Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver - Update 2020 - WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS.

The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS), first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications.The 2012 guideline requires updating as previously the differences of the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including the United States Food and Drug Administration (FDA) approval as well as the extensive Asian experience, to produce a truly international perspective.These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCA) and are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis to improve the management of patients.

The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib.

OBJECTIVES: To identify dynamic contrast-enhanced (DCE) imaging parameters from MRI, CT and US that are prognostic and predictive in patients with metastatic renal cell cancer (mRCC) receiving sunitinib. METHODS: Thirty-four patients were monitored by DCE imaging on day 0 and 14 of the first course of sunitinib treatment. Additional scans were performed with DCE-US only (day 7 or 28 and 2 weeks after the treatment break). Perfusion parameters that demonstrated a significant correlation (Spearman p < 0.05) with progression-free survival (PFS) and overall survival (OS) were investigated using Cox proportional hazard models/ratios (HR) and Kaplan-Meier survival analysis. RESULTS: A higher baseline and day 14 value for Ktrans (DCE-MRI) and a lower pre-treatment vascular heterogeneity (DCE-US) were significantly associated with a longer PFS (HR, 0.62, 0.37 and 5.5, respectively). A larger per cent decrease in blood volume on day 14 (DCE-US) predicted a longer OS (HR, 1.45). We did not find significant correlations between any of the DCE-CT parameters and PFS/OS, unless a cut-off analysis was used. CONCLUSIONS: DCE-MRI, -CT and ultrasound produce complementary parameters that reflect the prognosis of patients receiving sunitinib for mRCC. Blood volume measured by DCE-US was the only parameter whose change during early anti-angiogenic therapy predicted for OS and PFS. KEY POINTS: • DCE-CT, -MRI and ultrasound are complementary modalities for monitoring anti-angiogenic therapy. • The change in blood volume measured by DCE-US was predictive of OS/PFS. • Baseline vascular heterogeneity by DCE-US has the strongest prognostic value for PFS.

Integration of Contrast-enhanced US into a Multimodality Approach to Imaging of Nodules in a Cirrhotic Liver: How I Do It.

Accurate characterization of cirrhotic nodules and early diagnosis of hepatocellular carcinoma (HCC) are of vital importance. Currently, computed tomography (CT) and magnetic resonance (MR) imaging are standard modalities for the investigation of new nodules found at surveillance ultrasonography (US). This article describes the successful integration of contrast material-enhanced US into a multimodality approach for diagnosis of HCC and its benefits in this population. The application of contrast-enhanced US immediately following surveillance US allows for prompt dynamic contrast-enhanced evaluation, removing the need for further imaging of benign lesions. Contrast-enhanced US also provides dynamic real-time assessment of tumor vascularity so that contrast enhancement can be identified regardless of its timing or duration, allowing for detection of arterial hypervascularity and portal venous washout. The purely intravascular nature of US contrast agents is valuable as the rapid washout of nonhepatocyte malignancies is highly contributory to their differentiation from HCC. The authors believe contrast-enhanced US provides complementary information to CT and MR imaging in the characterization of nodules in high-risk patients. © RSNA, 2017 Online supplemental material is available for this article.

Contrast enhanced ultrasound (CEUS) in the prenatal evaluation of suspected invasive placenta percreta.

BACKGROUND: Morbidly adherent placentation now complicates approximately 1 in 500 pregnancies. Our group and others have demonstrated that antenatal diagnosis of invasive placentation and team-based delivery reduce severe morbidity. Ultrasound and magnetic resonance imaging (MRI) are both employed in the antenatal evaluation of pregnancies with suspected placenta increta/percreta. Accurate diagnosis in this context is essential to direct resources appropriately. Ultrasound methods, including colour and power Doppler, are the mainstays of screening at-risk women, whereas MRI is reserved for diagnostic purposes because of its cost and limited accessibility. In current practice, both methods are significantly limited by an inability to accurately define aberrant utero-placental blood flow, the definitive sign of deeply invasive placentation. We describe here an adjunctive method to define aberrant blood flow using ultrasound. CASE: We employed contrast-enhanced ultrasound (CEUS) in the antenatal evaluation of suspected extensive invasive placentation in a woman at 18 weeks' gestation. Invasive placentation was confirmed following hysterectomy. CONCLUSION: CEUS, a technique that has been established as safe and well tolerated in the non-pregnant setting, has the potential to be deployed as a powerful adjunct to ultrasound to enhance both the screening and diagnostic components of care for women with suspected invasive placentation.

