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Background: Before making any treatment decisions for patients with non-small cell lung cancer (NSCLC), it is crucial to determine whether the cancer has spread to the mediastinal lymph nodes (LNs). The preferred method for mediastinal staging is Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA). However, EBUS-TBNA has been reported to generate inconclusive results as much as 40% of the time. Since this jeopardizes good patient care, there is near-universal consensus on the need to develop and study a novel method for LN staging. Recent research has shown that AI and deep learning are used to accurately interpret images with comparisons to clinicians in radiology, pathology, and cardiology. Additionally, EBUS-Elastography is a novel modality which could be used as an adjunct to EBUS-TBNA for LN staging. This technology uses impedance ultrasonography to measure tissue stiffness. Methods: There are three parts to this thesis. The first part involved the training, validating, and testing NeuralSeg, a deep neural network, to predict LN malignancy based on B-mode EBUS-TBNA images. The second part of this thesis involves EBUS-Elastography, defining the blue colour threshold and the optimal SAR cut-off value based on the blue threshold that most accurately distinguished benign and malignant LN. Finally, this thesis's third part involves validating part II's findings. Results: Part I resulted in an overall accuracy of 80.63% (76.93% to 83.97%), a sensitivity of 43.23% (35.30% to 51.41%), a specificity of 96.91% (94.54% to 98.45%), a positive predictive value of 85.90% (76.81% to 91.80%), a negative predictive value of 79.68% (77.34% to 81.83%), and an AUC of 0.701 (0.646 to 0.755). Part II Level 60 was chosen as the blue threshold with an AUC of 0.89 (95% CI: 0.77-1.00), and the optimal SAR cut off was found to be 0.4959 with a sensitivity of 92.30% (95% CI: 62.10% to 99.60%) and a specificity of 76.50% (95% CI: 49.80% to 92.20%). Using the blue threshold and SAR cut-off, the results of part III resulted in an overall accuracy of 70.59% (95% (CI) 63.50% to 77.01%), the sensitivity of 43.04% (CI: 31.94% to 54.67%), and a specificity of 90.74% (CI: 83.63% to 95.47%). Conclusion: It was observed that both AI and AI-powered EBUS-Elastography achieved high specificities on larger sample sizes, indicative that these methods may be helpful in identifying LN malignancy. However, due to the novelty of these technologies, more extensive multi-centre studies must be conducted before these processes can be standardized. / Thesis / Master of Health Sciences (MSc) / Non-Small Cell Lung Cancer (NSCLC) treatment decisions are made using vital information by performing biopsies to collect tissue from the lymph nodes near the lungs. The current method is called Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA), which involves a scope with a fine needle attached to it. This scope is led down the airway and guided by ultrasound to obtain the tissue needed to determine whether the lymph nodes have cancerous tissue. If the lymph nodes contain cancerous tissue, the patient may need chemotherapy; however, lung surgery may be the best treatment option if they do not. Many factors impact how successfully these tissue samples can be obtained, such as the skill and experience of the surgeon. These factors often lead to inconclusive results, making it difficult to make correct treatment decisions. Novel technologies such as Artificial Intelligence and Elastography are being used to diagnose lung cancer by interpreting images and providing information on tissue stiffness. We trained an Artificial Intelligence program to predict malignancy based on EBUS-TBNA images. Additionally, we trained the AI program to analyze Elastography images to aid us in understanding the relationship between the colour pattern of the elastography images and cancerous tissue. This thesis assesses how these novel technologies contribute to lung cancer diagnosis.

