Innovations in Radiotherapy Technology.

Many low- and middle-income countries, together with remote and low socioeconomic populations within high-income countries, lack the resources and services to deal with cancer. The challenges in upgrading or introducing the necessary services are enormous, from screening and diagnosis to radiotherapy planning/treatment and quality assurance. There are severe shortages not only in equipment, but also in the capacity to train, recruit and retain staff as well as in their ongoing professional development via effective international peer-review and collaboration. Here we describe some examples of emerging technology innovations based on real-time software and cloud-based capabilities that have the potential to redress some of these areas. These include: (i) automatic treatment planning to reduce physics staffing shortages, (ii) real-time image-guided adaptive radiotherapy technologies, (iii) fixed-beam radiotherapy treatment units that use patient (rather than gantry) rotation to reduce infrastructure costs and staff-to-patient ratios, (iv) cloud-based infrastructure programmes to facilitate international collaboration and quality assurance and (v) high dose rate mobile cobalt brachytherapy techniques for intraoperative radiotherapy

DEVELOPMENT AND CLINICAL VALIDATION OF KNOWLEDGE-BASED PLANNING MODELS FOR STEREOTACTIC BODY RADIOTHERAPY OF EARLY-STAGE NON-SMALL-CELL LUNG CANCER PATIENTS

Lung stereotactic body radiotherapy (SBRT) is a viable alternative to surgical intervention for the treatment of early-stage non-small-cell lung cancer (NSCLC) patients. This therapy achieves strong local control rates by delivering ultra-high, conformal radioablative doses in typically one to five fractions. Historically, lung SBRT plans are manually generated using 3D conformal radiation therapy, dynamic conformal arcs (DCA), intensity-modulated radiation therapy, and more recently via volumetric modulated arc therapy (VMAT) on a C-arm linear accelerator (linac). Manually planned VMAT is an advanced technique to deliver high-quality lung SBRT due to its dosimetric capabilities and utilization of flattening-filter free beams to improve patient compliance. However, there are limitations in manual treatment planning as the final plan quality heavily depends on a planner’s skill and available planning time. This could subject the plan quality to inter-planner variability from a single institution with multiple planners. Generally, the standard lung SBRT patient ‘simulation-to-treatment’ time is 7 working days. This delays clinic workflow and degrades the quality of treatment by eliminating adaptive re-planning capabilities. There is an ongoing effort to automate treatment planning by creating a model library of previously treated, high-quality plans and using it to prospectively generate new plans termed model-based knowledge-based planning (KBP). KBP aims to mitigate the previously mentioned limitations of manual planning and improve clinic workflow. As part of this dissertation, lung SBRT KBP models were created using a commercially available KBP engine that was trained using non-coplanar VMAT lung SBRT plans with the final dose reported from an advanced Acuros-based algorithm. The dissertation begins with the development of a robust and adaptable lung SBRT KBP model for early-stage, centrally-located NSCLC tumors that is fully compliant with Radiation Therapy Oncology Group (RTOG)-0813 protocol’s requirements. This new model provided similar or better plan quality to clinical plans, however it significantly increased total monitor units and plan complexity. This prompted the development and validation of an automated KBP routine for SBRT of peripheral lung tumors via DCA-based VMAT per RTOG-0618 criteria. This planning routine helped incorporate a historical DCA-based treatment planning approach with a VMAT optimization automated KBP engine that helps reduce plan complexity. For both central and peripheral lung lesions, the validated models are able to generate high-quality, standardized plans in under 30 min with minimal planner effort compared to an estimated 129 ± 34 min of a dedicated SBRT planner’s time. In practice, planners are expected to meticulously work on multiple plans at once, significantly increasing manual planning time. Thus, these KBP models will shorten the ‘simulation-to-treatment’ time down to as few as 3 working days, reduce inter-planer variability and improve patient safety. This will help standardize clinics and enable offline adaptive re-planning of lung SBRT treatment to account for physiological changes errors resulting from improper patient set-up. Lastly, this dissertation sought to further expand these KBP models to support delivering lung SBRT treatments on a new O-ring linac that was recently introduced to support underserved areas and fast patient throughput. Despite learning from a C-arm modality training dataset, these KBP models helped the O-ring linac to become a viable treatment modality for lung SBRT by providing an excellent plan quality similar to a C-arm linac in under 30 min. These KBP models will facilitate the easy transfer of patients across these diverse modalities and will provide a solution to unintended treatment course disruption due to lengthy machine downtime. Moreover, they will relieve the burden on a single machine in a high-volume lung SBRT clinic. Further adaptation and validation of these KBP models for large lung tumors (\u3e 5 cm) with multi-level dosing scheme and synchronous multi-lesion lung SBRT is ongoing

