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Esophageal squamous cell carcinoma (ESCC) is the second most common cancer in Malawi. Risk factors for this cancer in Malawi are poorly understood. Poor oral health has previously been linked to increased ESCC risk in other high-incidence regions, including parts of Eastern and Southern Africa. We assessed the relationship between oral health and ESCC risk in a sex, age and location frequency-matched case-control study based at two hospitals in Lilongwe, Malawi from 2017 to 2020. Trained interviewers used a structured questionnaire and direct observation to collect data on demographics; behaviors; oral hygiene habits; the sum of decayed, missing or filled teeth (DMFT score); oral mucosa status; lip depigmentation and dental fluorosis via a visual scale. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI), adjusted for known and suspected ESCC risk factors. During the study period, 300 cases and 300 controls were enrolled. Subjects in the highest tertile of DMFT score (≥7) had an increased risk of ESCC with an adjusted OR of 1.96 (95% CI: 1.16-3.36) compared to those with a DMFT score of 0. Severe dental fluorosis was associated with a statistically nonsignificant increased risk of ESCC (adjusted OR = 2.24, 95% CI: 0.97-5.49) compared to individuals with no fluorosis. Associations with oral mucosa status, lip depigmentation and toothbrushing method and frequency were mostly null or uncertain. Poor oral health, indicated by a higher DMFT score, was associated with increased ESCC risk in Malawi. Dental fluorosis is another possible risk factor in this population, but further evaluation is necessary to clarify any effects of fluorosis on ESCC risk., (© 2024 UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Esophageal squamous cell carcinoma (ESCC) comprises 90% of all esophageal cancer cases globally and is the most common histology in low-resource settings. Eastern Africa has a disproportionately high incidence of ESCC., Methods: We describe the genomic profiles of 61 ESCC cases from Tanzania and compare them to profiles from an existing cohort of ESCC cases from Malawi. We also provide a comparison to ESCC tumors in The Cancer Genome Atlas (TCGA)., Results: We observed substantial transcriptional overlap with other squamous histologies via comparison with TCGA PanCan dataset. DNA analysis revealed known mutational patterns, both genome-wide as well as in genes known to be commonly mutated in ESCC. TP53 mutations were the most common somatic mutation in tumors from both Tanzania and Malawi but were detected at lower frequencies than previously reported in ESCC cases from other settings. In a combined analysis, two unique transcriptional clusters were identified: a proliferative/epithelial cluster and an invasive/migrative/mesenchymal cluster. Mutational signature analysis of the Tanzanian cohort revealed common signatures associated with aging and cytidine deaminase activity (APOBEC) and an absence of signature 29, which was previously reported in the Malawi cohort., Conclusions: This study defines the molecular characteristics of ESCC in Tanzania, and enriches the Eastern African dataset, with findings of overall similarities but also some heterogeneity across two unique sites., Impact: Despite a high burden of ESCC in Eastern Africa, investigations into the genomics in this region are nascent. This represents the largest comprehensive genomic analysis ESCC from sub-Saharan Africa to date., (©2023 American Association for Cancer Research.)

Purpose: Esophageal cancer (EC) is the second most common cancer in Malawi, with esophageal squamous cell carcinoma (ESCC) representing >90% of all ECs. Despite significant morbidity and mortality, little is known about disease outcomes. In this study, we assess survival after ESCC diagnosis in Malawi., Methods: We report on ESCC cases enrolled in a case-control study at Kamuzu Central Hospital in Lilongwe from August 2017 to April 2020. Suspected cases completed a questionnaire interview; provided blood, urine, and saliva specimens; and underwent a tumor biopsy for histologic confirmation. Cases were followed up by phone biweekly from enrollment to the study end date (December 31, 2020), date of death, or loss to follow-up. Survival was assessed using Kaplan-Meier analysis with the log-rank test. We also examined associations between treatment and ESCC mortality using Cox regression models., Results: There were 300 patients with ESCC enrolled in this study, of whom 290 (97%) had known vital status at the end of follow-up and 10 (3%) were lost to follow-up. Among the 290 patients, 282 (97%) died during follow-up. The median age at enrollment was 55 years (IQR, 48-66), and the median time to death was 106 days (95% CI, 92 to 127). The 1-year, 2-year, and 3-year survival rates were 11% (95% CI, 8 to 15), 3% (95% CI, 1 to 6), and 0.9% (95% CI, 0.8 to 4), respectively. Palliative chemotherapy significantly improved the overall survival of patients with ESCC ( P log-rank = .038) and was significantly associated with reduced mortality (adjusted hazard ratio, 0.71 [95% CI, 0.51 to 0.99]). No significant association was observed between tobacco use, alcohol consumption, or HIV status and mortality., Conclusion: Survival after diagnosis of ESCC was poor in Malawi. Although palliative chemotherapy was associated with improved survival, prevention and earlier detection remain key priorities to improve ESCC mortality at a population level.

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients., (© 2022 UICC.)

