (24%), Kaposi sarcoma (15%), breast cancer (10%), or non-Hodgkin lymphoma (10%). Gaps were observed for several cancers with higher incidence/mortality burden in SSA; for example, prostate cancer accounted for only 4% of projects but 8% of cancer-related deaths and 10% of new cases. Approximately 26% were dedicated to etiology. Treatment-related research declined over the study period (14%-7% of all projects), while projects related to prevention (15%-20%) and diagnosis/prognosis (15%-29%) increased. Fifteen CIRGO projects were identified; seven were relevant across multiple cancer types, and 12 focused either wholly or partially on cancer control (representing 50% of the total research effort). CONCLUSION: This analysis shows notable discrepancies between cancer burden and research projects and identifies opportunities for future strategic investments in cancer care in SSA.

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.

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.