SUBJECT-SPECIFIC 4D ULTRASOUND LIVER MODEL AND DYNAMIC PHANTOM FOR ROBOTIC-ASSISTED LIVER BIOPSY STUDY

Ph.DDOCTOR OF PHILOSOPH

Development of an image guidance system for laparoscopic liver surgery and evaluation of optical and computer vision techniques for the assessment of liver tissue

Introduction: Liver resection is increasingly being carried out via the laparoscopic approach (keyhole surgery) because there is mounting evidence that it benefits patients by reducing pain and length of hospitalisation. There are however ongoing concerns about oncological radicality (i.e. ability to completely remove cancer) and an inability to control massive haemorrhage. These issues can partially be attributed to a loss of sensation such as depth perception, tactile feedback and a reduced field of view. Utilisation of optical imaging and computer vision may be able to compensate for some of the lost sensory input because these modalities can facilitate visualisation of liver tissue and structural anatomy. Their use in laparoscopy is attractive because it is easy to adapt or integrate with existing technology. The aim of this thesis is to explore to what extent this technology can aid in the detection of normal and abnormal liver tissue and structures. / Methods: The current state of the art for optical imaging and computer vision in laparoscopic liver surgery is assessed in a systematic review. Evaluation of confocal laser endomicroscopy is carried out on a murine and porcine model of liver disease. Multispectral near infrared imaging is evaluated on ex-vivo liver specimen. Video magnification is assessed on a mechanical flow phantom and a porcine model of liver disease. The latter model was also employed to develop a computer vision based image guidance system for laparoscopic liver surgery. This image guidance system is further evaluated in a clinical feasibility study. Where appropriate, experimental findings are substantiated with statistical analysis. / Results: Use of confocal laser endomicroscopy enabled discrimination between cancer and normal liver tissue with a sub-millimetre precision. This technology also made it possible to verify the adequacy of thermal liver ablation. Multispectral imaging, at specific wavelengths was shown to have the potential to highlight the presence of colorectal and hepatocellular cancer. An image reprocessing algorithm is proposed to simplify visual interpretation of the resulting images. It is shown that video magnification can determine the presence of pulsatile motion but that it cannot reliably determine the extent of motion. Development and performance metrics of an image guidance system for laparoscopic liver surgery are outlined. The system was found to improve intraoperative orientation more development work is however required to enable reliable prediction of oncological margins. / Discussion: The results in this thesis indicate that confocal laser endomicroscopy and image guidance systems have reached a development stage where their intraoperative use may benefit surgeons by visualising features of liver anatomy and tissue characteristics. Video magnification and multispectral imaging require more development and suggestions are made to direct this work. It is also highlighted that it is crucial to standardise assessment methods for these technologies which will allow a more direct comparison between the outcomes of different groups. Limited imaging depth is a major restriction of these technologies but this may be overcome by combining them with preoperatively obtained imaging data. Just like laparoscopy, optical imaging and computer vision use functions of light, a shared characteristic that makes their combined use complementary

Translational Research of Audiovisual Biofeedback: An investigation of respiratory-guidance in lung and liver cancer patient radiation therapy

Through the act of breathing, thoracic and abdominal anatomy is in constant motion and is typically irregular. This irregular motion can exacerbate errors in radiation therapy, breathing guidance interventions operate to minimise these errors. However, much of the breathing guidance investigations have not directly quantified the impact of regular breathing on radiation therapy accuracy. The first aim of this thesis was to critically appraise the literature in terms of the use of breathing guidance interventions via systematic review. This review found that 21 of the 27 identified studies yielded significant improvements from the use of breathing guidance. None of the studies were randomised and no studies quantified the impact on 4DCT image quality. The second aim of this thesis was to quantify the impact of audiovisual biofeedback breathing guidance on 4DCT. This study utilised data from an MRI study to program the motion of a digital phantom prior to then simulating 4DCT imaging. Audiovisual biofeedback demonstrated to significantly improved 4DCT image quality over free breathing. The third aim of this thesis was to assess the impact of audiovisual biofeedback on liver cancer patient breathing over a course of stereotactic body radiation therapy (SBRT). The findings of this study demonstrated the effectiveness of audiovisual biofeedback in producing consistent interfraction respiratory motion over a course of SBRT. The fourth aim of this thesis was to design and implement a phase II clinical trial investigating the use and impact of audiovisual biofeedback in lung cancer radiation therapy. The findings of a retrospective analysis were utilised to design and determine the statistics of the most comprehensive breathing guidance study to date: a randomised, stratified, multi-site, phase II clinical trial.. The fifth aim of this thesis was to explore the next stages of audiovisual biofeedback in terms of translating evidence into broader clinical use through commercialisation. This aim was achieved by investigating the the product-market fit of the audiovisual biofeedback technology. The culmination of these findings demonstrates the clinical benefit of the audiovisual biofeedback respiratory guidance system and the possibility to make breathing guidance systems more widely available to patients