Access to antiretroviral therapy (ART) led to epidemiological changes in human immunodeficiency virus (HIV) associated lymphoma in high-income countries such as reductions in diffuse large B-cell lymphoma (DLBCL) and stable or increased Hodgkin lymphoma (HL) and Burkitt lymphoma (BL). In 2016, Malawi implemented a universal ART (UART) policy, expanding ART eligibility to all persons living with HIV (PLWH). We compare the distribution of lymphoma subtypes and baseline HIV and prognostic characteristics for lymphoma patients in Malawi before and after implementation of UART. We enrolled patients with pathologically confirmed incident lymphoproliferative disorders into a observational clinical cohort. At diagnosis, a comprehensive clinicopathological evaluation was performed. Of 412 participants, 156 (38%) were pre-UART (2013-June 2016) and 256 (62%) post-UART (July 2016-2020). HIV prevalence was 50% in both groups. The most common pre-UART diagnoses were DLBCL [75 (48%)], low-grade non-Hodgkin lymphoma (NHL) [19 (12%)], HL [17 (11%)] and, BL [13 (8%)]. For post-UART they were DLBCL [111 (43%)], NHL [28 (11%)], BL [27 11%)] and, HL [20 (8%)]. Among PLWH, 44 (57%) pre-UART initiated ART prior to lymphoma diagnosis compared to 99 (78%) post-UART (p = 0.02). HIV-ribonucleic acid was suppressed <1000 copies/mL in 56% (33/59) pre-UART and 71% (73/103) post-UART (p = 0.05). CD4 T-cell counts were similar for both groups. We observed similar findings in the subset of participants with DLBCL. Overall, there were no significant changes in incident lymphoma subtypes (p = 0.61) after implementation of UART, but HIV was better controlled. Emerging trends bear monitoring and may have implications for prognosis and health system priority setting. Trial registration: ClinicalTrials.gov identifier: NCT02835911., Competing Interests: No commercial support was provided for this study. This work was completed while Dr. Satish Gopal was employed at the University of North Carolina at Chapel Hill. The opinions expressed in this article are the authors own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States Government.

Objective: Esophageal cancer is the second commonest cancer in Malawi, and 95% of all cases are esophageal squamous cell carcinoma (ESCC). Very little is known about the epidemiology of ESCC in Malawi including risk factors. The main objective of the study was to evaluate and describe risk factors of ESCC in Malawi., Methods: We conducted a case-control study from 2017 to 2020 at two hospitals in Lilongwe, Malawi and consenting adults were eligible for inclusion. Endoscopy was conducted on all cases and biopsies were obtained for histological confirmation. Controls were selected from patients or their guardians in orthopedic, dental and ophthalmology wards and they were frequency matched by sex, age, and region of origin to cases. An electronic structured questionnaire was delivered by a trained interviewer. Multivariate conditional logistic regression models were used to assess the associations between subject characteristics, habits, and medical history and risk of ESCC., Results: During the study period, 300 cases and 300 controls were enrolled into the study. Median age of cases and controls was 56 years and 62% of the cases were male. Among cases, 30% were ever cigarette smokers as were 22% of controls. Smoking cigarettes had an adjusted odds ratio of 2.4 (95% CI 1.4-4.2 p = 0.003). HIV+ status was present in 11% of cases and 4% controls, which resulted in an adjusted odds ratio was 4.0 (95% CI 1.8-9.0 p = 0.001). Drinking hot tea was associated with an adjusted odd ratio of 2.9 (95% CI 1.3-6.3 p = 0.007). Mold on stored grain has an adjusted odd ratio of 1.6 (95% CI 1.1-2.5 p = 0.021)., Conclusion: Reducing smoking cigarettes, consumption of scalding hot tea, and consumption of contaminated grain, could potentially help reduce the burden of ESCC in Malawi. Further investigation of the association between HIV status and ESCC are warranted., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Purpose: There are limited data on treatment and outcomes for acute lymphoblastic leukemia (ALL) among adolescents and young adults in sub-Saharan Africa. We describe a prospective observational cohort in Malawi., Methods: Patients age 15-39 years with newly diagnosed ALL at Kamuzu Central Hospital, Malawi, were enrolled from 2013 to 2019; follow-up was censored on December 2020. ALL diagnosis was confirmed on-site using immunohistochemistry and telepathology consultation involving pathologists in Malawi and the United States. All but four patients were treated with a modified pediatric-inspired regimen (Cancer and Leukemia Group B 10403 protocol). Key modifications included omission of asparaginase and no dose escalation for methotrexate., Results: Of 19 participants, the median age was 22 (range 15-36) years. Of the 15 patients who initiated treatment, 11 (73%) achieved remission after induction, one (7%) died during induction, two (13%) had refractory disease, and one (7%) absconded. No patients were lost to follow-up. Eventually, 10 of 11 patients (91%) with confirmed remission relapsed. The median duration of first remission was 10 (range 3-22) months. Twelve of 15 treated patients (80%) had died at the time of censoring. Among treated patients, the 12- and 24-month overall survival was 50% (95% CI, 23 to 72) and 17% (95% CI, 3 to 42), respectively. CNS involvement was associated with worse survival., Conclusion: It is possible to treat adolescents and young adults with ALL in low-resource settings using a low-cost, pediatric-inspired regimen; however, outcomes are poor. Both cost and limitations in supportive care infrastructure limit intensive cytotoxic approaches such as asparaginase. Patient-reported outcomes are needed to understand the quality of life and cost-effectiveness. Critically, innovative, leap-frog therapies, such as monoclonal or bispecific antibodies, and feasible economic models for resource-limited settings are urgently needed.

