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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