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The development and implementation of a multicancer early detection (MCED) test that is effective and affordable has the potential to change cancer care systems around the world. However, careful consideration is needed within the context of different health care settings (both low- and middle-income countries and high-income countries) to roll out an MCED test and promote equity in access.

Few data exist on Epstein-Barr virus (EBV) prevalence across the full spectrum of lymphoma subtypes, particularly in sub-Saharan Africa. The objective of our study was to test the presence of EBV in a nationally representative sample of malignant lymphomas diagnosed in the Butaro Cancer Center of Excellence (BCCOE) in Rwanda. Of 102 Hodgkin (HL) and 378 non-Hodgkin lymphomas (NHL) diagnosed in BCCOE between 2012 and 2018, 52 HL and 207 NHL were successfully tested by EBV-encoding RNA in situ hybridization. EBV prevalence was 54% in HL, being detected in all classical HL subtypes: mixed-cellularity (n = 3/8), nodular-sclerosis (n = 7/17) and lymphocyte-rich (n = 2/3). EBV prevalence was 9% in NHL, being 10% among 158 B-cell NHL, 3% among 35 T-cell NHL and the single NK-cell NHL was EBV-positive. Among B-cell NHL, EBV was present in the majority of Burkitt (n = 8/13), and was also rarely detected in follicular (n = 1/4) and acute B-cell lymphoblastic (n = 1/45) lymphomas. Five of the 45 (11%) diffuse large B-cell lymphomas (DLBCLs) were EBV-positive, including three out of five plasmablastic lymphoma (PBL). Of 39 HL and 163 NHL of known human immunodeficiency virus (HIV) status, 2 (5%) and 14 (9%) were HIV-positive, respectively, of which only four were also EBV-positive (2 PBL, 2 HL). In summary, we report rare regional-level data on the association of EBV with classical HL, Burkitt and DLBCLs, and report sporadic detection in other subtypes possibly related to EBV. Such data inform the burden of disease caused by EBV and can help guide application of future advances in EBV-specific prevention and therapeutics.

Objectives In response to requests for training in cancer pathology, two virtual training courses were organized: one in English for participants in Nigeria and another in French for participants in Francophone Africa. Each course had weekly 90-minute sessions covering essential topics in cancer pathology led by global experts. Methods Two research questions were investigated for both courses: (1) did the participants improve their knowledge of the topics covered during the course, and (2) did the course participants appreciate the virtual training format? Results The Nigeria course enrolled 85 participants from 26 Nigerian states; the Francophone Africa course enrolled 425 participants from 18 African countries. In the pre-post technical assessment, participants increased their scores on average by 3.4% (P > .05) in the Nigeria course and by 13.1% (P Conclusions Virtual training is a promising tool to improve cancer diagnosis in Africa, as the experience of the courses illustrates that participants appreciate the virtual format. Continued training is required to reinforce skills and enable participants to appropriately apply new knowledge to their daily practice.

Correct use of statistical methods is important to ensure the reliability and value of the published experimental pathology literature. Considering increasing interest in the quality of statistical reporting in pathology, the statistical methods used in 10 recent issues of the American Journal of Pathology were reviewed. The statistical tests performed in the articles were summarized, with attention to their implications for contemporary pathology research and practice. Among the 195 articles identified, 93% reported using one or more statistical tests. Retrospective statistical review of the articles revealed several key findings. First, tests for normality were infrequently reported, and parametric hypothesis tests were overutilized. Second, studies reporting multisample hypothesis tests (eg, analysis of variance) infrequently performed post hoc tests to explore differences between study groups. Third, correlation, regression, and survival analysis techniques were underutilized. On the basis of these findings, a primer on relevant statistical concepts and tests is presented, including issues related to optimal study design, descriptive and comparative statistics, and regression, correlation, survival, and genetic data analysis.

The performance of complete post-mortem examinations of children with severe malaria has helped to explain the cause of death in cerebral malaria as well as show the global phenomenon of sequestration in tissues throughout the body, beyond the brain and eye. The pathology of the brain and other organs has been well described and shows a systemic disease with the most catastrophic features found in the brain (i.e., fatal cerebral edema).This chapter describes the materials and methods needed to study the pathological features of tissues outside of the eye, including the brain and other organs. The bulk of these techniques are standard to pathology including gross examination, histology, special stains, and immunohistochemistry.