Tumor radiation response enhancement by acoustical stimulation of the vasculature.

We have discovered that ultrasound-mediated microbubble vascular disruption can enhance tumor responses to radiation in vivo. We demonstrate this effect using a human PC3 prostate cancer xenograft model. Results indicate a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments. We further demonstrate with experiments in vivo that induction of ceramide-related endothelial cell apoptosis, leading to vascular disruption, is a causative mechanism. In vivo experiments with ultrasound and bubbles permit radiation doses to be decreased significantly for comparable effect. We envisage this unique combined ultrasound-based vascular perturbation and radiation treatment method being used to enhance the effects of radiation in a tumor, leading to greater tumor eradication.

Spatially segmented SVD clutter filtering in cardiac blood flow imaging with diverging waves.

Ultrafast ultrasound imaging enables the visualization of rapidly changing blood flow dynamics in the chambers of the heart. Singular value decomposition (SVD) filters outperform conventional high pass clutter rejection filters for ultrafast blood flow imaging of small and shallow fields of view (e.g., functional imaging of brain activity). However, implementing SVD filters can be challenging in cardiac imaging due to the complex spatially and temporally varying tissue characteristics. To address this challenge, we describe a method that involves excluding the proximal portion of the image (near the chest wall) and divides the reduced field of view into overlapped segments, within which tissue signals are expected to be spatially and temporally coherent. SVD filtering with automatic selection of cut-off singular vector orders to remove tissue and noise signals is implemented for each segment. Auto-thresholding is based on the coherence of spatial singular vectors, delineating tissue, blood, and noise subspaces within a spatial similarity matrix calculated for each segment. Filtered blood flow signals from the segments are reconstructed and then combined and Doppler processing is used to form a set of blood flow images. Preliminary experimental results suggest that the spatially segmented approach improves the separation of the tissue and blood subsets in the spatial similarity matrix so that automatic thresholding is significantly improved, and tissue clutter can then be rejected more effectively in cardiac ultrafast imaging, compared to using the full field of view. In the case studied, spatially segmented SVD improved the rate of correct automatic selection of thresholds from 78% to 98.7% for the investigated cases and improved the post-filter power of blood signals by an average of more than 10 dB during a cardiac cycle.

Dynamic microbubble contrast-enhanced US to measure tumor response to targeted therapy: a proposed clinical protocol with results from renal cell carcinoma patients receiving antiangiogenic therapy.

PURPOSE: To develop and implement an evidence-based protocol for characterizing vascular response of renal cell carcinoma (RCC) to targeted therapy by using dynamic contrast material-enhanced (DCE) ultrasonography (US). MATERIALS AND METHODS: The study was approved by the institutional research ethics board; written informed consent was obtained from all patients. Seventeen patients (four women; median age, 58 years; range, 42-72 years; 13 men, median age, 62 years; range, 45-81 years) with metastatic RCC were examined by using DCE US before and after 2 weeks of treatment with sunitinib (May 2007 to October 2009). Two contrast agent techniques--bolus injection and disruption-replenishment infusion of microbubbles--were compared. Changes in tumor blood velocity and fractional blood volume were measured with both methods, together with reproducibility and effect of compensation for respiratory motion. Tumor changes were assessed with computed tomography, by using the best response with the Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free survival (PFS). Follow-up RECIST measurements were performed at 6-week intervals until progressive disease was detected. RESULTS: In response to treatment, median tumor fractional blood volume measured with the disruption-replenishment infusion method decreased by 73.2% (interquartile range, 46%-87%) (P < .002), with repeated-measure reproducibility of 9%-15%. Significant decreases were also seen with the bolus method, but with poor correlation of changes in bolus peak (r = 0.46, P = .066) and area under the curve (r = 0.47, P = .058), compared with infusion measurements. Changes in DCE US parameters over 2 weeks did not correlate with PFS and could not be used to predict long-term assessment of best response by using RECIST. Follow-up times ranged 28-501 days; the median was 164 days. CONCLUSION: DCE US provides reproducible and sensitive assessment of vascular changes in response to antiangiogenic therapy. The disruption-replenishment infusion protocol is a flexible method suitable for many tumor types, but further studies are needed to assess whether this protocol may be predictive of patient outcome.

Lateral Position-Dependent Velocity Estimation Error in Plane-Wave Doppler Ultrasound Systems.