<p>This thesis is composed of six chapters. First MRE is briefly introduced together with some relevant literature in Chapter one. The second chapter is about the principles and theory of magnetic resonance imaging, with the MRE theory, software and hardware addressed in Chapter 3. Chapters 4 and 5 describe the hardware design, software programming, experimental setup and elasticity reconstruction. Chapter 6 is a general discussion, introducing challenges and future directions.</p> <p>A vibration actuator and coil was designed and constructed, then combined with the necessary hardware required to induce the motion in the actuator. A Gradient Echo pulse sequence was modified using the Siemens IDEA environment for MRE application. A phantom was made with concentrations of 1%, 2%, and 3% agar gel.</p> <p>The phantom was scanned using the MRE sequence while inducing the propagating waves. Waves were selected to have frequencies of 125 Hz and 250 Hz. Magnitude and phase images acquired at these frequencies were used to construct the elasticity map using the MRE/Wave reconstruction software. Mean Shear Modulus measured in 1% gel cylinder is 10 kPa and standard deviation (SD) is 6 kPa. Mean elasticity value measured in 3% gel is 49 kPa and SD is 9 kPa. Mean value measured in the background which is 2% gel is 28 kPa and SD is 6 kPa. The results obtained are comparable to the values calculated in literature.</p> / Master of Applied Science (MASc)

Yes / In recent years, imaging has played an increasing role in the clinical management of patients with rheumatic diseases with respect to aiding diagnosis, guiding therapy and monitoring disease progression. These roles have been underpinned by research which has enhanced our understanding of disease pathogenesis and pathophysiology of rheumatology conditions, in addition to their key role in outcome measurement in clinical trials. However, compared to joints, imaging research of muscles is less established, despite the fact that muscle symptoms are very common and debilitating in many rheumatic diseases. Recently, it has been shown that even though patients with rheumatoid arthritis may achieve clinical remission, defined by asymptomatic joints, many remain affected by lingering constitutional systemic symptoms like fatigue, tiredness, weakness and myalgia, which may be attributed to changes in the muscles. Recent improvements in imaging technology, coupled with an increasing clinical interest, has started to ignite new interest in the area. This perspective discusses the rationale for using imaging, particularly ultrasound and MRI, for investigating muscle pathology involved in common inflammatory rheumatic diseases. The muscles associated with rheumatic diseases can be affected in many ways, including myositis—an inflammatory muscle condition, and myopathy secondary to medications, such as glucocorticoids. In addition to non-invasive visual assessment of muscles in these conditions, novel imaging techniques like shear wave elastography and quantitative MRI can provide further useful information regarding the physiological and biomechanical status of the muscle. / This research is funded by the NIHR infrastructure at Leeds.

Heart disease remains the leading cause of death globally, and prevalence has nearly doubled over the past three decades. It is estimated that up to 90% of cardiovascular events are preventable, but early detection and treatment is crucial. In this dissertation, we report on the optimization of the ultrasound-based cardiac strain imaging technique known as Myocardial Elastography (ME), a method for the detection of the most common and most lethal forms of heart disease: Coronary Artery Disease (CAD) which affects the major coronary arteries, and Coronary Microvascular Disease (CMD) which affects smaller coronary vessels. CAD has historically been the primary focus of clinical cardiac imaging, whereas CMD has been under-diagnosed due to a lack of awareness and challenges associated with imaging at the microvascular level. Ultrasound-based cardiac strain imaging has been shown capable of detecting functional changes due to CAD and may be effective in CMD detection, although the latter has not yet been sufficiently investigated. However, the diagnostic accuracy of strain imaging is reduced by noise from transcostal imaging, known as clutter, and by the limited lateral resolution of high framerate ultrasound. These factors preclude accurate strain imaging in up to 30% of patients. Myocardial elastography is a precise high framerate strain imaging technique that analyzes radiofrequency (RF) signals to quantify myocardial deformation. We hypothesize that ME can effectively image and diagnose the functional effects of CMD and CAD, and that novel beamforming and clutter-filtering techniques can improve ME imaging and strain estimation quality, thereby increasing diagnostic accuracy. To improve disease detection, Stress ME (S-ME) was proposed as a method to compare strain measurements at rest to strain during induced cardiac stress. A novel strain difference (Δ𝜺) metric was presented and investigated in a canine model of induced acute ischemia, as well as in a human CAD patient study with validation by myocardial perfusion imaging. In the canine model, flow-limiting stenosis was induced by partial ligation in N=2 canines, and stenosis was found to significantly reduce Δ𝜺 in the affected myocardial