Background Differential etiologies of pediatric acute febrile respiratory illness pose challenges for all populations globally, but especially in malaria-endemic settings because the pathogens responsible overlap in clinical presentation and frequently occur together. Rapid identification of bacterial pneumonia with high-quality diagnostic tools would enable appropriate, point-of-care antibiotic treatment. Current diagnostics are insufficient, and the discovery and development of new tools is needed. We report a unique biomarker signature identified in blood samples to accomplish this. Methods Blood samples from 195 pediatric Mozambican patients with clinical pneumonia were analyzed with an aptamer-based, high-dynamic-range, quantitative assay (~1200 proteins). We identified new biomarkers using a training set of samples from patients with established bacterial, viral, or malarial pneumonia. Proteins with significantly variable abundance across etiologies (false discovery rate 90% sensitivity and >80% specificity, regardless of number of pathogen classes. Bacterial pneumonia was strongly associated with neutrophil markers—in particular, degranulation including HP, LCN2, LTF, MPO, MMP8, PGLYRP1, RETN, SERPINA1, S100A9, and SLPI. Conclusions Blood protein signatures highly associated with neutrophil biology reliably differentiated bacterial pneumonia from other causes. With appropriate technology, these markers could provide the basis for a rapid diagnostic for field-based triage for antibiotic treatment of pediatric pneumonia., Identification of new biomarkers to distinguish between viral and bacterial pneumonia is needed. These markers could provide the basis for a rapid diagnostic for field-based triage for antibiotic treatment of pediatric pneumonia.

In order to understand the structure and effectiveness of national cancer control systems, the International Cancer Control Partnership, the World Health Organization, the National Cancer Institute and the Union for International Cancer Control underwent a review of available national cancer health plans (NCCPs) and noncommunicable diseases plans (NCDPs) worldwide. Pathology and Laboratory Medicine (PALM) plays a major role in cancer management, from prevention and screening to patient care (diagnosis and treatment) and population-level cancer surveillance. This review concentrates on the analysis of elements in national cancer care plans pertaining to PALM. Of 157 countries surveyed, 90 (57%) had a NCCP and 123 (78%) had a NCDP. While 54% of plans included guidelines on cancer diagnosis or plans to develop standards protocols for diagnosis, only 14% included PALM as a component of the plan. PALM-related variables such as synoptic pathology reporting, cancer staging guidelines and cancer genetics programs were similarly underrepresented (being mentioned in only 6%, 17% and 16% of plans, respectively). Absence of PALM-related variables tended to be more frequent in lower-income countries. Our analysis highlights an important gap in national cancer control initiatives worldwide represented by the overall lack of inclusion of PALM resources. Cancer control will only be effective if laboratory sciences are placed as a priority. Based on the data presented herein, there is a need to increase awareness about the importance of PALM in cancer care, and to incorporate this discipline in the design and implementation of multilevel cancer control strategies.

Objectives We developed and participated in a 1-week laboratory medicine training presented from June 3, 2019, to June 7, 2019. Methods The training was a combination of daily morning lectures and case presentations as well as afternoon practical sessions in the clinical laboratory. The content was selected over months by local organizers and the visiting faculty and further modified on site to reflect local needs. Results Participants identified practice changes that could be realized in the short term but most faced significant barriers to implementation in the absence of structured and long-term follow-up. Conclusions In this report, we review insights learned from our experience and reflect on strategies for realistic, meaningful, and relevant contributions in the setting of laboratory medicine–oriented short-term programs.

Background Before initiating cancer therapy, a diagnostic tumor tissue sample evaluated within a pathology laboratory by a pathologist is essential to confirm the malignancy type and provide key prognostic factors that direct the treatment offered. Methods Pathology evaluation includes multiple expensive reagents, complex equipment, and both laboratory and pathologist technical skills. By using breast cancer as an example, at a minimum, key tumor prognostic information required before the initiation of treatment includes subtype, tumor grade, tumor size, lymph node status when possible, and biomarker expression determined by immunohistochemistry for estrogen receptor. The additional determination of biomarker expression of progesterone receptor and human epidermal growth factor receptor (HER2) is the standard of care in high-resource settings, but assays may not be affordable in low-income and middle-income countries. Results With positive tests, patients are eligible for either tamoxifen (for estrogen receptor-positive/progesterone receptor-positive cancers) or monoclonal antibody therapy (for HER2-positive cancers). For settings in which endocrine therapy and/or HER2-targeted therapy is unavailable, biomarker studies have no utility, and high-resource setting standards for pathology evaluation and reporting are unachievable. Resource-stratified pathology evaluation guidelines in cancer diagnosis have not been developed, in contrast to excellent comprehensive, resource-stratified clinical guidelines for use in low-income and middle-income countries, and these are long overdue. Conclusions The challenges of pathology evaluation in the context of global health are being met by innovative solutions, which may change the face of pathology practice.

