ICUS Weekly News Monitor 6-17-2016

  1. Ultraschall in Med 2016,  Jun 8, 2016,  A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA
    Ein Meilenstein: Zulassung von CEUS zur Leberdiagnostik an Erwachsenen und Kindern in den USA     Authors:  K. Seitz, D. Strobe
    2.  American Chemical Society,  Jun 1, 2016,  Enzyme-degradable hybrid polymer/silica microbubbles as ultrasound contrast agents       Authors:  Nadia H Tsao and Elizabeth Anne Howlett Hall
    3.  Journal of the American Society of Echocardiography,  June, 2016,  Detection of Carotid Atherosclerotic Plaque Neovascularization Using Contrast Enhanced Ultrasound: A Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies      Authors: Runqing Huang, PhD, et al
    4.  Echo Research and Practice,  Jun 1, 2016,  Echo your Work!
    Ultraschall in Med 2016
    37(03): 229-232
    DOI: 10.1055/s-0042-107411
    Jun 8, 2016
    A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA
    Ein Meilenstein: Zulassung von CEUS zur Leberdiagnostik an Erwachsenen und Kindern in den USA
    Authors:  K. Seitz, D. Strobe


The approval of microbubbles with the inert gas sulfur hexafluoride (SF6) and a palmitic acid shell (SonoVue®, Bracco Geneva, CH) for the diagnostic imaging of liver tumors in adults and children by the FDA in the United States represents a milestone for contrast-enhanced ultrasound (CEUS).

This warrants a look back at the history of the development of CEUS. The first publications based on echocardiographic observations of right ventricular contrast phenomena caused by tiny air bubbles following i. v. injection of indocyanine green appeared around 1970 [1] [2] [3]. A longer period of sporadic publications but no real progress then followed since, in contrast to X-ray methods, ultrasound works quite well without a contrast agent.

It is noteworthy that the foundations for further development were primarily laid in Europe. The development and approval (1991) of the contrast agent Echovist® by a German contrast manufacturer for echocardiography unsuitable for passing through lungcapillaries [4] [5] resulted in the first extracardiac indications, e. g. for detecting retrovesical reflux and tubal patency, in the mid-1980 s [6] [7] [8]. The sensitivity of color Doppler was not able to compensate for the lack of an ultrasound contrast agent compared to CT with its obligatory contrast administration.

Studies of SHU 508 – microbubbles of air moderately stabilized with galactose and palmitic acid – began in 1990 [9] [10] [11] [12] [13] [14] [15] and the contrast agent was then introduced in 1995 in Germany as Levovist®. The most important publications by Blomley, Cosgrove, Leen, and Albrecht are named here on a representative basis [16] [17] [18] [19] [20].

SHU 508 along with other US contrast agents provided impressive proof of the superiority of CEUS for the diagnosis of liver metastases. However, practical application remained complicated and required skill and technical know-how because of a lack of suitable software on US units [21] [22] [23] [24] [25]. The monograph regarding the use of contrast agent in the liver by Wermke and Gaßmann is impressive but unfortunately only available in German [26]. In addition to being applied in the heart and the liver, CEUS was first used in transcranial applications [27] and in vessels [28], the kidneys [29], and the breast [30]. Measurements at transit times were also of particular interest [31]. It was difficult to convince ultrasound device manufacturers of the need to adapt US units to US contrast agents and not vice versa.

The breakthrough came with low MI phase contrast inversion and the introduction of SonoVue® in many European countries in 2001. This more stable US contrast agent is easy to use and is becoming indispensable in diagnostic imaging of the liver [32] [33] [34] [35] [36] [37] [38] [39] [40]. Studies have shown its excellent tolerability [41] and diagnostic reliability comparable to that of MDCT and MRI in the liver [42] [43]. Today it would be unimaginable to diagnose liver tumors without CEUS [44]. This also applies to very small lesions [45] [46].

EFSUMB published the first CEUS guidelines in 2004 [47] which have since been reissued and divided into hepatic [48] and extrahepatic applications [49]. The first recommendations regarding quantitative assessment have also been published [50].

The increasing scientific interest in CEUS is evident based on the greater number of PubMed hits for Echovist®(ca. 130), Levovist® (ca. 500) and SonoVue® (ca. 1500) as well as on the fact that publications regarding CEUS comprise almost 20 % of UiM/EJU articles in the last 10 years. The number of CEUS articles in UiM/EJU continues to be high [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75].