regions. In the clinical study, radial and circumferential ME strain and radial Δ𝜺 was measured in N=49 myocardial segments from 8 patients suspected to have ischemia or infarction due to CAD. The median Δ?, radial strain, and circumferential strain magnitudes were lowest in infarcted regions and highest in regions with normal perfusion, while measurements in ischemic regions fell in between. ROC analysis of radial strain metrics revealed that Δ𝜺 had the highest AUC for detecting ischemia (AUC=0.788 p<0.01) and infarction (AUC=0.792, p<0.05), followed by radial strain during stress (ischemia AUC=0.774 p<0.05, infarct AUC=0.758 p<0.05) while the AUC was lowest when considering only the radial strain at rest (ischemia AUC=0.52 p>0.05, infarct AUC=0.58 p>0.05). The results thus indicate that S-ME may improve detection of mild CAD cases that are functionally asymptomatic at rest. Despite these promising findings, accurate strain imaging remains hindered by clutter noise and poor image quality. Two complementary techniques were thus developed to improve image quality and strain estimation in high frame rate cardiac strain imaging; a novel Sliding Window implementation of the Minimum Variance beamformer (SWMV) was proposed to enhance speckle quality, while a spatiotemporal singular value decomposition filter (SVD) was developed to increase tissue visibility and contrast by suppressing static clutter signals using automated cutoff selection. SWMV and SVD were shown to effectively improve image quality in simulation studies and phantom imaging experiments. In vivo performance evaluation consisted of applying SWMV beamforming and SVD filtering techniques to a dataset of N=70 strain images from 13 patients suspected to have CAD. CCTA imaging was used for validation of strain estimation. Tracking was improved in 92% of cases with a median improvement of 15% in displacement estimation accuracy as evaluated by an intersection-over-union (IoU) metric. The proposed techniques also improve agreement with CCTA results; ROC analysis shows improved AUC with SWMV+SVD compared to DAS when comparing healthy regions to those with any degree of stenosis (AUC 0.64 vs 0.56) as well as when comparing healthy to severely stenosed regions (AUC 0.69 vs 0.60). The observed results point to significant improvement in strain estimation reliability due to SWMV beamforming combined with SVD processing. The final aim and the overarching goal of this work is a culmination of the previous sections for a clinical evaluation of ME as a diagnostic tool for CAD and CMD. In this clinical study, the enhanced ME technique utilizing SWMV and SVD filtering was applied to a cohort of N=201 patients with suspected coronary disease. All patients underwent invasive angiography or noninvasive cardiac imaging in the form of coronary computed tomography or nuclear stress testing. In addition, demographic information and patient clinical history were collected and accounted for in a multivariate statistical analysis. A K-nearest-neighbor (KNN) classifier was trained to distinguish between healthy and stenosed myocardial regions, and achieved an AUC of 0.91, with sensitivity of 86% and a specificity of 85% after training with 10-fold cross validation. CMD was also shown to significantly reduce regional strain measurements. This retrospective study identified the clinical factors which impact strain, and assessed the potential advantages of incorporating ME imaging to the existing clinical imaging pipeline for CAD and CMD diagnosis.

Die vorliegende medizinische Dissertation untersucht nicht-invasive bildgebende Verfahren wie die konventionelle Sonographie, die Acoustic radiation force impulse (ARFI)-Elastographie sowie die Transiente Elastographie (TE) zur Detektion von Komplikationen in der Frühphase nach allogener Stammzelltransplantation. Dem kurativen Therapieansatz der Stammzelltransplantation steht ein hohes Komplikationspotential gegenüber. Besonders hepatobiliär treten Graft-versus-host Erkrankungen (GvHD) sowie Gefäßkomplikationen (VOD) auf. Der bisherige diagnostische Goldstandard, die Leberbiopsie, ist als invasives Verfahren mit einer hohen Intra- und Inter-Untersucher-Variabilität sowie der geringen Repräsentativität als Screeningmethode ungeeignet. Die Elastographieverfahren ARFI und TE als nicht-invasive Alternativen ermitteln die Lebergewebesteifigkeit als Surrogatparameter fibrotischer Veränderungen und wurden bereits in zahlreichen Studien als geeignete Diagnoseverfahren für Leberfibrose und -zirrhose unterschiedlicher Ätiologie definiert. Ziel dieser prospektiven Pilotstudie war die Evaluation der genannten Methoden zur Detektion von Frühkomplikationen nach allogener Stammzelltransplantation. Die Ergebnisse der Studie zeigen, dass sowohl die konventionelle Sonographie als auch die Transiente Elastographie pathologische Organveränderungen vor allem des hepatobiliären Systems detektieren können. Allerdings erscheinen diese Veränderungen unspezifisch. Es bestehen keine signifikanten Unterschiede zwischen Patienten mit und ohne Komplikationen. Anders bei der ARFI-Elastographie. Hier zeigten die Messwerte im linken Leberlappen signifikant höhere Werte bei Patienten mit Komplikationen. Zusammenfassend ist die ARFI-Elastographie zur Prädiktion möglicher Komplikationen nach allogener Stammzelltransplantation geeignet, sollte allerdings mit anderen diagnostischen Verfahren ergänzt werden.