Diagnostic pathology services for oncology health systems are essential; yet, surveys, observations, and hard data from across low- and middle-income countries have revealed that these services are almost always lacking adequate quality and often missing completely. The City Cancer Challenge Foundation (C/Can), the American Society for Clinical Pathology, and C/Can partner cities undertook intense analysis of their existing pathology services as part of a year-long assessment process including the specific formation of a pathology-focused team. Internal and external expert assessments identified sustainable solutions adapted to the local context and level of resources and created specific local implementation projects. Through local leadership, capacity development, and collaboration, services were improved city-wide in three cities: Cali, Colombia; Asunción, Paraguay; and Yangon, Myanmar. Common problems identified across cities included deficiencies in personnel training, equipment, reagents, processes, quality, and coordination. Specific solutions included quality training, standard process development and regulation, implementation of new services, and public-private collaboration. As the first cities joining the C/Can initiative, Cali, Asunción, and Yangon demonstrate the success of the approach and the value of local expertise in identifying problems and solutions. The additional value of international partners' expertise created opportunities for growth through mentorship and technical support. Importantly, the power of healthcare programs with strong political support is emphasized.

Molecular pathological epidemiology (MPE) is an integrative transdisciplinary field that addresses heterogeneous effects of exogenous and endogenous factors (collectively termed 'exposures'), including microorganisms, on disease occurrence and consequences, utilising molecular pathological signatures of the disease. In parallel with the paradigm of precision medicine, findings from MPE research can provide aetiological insights into tailored strategies of disease prevention and treatment. Due to the availability of molecular pathological tests on tumours, the MPE approach has been utilised predominantly in research on cancers including breast, lung, prostate, and colorectal carcinomas. Mounting evidence indicates that the microbiome (inclusive of viruses, bacteria, fungi, and parasites) plays an important role in a variety of human diseases including neoplasms. An alteration of the microbiome may be not only a cause of neoplasia but also an informative biomarker that indicates or mediates the association of an epidemiological exposure with health conditions and outcomes. To adequately educate and train investigators in this emerging area, we herein propose the integration of microbiology into the MPE model (termed 'microbiology-MPE'), which could improve our understanding of the complex interactions of environment, tumour cells, the immune system, and microbes in the tumour microenvironment during the carcinogenic process. Using this approach, we can examine how lifestyle factors, dietary patterns, medications, environmental exposures, and germline genetics influence cancer development and progression through impacting the microbial communities in the human body. Further integration of other disciplines (e.g. pharmacology, immunology, nutrition) into microbiology-MPE would expand this developing research frontier. With the advent of high-throughput next-generation sequencing technologies, researchers now have increasing access to large-scale metagenomics as well as other omics data (e.g. genomics, epigenomics, proteomics, and metabolomics) in population-based research. The integrative field of microbiology-MPE will open new opportunities for personalised medicine and public health. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Context.— The original guideline, “Validating Whole Slide Imaging for Diagnostic Purposes in Pathology,” was published in 2013 and included 12 guideline statements. The College of American Pathologists convened an expert panel to update the guideline following standards established by the National Academies of Medicine for developing trustworthy clinical practice guidelines. Objective.— To assess evidence published since the release of the original guideline and provide updated recommendations for validating whole slide imaging (WSI) systems used for diagnostic purposes. Design.— An expert panel performed a systematic review of the literature. Frozen sections, anatomic pathology specimens (biopsies, curettings, and resections), and hematopathology cases were included. Cytology cases were excluded. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, the panel reassessed and updated the original guideline recommendations. Results.— Three strong recommendations and 9 good practice statements are offered to assist laboratories with validating WSI digital pathology systems. Conclusions.— Systematic review of literature following release of the 2013 guideline reaffirms the use of a validation set of at least 60 cases, establishing intraobserver diagnostic concordance between WSI and glass slides and the use of a 2-week washout period between modalities. Although all discordances between WSI and glass slide diagnoses discovered during validation need to be reconciled, laboratories should be particularly concerned if their overall WSI–glass slide concordance is less than 95%.