Purpose: Low health literacy is a leading cause of treatment abandonment among patients receiving cancer care at Kamuzu Central Hospital (KCH) in Malawi., Methods: We developed cancer educational videos featuring Malawian providers and played them in the KCH oncology clinic. The videos addressed cancer-related topics, including disease biology, common myths, diagnostic procedures, treatment, side effects, and survivorship. After 6 months of implementation, we compared results from 50 pre- and postintervention surveys to assess change in cancer knowledge and care experience., Results: Both pre- and postintervention cancer knowledge were good: a median of nine questions were answered correctly of 11 in both assessments. Despite the intervention, most continued to incorrectly identify cancer as an infection (pre: n = 26, 52%; post: n = 25, 50%; P = 1.0), although improvements were observed in patients' knowledge of correct actions for fever at home (pre: n = 38, 76%; post: n = 43, 86%; P = .31). Care experiences were overall good. Postintervention results indicate that more patients felt always listened to by their providers (pre: n = 18, 36%; post: n = 29, 58%; P < .01). However, we also noted a higher rate of patient dissatisfaction of care as more patients felt that they could not understand chemotherapy counseling (pre: n = 11, 22%; post: n = 22, 44%; P < .01). Assessments of video satisfaction indicate that patients found the videos very helpful in terms of understanding their disease (n = 47, 96%) and side effects (n = 48, 98%) and felt empowered to speak up with their providers (n = 46, 96%)., Conclusion: Standardized education materials for patients that can be feasibly implemented throughout sub-Saharan Africa are urgently needed. Cancer educational videos are a low-cost way to educate and empower patients with cancer in resource-constrained settings although in-person discussions remain a crucial part of care.

Background: Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer morbidity and mortality in Eastern Africa. The majority of patients with ESCC in Eastern Africa present with advanced disease at the time of diagnosis. Several palliative interventions for ESCC are currently in use within the region, including chemotherapy, radiation therapy with and without chemotherapy, and esophageal stenting with self-expandable metallic stents; however, the comparative effectiveness of these interventions in a low resource setting has yet to be examined., Methods: This prospective, observational, multi-center, open cohort study aims to describe the therapeutic landscape of ESCC in Eastern Africa and investigate the outcomes of different treatment strategies within the region. The 4.5-year study will recruit at a total of six sites in Kenya, Malawi and Tanzania (Ocean Road Cancer Institute and Muhimbili National Hospital in Dar es Salaam, Tanzania; Kilimanjaro Christian Medical Center in Moshi, Tanzania; Tenwek Hospital in Bomet, Kenya; Moi Teaching and Referral Hospital in Eldoret, Kenya; and Kamuzu Central Hospital in Lilongwe, Malawi). Treatment outcomes that will be evaluated include overall survival, quality of life (QOL) and safety. All patients (≥18 years old) who present to participating sites with a histopathologically-confirmed or presumptive clinical diagnosis of ESCC based on endoscopy or barium swallow will be recruited to participate. Key clinical and treatment-related data including standardized QOL metrics will be collected at study enrollment, 1 month following treatment, 3 months following treatment, and thereafter at 3-month intervals until death. Vital status and QOL data will be collected through mobile phone outreach., Discussion: This study will be the first study to prospectively compare ESCC treatment strategies in Eastern Africa, and the first to investigate QOL benefits associated with different treatments in sub-Saharan Africa. Findings from this study will help define optimal management strategies for ESCC in Eastern Africa and other resource-limited settings and will serve as a benchmark for future research., Trial Registration: This study was retrospectively registered with the ClinicalTrials.gov database on December 15, 2021,  NCT05177393 ., (© 2022. The Author(s).)

