Generation Contrast Agent Research Articles

Properties of a Versatile Nanoparticle Platform Contrast Agent To Image and Characterize Atherosclerotic Plaques by Magnetic Resonance Imaging

The need for more specific and selective contrast agents for magnetic resonance imaging motivated us to prepare a new nanoparticle agent based on high-density lipoproteins (HDL). This second generation contrast agent can be prepared in three different ways. The HDL nanoparticles (rHDL) were fully characterized by FPLC and gel electrophoresis. The flexibility of the platform also allows us to incorporate optical probes into rHDL for localization ex vivo by confocal fluorescence microscopy. The contrast-agent-containing nanoparticles were injected into mice that develop atherosclerotic lesions. Magnetic resonance imaging of the animals showed clear enhancement of the atherosclerotic plaques.

1153: Intraoperative ultrasonography as guidance for resective liver surgery

Imaging-guided therapeutic procedures have modified the approach to liver tumors, both introducing new treatment modalities and also changing the policy of hepatectomies. Indeed with intraoperative ultrasonography (IOUS) it is possible to achieve better knowledge about tumor diagnosis, location and staging. Nowadays, new techniques such as contrast-enhanced IOUS (CEIOUS) using second generation contrast agents has further expanded and optimised these applications. Indeed, CEIOUS has allowed better detectability of tiny nodules in surgery for colorectal cancer liver metastases, and better differentiation of those new lesions detected at IOUS during surgery for hepatocellular carcinoma (HCC) in liver cirrhosis.

1244: Contrast imaging in every day practice

Contrast agents are part of the every day sonographic practice in Italy and Europe. The reason for this wide acceptance resides in two major causes: the availability of new generation contrast agents capable to be insonated at low US power without destruction, thus permitting a real time examination of target organs for a sufficient period of time, avoiding any change in the normal sonographic behavior. New contrast specific software designed to visualize the presence of contrast at very low power engendering two simultaneous goals: preserve the bubble life in the blood circulation and cancel the signal deriving from stationary tissues.

Diagnostic efficacy of SonoVue®, a second generation contrast agent, in the assessment of extracranial carotid or peripheral arteries using colour and spectral Doppler ultrasound: a multicentre study

The purpose of this study was to demonstrate the improvement in diagnostic quality and diagnostic accuracy of SonoVue microbubble contrast-enhanced ultrasound (CE-US) versus unenhanced ultrasound imaging during the investigation of extracranial carotid or peripheral arteries. 82 patients with suspected extracranial carotid or peripheral arterial disease received four SonoVue doses (0.3 ml, 0.6 ml, 1.2 ml and 2.4 ml) with Doppler ultrasound performed before and following each dose. Diagnostic quality of the CE-US examinations was evaluated off-site for duration of clinically useful contrast enhancement, artefact effects and percentage of examinations converted from non-diagnostic to diagnostic. Accuracy, sensitivity and specificity were assessed as agreement of CE-US diagnosis evaluated by an independent panel of experts with reference standard modality. The median duration of clinically useful signal enhancement significantly increased with increasing SonoVue doses (p< or =0.002). At the dose of 2.4 ml of SonoVue, diagnostic quality evaluated as number of inconclusive examinations significantly improved, falling from 40.7% at baseline down to 5.1%. Furthermore, SonoVue significantly (p<0.01) increased the accuracy, sensitivity and specificity of assessment of disease compared with baseline ultrasound. SonoVue increases the diagnostic quality of Doppler images and improves the accuracy of both spectral and colour Doppler examinations of extracranial carotid or peripheral arterial disease.

Contrast Enhanced Sonography of Focal Splenic Lesions with a Second-Generation Contrast Agent