Doppler ultrasound has become a standard method used to diagnose and grade vascular diseases and monitor their progression. Conventional focused-beam color Doppler imaging is routinely used in clinical practice, but suffers from inherent trade-offs between spatial, temporal and velocity resolution. Newer, plane-wave Doppler imaging offers rapid simultaneous acquisition of B-mode, color and spectral Doppler information across large fields of view, making it a potentially useful method for quantitative estimation of blood flow velocities in the clinic. However, plane-wave imaging can lead to a substantial error in velocity estimation, which is dependent on the lateral location within the image. This is seen in both clinical and experimental plane-wave systems. In the work described in this article, we quantified this velocity error under different geometric and beamforming conditions using numerical simulation and experimental phantoms. We found that the lateral-dependent velocity errors are caused by asymmetrical geometric spectral broadening, and outline a correction algorithm that can mitigate these errors.

A novel, hands-free ultrasound patch for continuous monitoring of quantitative Doppler in the carotid artery.

Quantitative Doppler ultrasound of the carotid artery has been proposed as an instantaneous surrogate for monitoring rapid changes in left ventricular output. Tracking immediate changes in the arterial Doppler spectrogram has value in acute care settings such as the emergency department, operating room and critical care units. We report a novel, hands-free, continuous-wave Doppler ultrasound patch that adheres to the neck and tracks Doppler blood flow metrics in the common carotid artery using an automated algorithm. String and blood-mimicking test objects demonstrated that changes in velocity were accurately measured using both manually and automatically traced Doppler velocity waveforms. In a small usability study with 22 volunteer users (17 clinical, 5 lay), all users were able to locate the carotid Doppler signal on a volunteer subject, and, in a subsequent survey, agreed that the device was easy to use. To illustrate potential clinical applications of the device, the Doppler ultrasound patch was used on a healthy volunteer undergoing a passive leg raise (PLR) as well as on a congestive heart failure patient at resting baseline. The wearable carotid Doppler patch holds promise because of its ease-of-use, velocity measurement accuracy, and ability to continuously record Doppler spectrograms over many cardiac and respiratory cycles.

Microbubble-enhanced US in body imaging: what role?

Contrast agents for ultrasonography (US) comprise microscopic bubbles of gas in an encapsulating shell. They are unique in that they interact with the imaging process, oscillating in response to a low-intensity ultrasound field and disrupting in response to a high-intensity field. New contrast-specific imaging modes allow US to show exquisite vascularity and tissue perfusion in real time and with excellent spatial resolution. In Europe, Asia, and Canada, to name only the most obvious, characterization of focal liver masses is the first and best established use of contrast-enhanced (CE) US, allowing for the noninvasive diagnosis of commonly encountered liver masses with comparable accuracy to that of computed tomography and magnetic resonance studies. CE US is a preferred modality for the difficult task of diagnosis of liver nodules detected on surveillance scans in those at risk for hepatocellular carcinoma. Newer body applications include the guidance of ablative intervention, monitoring activity of bowel inflammation in Crohn disease, characterization of kidney masses, especially cystic renal cell carcinoma, diagnosis of prostate cancer, and monitoring the response of tumors to antivascular drug therapies. Microbubble contrast agents are easy to use and robust; their use poses no risk of nephrotoxicity and requires no ionizing radiation. CE US plays a vital and expanding role that improves management and patient care.

Hypervascular liver masses on contrast-enhanced ultrasound: the importance of washout.

OBJECTIVE: The objective of our study was to determine the role of negative enhancement (washout), its presence and timing, in the differential diagnosis of hypervascular liver masses on contrast-enhanced ultrasound. MATERIALS AND METHODS: One-hundred forty-six hypervascular liver lesions (mean size, 3.9 cm; range, 1.0-17.0 cm) were evaluated with contrast-enhanced ultrasound over a 6-month period. Seventy-four were benign (29 hemangiomas, 31 focal nodular hyperplasia [FNH] lesions, seven adenomas, five inflammatory lesions, two other) and 72, malignant (41 hepatocellular carcinomas [HCCs], 25 metastases, six other). Two independent reviewers retrospectively recorded the presence and timing of washout in the portal venous phase, observing until 4 minutes after injection, of a contrast agent (perflutren microspheres). Diagnoses were confirmed by histopathology (n = 68) or clinicoradiologic follow-up (n = 78). Timing of washout was compared between types of lesion using Fisher's exact test. RESULTS: Washout occurred in both benign (27/74, 36%) and malignant (70/72, 97%) lesions but was more frequently seen in malignancy (p < 0.001) (kappa = 0.91). Metastases showed more rapid washout than HCCs (p < 0.001): 20 of 25 metastases showed washout by 30 seconds after injection and 23 of 41 HCCs, later than 75 seconds. All malignant lesions without washout were HCCs (2/41). Among the benign lesions, all five inflammatory lesions showed rapid washout before 75 seconds and six of seven adenomas showed washout, mostly later than 75 seconds (5/6). Washout also occurred in hemangiomas (6/29) and FNH lesions (9/31), mostly later than 75 seconds after injection (12/15). CONCLUSION: Hypervascular malignant lesions show washout except infrequent cases of HCC. Rapid washout characterizes metastases, whereas HCCs show variable, often slow, washout. However, washout is not unique to malignancy and may be seen in benign lesions.

