Ultrasound markers for cancer Citation for published version (APA): van Sloun, R. J. G. (2018). Ultrasound markers for cancer. Technische Universiteit Eindhoven. Document status and date: Published: 17/01/2018 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. 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If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 07. Oct. 2021 U±§Z«¶o MZ§u§« § CZhu§ e research presented in this thesis was nancially supported by the European Research Council (ERC), the Dutch Technology Foundation STW, and the Dutch Cancer Society (KWF). Financial support for the printing of this thesis was kindly provided by Bracco Suisse SA. Cover design by Jelle Janssen (www.jellejanssen.nl). Printed by Gildeprint. ©Copyright óþÕß, Ruud J.G. van Sloun. Copyright of the individual chapters containing published articles belongs to the publisher of the journal listed at the beginning of the respective chapters. All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the copyright owner. A catalogue record is available from the Eindhoven University of Technology Library. ISBN: Éß-Éþ-ìä-¦¦óì-ì U±§Z«¶o MZ§u§« § CZhu§ PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Technische Universiteit Eindhoven, op gezag van de rector magnicus prof. dr. ir. F. P. T. Baaijens, voor een commissie aangewezen door het College voor Promoties, in het openbaar te verdedigen op woensdag Õß januari óþÕ om Õä:þþ uur door Ruud Johannes Gerardus van Sloun geboren te Roermond Dit proefschri is goedgekeurd door de promotoren en de samenstelling van de pro- motiecommissie is als volgt: voorzitter prof.dr.ir. A.B. Smolders promotor: prof.dr.ir. H. Wijkstra copromotor: dr.ir. M. Mischi leden: prof.dr.ing. G. Schmitz (Ruhr-Universität) prof.dr. J. D’hooge (KU Leuven) dr. M. Averkiou (University of Washington) dr.ir. R.G.P. Lopata adviseur: dr. H.P. Beerlage (Jeroen Bosch Ziekenhuis) Het onderzoek dat in dit proefschri wordt beschreven is uitgevoerd in overeenstem- ming met de TU/e Gedragscode Wetenschapsbeoefening. S¶Z§í U±§Z«¶o MZ§u§« § CZhu§ Each year, about Õ¦ million new cancer cases occur worldwide and over mil- lion people die from it. Diagnostic imaging plays a critical role in cancer care, being a fundamental asset for timely cancer diagnosis, disease staging and management as well as for treatment choice, planning, guidance, and follow up. Despite this, imaging technologies that play a central role in this process, i.e. magnetic resonance imaging (MRI) and X-ray computed tomography (CT), have major drawbacks; MRI remains a highly expensive modality, and CT induces ionizing radiation. Moreover, in most cases their limited accuracy poses the need for invasive verication with biopsies. Ultrasound (US) imaging has the potential to shine as a non-ionizing and cost-eective technique that can limit the diagnostic burden on the healthcare system and the patient via an eective and accurate imaging protocol. In this dissertation, we aim to advance and extend ultrasound imaging to a level which will ultimately permit accurate cancer diagnosis based on ultrasound alone. To this end, we focus on imaging both vascular and tissue markers that are characteristic for cancer. At the vascular level the impact of cancer is striking. Cancer vasculature is chaotic, characterized by increased microvascular density and tortuosity, as well as by the pres- ence of irregular branching and arteriovenous shunts. e process that governs these vascular alterations is angiogenesis, a biomarker that is strongly associated to lethal cancer phenotypes. In the rst part of this thesis, we therefore propose several novel methods based on contrast-enhanced ultrasound (CEUS) that characterize the vas- culature, ranging from macroscopic features to microscopic features. CEUS enables these particular analyses by imaging intravenously administered microbubbles (sized similarly to red blood cells) owing through the (micro)vasculature like red blood cells. On a macroscopic scale, we developed multiple signal processing systems that adequately assess microbubble dispersion, microbubble ow elds and ow heterogene- ity. Clinically, all these markers proved to have diagnostic value for prostate cancer localization. At a smaller scale, we aim at evaluating features of the vascular net di- rectly. We rst introduce contrast-enhanced ultrasound tractography, setting a basis for characterization of microbubble trajectories. We proved that the proposed approach can directly be applied to clinically acquired ¦D-CEUS datasets. Comparison with histopathology aer prostate resection revealed higher densities and more tortuous geometries in malignant areas. Finally, at an even smaller scale, we adopted sparse reconstruction techniques to generate super-resolution ultrasound images of the vas- culature using clinical CEUS, revealing features that were previously hidden by the diraction limit. ese developments open up additional opportunities for vascular characterization. e above described methods rely on accurate detection and quantication of mi- crobubbles. Yet, commercial CEUS imaging modes are not completely specic to microbubbles, leading to several artefacts. In this context, we investigated the use of a microbubble-specic marker for CEUS, a cumulative phase-shi between the second harmonic and fundamental of the ultrasound wave. A proof of concept aimed at quan- tication of microbubbles in a tomographic fashion showed the potential of this new technique. Along with these vascular features, cancer tissue exhibits a specic set of charac- teristics. First of all, cancers are sti compared to benign tissue. Physicians assess nodular rmness by palpation, a subjective technique with a long history in medicine. A fully quantitative measure of lesion stiness can be obtained by shear wave elasticity imaging (SWEI), a method that uses a high-intensity acoustical “push” pulse to produce laterally propagating shear waves whose velocity can be estimated to obtain the shear modulus. However, not only elasticity, but also viscosity plays an important role in the propagation process of shear waves. In fact, viscosity is in itself a parameter of diag- nostic value for detection and characterization of malignant lesions. In this thesis we therefore propose a new method that enables imaging of viscosity from SWEI by local model-based system identication. Our in-vitro studies indicated how this approach was for the rst time able to provide high resolution viscosity maps, opening up the way for imaging this marker in the context of cancer diagnostics. Besides viscoelastic remodelling, cancer tissue is dense with reduced uid, as con- rmed by diusion-weighted MRI. e established link between uid content and US nonlinear behaviour hence motivates towards the estimation of a marker that is able to quantify the nonlinear nature of ultrasound propagation. e acoustical coecient of nonlinearity is a suitable marker, and we set the theoretical basis for a new method to image this parameter. Although it is reasonable to belief that the new diagnostic options provided by this work will allow clinicians to harvest a broad and useful spectrum of information, the possibilities may be overwhelming. erefore, incorporating the full set of US tools into a clearly dened multi-parametric protocol (mpUS) is of signicant importance for clinical implementation of these techniques. Future work should therefore include the development an mpUS solution that suits the clinical workow, and enables not only the detection and localisation of malignancies, but also their grading. L«± Z¶±§’« £¶fhZ±« J¶§Z Z§±hu« [J-Õ] van Sloun, R.J.G., Demi, L., Schalk, S.G., Caresio, C., Huang, J., Li, J., Postema, A.W., Mannaerts, Molinari, F., C., van der Linden, H., Huang, P.,