Contrast enhanced sonography (CES) of second generation contrast media have shown a spleen-specific uptake of the microbubble contrast agent. The aim of this study was to investigate the ability of a second generation contrast agent to enhance splenic lesions. From October 2003 to September 2004, 46 consecutive patients with focal (peri-) splenic lesions on B-mode sonography were studied by CES using a transpulmonary second-generation contrast agent (SonoVue). Data were retrospectively evaluated. Diagnosis of the patients were infarction (n = 9), lymphoma (n = 7), metastasis (n = 6), injury (n = 4), haemangioma/splenoma (n = 6), accessory spleen (n = 3), cyst (n = 2), and unknown cause (n = 9). Diagnosed of splenic lesions was confirmed by histology (n = 5), contrast enhanced computed tomography (n = 25), MRI (n = 4), scintigraphy (n = 1), and follow up (n = 38). Extent of enhancement (EE) was evaluated during the arterial phase (5-30 s) and the parenchymal phase (3-5 minutes): EE of focal splenic lesions was determined using the surrounding splenic tissue as an in vivo reference, and classified as anechoic vs. hypoechoic vs. isoechoic vs. hyperechoic vs. mixed. The contribution of CES to the final diagnosis was classified as low, helpful or highly necessary. In all but one patient enhancement of normal splenic tissue occurred. During the arterial and parenchymal phase, lesions were found to have anechoic 10/10, hypoechoic 12/24, isoechoic 12/7, hyperechoic 7/0 and mixed enhancement 5/5, respectively. Value of CES for final diagnosis was low n = 24 (52%) (7 lymphomas, 6 metastases, 2 cysts, 9 unknown), helpful n = 9 (20%) (4 infarctions, 2 ruptures, 3 accessory spleens) and highly necessary n = 13 (28%) (5 infarctions, 2 ruptures, 6 haemangiomas/splenomas). Contrast-enhanced sonography is of diagnostic value in subgroups of patients with (peri-)splenic lesions (48%): including splenic infarction, splenic rupture, splenic haemangioma/splenoma, and accessory spleen.

Echographic examination with new generation contrast agent of choroidal malignant melanomas

To determine the efficacy of echography with new generation contrast agents in visualizing vascularization of choroidal malignant melanomas. An echographic contrast medium consisting of phospholipidic microbubbles filled with sulphur hexafluoride (Sonovue) was used to visualize microcirculation in 25 cases of choroidal lesions already diagnosed with standardized echography (21 choroidal malignant melanomas, four disciform lesions). In untreated malignant melanomas contrast agent echography revealed the presence of a dense microcirculation inside the mass. In one case vitreal seeding of the contrast agent was detectable before enucleation and histological examination revealed the presence of tumoral cells. In 12 cases treated with transpupillary thermotherapy, contrast agent echographic evaluation showed heavy regression of microcirculation after 1 week, confirmed in one case by histology, and a reduction of 70-80% in dimensions after 6 months (which appeared to have stabilized at subsequent examinations). In four cases treated with proton beam brachytherapy 2 years prior to our examination, contrast agent echography showed the absence of a microvascular network and the presence of large vessels and blood lakes. In four cases of disciform lesion, deep and superficial retina-associated vascularization was observed, with a weak spread of contrast agent inside the lesion. Live representation with good resolution of choroidal malignant melanoma microcirculation was obtained.

Intravenous contrast ultrasound in gynecology

Contrast Tuned Imaging (CnTI), is a new contrast dedicated technology, applied on the transvaginal probe utilizing the second generation contrast agent SonoVue®, which consists of sulphur hexafluoride microbubbles. We evaluated the efficacy of this technology as compared with the standard examination in different gynecological pathologies in order to detect and characterize ovarian and uterine lesions. Each patient underwent an unenhanced (baseline) and a contrast enhanced ultrasound evaluation. In patients with uncertain pelvic masses and tumors suspected to represent recurrence of malignancy, the application of CnTI-SonoVue was helpful to exclude malignancy; lesions that did not show any kind of vascularization proved to be benign. In the malignant cases where color Doppler mode could not detect blood flow, CnTI-SonoVue® usually detected vascularization or enhanced the blood vessels already seen with color Doppler. As far as endometrial cancer, endometrial hyperplasia and endometrial polyps are concerned, the CnTI-SonoVue® technology did not show superiority over the B-mode evaluation in defining the margins of the lesion and in assessing the depth of myometrial invasion of endometrial cancer. In conclusion, the qualitative use of CnTI-SonoVue® technology has improved our confidence in excluding pelvic malignancy. Furthermore, the quantitative assessment seems to be a promising tool for a better distinction between malignant and benign adnexal tumors.