White blood cell apoptosis has been demonstrated and is suspected to contribute to the decrease in peripheral leukocyte count and the severity of the disease during acute T. brucei infection in rats. Thus, an investigation of blood and tissue leukocyte apoptosis during T. brucei infections in two natural hosts (Red Sokoto (RS) and West African dwarf (WAD) goats (12 per group)), with differing levels of trypanosusceptibility was conducted. Nine out of 12 animals in each breed group were infected intraperitoneally with 10

PURPOSE At the 12th meeting of AORTIC (African Organization for Research and Training in Cancer) in Maputo, Mozambique, held between November 5 and November 8, 2019, a special workshop was organized to focus on the need for collaboration and coordination between governments and health systems in Africa with academic, industry, association, and other nongovernmental organizations to effect sustainable positive change for the care of patients with cancer. METHODS Representatives from seven different projects in Africa presented implementation science and demonstration projects of their to date efforts in cancer system improvement including patient access, South-South partnerships, in-country specialized training, palliative care consortium, treatment outcomes, and focused pathology and diagnostic capacity building. Key partners of the various projects served as moderators and commentators during the session. RESULTS From across all the presentations, lessons learned and exemplary evidence of the value of partnerships were gathered and summarized. CONCLUSION The concluding synthesis of the presentations determined that with the broad needs across cancer requiring in-depth expertise at each point on a patient’s journey, no single organization can effect change alone. Multipartner collaborations not only should be the norm but should also be coordinated so that efforts are not duplicated and maximum patient access to cancer diagnosis and care is achieved.

Adipose parasite sequestration increases mTORC1-dependent leptin production and is linked to cerebral malaria in mice and humans., Circulating levels of the adipokine leptin are linked to neuropathology in experimental cerebral malaria (ECM), but its source and regulation mechanism remain unknown. Here, we show that sequestration of infected red blood cells (iRBCs) in white adipose tissue (WAT) microvasculature increased local vascular permeability and leptin production. Mice infected with parasite strains that fail to sequester in WAT displayed reduced leptin production and protection from ECM. WAT sequestration and leptin induction were lost in CD36KO mice; however, ECM susceptibility revealed sexual dimorphism. Adipocyte leptin was regulated by the mechanistic target of rapamycin complex 1 (mTORC1) and blocked by rapamycin. In humans, although Plasmodium falciparum infection did not increase circulating leptin levels, iRBC sequestration, tissue leptin production, and mTORC1 activity were positively correlated with CM in pediatric postmortem WAT. These data identify WAT sequestration as a trigger for leptin production with potential implications for pathogenesis of malaria infection, prognosis, and treatment.

Correct use of statistical methods is important to ensure the reliability and value of the published experimental pathology literature. Considering increasing interest in the quality of statistical reporting in pathology, the statistical methods used in 10 recent issues of the American Journal of Pathology were reviewed. The statistical tests performed in the articles were summarized, with attention to their implications for contemporary pathology research and practice. Among the 195 articles identified, 93% reported using one or more statistical tests. Retrospective statistical review of the articles revealed several key findings. First, tests for normality were infrequently reported, and parametric hypothesis tests were overutilized. Second, studies reporting multisample hypothesis tests (eg, analysis of variance) infrequently performed post hoc tests to explore differences between study groups. Third, correlation, regression, and survival analysis techniques were underutilized. On the basis of these findings, a primer on relevant statistical concepts and tests is presented, including issues related to optimal study design, descriptive and comparative statistics, and regression, correlation, survival, and genetic data analysis.

Background In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. Methods We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. Results Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21–33.78 and OR = 8.58, 95% CI = 2.56–29.08, respectively) and brain swelling (P Conclusions Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.