Background and study aims  Limited evidence suggests that endoscopy capacity in sub-Saharan Africa is insufficient to meet the levels of gastrointestinal disease. We aimed to quantify the human and material resources for endoscopy services in eastern African countries, and to identify barriers to expanding endoscopy capacity. Patients and methods  In partnership with national professional societies, digestive healthcare professionals in participating countries were invited to complete an online survey between August 2018 and August 2020. Results  Of 344 digestive healthcare professionals in Ethiopia, Kenya, Malawi, and Zambia, 87 (25.3 %) completed the survey, reporting data for 91 healthcare facilities and identifying 20 additional facilities. Most respondents (73.6 %) perform endoscopy and 59.8 % perform at least one therapeutic modality. Facilities have a median of two functioning gastroscopes and one functioning colonoscope each. Overall endoscopy capacity, adjusted for non-response and additional facilities, includes 0.12 endoscopists, 0.12 gastroscopes, and 0.09 colonoscopes per 100,000 population in the participating countries. Adjusted maximum upper gastrointestinal and lower gastrointestinal endoscopic capacity were 106 and 45 procedures per 100,000 persons per year, respectively. These values are 1 % to 10 % of those reported from resource-rich countries. Most respondents identified a lack of endoscopic equipment, lack of trained endoscopists and costs as barriers to provision of endoscopy services. Conclusions  Endoscopy capacity is severely limited in eastern sub-Saharan Africa, despite a high burden of gastrointestinal disease. Expanding capacity requires investment in additional human and material resources, and technological innovations that improve the cost and sustainability of endoscopic services., Competing Interests: Competing interests Dr. Mwachiro is a consultant for Boston Scientific., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Cost-effectiveness data for cancer treatment are needed from sub-Saharan Africa, where diffuse large B-cell lymphoma (DLBCL) is a common, curable cancer. In high-income countries, the standard of care for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemoimmunotherapy. Rituximab is often not available in sub-Saharan Africa due to perceived unaffordability, and treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is common. We aimed to evaluate the cost-effectiveness of treatment in Malawi, comparing best supportive care, CHOP, or R-CHOP in patients with DLBCL., Methods: For this cost-effectiveness analysis, we used published Malawi microcosting data, clinical data from a prospective cohort treated with CHOP, and clinical trial data evaluating R-CHOP. We used a decision-tree model to calculate costs per disability-adjusted life-year (DALY) averted from the health system perspective for the treatment of patients with DLBCL with best supportive care, CHOP, or R-CHOP, running the model on a per-patient basis and a Malawi population-level basis. We used the WHO definitions of cost-effective (three times the GDP per capita of the country) and extremely cost-effective (equal to the GDP per capita of the country) as willingness-to-pay thresholds for Malawi., Findings: On a per-patient level, compared with best supportive care, CHOP was estimated to avert a mean 7·4 DALYs at an incremental cost of US$1384, for an incremental cost-effectiveness ratio (ICER) of $189 per DALY averted, which is substantially lower than the willingness-to-pay threshold (extremely cost-effective). Compared with CHOP, R-CHOP was estimated to avert 2·8 DALYs at an incremental cost of $3324, resulting in an ICER of $1204 per DALY averted, which is slightly higher than the cost-effective willingness-to-pay threshold. In probabilistic sensitivity analyses, CHOP remained cost-effective for DLBCL treatment in more than 99% of simulations, whereas R-CHOP was lower than the threshold in 46% of simulations., Interpretation: We estimated CHOP to be cost-effective for DLBCL treatment in Malawi, and that the addition of rituximab might be cost-effective. Despite upfront costs, DLBCL treatment is probably a prudent investment relative to other accepted health interventions in sub-Saharan Africa., Funding: National Institutes of Health., Competing Interests: Declaration of interests SG and MSP report grants from National Institutes of Health (NIH) during the conduct of the study. SW reports grants from the Pfizer Foundation, outside the submitted work. All other authors report no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: There are no clinical trials involving patients with diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa since antiretroviral therapy (ART) for HIV became widely available in this region. We aimed to establish the safety and efficacy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL in Malawi., Methods: This prospective, single-arm, non-randomised phase 1/2 clinical trial was done at Kamuzu Central Hospital Cancer Clinic (Lilongwe, Malawi). Eligible patients were adults (aged 18-60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0-2, a CD4 count of 100 cells per μL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000 × 10 9 cells per L or higher, a platelet count of 100 × 10 9 platelets per L or higher, a serum creatinine concentration of 132·60 μmol/L or less, a total bilirubin concentration of 34·21 μmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities that would compromise the protocol objectives were excluded. Eligible patients received intravenous rituximab 375 mg/m 2 , cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , and vincristine 1·4 mg/m 2 (maximum 2 mg/m 2 ), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. HIV-positive patients received concurrent ART. The primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Secondary efficacy outcomes included the proportion of patients with a complete response after six cycles of treatment, and progression-free survival and overall survival at 12 months and 24 months. This trial is registered with ClinicalTrials.gov, NCT02660710., Findings: Between Aug 1, 2016, and July 31, 2019, 76 patients were screened, of whom 37 were eligible for the study and received R-CHOP. The median age of patients was 44 years (IQR 39-49) and 16 (43%) were women. Of all 37 patients, 20 (54%) had stage III or IV DLBCL, and the age-adjusted international prognostic index was 2 or higher in 25 (68%) patients. 27 (73%) patients were HIV-positive, with a median CD4 count of 208 cells per μL (IQR 144-422), and 21 (78%) patients were receiving ART at enrolment. Patients completed a median of six cycles (IQR 4-6). Grade 3 or 4 non-haematological toxic effects were reported in 12 (32% [95% CI 19-49]) patients, the most common of which was infection (nine [24%] patients). Of 16 (43%) deaths, ten were due to progression of DLBCL, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4-26%). Grade 3 or 4 neutropenia was observed in 26 (70%) patients, and grade 3 or 4 anaemia was observed in 11 (29%) patients. A total of 22 (59%) patients had a complete response. Overall survival was 68% (95% CI 50-80) at 12 months and 55% (37-70) at 24 months, and progression-free survival was 59% (42-73) at 12 months and 53% (35-68) at 24 months., Interpretation: R-CHOP could be feasible, safe, and efficacious in patients with DLBCL in Malawi. This is the first completed clinical trial on DLBCL focused on sub-Saharan African populations. Given the paucity of data on treatment of DLBCL from this region, these results could inform emerging cancer treatment programmes in sub-Saharan Africa., Funding: The University of North Carolina Lineberger Comprehensive Cancer Center., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer outcomes in sub-Saharan Africa (SSA) remain suboptimal, in part due to poor patient retention. Many patients travel long distances to receive care, and transportation costs are often prohibitively expensive. These are well-known and established causes of delayed treatment and care abandonment in Malawi and across SSA., Methods: We sent visit reminder texts and offered upfront money to cover transportation costs through a mobile money transfer (MMT) platform to lymphoma patients enrolled in a prospective cohort in Malawi. The primary aim was to test the feasibility of upfront MMTs., Results: We sent 1034 visit reminder texts to 189 participating patients. Of these texts, 614 (59%) were successfully delivered, with 536 (52%) responses. 320/536 (60%) MMTs were sent to interested patients and 312/320 (98%) came to their appointment on time. Of 189 total patients, 120 (63%) were reached via text and 84 (44%) received MMTs a median of three times (IQR 2-5). Median age of reachable patients was 41 (IQR 30-50), 75 (63%) were male, 62 (52%) were HIV+ and 79 (66%) resided outside of Lilongwe., Conclusion: MMTs were a feasible way to cover upfront transportation costs for patients reachable via text, however many of our patients were unreachable. Future studies exploring barriers to care, particularly among unreachable patients, may help improve the efficacy of MMT initiatives and guide retention strategies throughout SSA., (© The Author(s) 2020. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