Contrôle en temps réel de la précision du suivi indirect de tumeurs mobiles en radiothérapie

Le but de la radiothérapie est d’irradier les cellules cancéreuses tout en préservant au maximum les tissus sains environnants. Or, dans le cas du cancer du poumon, la respiration du patient engendre des mouvements de la tumeur pendant le traitement. Une solution possible est de repositionner continuellement le faisceau d’irradiation sur la cible tumorale en mouvement. L’e cacité et la sûreté de cette approche reposent sur la localisation précise en temps réel de la tumeur. Le suivi indirect consiste à inférer la position de la cible tumorale à partir de l’observation d’un signal substitut, visible en continu sans nécessiter de rayonnement ionisant. Un modèle de corrélation spatial doit donc être établi. Par ailleurs, pour compenser la latence du système, l’algorithme de suivi doit pouvoir également anticiper la position future de la cible. Parce que la respiration du patient varie dans le temps, les modèles de prédiction et de corrélation peuvent devenir imprécis. La prédiction de la position de la tumeur devrait alors idéalement être complétée par l’estimation des incertitudes associées aux prédictions. Dans la pratique clinique actuelle, ces incertitudes de positionnement en temps réel ne sont pas explicitement prédites. Cette thèse de doctorat s’intéresse au contrôle en temps réel de la précision du suivi indirect de tumeurs mobiles en radiothérapie. Dans un premier temps, une méthode bayésienne pour le suivi indirect en radiothérapie est développée. Cette approche, basée sur le filtre de Kalman, permet de prédire non seulement la position future de la tumeur à partir d’un signal substitut, mais aussi les incertitudes associées. Ce travail o re une première preuve de concept, et montre également le potentiel du foie comme substitut interne, qui apparait plus robuste et fiable que les marqueurs externes communément utilisés dans la pratique clinique. Dans un deuxième temps, une adaptation de la méthode est proposée afin d’améliorer sa robustesse face aux changements de respiration. Cette innovation permet de prédire des régions de confiance adaptatives, capables de détecter les erreurs de prédiction élevées, en se basant exclusivement sur l’observation du signal substitut. Les résultats révèlent qu’à sensibilité élevée (90%), une spécificité d’environ 50% est obtenue. Un processus de validation innovant basé sur ces régions de confiance adaptatives est ensuite évalué et comparé au processus conventionnel qui consiste en des mesures de la cible à intervalles de temps fixes et prédéterminés. Une version adaptative de la méthode bayésienne est donc développée afin d’intégrer des mesures occasionnelles de la position de la cible. Les résultats confirment que les incertitudes prédites par la méthode bayésienne permettent de détecter les erreurs de prédictions élevées, et démontrent que le processus de validation basé sur ces incertitudes a le potentiel d’être plus e cace que les validations régulières. Ces approches bayésiennes sont validées sur des séquences respiratoires de volontaires, acquises par imagerie par résonance magnétique (IRM) dynamique et interpolées à haute fréquence. Afin de compléter l’évaluation de la méthode bayésienne pour le suivi indirect, une validation expérimentale préliminaire est conduite sur des données cliniques de patients atteints de cancer du poumon. Les travaux de ce projet doctoral promettent une amélioration du contrôle en temps réel de la précision des prédictions lors des traitements de radiothérapie. Finalement, puisque l’imagerie ultrasonore pourrait être employée pour visualiser les substituts internes, une étude préliminaire sur l’évaluation automatique de la qualité des images ultrasonores est présentée. Ces résultats pourront être utilisés ultérieurement pour le suivi indirect en radiothérapie en vue d’optimiser les acquisitions ultrasonores pendant les traitements et faciliter l’extraction automatique du mouvement du substitut.The goal of radiotherapy is to irradiate cancer cells while maintaining a low dose of radiation to the surrounding healthy tissue. In the case of lung cancer, the patient’s breathing causes the tumor to move during treatment. One possible solution is to continuously reposition the irradiation beam on the moving target. The e ectiveness and safety of this approach rely on accurate real-time localization of the tumor. Indirect strategies derive the target positions from a correlation model with a surrogate signal, which is continuously monitored without the need for radiation-based imaging. In addition, to compensate for system latency, the tracking algorithm must also be able to anticipate the future position of the target. Because the patient’s breathing varies over time, prediction and correlation models can become inaccurate. Ideally, the prediction of the tumor location would also include an estimation of the uncertainty associated with the prediction. However, in current clinical practice, these real-time positioning uncertainties are not explicitly predicted. This doctoral thesis focuses on real-time control of the accuracy of indirect tracking of mobile tumors in radiotherapy. First, a Bayesian method is developed. This approach, based on Kalman filter theory, allows predicting both future target motion in real-time from a surrogate signal and associated uncertainty. This work o ers a first proof of concept, and also shows the potential of the liver as an internal substitute as it appears more robust and reliable than the external markers commonly used in clinical practice. Second, an adaptation of the method is proposed to improve its robustness against changes in breathing. This innovation enables the prediction of adaptive confidence regions that can be used to detect significant prediction errors, based exclusively on the observation of the surrogate signal. The results show that at high sensitivity (90%), a specificity of about 50% is obtained. A new validation process based on these adaptive confidence regions is then evaluated and compared to the conventional validation process (i.e., target measurements at fixed and predetermined time intervals). An adaptive version of the Bayesian method is therefore developed to valuably incorporate occasional measurements of the target position. The results confirm that the uncertainties predicted by the Bayesian method can detect high prediction errors, and demonstrate that the validation process based on these uncertainties has the potential to be more e cient and e ective than regular validations. For these studies, the proposed Bayesian methods are validated on respiratory sequences of volunteers, acquired by dynamic MRI and interpolated at high frequency. In order to complete the evaluation of the Bayesian method for indirect tracking, experimental validation is conducted on clinical data of patients with lung cancer. The work of this doctoral project promises to improve the real-time control of the accuracy of predictions during radiotherapy treatments. Finally, since ultrasound imaging could be used to visualize internal surrogates, a preliminary study on automatic ultrasound image quality assessment is presented. These results can later be used for indirect tracking in radiotherapy to optimize ultrasound acquisitions during treatments and facilitate the automatic estimation of surrogate motion

