Title: Evaluation and Transfer of mobile whole slide tissue scanners and liquid biopsies to deliver fast and precise diagnosis for improved outcomes of children and young adults with EBV-driven lymphoma: a joint Tanzanian and Ugandan Paediatric Oncology Network Initiative
Funder: Department of Health and Social Care

Abstract: Lymphomas caused by Epstein-Barr virus (EBVL) present a significant healthcare burden to sub-Saharan Africa as they are common, affect primarily children and young adults, and are invariably fatal without treatment. Effective therapies are available in sub-Saharan Africa and could cure 90% of patients if diagnosed early. However, currently, most children either remain undiagnosed, present late to hospital or are diagnosed late. One of the main reasons behind this is the lack of fast, reliable hospital-based diagnostics services that deliver safe invasive tissue biopsy collection and specialist histopathology examination. Here we propose to test two new technologies which, by leapfrogging conventional diagnostic approaches, could bring fast and precise diagnosis of EBVL to sub-Sahara Africa: Thanks to significant improvements in optics and compute power, scanning of entire histological tissue slides using a mobile camera that can be attached to any microscope (mobile whole slide imaging; WSI) is now possible. Contrary to conventional telepathology, WSI promises to provide a complete image of the tumour tissue. Liquid biopsies of tumour and viral DNA circulating in blood (DNA-based diagnostics) are non-invasive and have already been used for early diagnosis of other EBV-related cancers and other types of lymphomas. We have now developed this technology specifically for the EBV-related lymphomas in sub-Saharan Africa. In addition to delivering faster, more precise diagnosis, the tool will generate viral and tumour sequence information to inform the design of future screening programmes and vaccine development and can be adapted for point-of-care testing. To test these novel diagnostic tools, we have partnered with the Tanzanian Paediatric Oncology Team (T-POT), the Kilimanjaro Christian Medical Centre (Moshi, Northern Tanzania) and the Epidemiology of Burkitt s Lymphoma in East-African Children and Minors (EMBLEM) Hospital (Lacor, Uganda) represented by the African Field Epidemiology Network (AFENET) to recruit 280 children and young adults. Following on-site and online training of study pathologists and technical staff, we will perform a clinical validation of our diagnostic tools and then a CONTROLLED BEFORE-AFTER study to test whether these speed up diagnosis, increase the number of children diagnosed and treated, and ultimately improve survival compared to gold-standard pathology. Finally, we will examine cost-effectiveness. Our proposal brings together a network of clinicians, pathologists and technicians, NGOs, research organisations, and patient and parent groups in Tanzania and Uganda. Through this network, we have already obtained support from senior representatives of the Ministries of Health in both countries. Our plan for long-term sustainability includes the creation of a financially sustainable social enterprise for the provision of diagnostics services, and the leverage of existing initiatives for public and patient engagement to raise awareness of EBVL and the importance of early diagnosis. If successful, children and young adults in two of the poorest countries in the region will have sustainable access to early, precise EBVL diagnosis and effective therapy close to home. Other disease areas will also benefit from increased diagnostic capacity. Collectively, our objectives will provide the essential basis for future epidemiological research, design of screening programmes and the development of novel therapeutic strategies including vaccination.

Lay abstract: Over 90% of children in the world with special types of blood cancers called lymphomas are from sub-Saharan Africa. This is because a virus called Epstein-Barr virus (EBV), malaria and HIV all contribute to causing these specific types of lymphomas. Their treatment is widely available and free-of-charge in most sub-Saharan countries. However, currently, most children either remain undiagnosed, present late to hospital, or are diagnosed late while in hospital. One of the main reasons for this is the lack of reliable hospital-based diagnostics services with enough surgeons and pathologists to establish the precise diagnosis fast enough. Here, we propose to test two new diagnostic technologies that can help provide fast and reliable diagnosis in sub-Saharan Africa. The first takes complete pictures of tissue biopsies with a small and affordable mobile camera that can be attached to any microscope. These pictures can then be sent anywhere in the world for interpretation. It means that fewer pathologists would be required for diagnosis, which would be hugely beneficial, especially in remote places. The second technology uses a simple blood test to make the diagnosis of lymphoma. This technology (also known as liquid biopsy) relies on tracing DNA from tumours and viruses that cause the cancer. It has been used already in other EBV-related cancers and in lymphomas in other areas to detect the disease much earlier than with conventional methods. We have now developed this technology specifically for the EBV-related lymphomas in sub-Saharan Africa. It means that children might not need an invasive biopsy anymore to make the diagnosis. We would like to test our technologies in Tanzania and Uganda. After an initial period of training of local staff involved in the study, we will recruit 280 children and young adults to clinically validate our technologies, and to test whether they speed up the diagnosis, increase the number of diagnosed children (especially among those too unwell to undergo invasive biopsy testing), and if it improves survival. We will also examine whether our approach is cost-effective and affordable for sub-Saharan countries. At the same time as providing a diagnosis, our liquid biopsy test will help with future vaccine design and the development of a future screening programme and can be transferred onto a point-of-care platform. Our proposal brings together a network of clinicians, pathologists and technicians, NGOs, research organisations, and patient and parent groups in Tanzania and Uganda. Through these we have already obtained support by senior representatives at the Ministries of Health. Our plan for long-term sustainability includes the creation of a financially sustainable social enterprise to provide many diagnostic services, and the leverage of existing initiatives for public and patient engagement to raise awareness of EBVL and the importance of early diagnosis.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION;CANCER AND NEOPLASMS