Point-of-care testing for HIV and TB integration of services

A thesis submitted to the Faculty of Health Sciences, university of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the Degree of Doctor of Philosophy Johannesburg, 2015The United Nations Programme on HIV/AIDS (UNAIDS) have recently released challenging new Human Immunodeficiency Virus (HIV) treatment targets to be achieved globally by 2020; all of which require concentrated efforts in scaling up laboratory testing capacity for HIV diagnosis, treatment initiation and treatment monitoring. The Global Tuberculosis (TB) Strategy have also put forth a list of ambitious goals which include reducing the number of deaths due to TB by 95% and the number of new TB cases by 90%. In South Africa, which has the highest national prevalence of HIV described globally and ranks fifth in the world in terms of TB incident cases, further integration of HIV and TB services will be needed to achieve these targets. A major challenge to successful integration of these programs however, will be the ability to diagnose and monitor the progress of both infections, a process that in South Africa, is hampered by lack of access to laboratory testing. Although public pathology laboratory service providers, such as the National Health Laboratory Service (NHLS), are responding to increasing testing demands by scaling up centralised laboratory capacity, limitations such as the need for expertise, infrastructure, space, cold-chain, maintenance, logistics and cost, are challenging full implementation and scale up. Many international organisations believe that one of the ways to successfully achieve the global HIV ‘90-90-90’ and TB targets, will be through the development and scaling up of innovative, simpler and more affordable technology approaches such as Point-of-Care testing (POCT), a view shared by the South African National Department of Health (NDoH). POCT refers to testing that is performed near or at the site of the patient with the result leading to a possible or immediate change in patient management or outcome and holds promise as a strategy to extend laboratory testing capacity. Prior to large-scale POC implementation efforts can begin, defining the difficulties and potential solutions which are likely to arise, particularly in high disease burden clinical settings need to be addressed. The main objective of this study was to investigate the feasibility, performance and operational considerations of multidisciplinary POCT in South Africa, including the development of a best practice framework to guide implementation efforts. This was achieved by performing a clinical needs assessment and engaging with government, evaluating POC technologies for HIV and TB diagnosis and/or monitoring and developing a framework for how to implement POCT in the field including quality, site and training requirements. The operational requirements for healthcare workers to perform multiple POCT in the South African clinical setting, was also determined. The assays required were based on the South African National Treatment guidelines in the period of review (2011-2014). In July 2013, the South African NDoH called a meeting with various stakeholders to provide the context for POCT in South Africa and strong emphasis was placed on HIV and TB and how POCT could expand on existing laboratory infrastructure for these diseases. Outcomes from this meeting prompted a thorough literature review on the challenges likely to be faced by large-scale POC implementation efforts. One of the key issues highlighted was the lack of evaluation data on numerous HIV and TB POC technologies available and/or in the pipeline. Even though viral load (VL) testing has been available in South Africa since 2004, the global treatment guidelines (World Health Organization) now recommend a VL test for HIV antiretroviral treatment (ART) monitoring and there are talks around the possibilities of a ‘test and treat’ strategy. In light of this, two potential POC plasma-based VL technologies available at the time were evaluated in the laboratory. The Liat™ HIV-1 Plasma Quant (IQuum Inc, MA, USA; now Roche Molecular, Branchburg, MJ, USA) and the Xpert® HIV-1 VL (Cepheid, Sunnyvale, CA) assays both demonstrated good performance and were proven to be interchangeable with existing in-country high-throughput VL laboratory platforms. Both however, require centrifugation to obtain the plasma sample and thus may be more suited to a district level facility as opposed to a ‘true’ POC environment. In light of these operational challenges, two further blood-based POC VL platforms were also evaluated, the Liat™ HIV-1 Blood Quant VL assay (IQuum, Inc) and the Alere™ q HIV-1/2 assay (Alere Technologies GmbH, Jena, Germany). Both assays identified more patients as treatment failures at the 1000 copies/ml treatment failure threshold (WHO and South African treatment guideline recommended threshold) compared to plasma VL, due to their total nucleic acid extraction protocols. Thus, if either were implemented at POC, one could expect a significant upward misclassification, increasing the number of HIV-positive patients requiring follow up VL testing and programmatic costs. Application therefore, could be niched VL testing; utilising a blood-based POC VL assay in maternity wards to diagnose HIV in new-borns; plasmabased POCT for mothers to reduce risk of transmission. POCT may not be the only solution to increasing access to laboratory testing services, and thus alternative strategies for improving access were also investigated. Dried blood spots (DBS) and PrimeStore media (a sample transport media; Longhorn Vaccines and Diagnostics, San Antonio, TX, USA) were