Hybrid Gamma Camera Imaging: Translation from Bench to Bedside A thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy by Aik Hao Ng MMed.Phys. Radiological Sciences, Division of Clinical Neuroscience, School of Medicine September 2017 Declaration I, Aik Hao Ng declare that the work presented in this thesis is my own original work based on the research undertaken during my PhD study period unless otherwise referenced or acknowledged. ii “Life is like riding a bicycle. To keep your balance, you must keep moving.” - Albert Einstein Abstract There is increasing interest in the use of small field of view (SFOV) portable gamma cameras in medical imaging. A novel hybrid optical-gamma camera (HGC) has been developed through a collaboration between the Universities of Leicester and Nottingham. This system offers high resolution gamma and optical imaging and shows potential for use at the patient bedside, or in the operating theatre. The aim of this thesis was to translate the HGC technology from in vitro laboratory studies to clinical use in human subjects. Pilot studies were undertaken with the HGC as part of this thesis. Furthermore, efforts have been made to transform the HGC technologies into a new medical device, known as Nebuleye. Initial physical evaluation of the pre-production prototype camera was carried out as part of the device developmental process, highlighting some aspects of the design that require further modification. A complete and rigorous testing scheme to assess the pre-production prototype camera has been developed and successfully implemented. The newly introduced tests enabled the system uniformity, system sensitivity, detector head shielding leakage, optical-gamma image alignment and optical image quality of the hybrid camera to be assessed objectively. This harmonised testing scheme allows characterisation and direct comparison of SFOV gamma cameras. In vitro and in vivo preclinical imaging was undertaken to examine the performance of the SFOV gamma cameras for experimental animal studies. The results of animal study have shown for the first time the feasibility and performance of these SFOV gamma cameras for imaging mice injected with a newly developed 111In labelled hybrid tracer. Further investigations are needed to improve the system resolution and prepare the camera system for combined gamma-near infrared fluorescence imaging in future. A systematic in vitro laboratory assessment method has been established to examine the imaging performance of the SFOV gamma camera in radioguided sentinel lymph node biopsy (SLNB) and radioactive seed localisation procedures for breast cancer surgery. Further preparatory work was undertaken to carry out a pilot clinical trial of iv Abstract| v the use of the pre-production prototype camera in sentinel node localisation procedures during breast cancer surgery. The clinical study protocol and routine quality control procedures have been established and are suitable for future use. Baseline data on the camera performance assessed using the routine quality control scheme have been obtained. Finally, the capabilities of the SFOV gamma camera were assessed. This has provided baseline data on user feedback and the imaging consequences on operator motion effects, as well as examining the detectability of a range of radionuclides, including 99mTc, 111In, 123I, 125I and 75Se. The first clinical results of the use of the HGC in clinical hybrid optical-gamma imaging in patients administered with 99mTc and 123I labelled radiopharmaceuticals have been reported. This clinical study has demonstrated the feasibility and capability of HGC in various clinical applications performed at the patient bedside, which included patients undergoing bone, thyroid, lacrimal drainage and lymphatic imaging as well as DaTscan studies. In conclusion, the work in this thesis has demonstrated the successful translation of an SFOV hybrid gamma camera for clinical use. This system would be ideally suited for use in the operating theatre for radioguided procedures such as sentinel node detection and tumour localisation. This system also offers potential for use with the new generation of hybrid fluorescent-radionuclide tracers currently under development. Acknowledgements In autumn 2013, I left my comfort zone, full with family and friends love, and the nice hot weather that I am familiar with, to a four seasons country to embark on my PhD journey. From that time point, I knew it would be a tough doctoral world, from settling my family and myself in the new environment, to the discovery of sciences in my study field. I consider myself very fortunate indeed to have the opportunity to meet so many wonderful people and have had an enriched life experience in the United Kingdom. There are many organisations or people whom I would like to express my sincere gratitude for their help and support along my PhD journey. Firstly, I would like to thank my three supervisors, Professor Alan C. Perkins, Professor John E. Lees and Professor Paul S. Morgan for sharing their knowledge and experiences. Without their