BACKGROUNDDifferentiating the etiology of acute febrile respiratory illness in children is a challenge in low-income, malaria-endemic settings because the main pathogens responsible (viruses, bacteria, and malaria parasites) overlap in clinical presentation and frequently occur together as mixed infections. The critical task is to rapidly identify bacterial pneumonia to enable appropriate antibiotic treatment, ideally at point of care. Current diagnostic tests are insufficient and there is a need for the discovery and development of new tools. Here we report the identification of a unique biomarker signature that can be identified in blood samples.METHODSBlood samples from 195 pediatric Mozambican patients with clinical pneumonia were analyzed with an aptamer-based high dynamic range assay to quantify ∼1200 proteins. For discovery of new biomarkers, we identified a training set of patient samples in which the underlying etiology of the pneumonia was established as bacterial, viral or malaria. Proteins whose abundances varied significantly between patients with verified etiologies (FDRRESULTS219 proteins had significantly different abundances between bacterial and viral infections, and 151 differed between bacterial infections and a mixed pool of viral and malaria infections. Predictive diagnostic models achieved >90% sensitivity and >80% specificity, regardless of whether one or two pathogen classes were present. Bacterial pneumonia was strongly associated with markers of neutrophil activity, in particular neutrophil degranulation. Degranulation markers included HP, LCN2, LTF, MPO, MMP8, PGLYRP1, RETN, SERPINA1, S100A9, and SLPI.CONCLUSIONBlood protein signatures highly associated with neutrophil biology reliably differentiated bacterial pneumonia from other causes. With appropriate technology, these markers could provide the basis for a rapid diagnostic for field-based triage for antibiotic treatment of pediatric pneumonia.

The Strengthening Laboratory Management Toward Accreditation (SLMTA) program and subsequent Stepwise Laboratory Quality Improvement Process Toward Accreditation (SLIPTA) checklist were a response to the need for high-quality laboratories to combat the human immunodeficiency virus (HIV) epidemic and provide patients with the highest-quality care. The two tools work together to create a culture of quality in laboratories and allow the identification of gaps. The ultimate goal for any laboratory is to achieve a standard benchmark for quality and these programs have been highly successful in initially affecting the HIV epidemic but continuously improving laboratory quality across all diseases.

The diagnostic laboratory is essential to patient care and to the achievement of health equity. Through the development of quality laboratories in settings burdened by poverty and weak health systems, Partners In Health has demonstrated the critical contributions of clinical laboratories to the care of patients with HIV, tuberculosis, and cancer, among other conditions. The lessons learned through the organization's experience include the importance of well-trained and well-supported staff; reliable access to supplies, reagents, and diagnostic equipment; adequate facilities to provide diagnostic services; the integration of laboratories into networks of care; and accompaniment of the public health sector.

The hallmark of pediatric cerebral malaria (CM) is sequestration of parasitized red blood cells in the cerebral microvasculature. Malawi-based research using 0.35 Tesla (T) magnetic resonance imaging (MRI) established that severe brain swelling is associated with fatal CM, but swelling etiology remains unclear. Autopsy and clinical studies suggest several potential etiologies, but limitations of 0.35 T MRI precluded optimal investigations into swelling pathophysiology. A 1.5 T MRI in Zambia allowed for further investigations including susceptibility-weighted imaging (SWI). SWI is an ideal sequence for identifying regions of sequestration and microhemorrhages given the ferromagnetic properties of hemozoin and blood. Using 1.5 T MRI, Zambian children with retinopathy-confirmed CM underwent imaging with SWI, T2, T1 pre- and post-gadolinium, diffusion-weighted imaging (DWI) with apparent diffusion coefficients and T2/fluid attenuated inversion recovery sequences. Sixteen children including two with moderate/severe edema were imaged; all survived. Gadolinium extravasation was not seen. DWI abnormalities spared the gray matter suggesting vasogenic edema with viable tissue rather than cytotoxic edema. SWI findings consistent with microhemorrhages and parasite sequestration co-occurred in white matter regions where DWI changes consistent with vascular congestion were seen. Imaging findings consistent with posterior reversible encephalopathy syndrome were seen in children who subsequently had a rapid clinical recovery. High field MRI indicates that vascular congestion associated with parasite sequestration, local inflammation from microhemorrhages and autoregulatory dysfunction likely contribute to brain swelling in CM. No gross radiological blood brain barrier breakdown or focal cortical DWI abnormalities were evident in these children with nonfatal CM.