Contrast-enhanced intraoperative ultrasonography in surgery for liver tumors

IOUS is the most accurate diagnostic technique for assessing focal liver lesions, but still has some drawbacks. Contrast-enhanced ultrasound examination done intraoperatively (CE-IOUS), using second generation contrast agents (SonoVue ®, Bracco-Imaging, Milan, Italy), seems able to overcome those aforementioned lacking aspects of IOUS. In cirrhotic patients with hepatocellular carcinoma (HCC), CE-IOUS provides information about tumor vascularity which are useful for nodules differentiation: this should improve the surgical radicality. Furthermore, two different pattern of enhancement are also recognizable at CE-IOUS in those HCC nodules depicted preoperatively: one of them has no similarity with that observed at computed tomography (CT). In patients who undergo surgery for colorectal liver metastases, CE-IOUS seems to improve the sensitivity of IOUS to small, hypoechoic lesions, reducing the risk to down-stage the disease and enhancing the rate of treatment with curative intent. In conclusion, IOUS accuracy is improved by CE-IOUS with an impact on surgical strategy either for primary than for metastatic tumors. Furthermore, a wider experience with vascular enhancement patterns at CE-IOUS could provide new classification for liver lesions.

Usefulness of contrast-enhanced perfusional sonography in the assessment of hepatocellular carcinoma hypervascular at spiral computed tomography

Background/Aims Diagnosis of hepatocellular carcinoma (HCC) relies strongly on the detection of hypervascularity in the arterial phase and, in this setting, spiral computed tomography (CT) is the most widely used method. This prospective study aimed to investigate the usefulness of low mechanical index harmonic ultrasound (US), using a second generation contrast-enhanced technique, in the assessment of vascular pattern of HCC shown to be hypervascular at spiral CT. Methods A total of 79 cirrhotic patients with 103 nodules (mean±SD 28±13 mm) with arterial hypervascularity at spiral CT were studied. US examination was performed by perfusional sonography, using a new dedicated technology (CnTI-Esaote™), operating at low mechanical index, after injection of a second generation contrast agent (SonoVue™-Bracco), allowing detection of tumoral flow during arterial phase. Results Selective arterial enhancement on perfusional sonography was observed in 94 /103 nodules (91.3%), with a sensitivity of 66.6, 87.5, 91.7, and 97.3% in nodules ≤1 cm, >1≤2 cm, >2≤3 cm, and >3 cm respectively. Conclusions Perfusional sonography shows good diagnostic agreement with spiral CT in hypervascular HCC and may be proposed for the immediate vascular characterization of nodules detected at US and used as second imaging technique to confirm hypervascularity in cirrhotic nodules.

Échographie de contraste dans l’exploration des lésions focales hépatiques : valeur diagnostique et recommandations

The recent introduction of high quality scanners and contrast agents for ultrasound deeply modifies diagnosis strategy in focal liver lesions by using validated criteria. Non-linear imagingmethods using low mechanical index (MI< 0.2) and second generation contrast agents allow real-time continuous imaging withconcomitant limitation in background tissue signal and also in agent collapse for a high quality contrast imaging giving dramatic improvement in detection and characterization of lesions. Interpretation is based on the presence of contrast agent within the lesion or not (hyper-, hypo- or isosignal) and the delay after injection (arterial, portal or parenchymal or late phase) as previously used by non-ultrasound methods. This allows an easy differentiation of benign from malignant lesions. Moreover, this allowscomplete characterization in 85 to 95% of all focal liver lesions and 75% in hepatocellular carcinomas. Those results markedly improve ultrasound accuracy compared to conventional sonography and so put contrast-enhanced sonography among recommended non-invasive imaging methods for focal liver lesions with changes in diagnostic strategy according to the lesion type and actual place of US methods. It is recommended to use contrast ultrasound methods in cancer staging for an optimaldetection of liver metastases as well as in characterization of lesions detected during conventional sonography with a consecutive decrease of cost-diagnosis ratio.

Simultaneous acquisition of multiple orders of intermolecular multiple-quantum coherence images in vivo

Until recently, NMR imaging with intermolecular multiple-quantum coherences (iMQCs) has been based on the acquisition of a single echo. In vivo studies of iMQC image contrast would greatly benefit from a method that could acquire several orders of quantum coherence during the same acquisition. This would enable comparison of the image contrast for various orders and eliminate image coregistration problems between scans. It has previously been demonstrated that multiple orders of iMQC images can be simultaneously acquired of a simple phantom. Here, we examine the technique and its effect on biological tissue, both in vivo and in vitro. First, we establish the effectiveness of the iMQC sequence in vivo using earthworms as specimens. We then further show that the multi-CRAZED sequence enhances detection of next generation (nanoparticle) contrast agents on excised tumor tissue.