Technologies for Biomechanically-Informed Image Guidance of Laparoscopic Liver Surgery

Laparoscopic surgery for liver resection has a number medical advantages over open surgery, but also comes with inherent technical challenges. The surgeon only has a very limited field of view through the imaging modalities routinely employed intra-operatively, laparoscopic video and ultrasound, and the pneumoperitoneum required to create the operating space and gaining access to the organ can significantly deform and displace the liver from its pre-operative configuration. This can make relating what is visible intra-operatively to the pre-operative plan and inferring the location of sub-surface anatomy a very challenging task. Image guidance systems can help overcome these challenges by updating the pre-operative plan to the situation in theatre and visualising it in relation to the position of surgical instruments. In this thesis, I present a series of contributions to a biomechanically-informed image-guidance system made during my PhD. The most recent one is work on a pipeline for the estimation of the post-insufflation configuration of the liver by means of an algorithm that uses a database of segmented training images of patient abdomens where the post-insufflation configuration of the liver is known. The pipeline comprises an algorithm for inter and intra-subject registration of liver meshes by means of non-rigid spectral point-correspondence finding. My other contributions are more fundamental and less application specific, and are all contained and made available to the public in the NiftySim open-source finite element modelling package. Two of my contributions to NiftySim are of particular interest with regards to image guidance of laparoscopic liver surgery: 1) a novel general purpose contact modelling algorithm that can be used to simulate contact interactions between, e.g., the liver and surrounding anatomy; 2) membrane and shell elements that can be used to, e.g., simulate the Glisson capsule that has been shown to significantly influence the organ’s measured stiffness

Multislice computed tomography coronary angiography

__Abstract__ Computed Tomography (CT) imaging is also known as "CAT scanning" (Computed Axia