Purpose: In order to address the unmet needs of international histopathology laboratories with regard to procurement of laboratory equipment and consumables, the ASCP Center for Global Health has established a program which facilitates donation of these goods to laboratories in need. Methods: Using a member-based outreach approach, donors with key histopathology laboratory equipment or consumables submit an interest in donation to ASCP. ASCP performs an assessment of the quality and longevity of the donated item. ASCP pairs the donation with a laboratory within the Partners for Cancer Diagnosis and Treatment Initiative network which has expressed need. Recipient lab-specific parameters are further evaluated (e.g. space, voltage compatibility, need for service contract, etc.). Should the donation be a compatible fit, ASCP works with both recipient and international shippers to facilitate the donation. Results: Since August 2018, ASCP has supported nearly 20 international equipment donations (fair market value of goods totaling approximately $120K) to 12 countries. These donations are composed of routine histopathology lab consumables (e.g. tissue cassettes, glass slides, etc.) as well as specialized equipment (e.g. whole slide imaging scanners, microtomes, microscopes, etc.), basic laboratory operations equipment (e.g. computers, keyboards, etc), and educational materials (e.g. textbooks, etc.). Conclusions: This donation program allows for redistribution of key histopathology lab equipment and consumables to laboratories in needs. The impact of this program has been far-reaching, both relieving laboratory strain associated with under-procurement often experienced in international laboratories to expanding capacitation of diagnostic testing services including, in some cases, telepathology-based secondary consultations from subspecialty pathologists unavailable in-country. Citation Format: Debby Basu, Lola Tashpulatova, Dan Milner, Kenneth Landgraf. Establishment of ASCP Equipment Donation Program to Support International Histopathology Laboratories [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 5.

Background. In modern academic medicine, especially in the fields of infectious diseases and global health, aspiring physician-scientists often wait years before achieving independence as basic, translational, and clinical investigators. This study employed mixed methods to evaluate the success of the Burroughs Wellcome Fund/American Society for Tropical Medicine and Hygiene (BWF/ASTMH) global health postdoctoral fellowship in promoting scientific independence. Methods. We examined quantitative data obtained from the National Institutes of Health (NIH) and qualitative data provided by the ASTMH and program participants to assess BWF/ASTMH trainees' success in earning NIH grants, publishing manuscripts, and gaining faculty positions. We also calculated the return on investment (ROI) associated with the training program by dividing direct costs of NIH research grants awarded to trainees by the direct costs invested by the BWF/ASTMH fellowship. Results. Forty-one trainees received fellowships between 2001 and 2015. Within 3 years of completing their fellowships, 21 of 35 (60%) had received career development awards, and within 5 years, 12 of 26 (46%) had received independent research awards. Overall, 22 of 35 (63%) received 1 or more research awards. BWF/ASTMH recipients with at least 3 years of follow-up data had coauthored a mean of 36 publications (range, 2-151) and 29 of 35 (82%) held academic positions. The return on investment was 11.9 overall and 31.8 for fellowships awarded between 2001 and 2004. Conclusions. Between 2001 and 2015, the BWF/ASTMH postdoctoral training program successfully facilitated progress to scientific independence. This program model underscores the importance of custom-designed postdoctoral training as a bridge to NIH awards and professional autonomy.

Diagnostics and supportive care for patients with non-Hodgkin lymphoma (NHL) in lower- and middle-income countries (LMICs) are lacking. We hypothesized that high-throughput transcription-based diagnostics could classify NHL specimens from Malawi amenable to targeted therapeutics. We established tissue microarrays and classified 328 cases diagnosed by hematoxylin and eosin as NHL at University of Malawi College of Medicine using immunohistochemistry (IHC) for conventional markers and therapeutic targets. A subset was analyzed using NanoString-based expression profiling with parsimonious transcriptional classifiers. Overall, 72% of lymphomas were high-grade B-cell tumors, subsets of which were enriched for expression of MYC, BCL2, and/or PD-L1. A 21-gene transcriptional classifier, previously validated in Western cohorts, divided 96% of diffuse large B-cell lymphomas (DLBCLs) with 100% of B-cell lymphomas, unclassifiable, into 1 cluster and 88% of Burkitt lymphomas into a separate cluster. Cell-of-origin categorization of 36 DLBCLs by NanoString lymphoma subtyping test (LST) revealed 69% concordance with IHC. All discordant cases were classified as germinal center B cell-like (GCB) by LST but non-GCB by IHC. In summary, utilization of advanced diagnostics facilitates objective assessment and segregation of biologically defined subsets of NHL from an LMIC without expert review, thereby establishing a basis for the implementation of effective and less toxic targeted agents.

Malaria remains a major public health threat in tropical and subtropical regions across the world. Even though less than 1% of malaria infections are fatal, this leads to about 430,000 deaths per year, predominantly in young children in sub-Saharan Africa. Therefore, it is imperative to understand why a subset of infected individuals develop severe syndromes and some of them die and what differentiates these cases from the majority that recovers. Here, we discuss progress made during the past decade in our understanding of malaria pathogenesis, focusing on the major human parasite Plasmodium falciparum.

