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

Ph.DDOCTOR OF PHILOSOPH

Respiratory-induced organ motion compensation for MRgHIFU

Summary: High Intensity Focused Ultrasound is an emerging non-invasive technology for the precise thermal ablation of pathological tissue deep within the body. The fitful, respiratoryinduced motion of abdominal organs, such as of the liver, renders targeting challenging. The work in hand describes methods for imaging, modelling and managing respiratoryinduced organ motion. The main objective is to enable 3D motion prediction of liver tumours for the treatment with Magnetic Resonance guided High Intensity Focused Ultrasound (MRgHIFU). To model and predict respiratory motion, the liver motion is initially observed in 3D space. Fast acquired 2D magnetic resonance images are retrospectively reconstructed to time-resolved volumes, thus called 4DMRI (3D + time). From these volumes, dense deformation fields describing the motion from time-step to time-step are extracted using an intensity-based non-rigid registration algorithm. 4DMRI sequences of 20 subjects, providing long-term recordings of the variability in liver motion under free breathing, serve as the basis for this study. Based on the obtained motion data, three main types of models were investigated and evaluated in clinically relevant scenarios. In particular, subject-specific motion models, inter-subject population-based motion models and the combination of both are compared in comprehensive studies. The analysis of the prediction experiments showed that statistical models based on Principal Component Analysis are well suited to describe the motion of a single subject as well as of a population of different and unobserved subjects. In order to enable target prediction, the respiratory state of the respective organ was tracked in near-real-time and a temporal prediction of its future position is estimated. The time span provided by the prediction is used to calculate the new target position and to readjust the treatment focus. In addition, novel methods for faster acquisition of subject-specific 3D data based on a manifold learner are presented and compared to the state-of-the art 4DMRI method. The developed methods provide motion compensation techniques for the non-invasive and radiation-free treatment of pathological tissue in moving abdominal organs for MRgHIFU. ---------- Zusammenfassung: High Intensity Focused Ultrasound ist eine aufkommende, nicht-invasive Technologie für die präzise thermische Zerstörung von pathologischem Gewebe im Körper. Die unregelmässige ateminduzierte Bewegung der Unterleibsorgane, wie z.B. im Fall der Leber, macht genaues Zielen anspruchsvoll. Die vorliegende Arbeit beschreibt Verfahren zur Bildgebung, Modellierung und zur Regelung ateminduzierter Organbewegung. Das Hauptziel besteht darin, 3D Zielvorhersagen für die Behandlung von Lebertumoren mittels Magnetic Resonance guided High Intensity Focused Ultrasound (MRgHIFU) zu ermöglichen. Um die Atembewegung modellieren und vorhersagen zu können, wird die Bewegung der Leber zuerst im dreidimensionalen Raum beobachtet. Schnell aufgenommene 2DMagnetresonanz- Bilder wurden dabei rückwirkend zu Volumen mit sowohl guter zeitlicher als auch räumlicher Auflösung, daher 4DMRI (3D + Zeit) genannt, rekonstruiert. Aus diesen Volumen werden Deformationsfelder, welche die Bewegung von Zeitschritt zu Zeitschritt beschreiben, mit einem intensitätsbasierten, nicht-starren Registrierungsalgorithmus extrahiert. 4DMRI-Sequenzen von 20 Probanden, welche Langzeitaufzeichungen von der Variabilität der Leberbewegung beinhalten, dienen als Grundlage für diese Studie. Basierend auf den gewonnenen Bewegungsdaten wurden drei Arten von Modellen in klinisch relevanten Szenarien untersucht und evaluiert. Personen-spezifische Bewegungsmodelle, populationsbasierende Bewegungsmodelle und die Kombination beider wurden in umfassenden Studien verglichen. Die Analyse der Vorhersage-Experimente zeigte, dass statistische Modelle basierend auf Hauptkomponentenanalyse gut geeignet sind, um die Bewegung einer einzelnen Person sowie einer Population von unterschiedlichen und unbeobachteten Personen zu beschreiben. Die Bewegungsvorhersage basiert auf der Abschätzung der Organposition, welche fast in Echtzeit verfolgt wird. Die durch die Vorhersage bereitgestellte Zeitspanne wird verwendet, um die neue Zielposition zu berechnen und den Behandlungsfokus auszurichten. Darüber hinaus werden neue Methoden zur schnelleren Erfassung patienten-spezifischer 3D-Daten und deren Rekonstruktion vorgestellt und mit der gängigen 4DMRI-Methode verglichen. Die entwickelten Methoden beschreiben Techniken zur nichtinvasiven und strahlungsfreien Behandlung von krankhaftem Gewebe in bewegten Unterleibsorganen mittels MRgHIFU

Clinical practice vs. state-of-the-art research and future visions:Report on the 4D treatment planning workshop for particle therapy - Edition 2018 and 2019