In this issue, Mmbaga and colleagues present results of a case-control study to investigate environmental and lifestyle risk factors for esophageal cancer in Tanzania, East Africa. The results contribute to the early stage of a growing evidence base aimed to inform primary prevention of a major poor prognosis cancer in East Africa. In this commentary, we first discuss considerations needed to evaluate causality of associations, a feature needed for primary prevention. There is a need for further studies across the African esophageal cancer corridor, for more refined exposure assessment and a careful consideration of potential epidemiologic biases within study designs for real-life situations in the setting. This study also forms a prime example of the broader research needs for cancer in low- and middle-income countries and in Sub-Saharan Africa, a setting with distinct and underresearched cancers and exposure patterns. While this etiologic research is challenging, it is an essential component of the ground-shot approach to global health research needed to inform primary prevention. See related article by Mmbaga et al., p. 305 ., (©2021 American Association for Cancer Research.)

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.

Aggressive non-Hodgkin lymphoma (NHL) is among the most common cancers in sub-Saharan Africa (SSA), where CHOP is standard treatment and outcomes are poor. To address this, we treated 17 newly diagnosed adult patients in Malawi with Burkitt (n = 8), plasmablastic (n = 8), and primary effusion lymphoma (n = 1) with a modified EPOCH regimen between 2016 and 2019. Twelve patients (71%) were male and the median age was 40 years (range 16-63). Eleven (65%) were HIV infected, median CD4 count was 218 cells/µL (range 9-460), and nine (82%) had suppressed HIV RNA < 400 copies/mL. Patients received a median of six cycles (range 2-8) and median follow-up was 14 months (range 2-34) among patients still alive. Grade 3/4 neutropenia was observed in 26% of cycles and in 65% of patients. Sixteen (94%) responded to EPOCH and 10 (59%) achieved a complete response. One-year overall survival (OS) was 62% (95% confidence interval [CI], 42%-91%). Five patients (29%) died from progressive NHL and three (18%) from treatment-related complications. These data suggest EPOCH with setting-appropriate modifications may be a practical, safe, and effective option for improving high-risk NHL outcomes in Malawi and comparable settings, which deserves further prospective evaluation., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Plasma Epstein-Barr virus (EBV) DNA measurement has established prognostic utility in EBV-driven lymphomas, where it serves as a circulating tumor DNA marker. The value of plasma EBV measurement may be amplified in sub-Saharan Africa (SSA), where advanced imaging and molecular technologies for risk stratification are not typically available. However, its utility in diffuse large B-cell lymphoma (DLBCL) is less certain, given that only a subset of DLBCLs are EBV-positive. To explore this possibility, we measured plasma EBV DNA at diagnosis in a cohort of patients with DLBCL in Malawi. High plasma EBV DNA at diagnosis (≥3.0 log 10 copies/mL) was associated with decreased overall survival (OS) (P = .048). When stratified by HIV status, the prognostic utility of baseline plasma EBV DNA level was restricted to HIV-positive patients. Unexpectedly, most HIV-positive patients with high plasma EBV DNA at diagnosis had EBV-negative lymphomas, as confirmed by multiple methods. Even in these HIV-positive patients with EBV-negative DLBCL, high plasma EBV DNA remained associated with shorter OS (P = .014). These results suggest that EBV reactivation in nontumor cells is a poor prognostic finding even in HIV-positive patients with convincingly EBV-negative DLBCL, extending the potential utility of EBV measurement as a valuable and implementable prognostic marker in SSA., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To describe the cost of treating diffuse large B-cell lymphoma (DLBCL) in Malawi under the following circumstances: (1) palliation only, (2) first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), (3) salvage etoposide, ifosfamide, and cisplatin (EPIC), and (4) salvage gemcitabine and oxaliplatin (GEMOX)., Methods: We conducted a microcosting analysis from the health system perspective in the context of a prospective cohort study at a national teaching hospital in Lilongwe, Malawi. Clinical outcomes data were derived from previously published literature from the cohort. Cost data were collected for treatment and 2-year follow-up, reflecting costs incurred by the research institution or referral hospital for goods and services. Costs were collected in Malawian kwacha, inflated and converted to 2017 US dollars., Results: On a per-patient basis, palliative care alone cost $728 per person. Total costs for first-line treatment with CHOP chemotherapy was $1,844, of which chemotherapy drugs made up 15%. Separate salvage EPIC and GEMOX cost $2,597 and $3,176, respectively. Chemotherapy drugs accounted for 30% of EPIC and 47% of GEMOX., Conclusion: To our knowledge, this is among the first published efforts to characterize detailed costs of cancer treatment in sub-Saharan Africa. The per-patient cost of first-line treatment of DLBCL in Malawi is low relative to high-income countries, suggesting that investments in fixed-duration, curative-intent DLBCL treatment may be attractive in sub-Saharan Africa. Salvage treatment of relapsed/refractory DLBCL costs much more than first-line therapy. Formal cost-effectiveness modeling for CHOP and salvage treatment in the Malawian and other low-resource settings is needed to inform decision makers about optimal use of resources for cancer treatment.