In the clinical reality, CEUS has been able to become established alongside CT and MRI according to the saying “better is the enemy of good” [76] as the method of choice after B-mode ultrasound in the evaluation of liver tumor malignancy in Germany, where the technically challenging method is promoted. In the case of unclear CT and MRI findings, CEUS performed by an experienced examiner/clinician often provides the solution, particularly in the case of small lesions, and is the last resort before US-guided biopsy [45] [46]. However, there is a lack of competent CEUS examiners and Germany continues to be the world champion of X-ray examinations with no noticeable reverse trend. In almost every doctor’s office and hospital, ultrasound costs are by far not fully covered, resulting in an extremely high frequency of CT use with CT being available to everyone regardless of insurance status.

The USA is now in the starting position for CEUS. It will be exciting to see how the method will develop there. The FDA’s decision to approve sulfur hexafluoride (Lumason® = SonoVue®) should be considered against the background of the radiation exposure caused by CT examinations and the fact that MRI using gadolinium-containing contrast agents is no longer considered noninvasive because of nephrogenic systemic fibrosis (NSF) and the accumulation of the agent in the cerebrum. An essential point of the campaign regarding the avoidance of diagnostic radiation exposure triggered in the USA by the publications of Brenner et al. [77] [78] was that the agent was approved for use in the liver even for children [79] [80] – still off label in Europe – without additional comprehensive studies due to the available scientific results and the very low side effects profile of Lumason® (= SonoVue®). It is admittedly unclear why other indications (except the heart which has been approved since 2014) are excluded even though the microbubbles as a pure blood pool contrast agent can be diagnostically used in the entire vascular system and bed of all organs. To our knowledge, there is no such restriction on the approval of X-ray contrast agents.

Like echocardiography and emergency ultrasound, CEUS began in Europe but will probably only establish its final diagnostic value as a “reimport”.

This is a major opportunity to permanently define the role of Ultrasound as a highly valuable, patient-centered imaging method in the German health care system.

This may prompt some of our international readers to reflect upon the role of CEUS in their own countries.