Pseudoenhancement within the local ablation zone of hepatic tumors due to a nonlinear artifact on contrast-enhanced ultrasound.

OBJECTIVE: Pseudoenhancement of an avascular region on contrast-enhanced ultrasound often occurs within an echogenic region of a radiofrequency ablation zone due to nonlinear ultrasound propagation through intervening microbubble-perfused tissue. The purpose of this study was to describe the imaging features of this artifact. MATERIALS AND METHODS: Twenty-six patients with no tumor recurrence within ablation zones were included. Two radiologists assessed contrast-enhanced ultrasound pseudoenhancement in the arterial (< 30 seconds), portal (30-90 seconds), and late (> 90 seconds) phases. If pseudoenhancement was present, the following information was recorded: the degree, time to first appearance, progression over time, and location. The corresponding gray-scale echogenicity (hypo-, iso-, or hyperechoic) and lesion depth were also noted. RESULTS: Fourteen lesions (14/26, 54%) showed pseudoenhancement on contrast-enhanced ultrasound. Fourteen (100%) corresponded to the hyperechoic area within the ablation zone on gray-scale ultrasound and were nonmarginal in location. Pseudoenhancement occurred more frequently in deep lesions (> or = 5 cm) than in superficial lesions (< 5 cm) (p = 0.002). Pseudoenhancement was initiated most frequently in the portal phase (9/14, 64%), followed by the arterial phase (4/14, 29%) and late phase (1/14, 7%). Progression in the degree of pseudoenhancement was shown in most cases (12/14, 86%) and no washout was seen. CONCLUSION: Pseudoenhancement is frequently seen within ablation zones on contrast-enhanced ultrasound, particularly in deep echogenic lesions. However, pseudoenhancement follows enhancement of the parenchyma between the transducer and target. This observation is consistent with nonlinear propagation of the ultrasound beam, which increases with bubble concentration. Pseudoenhancement shows relatively late initiation, progression over time, and nonmarginal location; these findings are different from those seen in typical tumor recurrence, which shows early enhancement and washout at the margin of the ablation zone.

Contrast-Enhanced Ultrasound of Focal Liver Masses: A Success Story.

The epidemic of increasing fatty liver disease and liver cancer worldwide, and especially in Western society, has given new importance to non-invasive liver imaging. Contrast-enhanced ultrasound (CEUS) using microbubble contrast agents provides unique advantages over computed tomography (CT) and magnetic resonance imaging (MRI), the currently established methods. CEUS provides determination of malignancy and allows excellent differential diagnosis of a focal liver mass, based on arterial phase enhancement patterns and assessment of the timing and intensity of washout. Today, increased use of CEUS has provided safe and rapid diagnosis of incidentally detected liver masses, improved multidisciplinary management of nodules in a cirrhotic liver, facilitated ablative therapy for liver tumors and allowed diagnosis of hepatocellular carcinoma without biopsy. Benefits of CEUS include the dynamic real-time depiction of tumor perfusion and the fact that it is a purely intravascular agent, accurately reflecting tumoral and inflammatory blood flow. CEUS has many similarities to contrast-enhanced CT and MRI but also unique differences, which are described. The integration of CEUS into a multimodality imaging setting optimizes patient care.

High-Frequency Nonlinear Doppler Contrast-Enhanced Ultrasound Imaging of Blood Flow.

