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Advanced Ultrasound Technologies for Diagnosis and Therapy

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Advanced Ultrasound Technologies for Diagnosis and Therapy Journal of Nuclear Medicine, published on March 1, 2018 as doi:10.2967/jnumed.117.200030 1 Advanced Ultrasound Technologies for Diagnosis and Therapy Anne Rix1, Wiltrud Lederle1, Benjamin Theek1, Twan Lammers1,2, Chrit Moonen3, Georg Schmitz4, Fabian Kiessling1* 1Institute for Experimental Molecular Imaging, RWTH-Aachen University, Aachen, Germany 2Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands 3Imaging Division, University Medical Center Utrecht, Utrecht, The Netherland 4Department of Medical Engineering, Ruhr-University Bochum, Bochum, Germany * Corresponding author: Fabian Kiessling MD, Institute for Experimental Molecular Imaging, University Aachen (RWTH), Forckenbeckstrasse 55, 52074 Aachen, Germany. Phone:+49-241- 8080116; fax:+49-241-8082442; e-mail: [email protected] First author: Anne Rix B.Sc., Institute for Experimental Molecular Imaging, University Aachen (RWTH), Forckenbeckstrasse 55, 52074 Aachen, Germany. Phone:+49-241-8080839; fax:+49- 241-8082442; e-mail: [email protected] Running title Advanced Ultrasound Imaging and Therapy 1 2 ABSTRACT Ultrasound is among the most rapidly advancing imaging techniques. Functional methods such as elastography have been clinically introduced, and tissue characterization is improved by contrast- enhanced scans. Here, novel super-resolution techniques provide unique morphological and functional insights into tissue vascularisation. Functional analyses are complemented with molecular ultrasound imaging, to visualize markers of inflammation and angiogenesis. The full potential of diagnostic ultrasound may become apparent by integrating these multiple imaging features in radiomics approaches. Emerging interest in ultrasound also results from its therapeutic potential. Various applications on tumor ablation with high intensity focused ultrasound (HIFU) are clinically evaluated and its performance strongly benefits from the integration into Magnetic Resonance Imaging (MRI). Additionally, oscillating microbubbles mediate sonoporation to open biological barriers, thus improving the delivery of drugs or nucleic acids that are co-administered or co-formulated with microbubbles. This article provides an overview of recent developments in diagnostic and therapeutic ultrasound, highlighting multiple innovation tracks and their translational potential. KEYWORDS Drug Delivery, HIFU, Molecular Imaging, Super-resolution, Ultrasound 2 3 INTRODUCTION Ultrasound is among the most frequently used imaging modalities in the clinic. However, in comparison to other tomographic imaging modalities, it is less reproducible because identical image slices are difficult to regain at repetitive examinations. Furthermore, the skills and experience of the examining physician have strong impact on its diagnostic reliability. These limitations may be overcome by the implementation of true 3D imaging, automated image analysis and postprocessing tools as well as by further standardisation of scan protocols and data documentation. Solving these issues may also stimulate the clinical implementation of emerging ultrasound technologies and contrast agents for diagnosis and therapy, which were discussed in our previous article in 2012 (1). At this time, most examples were related to preclinical studies. Since then, much clinical translation can be noted, e.g. in contrast-enhanced functional and molecular ultrasound imaging, focussed ultrasound and sonoporation. The present article highlights the recent technological advancements in ultrasound diagnosis and therapy that are in the process of clinical translation and that are strongly expected to shape the future clinical appearance of this modality. NEW ULTRASOUND CONTRASTS The contrast in ultrasound grayscale imaging originates mainly from variations in tissue’s compressibility and density. However, imaging methods used in current ultrasound systems cannot reconstruct absolute material parameters directly from the received echo signals. In principle, this is possible with full wavefield inversion techniques, even with conventional ultrasound array setups, but the computational burden of these methods is still too high for real time imaging (2). Elastography methods that can image tissues’ mechanical properties have been developed in the last two decades, first as strain imaging techniques using external sources of deformation, then by line-based measurements of shear wave speed using no external compression but acoustic radiation 3 4 force imaging. Later, full two-dimensional shear-wave imaging (Fig. 1A) based on ultrafast plane- wave acquisitions with repetition rates in the kilohertz range was added: By observing shear waves travelling at low