American Chemical Society
DOI: 10.1021/acs.langmuir.6b01075
Jun 1, 2016
Enzyme-degradable hybrid polymer/silica microbubbles as ultrasound contrast agents
Authors:  Nadia H Tsao and Elizabeth Anne Howlett Hall
The fabrication of an enzyme-degradable polymer/silica hybrid microbubble is reported that produces an ultrasound contrast image. The polymer, a triethoxysilane end-capped polycaprolactone (SiPCL), is used to incorporate enzyme-degradable components into a silica microbubble synthesis, and to impart increased elasticity for enhanced acoustic responsiveness. Formulations of 75, 85 and 95 wt% SiPCL in the polymer feed, produced quite similar ratios of SiPCL and silica in the final bubble but different surface properties. The data suggest that different regions of the microbubbles were SiPCL-rich: the inner layer next to the polystyrene template core and the outer surface layer, thereby creating a sandwiched silica-rich layer of the bubble shell. Overall, the thickness of the microbubble shell was dependent on the starting TEOS concentration and the reaction time. Despite the layered structure, the microbubble could be efficiently degraded by lipase enzyme, but was stable without enzyme. The ultrasound contrast showed a general trend of increase in image intensity with SiPCL feed ratio, although the 95 wt% SiPCL bubbles did not produce a contrast image, probably due to bubble collapse. At higher normalized peak negative acoustic pressure (mechanical index, MI), a non-linear frequency response also emerges, characterized by the third harmonic at around 3f0, and increases with MI. The threshold MI transition from linear to non-linear response increased with decrease in SiPCL.
Journal of the American Society of Echocardiography
Volume 29, Issue 6, June 2016, Pages 491–502
June, 2016
Detection of Carotid Atherosclerotic Plaque Neovascularization Using Contrast Enhanced Ultrasound: A Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies
Authors: Runqing Huang, PhDa, d, Sahar S. Abdelmoneim, MB, BCha, Caroline A. Ball, MDb,
Lara F. Nhola, MDa, Ann M. Farrell, MLSc, Steven Feinstein, MDe, Sharon L. Mulvagh, MDa, ,
Intraplaque neovascularization is considered an important indicator of plaque vulnerability. Contrast-enhanced ultrasound (CEUS) of carotid arteries improves imaging of carotid intima-media thickness and permits real-time visualization of neovascularization of the atherosclerotic plaque. The authors conducted a systematic review and meta-analysis to evaluate the accuracy of CEUS-detected carotid atherosclerotic plaque.
A systematic search was performed to identify studies published in the MEDLINE, Embase, Scopus, and Web of Science databases from 2004 to June 2015. Studies evaluating the accuracy of quantitative analysis and qualitative analysis (visual interpretation) for the diagnosis of intraplaque neovascularization compared with histologic specimens and/or clinical diagnosis of symptomatic plaque were included. Parameters evaluated were plaque quantitative CEUS intensity and the visual grading of plaque CEUS. A random-effects meta-analysis was used to pool the likelihood ratios (LRs), diagnostic odds ratios, and summary receiver operating characteristic curves. Corresponding areas under the curves were calculated.
The literature search identified 203 studies, 20 of which were selected for systematic review; the final meta-analysis included seven studies. For qualitative CEUS, pooled sensitivity was 0.80 (95% CI, 0.72–0.87), pooled specificity was 0.83 (95% CI, 0.76–0.89), the pooled positive LR was 3.22 (95% CI, 1.67–6.18), the pooled negative LR was 0.24 (95% CI, 0.09–0.64), the pooled diagnostic odds ratio was 15.57 (95% CI, 4.94–49.03), and area under the curve was 0.894. For quantitative CEUS, pooled sensitivity was 0.77 (95% CI, 0.71–0.83), pooled specificity was 0.68 (95% CI, 0.62–0.73), the pooled positive LR was 2.34 (95% CI, 1.69–3.23), the pooled negative LR was 0.34 (95% CI, 0.25–0.47), the pooled diagnostic odds ratio was 7.06 (95% CI, 3.6–13.82), and area under the curve was 0.888.
CEUS is a promising noninvasive diagnostic modality for detecting intraplaque neovascularization. Standardization of quantitative analysis and visual grading classification is needed to increase reliability and reduce technical heterogeneity.
Echo Research and Practice
Jun 1, 2016
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ICUS Weekly News Monitor 5-6-2016