The 4D Treatment Planning Workshop for Particle Therapy, a workshop dedicated to the treatment of moving targets with scanned particle beams, started in 2009 and since then has been organized annually. The mission of the workshop is to create an informal ground for clinical medical physicists, medical physics researchers and medical doctors interested in the development of the 4D technology, protocols and their translation into clinical practice. The 10th and 11th editions of the workshop took place in Sapporo, Japan in 2018 and Krakow, Poland in 2019, respectively. This review report from the Sapporo and Krakow workshops is structured in two parts, according to the workshop programs. The first part comprises clinicians and physicists review of the status of 4D clinical implementations. Corresponding talks were given by speakers from five centers around the world: Maastro Clinic (The Netherlands), University Medical Center Groningen (The Netherlands), MD Anderson Cancer Center (United States), University of Pennsylvania (United States) and The Proton Beam Therapy Center of Hokkaido University Hospital (Japan). The second part is dedicated to novelties in 4D research, i.e. motion modelling, artificial intelligence and new technologies which are currently being investigated in the radiotherapy field

Intelligent image-driven motion modelling for adaptive radiotherapy

Internal anatomical motion (e.g. respiration-induced motion) confounds the precise delivery of radiation to target volumes during external beam radiotherapy. Precision is, however, critical to ensure prescribed radiation doses are delivered to the target (tumour) while surrounding healthy tissues are preserved from damage. If the motion itself can be accurately estimated, the treatment plan and/or delivery can be adapted to compensate. Current methods for motion estimation rely either on invasive implanted fiducial markers, imperfect surrogate models based, for example, on external optical measurements or breathing traces, or expensive and rare systems like in-treatment MRI. These methods have limitations such as invasiveness, imperfect modelling, or high costs, underscoring the need for more efficient and accessible approaches to accurately estimate motion during radiation treatment. This research, in contrast, aims to achieve accurate motion prediction using only relatively low-quality, but almost universally available planar X-ray imaging. This is challenging since such images have poor soft tissue contrast and provide only 2D projections through the anatomy. However, our hypothesis suggests that, with strong priors in the form of learnt models for anatomical motion and image appearance, these images can provide sufficient information for accurate 3D motion reconstruction. We initially proposed an end-to-end graph neural network (GNN) architecture aimed at learning mesh regression using a patient-specific template organ geometry and deep features extracted from kV images at arbitrary projection angles. However, this approach proved to be more time-consuming during training. As an alternative, a second framework was proposed, based on a self-attention convolutional neural network (CNN) architecture. This model focuses on learning mappings between deep semantic angle-dependent X-ray image features and the corresponding encoded deformation latent representations of deformed point clouds of the patient's organ geometry. Both frameworks underwent quantitative testing on synthetic respiratory motion scenarios and qualitative assessment on in-treatment images obtained over a full scan series for liver cancer patients. For the first framework, the overall mean prediction errors on synthetic motion test datasets were 0.16±0.13 mm, 0.18±0.19 mm, 0.22±0.34 mm, and 0.12±0.11 mm, with mean peak prediction errors of 1.39 mm, 1.99 mm, 3.29 mm, and 1.16 mm. As for the second framework, the overall mean prediction errors on synthetic motion test datasets were 0.065±0.04 mm, 0.088±0.06 mm, 0.084±0.04 mm, and 0.059±0.04 mm, with mean peak prediction errors of 0.29 mm, 0.39 mm, 0.30 mm, and 0.25 mm

Real-time intrafraction motion monitoring in external beam radiotherapy

© 2019 Institute of Physics and Engineering in Medicine. Radiotherapy (RT) aims to deliver a spatially conformal dose of radiation to tumours while maximizing the dose sparing to healthy tissues. However, the internal patient anatomy is constantly moving due to respiratory, cardiac, gastrointestinal and urinary activity. The long term goal of the RT community to 'see what we treat, as we treat' and to act on this information instantaneously has resulted in rapid technological innovation. Specialized treatment machines, such as robotic or gimbal-steered linear accelerators (linac) with in-room imaging suites, have been developed specifically for real-time treatment adaptation. Additional equipment, such as stereoscopic kilovoltage (kV) imaging, ultrasound transducers and electromagnetic transponders, has been developed for intrafraction motion monitoring on conventional linacs. Magnetic resonance imaging (MRI) has been integrated with cobalt treatment units and more recently with linacs. In addition to hardware innovation, software development has played a substantial role in the development of motion monitoring methods based on respiratory motion surrogates and planar kV or Megavoltage (MV) imaging that is available on standard equipped linacs. In this paper, we review and compare the different intrafraction motion monitoring methods proposed in the literature and demonstrated in real-time on clinical data as well as their possible future developments. We then discuss general considerations on validation and quality assurance for clinical implementation. Besides photon RT, particle therapy is increasingly used to treat moving targets. However, transferring motion monitoring technologies from linacs to particle beam lines presents substantial challenges. Lessons learned from the implementation of real-time intrafraction monitoring for photon RT will be used as a basis to discuss the implementation of these methods for particle RT

Clinical implementations of 4D pencil beam scanned particle therapy: Report on the 4D treatment planning workshop 2016 and 2017