CD8+ T cells have been shown to play a critical role in the pathogenesis of experimental cerebral malaria (ECM) in mice, but their role in development of human cerebral malaria (HCM) remains unclear. Thus, in this study we have provided the first direct contrast of the accumulation of CD8+ T cells in the brain during HCM and ECM. HCM cases were from children who died of Plasmodium falciparum cerebral malaria at Queen Elizabeth Central Hospital (Malawi) between 2003 and 2010. ECM was induced by infecting C57BL/6J mice with P. berghei ANKA. We demonstrate similarities in the intracerebral CD8+ T cell responses in ECM and HCM, in particular an apparent shared choroid plexus – meningeal route of CD8+ T cell accumulation in the brain. Nevertheless, we also reveal some potentially important differences in compartmentalisation of CD8+ T cells within the cerebrovascular bed in HCM and ECM.

Incidence and mortality from cancer is increasing in most countries in the world, with the highest burden in developing countries. City Cancer Challenge (C/Can), an initiative launched in 2017, aims to improve access to quality cancer care in metropolitan areas (1 million inhabitants or more) in low- and upper-middle income countries by transforming the way stakeholders at the city, regional, and national levels collectively design, plan, and implement local cancer solutions. The approach is built on the core principle that local leaders in cities define their own needs and craft solutions with the support of a network of global, regional, and local partners that reflect an understanding of the unique local context. C/Can aims to build a collective movement of cities that can together deliver quality, equitable, and sustainable cancer control solutions for all.

The study aim was to describe human papillomavirus (HPV)‐attributable cancer burden in Rwanda, according to anogenital cancer site, HPV type, age and HIV status. Tissue specimens of cervical, vulvar, vaginal, penile and anal cancer diagnosed in 2012–2018 were retrieved from three cancer referral hospitals and tested for high‐risk (HR) HPV DNA. Cervical cancer represented the majority of cases (598 of 738), of which 96.0% were HR‐HPV positive. HPV‐attributable fractions in other cancer sites varied from 53.1% in 81 penile, through 76.7% in 30 vulvar, 83.3% in 24 vaginal, up to 100% in 5 anal cases. HPV16 was the predominant HR‐HPV type in cervical cancer (55.0%), followed by HPV18 (16.6%) and HPV45 (13.4%). HPV16 also predominated in other cancer sites (60–80% of HR‐HPV‐attributable fraction). For cervical cancer, type‐specific prevalence varied significantly by histology (higher alpha‐9 type prevalence in 509 squamous cell carcinoma vs. higher alpha‐7 type prevalence in 80 adenocarcinoma), but not between 501 HIV‐negative and 97 HIV‐positive cases. With respect to types targeted, and/or cross‐protected, by HPV vaccines, HPV16/18 accounted for 73%, HPV31/33/45/52/58 for an additional 22% and other HR‐HPV types for 5%, of HPV‐attributable cancer burden, with no significant difference by HIV status nor age. These data highlight the preventive potential of the ongoing national HPV vaccination program in Rwanda, and in sub‐Saharan Africa as a whole. Importantly for this region, the impact of HIV on the distribution of causal HPV types was relatively minor, confirming type‐specific relevance of HPV vaccines, irrespective of HIV status., What's new? Sub‐Saharan Africa suffers the highest cervical‐cancer rates in the world, due in part to a lack of cervical‐cancer screening programs. In 2011, Rwanda initiated a national HPV‐vaccination program, achieving >90% coverage. In this study, the authors characterized the subsequent burden of all forms of anogenital cancer attributable to high‐risk (HR) HPV types, including cervical, anal, etc. These results illustrate the preventive potential of a national HPV‐vaccination program. They also enhance our understanding of the HPV‐attributable fraction of non‐cervical anogenital cancers in sub‐Saharan Africa overall.

CD8+ T cells have been shown to play a critical role in the pathogenesis of experimental cerebral malaria (ECM) in mice, but their role in development of human cerebral malaria (HCM) remains unclear. Thus, in this study we have provided the first direct contrast of the accumulation of CD8+ T cells in the brain during HCM and ECM. HCM cases were from children who died of Plasmodium falciparum cerebral malaria at Queen Elizabeth Central Hospital (Malawi) between 2003 and 2010. ECM was induced by infecting C57BL/6J mice with P. berghei ANKA. We demonstrate similarities in the intracerebral CD8+ T cell responses in ECM and HCM, in particular an apparent shared choroid plexus—meningeal route of CD8+ T cell accumulation in the brain. Nevertheless, we also reveal some potentially important differences in compartmentalization of CD8+ T cells within the cerebrovascular bed in HCM and ECM.

Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity-related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical / radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology (MPE) Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational / systems biology, there are wide open opportunities in MPE to contribute to public health.

Purpose Connecting a cancer patient to the appropriate treatment requires the correct diagnosis provided in a timely manner. In resource-limited settings, the anatomic pathology bridge to efficient, accurate, and timely cancer care is often challenging. In this study, we present the first phase of an anatomic telepathology triage system, which was implemented and validated at the Butaro District Hospital in northern rural Rwanda. Methods Select cases over a 9-month period in three segments were evaluated by static image telepathology and were independently evaluated by standard glass slide histology. Each case via telepathology was classified as malignant, benign, infectious/inflammatory, or nondiagnostic and was given an exact histologic diagnosis. Results For cases triaged as appropriate for telepathology, correlation with classification and exact diagnosis demonstrated greater than 95% agreement over the study. Cases in which there was disagreement were analyzed for cause, and the triage process was adjusted to avoid future problems. Conclusion Challenges to obtaining a correct and complete diagnosis with telepathology alone included the need for immunohistochemistry, assessment of the quality of images, and the lack of images representing an entire sample. The next phase of the system will assess the effect of telepathology triage on turnaround time and the value of on-site immunohistochemistry in reducing that metric and the need for evaluation outside of telepathology.

The spleen has an important role in the clearance of malaria parasites, and the role of HIV co-infection on this process is yet to be described. Using a combination of histological and molecular methods, we systematically evaluated parasite load across multiple organs from HIV-positive and HIV-negative cases of an autopsy study of pediatric comatose children with malaria infection (n=103) in Blantyre, Malawi. Quantification of parasite load across organs was done using histology. A subset of cases was further characterized for parasite localization and stage of development using immunohistochemistry-based labeling of parasite and host cells (5 HIV-positive, 10 HIV-negative), and quantitative RT-PCR (qRT-PCR) of asexual and sexual-specific genes (4 HIV-positive, 5 HIV-negative). The results were compared with clinical information including HIV status. The HIV-positive rate was 21% for the group studied (20 of 95) and HIV-positive patients had a significantly shorter duration of time between onset of illness and death, and were significantly older than HIV-negative patients. We found that spleens of HIV-positive cases had significantly higher parasite loads compared with those of HIV-negative cases in each of the three methods we used: (i) standard histology, (ii) immunohistochemistry-based labeling of Plasmodium lactate dehydrogenase (pLDH), and (iii) molecular detection of asexual parasite transcript apical membrane antigen 1 (AMA1). Immunohistochemistry-based labeling of macrophage marker CD163 in a subset of spleens revealed fewer activated macrophages containing engulfed parasites and a greater number of free unphagocytosed parasites in the HIV-positive cases. The mechanism by which HIV infection is associated with more rapid progression to severe cerebral malaria disease is possibly impairment of parasite destruction by splenic macrophages, supported by published in vitro studies showing inefficient phagocytosis of malaria parasites by HIV-infected macrophages.

The connection of a clinician who identifies a patient with signs and symptoms of malignancy to an oncologist who has the tools to treat a patient's cancer requires a diagnostic pathology laboratory to receive, process, and diagnose the tumor. Without an accurate classification, nothing is known of diagnosis, prognosis, or treatment by the clinical team, and most important, the patient is left scared, confused, and without hope. The vast majority of deaths from malignancies occur in sub-Saharan Africa primarily as a result of lack of public awareness of cancer and how it is diagnosed and treated in the setting of a severe lack of resources (physical and personnel) to actually diagnose tumors. To correct this massive health disparity, a plan of action is required across the continent of Africa to bring diagnostic medicine into the modern era and connect patients with the care they desperately need. We performed a survey of resources in Africa for tissue diagnosis of cancer and asked quantitative questions about tools, personnel, and utilization. We identified a strong correlation between pathology staffing and capacity to provide pathology services. On the basis of this survey and through a congress of concerned pathologists, we propose strategies that will catapult the continent into an era of high-quality pathology services with resultant improvement in cancer outcomes.