1.  Dovepress,  May 2, 2016,  The advent of ultrafast ultrasound in vascular imaging: a review
By Mathieu Couade
2.  Reportlinker,  Apr 28, 2016,  Global Microbubbles/Ultrasound Contrast Agents Market Outlook: 2015-2021
May 2, 2016
The advent of ultrafast ultrasound in vascular imaging: a review
By Mathieu Couade
SuperSonic Imagine, Aix en Provence, France
In the last 10 years the advent of computational power and the availability of fully programmable research ultrasound imaging systems have allowed the emergence of ultrafast ultrasound imaging (<1000 frames per second), which has become a central research topic in the ultrasound community. Ultrafast ultrasound imaging relies deeply on the capability of massive parallel beamforming/processing of a single transmit ultrasound event insonifying a large field of view. This ultrafast acquisition capability opens up new tradeoffs in terms of processing and observations of transient rapid phenomena. Firstly, it can be used to improve conventional imaging modes such as B-mode, Doppler modes, Contrast Enhanced Ultrasound in terms of sensitivity, contrast, spatial, and/or temporal resolutions. It can also enrich conventional color flow imaging modes by providing quantitative and synchronous spectral information on the whole image. Secondly it can be used to capture transient phenomena that where unseen with conventional frame rates (<50 Hz) enabling completely novel imaging modes such as real time shear wave elastography (SWE), a technique for mapping quantitatively soft tissue elasticities, or ultrafast PWV, a technique for measuring locally the pulse wave velocity (PWV). In this review, we first introduce the theoretical basis of ultrafast imaging. We then present a state of the art of ultrafast ultrasound imaging in the specific field of arterial wall mechanical properties characterization.
Apr 28, 2016
Global Microbubbles/Ultrasound Contrast Agents Market Outlook: 2015-2021
(full report:
PRNewswire/ -- Microbubbles are composed of gas core stabilized by a shell of proteins, lipids, or polymers and have unique ability to respond to ultrasound, and thus are used as ultrasound contrast agents. The field of ultrasound contrast imaging has been literally bursting in the last decade. Incessant engineering advances in ultrasound technologies over the last decade have resulted in widespread usage of ultrasound for clinical applications.
The potential benefits of ultrasound such as low-cost, convenience, and real-time capability of ultrasound images has led to wide acceptance of this technology. When compared with other imaging modalities, the ultrasound molecular imaging has many advantages such as good temporal resolution, quantitative data, real-time practice, noninvasiveness, relatively inexpensive cost, and no ionizing radiation.
Microbubbles/ ultrasound contrast agents for medical imaging have been swiftly translated from exploratory research to clinical application. It helps to sharpen the image, improve the reliability of the scan and reduce the need for unnecessary downstream testing. In addition, microbubbles can be employed for diagnostic imaging and as a therapeutic tool. These are safe, convenient, completely radiation-free, versatile, and routinely used by physicians throughout the world to obtain a reliable ultrasound diagnosis.
The global microbubbles/ ultrasound contrast agents market is expected to grow at a CAGR of 28.7% to reach $797.5 million by 2021 from 2015. The research report on microbubbles market provides comprehensive analysis of the global market and helps in understanding the driving forces for the growth of this market. The report also provides analysis of major applications such as molecular imaging, gene therapy, drug delivery, and stem cell delivery with their application areas, trends, challenges, and opportunities in this market. In addition, the report analyzes the global microbubbles market by various disease areas such as renal disorder, cardiovascular, and neurology with their drivers, restraints, ongoing research, and future potential.
The market has been segmented by geography as North America, Europe, Asia-Pacific, and Rest of the World (RoW) with a detailed qualitative and quantitative analysis. North America is the major market in the global microbubble market and is expected to dominate this market during the forecast period followed by Europe, and Asia-Pacific.
Lantheus Medical Imaging with its DEFINITY ultrasound contrast imaging agent dominated the global microbubbles/ ultrasound contrast agents market in 2014. The other major players in the global microbubble market include Bracco Imaging S. p. A., Daiichi Sankyo Company, Limited, and GE Healthcare.
Source: Expert Interviews, Government Authorities, Related associations/Institutes, Related Research Publications, Government Publications, Company Press Releases, Company Annual Reports, Company Websites, Company Publications, SEC Filings, Meticulous Research Analysis.