shown to be as valuable as plasma VL for detecting HIV-positive patients failing ART at the 1000 copies/ml threshold and both solve logistical issues around sample transport and maintaining sample integrity for centralized testing. For TB diagnosis, the Xpert® MTB/RIF assay (Cepheid, Sunnyvale, CA) was evaluated to determine its appropriate placement within the South African setting. Although Xpert® MTB/RIF proved superior in performance to smear microscopy, it was originally modelled as too costly for POC placement in South Africa and was implemented into smear microscopy centres nationally. Subsequently, the complexity of the analyser maintenance and power issues has reinforced the original decision. Further potential POC TB technologies are in the development pipeline, but only one other was available for evaluation, namely the EasyNAT® detection kit (Ustar Biotechnologies, Hangzou, China). Initial laboratory evaluation results look promising but the technology is still a long way from clinical evaluation due to its laborious procedure. A further challenge identified for POCT is the lack of documented implementation science to ensure quality-assured multi-disciplinary POCT in the field. To address this, three key components of a quality testing framework were developed to ensure best practice for POCT; a clinic site readiness assessment tool, a POC training module and a quality monitoring program. The clinic site assessment checklist was developed to determine site readiness for POC placement. The POC training module included standard operating procedures, quick reference and workflow charts and a practical training component which was developed specifically with the non-laboratory trained user in mind. Both these components have been adopted and modified for use by the NHLS National Priority Program (NPP). Certain POC assays already have External Quality Assessment (EQA) material, while others had to be developed. For quality management of HIV VL technologies, a standardized plasma panel was developed to ensure molecular VL platforms are ‘fit-forpurpose’ (verification, a requirement of the laboratory accreditation process). This panel, termed SAVQA, is being manufactured and supplied to aid POC assay developers in assessing their product for the South African market, and will also be further developed for use by healthcare workers at POC. Due to the hurdles encountered with the biosafety regulations for transporting TB external quality assessment (EQA) material, a quality assessment program using dried culture spots (DCS) was also developed for TB diagnostic technologies consisting of two components; a verification and an EQA program. The DCS technology has become a global product and as of 2015 is being supplied to 20 different countries. DCS were successfully shown to be suitable for use at POC by non-laboratory trained staff. The versatility of the material has been confirmed by its expansion to other molecular TB diagnostic tests, most notably the Hain Genotype MTBDrplus assay for TB drug susceptibility testing (Hain LifeScience GmbH, Nehren, Germany). This work has been acknowledged through the Research and Development team involved in the development of the DCS program, winning three awards: the NHLS Top Award for Innovation 2013, the Gauteng Accelerator Program (GAP) Biosciences Award in 2014 and a special Social Impact award for Africa Innovations held in Morocco in 2015. Incorporating the quality components developed above, a clinical evaluation of nurse operated multidisciplinary POCT was performed. Although multiple POCT could be performed as accurately as laboratory testing on venepuncture specimens, it required dedicated staff and dramatically increased POC staff duties. It was further shown that multiple POCT could be accurately performed by a nurse on a single finger slice in order to obtain adequate blood volume to perform up to four POC tests, and that finger stick VL testing was also feasible by nurses at POC. Patients were also more willing to have up to three finger sticks performed than to have a single venepuncture specimen taken. The process of using finger sticks was further ratified by demonstrating that a single finger stick can provide up to 150μl of blood, which is sufficient to perform an array of POC tests. In spite of the feasibility of nurse based POCT, limitations of current technologies using finger stick were also realised, such as the performance of the Liat™ Quant blood assay which generated increased VL misclassification at the 1000 copies/ml treatment failure threshold (70% misclassification). This would impact programmatic costs, but this technology may have value as a diagnostic tool in key populations. The work described shows that multi-disciplinary POCT within a South African setting is achievable with appropriate clinic infrastructure, dedicated staff, training and stringent quality monitoring measures in place. The HIV and TB POC technologies evaluated were found to be as accurate as laboratory-based testing however, few meet the criteria of a ‘true’ POC device and thus further research and development is required. Based on South Africa’s testing needs, a tiered hybrid model which expands on centralized laboratory capacity through incorporating POCT into very remote, hard-to-reach areas and innovations around linkage to care efforts, may help meet ’90-90-90’ targets but will require costing/modelling and future assessments of the impact and outcome of the intervention. Much of this work presented contributed towards the development of a draft National POCT policy document in support of the national strategic plan for POCT for the management of HIV and TB in South Africa