485 Cost-effectiveness of second generation contrast agents in stress echocardiography

485 Cost-effectiveness of second generation contrast agents in stress echocardiography

The Added Clinical Value of Second Generation Ultrasound Contrast Agents

Intravenous contrast echocardiography using second generation contrast agents improves wall motion analysis in difficult-to-image patients and increases diagnostic accuracy of stress echocardiography. New and still experimental technology enables simultaneous evaluation of myocardial perfusion and wall motion. First clinical and experimental studies demonstrate an acceptable diagnostic accuracy of intravenous contrast echocardiography in detecting stress-induced ischemia and in differentiating viable from irreversibly damaged myocardium. Current data encourage the use of intravenous contrast echocardiography to evaluate microvascular integrity in patients with unstable angina and in acute infarction following coronary revascularization. However, attenuation artefacts may limit interpretation of findings in basal myocardial segments. Standardization of the method on the basis of more solid data derived from large clinical trials is needed before introducing intravenous myocardial contrast echocardiography into clinical practice.

P134: Transvaginal sonography associated with a second generation contrast agent (SonoVue) for evaluation of adnexal masses: a preliminary study

P134: Transvaginal sonography associated with a second generation contrast agent (SonoVue) for evaluation of adnexal masses: a preliminary study

Characterization of Focal Liver Lesions with Pulse Inversion Harmonic Imaging (PIHI) Using a Second Generation US Contrast Agent

First generation ultrasound (US) contrast agents are made by air microbubbles stabilized by albumin or D-galactose. Second generation US contrast agents comprise agents made of stabilized microbubbles of gases of high molecular weight and low solubility in water, which provide a higher resistance to US pulse pressure and a longer persistence in the bloodstream than first generation agents (1,2). Furthermore, the second generation contrast agents have a good harmonic response even at mid and low mechanical index (MI).

Which continuous US scanning mode is optimal for the detection of vascularity in liver lesions when enhanced with a second generation contrast agent?

Objectives: Microbubble echo-enhancers help in the assessment of focal liver masses by enhancing the signal from blood vessels. A variety of linear and nonlinear scanning modes are now available, but it is unclear which is optimal. A controlled comparison was performed during the infusion of such an agent (SonoVue: Bracco, Milan, Italy). Methods and materials: Ten patients with known focal liver lesions were studied. The diagnoses, confirmed on dual phase helical computed tomography (CT) at the same attendance were metastasis ( n=7), haemangioma ( n=2) and focal nodular hyperplasia FNH ( n=1). A dose of 12 ml SonoVue concentrated at 5 mg/ml was infused intravenously at a rate of 1 ml/min. The enhancement level was monitored with a continuous wave (CW) Doppler probe over the right radial artery and the intensity of the signal was registered at 1 s intervals. When a plateau of enhancement was reached, a single lesion in each patient was imaged using five different continuous scanning modes, fundamental grey scale (FGS); fundamental colour Doppler (FCD); fundamental power Doppler (FPD); second harmonic grey scale (HGS); and pulse inversion mode (Pim) using an HDI5000 scanner and C5-2 probe (ATL, Bothell, WA). The order of scanning modes was varied between patients using a predefined randomisation protocol. The videos (super video home system (SVHS)) were analysed offsite by two blinded readers, both experienced in contrast ultrasound of the liver. The readers were asked to score each mode in terms of its ability to detect vessels within/around the lesion at optimal enhancement. This was done using a ranking system (1, worst; 5, best) for each patient. Results: Both observers scored FPD as the optimal imaging method, followed by Pim. (Scores summed across all patients, observer 1: FPD 48, Pim 42, FCD 37, HGS 21, FGS 10; observer 2: FPD 49, Pim 40, FCD 38, HGS 21, FGS 10). The differences from FPD were significant for FCD, HGS and FGS using a unpaired analysis of variance (ANOVA) comparison, with Bonferroni multiple corrections, ( P<0.01, both observers). The differences between FPD and Pim were also significant both for observer 2 and for both observers combined ( P<0.01), but did not reach significance for observer 1 ( P=0.19). Conclusions: In this study, FPD performed best, and the non-linear modes, performed continuously (pulse inversion and second HGS), showed no clear advantage.

Microvessel injury induced by ultrasound exposure with first generation contrast agent: Dominantly damaged venular and capillary endothelium Nobuhiko Kobayashi, Takanori Yasu, Masatoshi Kuroki, Masanobu Kawakami, Muneyasu Saito. Jichi Medical School Omiya Medical Center, Omiya, Japan

Microvessel injury induced by ultrasound exposure with first generation contrast agent: Dominantly damaged venular and capillary endothelium Nobuhiko Kobayashi, Takanori Yasu, Masatoshi Kuroki, Masanobu Kawakami, Muneyasu Saito. Jichi Medical School Omiya Medical Center, Omiya, Japan

Characteristics of SonoVuetrade mark.