Burkitt lymphoma (BL) is common in sub-Saharan Africa (SSA). In high-income countries, BL is highly curable with chemotherapy. However, there are few prospective studies from SSA describing nonpediatric BL and no regional standard of care. Thirty-five participants age 15 years or older with newly diagnosed BL were enrolled in Malawi from 2013 to 2018. Chemotherapy was administered according to institutional guidelines, with concurrent antiretroviral therapy if HIV infected. Median age was 21 years (range, 15-61) and 15 participants (43%) were HIV infected. Twenty-seven participants (77%) had stage III to IV disease, and 19 (54%) had Eastern Cooperative Oncology Group performance status >1. Among HIV-infected participants, median CD4 count was 130 (range, 29-605) and 10 (67%) had suppressed HIV viral load. Four participants (11%) died before receiving chemotherapy. First-line chemotherapy consisted of: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (n = 22 [71%]); infusional etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (n = 4 [13%]); high-dose methotrexate-based chemotherapy (n = 4 [13%]); and rituximab plus CHOP (n = 1 [3%]). Among 28 evaluable participants, 14 (50%) achieved a complete response. Median overall survival (OS) was 7 months; 1-year OS was 40% (95% confidence interval [CI], 24%-56%). Sixteen (73%) of 22 deaths were a result of disease progression. Compared with CHOP, more intensive chemotherapy was associated with decreased mortality (hazard ratio, 0.24; 95% CI, 0.05-1.02; P = .05). This is among the best characterized prospective cohorts of nonpediatric BL in SSA. Most deaths resulted from progressive BL. Patients who received more intensive therapy seemed to have better outcomes. Defining optimal approaches is an urgent priority in SSA., (© 2019 by The American Society of Hematology.)

Outcomes for diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa (SSA) are poorly described. We report mature data from one of the first prospective SSA cohorts. Patients aged ≥18 years with DLBCL were enrolled in Malawi 2013-2017. Participants were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy and concurrent antiretroviral therapy (ART) if positive for human immunodeficiency virus (HIV+). Eighty-six participants (mean age 47 years, standard deviation 13) were enrolled: 54 (63%) were male and 51 (59%) were HIV+, of whom 34 (67%) were on ART at DLBCL diagnosis. Median CD4 count was 0·113 cells × 10 9 /l (interquartile range [IQR] 0·062-0·227) and 25 (49%) had HIV viral load <400 copies/μl. Participants received median six cycles CHOP (IQR 4-6). No patients were lost to follow-up and the 2-year overall survival was 38% (95% confidence interval 28-49). In multivariable analyses, Eastern Cooperative Oncology Group performance status (PS) ≥2 and lactate dehydrogenase (LDH) >2× upper limit of normal (ULN) were associated with mortality. HIV status was not associated with mortality. A simplified prognostic model of LDH >2× ULN and PS ≥2 performed at least as well as the age-adjusted International Prognostic Index. DLBCL can be successfully treated in SSA and outcomes did not differ by HIV status. A simplified prognostic model prognosticates well and may be easier to use in resource-limited settings but requires validation., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Esophageal cancer is the eighth most common cancer worldwide and the sixth most common cause of cancer-related death; however, worldwide incidence and mortality rates do not reflect the geographic variations in the occurrence of this disease. In recent years, increased attention has been focused on the high incidence of esophageal squamous cell carcinoma (ESCC) throughout the eastern corridor of Africa, extending from Ethiopia to South Africa. Nascent investigations are underway at a number of sites throughout the region in an effort to improve our understanding of the etiology behind the high incidence of ESCC in this region. In 2017, these sites established the African Esophageal Cancer Consortium. Here, we summarize the priorities of this newly established consortium: to implement coordinated multisite investigations into etiology and identify targets for primary prevention; to address the impact of the clinical burden of ESCC via capacity building and shared resources in treatment and palliative care; and to heighten awareness of ESCC among physicians, at-risk populations, policy makers, and funding agencies.