Feasibility of Post-Operative Mobile Health Monitoring Among Colorectal Surgery Patients

Post-operative readmission following colorectal surgery is a common and costly occurrence. Remote health monitoring via mobile applications has the potential to reduce post-operative readmissions by early identification of complications. This intervention depends on patient acceptance and compliance with available technology. The feasibility of home monitoring using automated daily surveys and wound photo uploads, delivered via a mobile health application, was tested in the immediate post-operative period after colorectal surgery. Patient compliance, the association between generated alerts and readmissions, and patient satisfaction were measured. Patient satisfaction was high; 80.5% of patients reported that they felt safer going home knowing that they were monitored and 76.2% of patients reported that they would use the current app for post-operative monitoring again. However, only 37.0% of patients answered the survey at least 80% of the time in the first 2 weeks following discharge. Patient compliance significantly limited the feasibility of post-operative monitoring using our mobile health application

Devices and Data Workflow in COPD Wearable Remote Patient Monitoring: A Systematic Review

Background: With global increase in Chronic Obstructive Pulmonary Disease (COPD) prevalence and mortality rates, and socioeconomical burden continuing to rise, current disease management strategies appear inadequate, paving the way for technological solutions, namely remote patient monitoring (RPM), adoption considering its acute disease events management benefit. One RPM’s category stands out, wearable devices, due to its availability and apparent ease of use. Objectives: To assess the current market and interventional solutions regarding wearable devices in the remote monitoring of COPD patients through a systematic review design from a device composition, data workflow, and collected parameters description standpoint. Methods: A systematic review was conducted to identify wearable device trends in this population through the development of a comprehensive search strategy, searching beyond the mainstream databases, and aggregating diverse information found regarding the same device. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed, and quality appraisal of identified studies was performed using the Critical Appraisal Skills Programme (CASP) quality appraisal checklists. Results: The review resulted on the identification of 1590 references, of which a final 79 were included. 56 wearable devices were analysed, with the slight majority belonging to the wellness devices class. Substantial device heterogeneity was identified regarding device composition type and wearing location, and data workflow regarding 4 considered components. Clinical monitoring devices are starting to gain relevance in the market and slightly over a third, aim to assist COPD patients and healthcare professionals in exacerbation prediction. Compliance with validated recommendations is still lacking, with no devices assessing the totality of recommended vital signs. Conclusions: The identified heterogeneity, despite expected considering the relative novelty of wearable devices, alerts for the need to regulate the development and research of these technologies, specially from a structural and data collection and transmission standpoints.Introdução: Com o aumento global das taxas de prevalência e mortalidade da Doença Pulmonar Obstrutiva Crónica (DPOC) e o seu impacto socioeconómico, as atuais estratégias de gestão da doença parecem inadequadas, abrindo caminho para soluções tecnológicas, nomeadamente para a adoção da monitorização remota, tendo em conta o seu benefício na gestão de exacerbações de