ICUS Weekly News Monitor 4-22-2016

1. Healio Rheumatology,  Apr 20, 2016,  Contrast-enhanced ultrasound may be effective in diagnosing large vessel vasculitis     By Shirley Pulawski
2.  Healio  HCV Next,  April 2016,  The March Toward Elastography for Assessing Fibrosis in HCV
3.,  April 19, 2016,  Key Factors Driving Pre-Clinical Imaging Market
Germanò G, et al. Arth Care Res. 2016;doi:10.1002/acr.22906.
Apr 20, 2016
Contrast-enhanced ultrasound may be effective in diagnosing large vessel vasculitis
By Shirley Pulawski
Carotid contrast-enhanced ultrasound vascularization grade and grade pf vascular inflammation shown on 18F-FDG positron emission tomography correlated well in patients with large vessel vasculitis, according to recently published research.
Researchers enrolled 31 patients with large vessel vasculitis (LVV), including four patients who were evaluated twice over a 12-month period. Standard color Doppler ultrasound (CDUS) evaluations of extra-cranial carotid arteries were administered to all patients and intima media thickness was measured at the far wall of both carotid arteries in proximity to the bifurcation. Vasculitis was determined in the presence of a hypoechoic, circumferential homogenous wall thickening, while inhomogenous, eccentric, thickening of the partly calcified arterial wall was deemed athermatosis. Criteria defined by Drielsma et al was used to define atherosclerotic
carotid plaques.
Within 5 to 10 seconds following the standard CDUS examination, an ultrasound contrast agent was infused to assess the right carotid artery with contrast-enhanced ultrasound (CEUS) and the degree of vascularization was classified.
Within 3 days of CEUS evaluation, patients underwent 18F-FDG PET/CT scans after fasting for 4 or more hours prior to injection.
Erythrocyte sedimentation rates and C-reactive protein were elevated during the testing point in 19 of the examinations. Abnormal vascular uptake was demonstrated in 10 examinations in the right carotid artery and in different vascular areas in nine examinations.
Patients with grade 2 vascularization at CEUS were more likely to have intima media thickness above 1 mm and FDG carotid uptake of 2 or greater and the maximum standardized uptake value (SUV) and the mean SUV in the right carotid artery and mean SUV in the superior vena cava were significantly higher in patients with severe vascularization on CEUS.
“In conclusion, CEUS is a cheap, non-invasive tool useful to examine large vessel wall vascularization in LVV,” the researchers wrote. “The correlation between CEUS and 18F-FDG uptake suggests an association between vascularization and inflammation and supports the use of CEUS as a noninvasive method able to detect disease activity in patients with LVV.”
HCV Next
April 2016
The March Toward Elastography for Assessing Fibrosis in HCV
There are a number of ways to assess fibrosis in HCV, but none are perfect. The long-time mainstay of measuring fibrosis — liver biopsy — may eventually fall out of fashion in the wake of advances in noninvasive measures. The clinical community has been seeking its replacement for two decades, and has largely turned to imaging techniques. Magnetic resonance and transient ultrasound elastography have become the twin pillars of the field. HCV Next spoke with a handful of experts regarding elastography, and it became clear that addressing serum biomarkers and other scoring systems along with ongoing use of biopsy is necessary. Each method comes with drawbacks. The arguments against these various non-invasive ways of assessing fibrosis range from cost, to small sample size, to limited ability to view the liver in its entirety……..Clinicians in the U.S. rely heavily on magnetic resonance elastography (MRE), whereas various forms of ultrasound elastography are used abroad, according to SimonTaylor-Robinson, MD, PhD, clinical consul for the Faculty of Medicine at Imperial College of London. “Ultrasound contrast agents are the gold standard outside the U.S., largely because access to MR machines is less common in other parts of the world,” he said. “In the U.S., people tend not to use ultrasound.”
April 19, 2016
Key Factors Driving Pre-Clinical Imaging Market
Transparency Market Research Releases
The global pre-clinical imaging market has been exhibiting immense growth since the last few years and the trend is expected to continue in the coming years. The advancement in molecular imaging technologies and the increasing adoption of pre-clinical imaging technology as a reliable drug development tool are likely to propel this market in the nearing future.
The global market for pre-clinical imaging is broadly analyzed on the basis of the imaging system, the imaging reagent, technology, and the regional spread of this market. Based on the imaging system, the market is classified into standalone imaging systems and multimodal imaging systems.
Based on the imaging reagent, the market is categorized into optical imaging agents, MRI contrasting reagents, CT contrast reagents, nuclear imaging agents, and ultrasound contrast reagents. Technology wise, the market includes PET + SPECT + CT, PET + MRI, and SPECT + MRI as the major segments.
On the regional basis, the worldwide pre-clinical imaging market is segmented into North America, Asia Pacific, Europe, and the Rest of the World.
This report on the global pre-clinical imaging market attempts to provide a comprehensive overview of this market on the basis of its current and historical performance as well as its future prospects. Driving forces, limitations, latest and upcoming trends, and opportunities of this market have also been discussed at length in this research study.
Overview of the Global Pre-Clinical Imaging Market
The global pre-clinical imaging market has experienced a surge in its valuation in the recent times. Various macro-environmental factors such as technical innovation and government grants and funding have boosted this market significantly over the past few years.
The standalone imaging systems market includes micro-MRI, micro-CT, micro-ultrasound, nuclear imaging, and optical imaging. Multimodal nuclear imaging devices and multimodal optical imaging devices are the major segments of the multimodal imaging systems market.
North America leads the worldwide pre-clinical imaging systems and is closely followed by Europe. Asia Pacific and the Rest of the World are also projected to emerge as lucrative markets for pre-clinical imaging in the near future.
Overall, the global market is witnessing a steady rise in demand. However, the increasing prices of imaging systems and the lack of awareness regarding technology in developing economies are hampering the market’s growth. The consolidation in the worldwide pharmaceutical industry is also expected to restrict this market from rising steadily in the forthcoming years.
Companies mentioned in the research report:
Bioscan Inc., PerkinElmer Inc., Siemens AG, Aspect Imaging, Life Technologies Corp., and Gamma Medica Inc. are leading the worldwide pre-clinical imaging market.

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