advice and guidance, this thesis would not be possible. I am fortunate to have had the opportunity to work with Professor Alan C. Perkins, an experienced leader in the world of nuclear medicine. He has been a wonderful mentor, supervisor and friend. His broad knowledge and experience in medical physics as well as his patience in imparting wisdom to me are inspirational. Thanks for giving me the opportunities to extend my professional horizon in regional research collaboration. I also express my heartfelt gratitude to him for the time and effort he had to spend to discuss, proofread and correct my thesis. I would like to thank Professor John E. Lees for his generosity and kindness in sharing his vast knowledge and expertise in the Hybrid Gamma Camera (HGC) technology and loaning me the camera and other necessary equipment for my experimental work. His enormous efforts in innovation and strong leadership has led the research team to develop a better camera for patient benefit. I would also like to thank Professor Paul S. Morgan for his advice and help with the image processing work and the use of MOCO software used in the operator motion effect study. He is a good friend and supervisor who provides continuous support and guidance whenever I needed during my study. Secondly, I would like to thank the colleagues from Space Research Centre, University of Leicester that worked together on this camera development and clinical trial, who vi Acknowledgement| vii were willing to share their knowledge and experience with me. They included Sarah Bugby, Bahadar Bhatia, Mohammed Alqahtani, Layal Jambi, Numan Dawood and William McKnight. My heartfelt thanks to Dr. Bugby for sharing her expertise in HGC technology, answering all my questions patiently, performing the preclinical radionuclide-NIRF imaging at Leiden University Medical Centre (LUMC) alongside me and proofreading my thesis. Special thanks to Layal Lambi who provided raw image data for HGC intrinsic sensitivity, uniformity and spatial resolution tests. I would also like to thank Mohammed Alqahtani for bringing the camera to Queen’s Medical Centre for experimental use. The School of Medicine, University of Nottingham and Clinical Engineering and Medical Physics Department, Nottingham University Hospitals (NUH) NHS Trust have provided conducive research environment for this work. Special thanks to Elaine Blackshaw for her help and for providing timely advice on the clinical trial design and application, as well as recruiting patients. I would like to thank Jeni Luckett for assisting me to acquire preclinical SPECT images. I am grateful to Helen Betts, Aristeidis Chiotellis, Ramla Awais, Helen Parker and Lina Yonekura for their help and friendship. The clinical trial undertaken in this thesis was led by Professor Alan C. Perkins and funded by Science Technology Facilities Council through CLASP Award. I would like to thank colleagues in the nuclear medicine clinic, including but not limited to Simon Lawes, Kevin Blackband, Mandy Blaze, Peter Hay, Clare Jacobs, Evelyn Shin and David Pye for their support and generosity in preparing radionuclides for the experimental work. Special thanks to Simon Lawes for his ever ready help whenever I looked for him especially in helping me to acquire SPECT-CT images. I would also like to acknowledge Mr. Kwok Leung Cheung for his expertise and invaluable information in guiding me to set up the new clinical trial for the use of the camera in SLNB, and to familiarise me with the surgical procedure. I am also grateful to the technical support provided by Clinical Engineering team. Thanks to David Clay and Micheal Jones for fabricating the bespoke phantoms that were needed in my experiment and providing the technical drawings. Special thanks to Beth Beeson for carrying out the medical device assessments in order to obtain approval Acknowledgement| viii for the HGC to be used in the clinical trial at NUH NHS Trust. I would also like to thank Jennifer Poveda, Mark Westby, Nick Gibson, Graham Love and Elizabeth Powell for their technical support. During my short trip to LUMC, I had the opportunity to work with Marieke Stammes, Hein Handgraaf and Pauline. Thanks for their hospitality and providing necessary research facilities for the preclinical imaging, including the mice with tumour model and the probe. I am grateful to Gamma Technologies Limited and Xstrahl Limited (Surrey, UK) for lending me the pre-production prototype Nebuleye, to LabLogic Systems Ltd. (Sheffield, UK) for allowing me to use CrystalCam gamma camera and to GE Healthcare (Arlington Heights, IL, USA) for providing the 125I seeds. I would like to express my gratitude and appreciation to the Ministry of Health and the Government of Malaysia for providing my PhD scholarship. Thanks to my colleagues in the MOH for your support and friendship. To my fellow office mates and friends: Thanks to everyone for sharing your laughter and support, in particular Dewen, Will, Stefan and Tom. Last but not least, I am extremely thankful to my family for their endless encouragement, care, trust and love.