doenças crónicas. Dentro destaca-se uma categoria, os dispositivos wearable, pela sua disponibilidade e aparente facilidade de uso. Objetivos: Avaliar as soluções existentes, tanto no mercado, como na área de investigação, relativas a dispositivos wearable utilizados na monitorização remota de pacientes com DPOC através de uma revisão sistemática, do ponto de vista da composição do dispositivo, fluxo de dados e descrição dos parâmetros coletados. Métodos: Uma revisão sistemática foi realizada para identificar tendências destes dispositivos, através do desenvolvimento de uma estratégia de pesquisa abrangente, procurando pesquisar para além das databases convencionais e agregar diversas informações encontradas sobre o mesmo dispositivo. Para tal, foram seguidas as diretrizes PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), e a avaliação da qualidade dos estudos identificados foi realizada utilizando a ferramenta CASP (Critical Appraisal Skills Programme). Resultados: A revisão resultou na identificação de 1590 referências, das quais 79 foram incluídas. Foram analisados 56 dispositivos wearable, com a ligeira maioria a pertencer à classe de dispositivos de wellness. Foi identificada heterogeneidade substancial nos dispositivos em relação à sua composição, local de uso e ao fluxo de dados em relação a 4 componentes considerados. Os dispositivos de monitorização clínica já evidenciam alguma relevância no mercado e, pouco mais de um terço, visam auxiliar pacientes com DPOC e profissionais de saúde na previsão de exacerbações. Ainda assim, é notória a falta do cumprimento das recomendações validadas, não estando disponíveis dispositivos que avaliem a totalidade dos sinais vitais recomendados. Conclusão: A heterogeneidade identificada, apesar de esperada face à relativa novidade dos dispositivos wearable, alerta para a necessidade de regulamentação do desenvolvimento e investigação destas tecnologias, especialmente do ponto de vista estrutural e de recolha e transmissão de dados

Technical and clinical validation of commercial automated volumetric MRI tools for dementia diagnosis-a systematic review

Developments in neuroradiological MRI analysis offer promise in enhancing objectivity and consistency in dementia diagnosis through the use of quantitative volumetric reporting tools (QReports). Translation into clinical settings should follow a structured framework of development, including technical and clinical validation steps. However, published technical and clinical validation of the available commercial/proprietary tools is not always easy to find and pathways for successful integration into the clinical workflow are varied. The quantitative neuroradiology initiative (QNI) framework highlights six necessary steps for the development, validation and integration of quantitative tools in the clinic. In this paper, we reviewed the published evidence regarding regulatory-approved QReports for use in the memory clinic and to what extent this evidence fulfils the steps of the QNI framework. We summarize unbiased technical details of available products in order to increase the transparency of evidence and present the range of reporting tools on the market. Our intention is to assist neuroradiologists in making informed decisions regarding the adoption of these methods in the clinic. For the 17 products identified, 11 companies have published some form of technical validation on their methods, but only 4 have published clinical validation of their QReports in a dementia population. Upon systematically reviewing the published evidence for regulatory-approved QReports in dementia, we concluded that there is a significant evidence gap in the literature regarding clinical validation, workflow integration and in-use evaluation of these tools in dementia MRI diagnosis