Current methods for in vivo microvascular imaging (<1 mm) are limited by the tradeoffs between the depth of penetration, resolution, and acquisition time. Ultrasound Doppler approaches combined at elevated frequencies (<7.5 MHz) are able to visualize smaller vasculature and, however, are still limited in the segmentation of lower velocity blood flow from moving tissue. Contrast-enhanced ultrasound (CEUS) has been successful in visualizing changes in microvascular flow at conventional diagnostic ultrasound imaging frequencies (<7.5 MHz). However, conventional CEUS approaches at elevated frequencies have met with limited success, due, in part, to the diminishing microbubble response with frequency. We apply a plane-wave acquisition combined with the non-linear Doppler processing of ultrasound contrast agents at 15 MHz to improve the resolution of microvascular blood flow while compensating for reduced microbubble response. This plane-wave Doppler approach of imaging ultrasound contrast agents also enables simultaneous detection and separation of blood flow in the microcirculation and higher velocity flow in the larger vasculature. We apply singular value decomposition filtering on the nonlinear Doppler signal to orthogonally separate the more stationary lower velocity flow in the microcirculation and higher velocity flow in the larger vasculature. This orthogonal separation was also utilized to improve time-intensity curve analysis of the microcirculation, by removing higher velocity flow corrupting bolus kinetics. We demonstrate the utility of this imaging approach in a rat spinal cord injury model, requiring submillimeter resolution.

Imaging Methods for Ultrasound Contrast Agents.

Microbubble contrast agents were introduced more than 25 years ago with the objective of enhancing blood echoes and enabling diagnostic ultrasound to image the microcirculation. Cardiology and oncology waited anxiously for the fulfillment of that objective with one clinical application each: myocardial perfusion, tumor perfusion and angiogenesis imaging. What was necessary though at first was the scientific understanding of microbubble behavior in vivo and the development of imaging technology to deliver the original objective. And indeed, for more than 25 years bubble science and imaging technology have evolved methodically to deliver contrast-enhanced ultrasound. Realization of the basic bubbles properties, non-linear response and ultrasound-induced destruction, has led to a plethora of methods; algorithms and techniques for contrast-enhanced ultrasound (CEUS) and imaging modes such as harmonic imaging, harmonic power Doppler, pulse inversion, amplitude modulation, maximum intensity projection and many others were invented, developed and validated. Today, CEUS is used everywhere in the world with clinical indications both in cardiology and in radiology, and it continues to mature and evolve and has become a basic clinical tool that transforms diagnostic ultrasound into a functional imaging modality. In this review article, we present and explain in detail bubble imaging methods and associated artifacts, perfusion quantification approaches, and implementation considerations and regulatory aspects.

Investigating the Accumulation of Submicron Phase-Change Droplets in Tumors.

Submicron phase-change droplets are an emerging class of ultrasound contrast agent. Compared with microbubbles, their relatively small size and increased stability offer the potential to passively extravasate and accumulate in solid tumors through the enhanced permeability and retention effect. Under exposure to sufficiently powerful ultrasound, these droplets can convert into in situ gas microbubbles and thus be used as an extravascular-specific contrast agent. However, in vivo imaging methods to detect extravasated droplets have yet to be established. Here, we develop an ultrasound imaging pulse sequence within diagnostic safety limits to selectively detect droplet extravasation in tumors. Tumor-bearing mice were injected with submicron perfluorobutane droplets and interrogated with our imaging-vaporization-imaging sequence. By use of a pulse subtraction method, median droplet extravasation signal relative to the total signal within the tumor was estimated to be Etumor=37±5% compared with the kidney Ekidney=-2±8% (p < 0.001). This work contributes toward the advancement of volatile phase-shift droplets as a next-generation ultrasound agent for imaging and therapy.

Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS.

The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound, first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology. The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as, previously, the differences in the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration approval and the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCAs) and are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis to improve the management of patients.

Ultrasound Imaging of Hepatocellular Adenoma Using the New Histology Classification.

Hepatocellular adenoma is a rare benign liver tumor. Predisposing factors include hepatic storage diseases and some genetic conditions. A new histology-based classification has been proposed but to date, the corresponding ultrasound imaging features have not been reported. Here we review the new classification scheme and discuss the corresponding features on contrast-enhanced ultrasound imaging.

Contrast-enhanced ultrasound approach to the diagnosis of focal liver lesions: the importance of washout.

Contrast-enhanced ultrasound (CEUS) is a powerful technique for differentiating focal liver lesions (FLLs) without the risks of potential nephrotoxicity or ionizing radiation. In the diagnostic algorithm for FLLs on CEUS, washout is an important feature, as its presence is highly suggestive of malignancy and its characteristics are useful in distinguishing hepatocellular from nonhepatocellular malignancies. Interpreting washout on CEUS requires an understanding that microbubble contrast agents are strictly intravascular, unlike computed tomography or magnetic resonance imaging contrast agents. This review explains the definition and types of washout on CEUS in accordance with the 2017 version of the CEUS Liver Imaging Reporting and Data System and presents their applications to differential diagnosis with illustrative examples. Additionally, we propose potential mechanisms of rapid washout and describe the washout phenomenon in benign entities.