Plasmablastic lymphoma (PBL) clinical descriptions are scarce from sub-Saharan Africa (SSA) where both HIV and EBV are highly endemic. We identified 12 patients with pathologically confirmed PBL from a prospective cohort in Lilongwe, Malawi. Median age was 46 (range 26-71), seven (58%) were male, and six (50%) were HIV-positive. Eight patients were treated with CHOP and four with a modified EPOCH regimen. One-year overall survival was 56% (95% CI 24-79%), without clear differences based on HIV status. PBL occurs in Malawi in HIV-positive and HIV-negative individuals and can be treated successfully with curative intent, even in a low-resource setting in SSA., Competing Interests: All patients provided written informed consent for participation in the Kamuzu Central Hospital Lymphoma Study, which was approved by the Malawi National Health Sciences Research Committee (1107) and University of North Carolina Biomedical Institutional Review Board (12–2255).Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Given scarce data from sub-Saharan Africa (SSA), we sought to describe CD4 count and HIV RNA trends over time among patients with HIV-positive lymphoproliferative disorders in Malawi. We prospectively enrolled HIV-positive individuals with pathologically confirmed lymphoproliferative disorders between 2013 and 2016. Chemotherapy was standardized with concurrent antiretroviral therapy (ART). We assessed CD4 count and HIV RNA at baseline and every 6 months for up to 2 years. Of 72 HIV-positive patients, 59 had non-Hodgkin lymphoma (NHL), 5 classical Hodgkin lymphoma (CHL), and 8 multicentric Castleman disease (MCD). Median age was 43 years (range 23-64). Fifty-five patients (76%) were on ART at enrollment for a median 47 months (range 1-387), with median CD4 count of 138 cells/μl (range 2-2,235) and median HIV RNA of 2.2 log 10 copies/ml (range 0.3-7.3). MCD patients had longer median ART durations, higher median CD4 counts, and lower median HIV RNA at baseline than NHL or CHL patients. CD4 count and HIV RNA steadily improved during follow-up, with different patterns in different histological groups. Twelve-month overall survival (OS) was 55% [95% confidence interval (CI) 42%-66%]. There were trends toward baseline CD4 count <100 cells/μl and HIV RNA >2.0 log 10 copies/ml being associated with worse OS. However, CD4 count and HIV RNA improvements during follow-up were independent of possible effects on OS. Distribution of HIV-positive lymphoproliferative disorders may change with continued ART scale-up in SSA. Chemotherapy and concurrent ART can lead to good immunological and virological outcomes.

Background: Contemporary descriptions of classical Hodgkin lymphoma (cHL) are lacking from sub-Saharan Africa where human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) are prevalent., Methods: We describe a prospective cHL cohort in Malawi enrolled from 2013 to 2015. Patients received standardized treatment and evaluation, including HIV status and EBV testing of tumors and plasma., Results: Among 31 patients with confirmed cHL, the median age was 19 years (range, 2-51 years) and 22 (71%) were male. Sixteen patients (52%) had stage III/IV, 25 (81%) B symptoms, and 16 (52%) performance status impairment. Twenty-three patients (74%) had symptoms >6 months, and 11 of 29 (38%) had received empiric antituberculosis treatment. Anemia was common with median hemoglobin 8.2 g/dL (range, 3.1-17.1 g/dL), which improved during treatment. No children and 5 of 15 adults (33%) were HIV+. All HIV+ patients were on antiretroviral therapy for a median 15 months (range, 2-137 months), with median CD4 count 138 cells/μL (range, 23-329 cells/μL) and four (80%) having undetectable HIV. EBV was present in 18 of 24 (75%) tumor specimens, including 14 of 20 (70%) HIV- and 4 of 4 (100%) HIV+. Baseline plasma EBV DNA was detected in 25 of 28 (89%) patients, with median viral load 4.7 (range, 2.0-6.7) log 10 copies/mL, and subsequently declined in most patients. At 12 months, overall survival was 75% (95% confidence interval [CI], 55%-88%) and progression-free survival 65% (95% CI, 42%-81%). Baseline plasma EBV DNA and persistent viremia during treatment were associated with poorer outcomes., Conclusion: cHL in Malawi is characterized by delayed diagnosis and advanced disease. Most cases were EBV associated and one-third of adults were HIV+. Despite resource limitations, 12-month outcomes were good., (© 2016 Wiley Periodicals, Inc.)