Improving the Access of Cardiac Magnetic Resonance in Low-Middle Income Countries to Improve Cardiac Care: Rapid CMR

Non-communicable diseases– cancer and cardiovascular disease - are the leading causes of death in high-income countries (HICs). Cardiovascular disease, however, is increasing in Low-Middle Income Countries (LMICs) and is the emergent primary cause of mortality. Part of the reason is suboptimal therapies– from primary prevention to more advanced tertiary care. Not only are advanced therapies scarce but advanced diagnostic tests which apply to them are not fully available, and so diagnoses could be inaccurate and treatments poorly targeted. Within the portfolio and hierarchy of cardiovascular diagnostic testing, Cardiac Magnetic Resonance (CMR) is a crucial diagnostic imaging test that redefines diagnosis and enables targeted therapies, but is expensive with inadequate training and poor availability in LMICs countries. I demonstrated that CMR could be made fast, easy, and cheap – sufficient for delivery in five LMICs countries in three continents. To achieve this, I developed an abbreviated CMR protocol, focused on the core of CMR - volumes, function, and scar imaging (with selected additions like iron quantification), and by embedding the technical quality protocol within clinical care, training, and mentoring, so it proved to have diagnostic utility and change management, as well being a self-sustaining and essential service. I also used CMR as a research method in LMICs specifically to complement research in areas of a specific need to those countries, exploiting opportunities that were previously unavailable, with one chapter dedicated to evaluating early cardiovascular involvement in treated and non-treated people living with HIV in Peru, and a second chapter of the potential utility of CMR for screening cardiotoxicity and its comparison in precision with other cardiac imaging modalities in the UK, potentially extending the role of rapid CMR in HICs. Unlike traditional PhDs in medicine, my research involved technology adaptation, transfer, and collaboration. The project was multi-layered with political, social, educational, training, and partnership aspects, along with more traditional aspects such as clinical effectiveness and cost-effectiveness analysis. I showed the use of advanced cardiac imaging in LMICs by breaking down barriers, demonstrating that Rapid CMR can be possible in new clinical environments where much need exists

Noninvasive rapid cardiac magnetic resonance for the assessment of cardiomyopathies in low-middle income countries

INTRODUCTION: Cardiac Magnetic Resonance (CMR) is a crucial diagnostic imaging test that redefines diagnosis and enables targeted therapies, but the access to CMR is limited in low-middle Income Countries (LMICs) even though cardiovascular disease is an emergent primary cause of mortality in LMICs. New abbreviated CMR protocols can be less expensive, faster, whilst maintaining accuracy, potentially leading to a higher utilization in LMICs. AREAS COVERED: This article will review cardiovascular disease in LMICs and the current role of CMR in cardiac diagnosis and enable targeted therapy, discussing the main obstacles to prevent the adoption of CMR in LMICs. We will then review the potential utility of abbreviated, cost-effective CMR protocols to improve cardiac diagnosis and care, the clinical indications of the exam, current evidence and future directions. EXPERT OPINION: Rapid CMR protocols, provided that they are utilized in potentially high yield cases, could reduce cost and increase effectiveness. The adoption of these protocols, their integration into care pathways, and prioritizing key treatable diagnoses can potentially improve patient care. Several LMIC countries are now pioneering these approaches and the application of rapid CMR protocols appears to have a bright future if delivered effectively