Notre objectif était de rechercher une méthode d’évaluation musculaire afin de déterminer des facteurs de non réponse tissulaire à une injection de toxine botulique (TB) dans un muscle spastique, chez l’adulte post AVC et chez l’enfant paralysé cérébral (PC). Une étude de reproductibilité et 3 revues systématiques de la littérature ont été réalisées. Les mesures échographiques de l’épaisseur et de l’angle des pennation des fibres du muscle gastrocnémien médial en 2D sont reproductibles. La mesure du module d’élasticité par Shear Wave Ultrasound Elastography délivre une information fiable sur la rigidité du muscle gastrocnémien médial spastique au repos.L’analyse du devenir du muscle post-injection rapporte que la TB participe au remodelage du muscle spastique avec une atrophie persistante, répétition d’injections dépendante.L’étude de l’impact des traitements adjuvants à la TB chez l’enfant PC montre que le renforcement musculaire intensif, y compris des muscles injectés, permet de lutter contre l’atrophie sans renforcer la spasticité. Les plâtres d’allongement permettent d’optimiser le fonctionnement articulaire mais les preuves sur la diminution de la raideur musculaire restent faibles. Dans la description des facteurs pronostics d’efficacité, plus de la moitié des patients identifiés comme secondairement non-répondeurs à la TB dans la spasticité des membres ne sont pas immunisés contre la TB. Les anticorps neutralisants ne sont donc pas la principale cause de non-réponse secondaire. Une évaluation de la qualité musculaire échographique comme facteur pronostic de réponse à la TB et pour mesurer l’impact des traitements adjuvants devrait être réalisée régulièrement afin de déterminer à quel moment ces traitements ne sont plus favorables au système musculaire. / The aim was to investigate a muscle evaluation method to determine tissue factors leading to non-responsiveness to an injection of botulinum toxin (BTX) into a spastic muscle in adult post stroke and children with cerebral palsy (CP). A reproducibility study and 3 systematic literature reviews were carried out. 2D ultrasound measurements of thickness and pennation angle of medialis gastrocnemius muscle fibers are reproducible. Measurement of the modulus of elasticity by shear wave ultrasound elastography provides a reliable information about the rigidity of the spastic medial gastrocnemius muscle at rest.Analysis of the post-injection muscle fate found that BTX participates in the remodeling of the spastic muscle with persistent atrophy that is dependent on the repetition of the injections.Analysis of the impact of BTX adjuvant therapies in CP children showed that intensive muscle strengthening, including of the injected muscles, may help combat atrophy without increasing spasticity. Stretching casts are used to optimize joint function, but there is little evidence for a reduction in muscle stiffness. In the description of prognostic efficacy factors, more than half of patients identified as secondariy non-responders to BTX in limb spasticity tests were not immunized against BTX. Neutralizing antibodies were therefore not the main cause for secondary non-responsiveness. An ultrasound evaluation of muscle quality as a prognostic factor for BTX response and to measure the impact of adjuvant treatments must be regularly performed to determine when these treatments are no longer favourable for the muscle system.

Le dépistage et le diagnostic de l’insuffisance placentaire (IP), qu’il s’agisse du retard de croissance intra-utérin (RCIU) ou de la prééclampsie (PE), sont des enjeux majeurs de santé publique. En pratique clinique, les propriétés mécaniques du placenta ne sont pas explorées, pourtant des modifications de son architecture tissulaire pourraient engendrer des variations d’élasticité. Parmi les méthodes d’élastographie ultrasonore (US), l’élastographie transitoire paraît adaptée pour une telle application. Cette technique consiste à calculer la vitesse de l’onde de cisaillement (Cs) générée par une vibration externe se propageant dans le milieu considéré. Les valeurs d’élasticité obtenues à partir des méthodes US actuelles ne sont calculées qu’à une fréquence unique. Une modification structurelle du tissu pouvant correspondre à une loi de puissance particulière de la dispersion fréquentielle de Cs, nous avons évalué l’intérêt d’une approche multifréquentielle pour distinguer l’élasticité des placentas normaux et celle de placentas présentant des signes d’IP au troisième trimestre de la grossesse. Nous avons développé un dispositif préliminaire en onde plane (pour l’exploration ex vivo) permettant de valider le principe de la méthode proposée, puis un dispositif d’élastographie transitoire 2D (exploration ex vivo et in vivo). Les données sont ajustées au moyen d’un modèle rhéologique fractionnaire dans lequel le comportement en fréquence est modélisé par une loi de puissance (exposant n du modèle). Nous avons montré que les placentas RCIU présentent des valeurs de Cs et n inférieures à celles des placentas normaux ou des PE. Cette