Burkitt lymphoma (BL) is the most common paediatric cancer in sub-Saharan Africa (SSA). Anthracyline-based treatment is standard in resource-rich settings, but has not been described in SSA. Children ≤18 years of age with newly diagnosed BL were prospectively enrolled from June 2013 to May 2015 in Malawi. Staging and supportive care were standardized, as was treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for six cycles. Among 73 children with BL, median age was 9·2 years (interquartile range 7·7-11·8), 48 (66%) were male and two were positive for human immunodeficiency virus. Twelve (16%) had stage I/II disease, 36 (49%) stage III and 25 (34%) stage IV. Grade 3/4 neutropenia occurred in 17 (25%), and grade 3/4 anaemia in 29 (42%) of 69 evaluable children. Eighteen-month overall survival was 29% (95% confidence interval [CI] 18-41%) overall. Mortality was associated with age >9 years [hazard ratio [HR] 2·13, 95% CI 1·15-3·94], female gender (HR 2·12, 95% CI 1·12-4·03), stage (HR 1·52 per unit, 95% CI 1·07-2·17), lactate dehydrogenase (HR 1·03 per 100 iu/l, 95% CI 1·01-1·05), albumin (HR 0·96 per g/l, 95% CI 0·93-0·99) and performance status (HR 0·78 per 10-point increase, 95% CI 0·69-0·89). CHOP did not improve outcomes in paediatric BL compared to less intensive regimens in Malawi., (© 2016 John Wiley & Sons Ltd.)

There are no prospective studies of aggressive non-Hodgkin lymphoma (NHL) treated with CHOP in sub-Saharan Africa. We enrolled adults with aggressive NHL in Malawi between June 2013 and May 2015. Chemotherapy and supportive care were standardized, and HIV+ patients received antiretroviral therapy (ART). Thirty-seven of 58 patients (64%) were HIV+. Median age was 47 years (IQR 39-56), and 35 (60%) were male. Thirty-five patients (60%) had stage III/IV, 43 (74%) B symptoms, and 28 (48%) performance status ≥ 2. B-cell NHL predominated among HIV+ patients, and all T-cell NHL occurred among HIV- individuals. Thirty-one HIV+ patients (84%) were on ART for a median 9.9 months (IQR 1.1-31.7) before NHL diagnosis, median CD4 was 121 cells/μL (IQR 61-244), and 43% had suppressed HIV RNA. HIV+ patients received a similar number of CHOP cycles compared to HIV- patients, but more frequently developed grade 3/4 neutropenia (84% vs 31%, p = 0.001), resulting in modestly lower cyclophosphamide and doxorubicin doses with longer intervals between cycles. Twelve-month overall survival (OS) was 45% (95% CI 31-57%). T-cell NHL (HR 3.90, p = 0.017), hemoglobin (HR 0.82 per g/dL, p = 0.017), albumin (HR 0.57 per g/dL, p = 0.019), and IPI (HR 2.02 per unit, p<0.001) were associated with mortality. HIV was not associated with mortality, and findings were similar among patients with diffuse large B-cell lymphoma. Twenty-three deaths were from NHL (12 HIV+, 11 HIV-), and 12 from CHOP (9 HIV+, 3 HIV-). CHOP can be safe, effective, and feasible for aggressive NHL in Malawi with and without HIV.

Introduction: Clinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region., Methods: We describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi's 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015., Results and Discussion: MCD patients had a median age of 42.4 years (range 37.2-51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6-9.3) than KS (11.0 g/dL, range 9.1-12.0, p=0.011) or NHL (11.2 g/dL, range 4.5-15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7-3.2) than KS (3.7 g/dL, range 3.2-3.9, p=0.013) or NHL (3.4 g/dL, range 1.8-4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108-1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2-105.3) than KS (14.2 months, range 6.8-21.9, p=0.039) or NHL (13.8 months, range 0.2-98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL., Conclusions: HIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and supportive care are needed to address this likely under-recognized public health problem in SSA.

Objective: To investigate comparative road user crash and fatality rates in Japan between 2000 and 2010 in the elderly and young., Methods: Data from the Japan Ministry of Health, Labor and Welfare Vital Statistics Database and the Institute for Traffic Accident Research and Data Analysis were used to calculate crash rates by age group, vehicle, and license category., Results: Fatal crash rates per 100,000 licensed drivers for 4-wheeled motor vehicle drivers decreased by 53, 56, and 42 percent among the 65-69, 70-74, and ≥75 age groups between 2000 and 2010, respectively, compared to 66 and 60 percent among the 16-19 and 20-24 age groups, respectively. Fatal crash rates per 100,000 licensed riders for 2-wheeled motor vehicles decreased by 64, 23, and 33 percent in the 65-69, 70-74, and ≥75 age groups, respectively. Similarly, fatal crash rates per million population among bicyclists and pedestrians decreased in all age groups but were highest in the elderly age group in all years; the annual fatal crash rate for elderly pedestrians was 3 to 10 times higher than that for younger pedestrians., Conclusions: Despite the overall decrease in the elderly crash and fatal crash rates in all road use categories, elderly pedestrians are more susceptible to road traffic crashes and are more likely to be killed than younger persons. Further research may reduce this risk.