speeds (1-10 m/s) with high-frame rate plane wave ultrasound acquisitions, the local shear wave speed can be measured. This modality allows the clinical imaging of the shear wave speed or the shear modulus of tissues (3). As the shear waves are excited by the acoustic radiation force induced by a focused ultrasound pulse, a major advantage of this technique is that it is less operator-dependent than strain imaging techniques relying on manual deformation. Its main clinical applications are diagnosis of liver fibrosis and the characterization of breast and thyroid tumors (Fig. 1B). However, the size and localization of the lesion, composition of the surrounding tissue and motion artefacts from breathing or pulsatile vessels limit the accuracy of shear wave elastography. Furthermore, the intense clinical use of elastography has also identified a high need for standardization as tissue properties measured with different systems were observed to differ (4). Additionally, in heterogeneous media the observed wave speed may not be determined by the average tissue properties alone but also by its boundaries that can guide the waves and change the observed speed. Proper modelling, e.g. of arteries as waveguides, allows exploiting these effects and characterizing arterial stiffness based on the observed wave speed (5). In the future, full wavefield inversion techniques applied to the measured tissue motion could solve this problem at the cost of increased computational complexity (2). A clinically emerging method that offers additional tissue contrasts is photoacoustic or optoacoustic imaging (6): The thermal expansion of tissue absorbing a short, typically near-infrared light pulse generates ultrasound that can be detected by transducers of ultrasound scanners. From this, images of tissues’ optical absorption can be reconstructed. Sweeping through different infrared wavelengths allows multispectral imaging with the prospect of tissue characterization and improved diagnosis. Recently, first clinical applications of photoacoustics were demonstrated as 4 5 functional overlays on ultrasound images: A dedicated breast scanner showed differences in the optical absorption between benign and malignant lesions in the breast (7), and a handheld portable clinical ultrasound system with integrated diode lasers was successfully used for the early detection of rheumatoid arthritis (8). In the near future, also clinical translation of intravascular photoacoustics combined with intravascular ultrasound is expected, which is capable to image lipids in atherosclerotic plaques to assess their vulnerability (9). CONTRAST-ENHANCED ULTRASOUND IMAGING Since many years contrast-enhanced ultrasound (CEUS) imaging has been established in the clinical routine for the characterization of suspicious lesions in many organs, especially the liver, and for detecting cardiovascular abnormalities (e.g. using echocardiography). In cardiovascular imaging microbubbles are predominantly used to enhance the signal in the vessel lumen and to visualize stenoses and aneurysms (10). Especially for the detection of endoleaks after endovascular aneurysm repair CEUS showed similar specificity and sensitivity as contrast enhanced computed tomography (CT) (10). The use of microbubbles to detect sentinel lymph nodes is a relatively novel approach. Here, microbubbles are injected peri-areolarly and then travel to regional lymphatic sites via subcutaneous lymphatic drainage after tissue massage (Fig. 1C) (11). Shimazu and coworkers claimed that the detection rate for the primary draining lymph node is 98% and that the accuracy of CEUS may even be higher than of clinical standard methods (injection of blue dye/radiotracer) (11). Besides using microbubbles to enhance the tissue contrast, functional parameters about tissue vascularisation can be obtained using parameters from time-intensity curves like area-under-curve, peak-enhancement or time-to-peak from bolus injection curves or blood velocity from disruption- 5 6 replenishment curves (Fig. 1D). Quaia and coworkers (12) evaluated several parameters resulting from bolus injection time-intensity curves for their capability to differentiate the response of patients with clinically active Crohn’s disease to pharmacological treatment. Here, CEUS clearly differentiated responders from nonresponders and was an objective measure to assess therapy response (12). Thus, the authors suggested CEUS as a potential alternative to magnetic resonance imaging (MRI) and CT for grading Crohn’s disease’s activity (12). To assess the reproducibility and reliability of CEUS biomarkers, Lassau and coworkers (13) performed a clinical study on hepatic and extrahepatic tumors. Particularly, area-under-curve and area-under-washout proved to be highly reliable (13). It is expected that new imaging procedures, refined
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