diminution de n pourrait s’expliquer par les lésions anatomopathologiques du RCIU et la diminution de Cs est cohérente avec l’étude d’un modèle murin de RCIU par ligature utérine. Enfin, l’analyse de la dispersion fréquentielle est faisable chez la femme enceinte. La valeur ajoutée de la méthode développée devrait désormais être testée lors d’une large étude clinique. / Screening and diagnosis of placental insufficiency (PI), whether intrauterine growth restriction (IUGR) or preeclampsia (PE) are major public health issues. In clinical practice, the mechanical properties of the placenta are not explored; however changes in its tissue architecture could cause variations in elasticity. Among the ultrasound (US) elastography methods, transient elastography seemed suitable for such an application. This technique consists in calculating the shear wave speed (Cs) generated by an external vibration propagating in the medium under consideration. Elasticity values obtained from current US methods are calculated at a single frequency. As a structural modification of the tissue may correspond to a particular power law of frequency dispersion of Cs, we evaluated the interest of a multifrequency approach to distinguish the elasticity of healthy placentas and that of placentas with PI signs in the third trimester of pregnancy. We have developed a preliminary plane wave device (for ex vivo exploration) to validate the principle of the proposed method, and then a 2D transient elastography device (ex vivo and in vivo exploration). The data is adjusted using a fractional rheological model where the frequency behavior is modeled by a power law (exponent n of the model). We have shown that IUGR placentas have Cs and n values lower than those of healthy placentas or PE. This decrease in the n value could be explained by histopathological lesions of IUGR. As for the decrease of Cs in cases of IUGR, this result is consistent with the study of an IUGR rat model by uterine ligation. Finally, the frequency dispersion analysis is feasible in pregnant women. The added value of this method should now be tested in a large clinical study.

Le terme élastographie désigne les techniques d'imagerie dédiées à l'étude des propriétés mécaniques des tissus biologiques in vivo. Au cours de cette thèse, nous nous sommes intéressés à deux de ces techniques. La première est l'élastographie quasi-statique par ultrasons permettant de mesurer les déformations locales induites dans un tissu sous l'action d'une contrainte globale. La seconde est l'élastographie par résonance magnétique (ERM) permettant d'accéder localement à une estimation du module de cisaillement. Pour cette dernière technique, une onde de cisaillement est générée au sein du milieu puis imagée a l'aide d'une séquence IRM spécifique. Les images d'ondes acquises permettent la reconstruction du module de cisaillement local. Dans le cadre de ces travaux, une nouvelle technique d'acquisition de l'image d'onde de cisaillement a été proposée, ainsi qu'une méthode de reconstruction du module de cisaillement basée sur l'estimation locale de fréquence par rapport de filtres. Un autre axe de recherche a consisté en l'étude de l'effet d'une précontrainte appliquée à un milieu sur son module de cisaillement mesuré par ERM. Cet effet a tout d'abord été étudié sur des milieux homogènes puis avec des milieux test hétérogènes. Dans ce dernier cas, l'utilisation de l'élastographie quasi-statique par ultrasons s'avère nécessaire pour accéder à la déformation locale du milieu. Cette dernière information a été combinée avec les informations obtenues en ERM pour extraire pour chaque région d'intérêt une courbe déformation/module de cisaillement / The term elastography refers to imaging techniques dedicated to the in vivo investigation of the mechanical properties of biological tissues. During this thesis, we focused on two elastography techniques. The first one is quasi-static ultrasound elastography, able to locally estimate tissue strain induced by a global deformation of a medium. The second one is Magnetic Resonance Elastography (MRE), able to measure the local shear modulus. In MRE, a shear wave is generated within the medium and imaged using a specific MRI sequence. The resulting wave images are then processed to estimate the local shear modulus. A new acquisition scheme of the shear wave images was proposed during this thesis. A method, based on local frequency estimation, was also developed for the estimation of the local shear modulus using the properties of a ratio of filters. Another research axis was the study of the effect of a prestrain application on the measured shear modulus. This effect was first studied with homogeneous media and then with heterogeneous test objects. In this last case, the use of quasi-static ultrasound elastography was necessary to locally access to the medium strain. This information was then combined with the information obtained using MRE to extract, for each region of interest, a strain/shear modulus curve

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