In 2016 and 2017, the 8th and 9th 4D treatment planning workshop took place in Groningen (the Netherlands) and Vienna (Austria), respectively. This annual workshop brings together international experts to discuss research, advances in clinical implementation as well as problems and challenges in 4D treatment planning, mainly in spot scanned proton therapy. In the last two years several aspects like treatment planning, beam delivery, Monte Carlo simulations, motion modeling and monitoring, QA phantoms as well as 4D imaging were thoroughly discussed. This report provides an overview of discussed topics, recent findings and literature review from the last two years. Its main focus is to highlight translation of 4D research into clinical practice and to discuss remaining challenges and pitfalls that still need to be addressed and to be overcome

REAL-TIME 4D ULTRASOUND RECONSTRUCTION FOR IMAGE-GUIDED INTRACARDIAC INTERVENTIONS

Image-guided therapy addresses the lack of direct vision associated with minimally- invasive interventions performed on the beating heart, but requires effective intraoperative imaging. Gated 4D ultrasound reconstruction using a tracked 2D probe generates a time-series of 3D images representing the beating heart over the cardiac cycle. These images have a relatively high spatial resolution and wide field of view, and ultrasound is easily integrated into the intraoperative environment. This thesis presents a real-time 4D ultrasound reconstruction system incorporated within an augmented reality environment for surgical guidance, whose incremental visualization reduces common acquisition errors. The resulting 4D ultrasound datasets are intended for visualization or registration to preoperative images. A human factors experiment demonstrates the advantages of real-time ultrasound reconstruction, and accuracy assessments performed both with a dynamic phantom and intraoperatively reveal RMS localization errors of 2.5-2.7 mm, and 0.8 mm, respectively. Finally, clinical applicability is demonstrated by both porcine and patient imaging

Opportunities in cancer imaging: a review of oesophageal, gastric and colorectal malignancies

The incidence of gastrointestinal (GI) malignancy is increasing worldwide. In particular, there is a concerning rise in incidence of GI cancer in younger adults. Direct endoscopic visualisation of luminal tumour sites requires invasive procedures, which are associated with certain risks, but remain necessary because of limitations in current imaging techniques and the continuing need to obtain tissue for diagnosis and genetic analysis; however, management of GI cancer is increasingly reliant on non-invasive, radiological imaging to diagnose, stage, and treat these malignancies. Oesophageal, gastric, and colorectal malignancies require specialist investigation and treatment due to the complex nature of the anatomy, biology, and subsequent treatment strategies. As cancer imaging techniques develop, many opportunities to improve tumour detection, diagnostic accuracy and treatment monitoring present themselves. This review article aims to report current imaging practice, advances in various radiological modalities in relation to GI luminal tumour sites and describes opportunities for GI radiologists to improve patient outcomes

What scans we will read: imaging instrumentation trends in clinical oncology

Oncological diseases account for a significant portion of the burden on public healthcare systems with associated costs driven primarily by complex and long-lasting therapies. Through the visualization of patient-specific morphology and functional-molecular pathways, cancerous tissue can be detected and characterized non- invasively, so as to provide referring oncologists with essential information to support therapy management decisions. Following the onset of stand-alone anatomical and functional imaging, we witness a push towards integrating molecular image information through various methods, including anato-metabolic imaging (e.g., PET/ CT), advanced MRI, optical or ultrasound imaging. This perspective paper highlights a number of key technological and methodological advances in imaging instrumentation related to anatomical, functional, molecular medicine and hybrid imaging, that is understood as the hardware-based combination of complementary anatomical and molecular imaging. These include novel detector technologies for ionizing radiation used in CT and nuclear medicine imaging, and novel system developments in MRI and optical as well as opto-acoustic imaging. We will also highlight new data processing methods for improved non-invasive tissue characterization. Following a general introduction to the role of imaging in oncology patient management we introduce imaging methods with well-defined clinical applications and potential for clinical translation. For each modality, we report first on the status quo and point to perceived technological and methodological advances in a subsequent status go section. Considering the breadth and dynamics of these developments, this perspective ends with a critical reflection on where the authors, with the majority of them being imaging experts with a background in physics and engineering, believe imaging methods will be in a few years from now. Overall, methodological and technological medical imaging advances are geared towards increased image contrast, the derivation of reproducible quantitative parameters, an increase in volume sensitivity and a reduction in overall examination time. To ensure full translation to the clinic, this progress in technologies and instrumentation is complemented by progress in relevant acquisition and image-processing protocols and improved data analysis. To this end, we should accept diagnostic images as “data”, and – through the wider adoption of advanced analysis, including machine learning approaches and a “big data” concept – move to the next stage of non-invasive tumor phenotyping. The scans we will be reading in 10 years from now will likely be composed of highly diverse multi- dimensional data from multiple sources, which mandate the use of advanced and interactive visualization and analysis platforms powered by Artificial Intelligence (AI) for real-time data handling by cross-specialty clinical experts with a domain knowledge that will need to go beyond that of plain imaging