The advances made by ultrasonography in the last decade, in parallel with the development of ultrasound contrast agents, have opened a wide range of potential breakthroughs in the field of ultrasound imaging. SonoVue(trade mark) is a new echocontrast agent made of microbubbles stabilized by phospholipids and containing sulphur hexafluoride (SF6), an innocuous gas. The suspension of the microbubbles is stable over the time following reconstitution. The bubble concentration of SonoVue(trade mark) is between 100 and 500 million per ml. The mean bubble diameter is 2.5 µm and more than 90% of the bubbles are smaller than 8 µm. Following intravenous injection, the bubble suspension is submitted to pressure increases. SF(6), a high molecular weight gas with low solubility in water, was selected since laboratory tests showed that it confers to the bubbles a good resistance to pressure changes as those that occur in the left ventricle, in the pulmonary capillaries, or in the coronary circulation. The high bubble concentration, combined with a favorable size distribution profile, provides SonoVue(trade mark) with a strong echogenicity. SonoVue(trade mark) shows a peak in the backscatter coefficient at about 3 MHz. With regard to the gas contained in the bubbles, its pharmacokinetics have been assessed during a study in human volunteers. Following intravenous administration of 0.3 ml/kg of SonoVue(trade mark) (i.e., approximately ten times the imaging dose), the blood level curve showed a distribution half-life of about 1 minute and an elimination half-life of about 6 minutes. More than 80% of the administered gas is exhaled via the lungs after 11 minutes. Extensive studies in animals and humans have confirmed the outstanding safety profile of this second generation contrast agent and its capability in providing a clinically useful ultrasound signal enhancement for the evaluation of cardiac function and extracardiac vessel abnormalities. Thanks to the long persistence of SF(6) microbubbles, SonoVue(trade mark) is also potentially useful in the assessment of myocardial perfusion, as well as microcirculatory disorders.

Contrast echocardiography as an intraoperative method to determine the area of myocardium perfused by transmyocardial laser channels: an experimental study.

Transmyocardial laser revascularization (TMLR) of the ischemic myocardium has been recognized as a potentially useful adjunct in the treatment of coronary arterial heart disease. Although there are methods to visualize the induced channels, they have been complex or concerned with long-term patency. The present work was designed as a feasibility study to determine whether contrast echocardiography could provide a simple and rapid method to assist the surgeon in determining the extent of the TMLR-treated area. Transmyocardial channels were created in five Targhee adult sheep myocardium using a Holmium-YAG laser over the area supplied by the second diagonal branch. A commercially developed echocontrast agent (Optison) was injected into the left atrium. Passage of the dye through the myocardium was observed by epicardial echocardiography in all the animals. The current study shows that contrast echocardiography using a newer generation contrast agent capable of enhanced and persistent opacification of left ventricular cavity may serve as an effective tool in delineating intraoperatively the area of myocardium treated with TMLR.

Evaluation of dynamic changes in microvascular flow during ischemia-reperfusion by myocardial contrast echocardiography

Background. Dynamic changes of myocardial blood flow have been observed after reperfusion of an occluded coronary artery. MCE performed by intracoronary contrast injection can provide an estimate of microvascular flow. We hypothesized that MCE performed using intravenous infusion of a new generation contrast agent and electrocardiogram-gated harmonic imaging would be able to assess serial changes of microvascular perfusion.Objective. To study the potential of myocardial contrast echocardiography (MCE) to assess serial changes of microvascular flow during ischemia-reperfusion.Methods. Sixteen dogs underwent 90 or 180 min of left anterior descending coronary occlusion, followed by 180 min of reperfusion. Regional blood flow (RBF) was measured with fluorescent microspheres at baseline, during coronary occlusion, and at 5, 30, 90, and 180 min during reperfusion. At the same time points, MCE was performed with intravenous infusion of AF0150 (4 mg/min). Gated end-systolic images in short axis were acquired in harmonic mode and digitized on-line. Background-subtracted videointensity measured from MCE and RBF obtained from fluorescent microspheres were calculated for the risk area and for a control area, and were expressed as the ratio of the two areas.Results. After initial hyperemia, a progressive reduction in flow was observed during reperfusion. MCE correctly detected the time course of changes in flow during occlusion-reperfusion. Videointensity ratio significantly correlated with RBF data (r = 0.79; p < 0.0001).Conclusions. The progressive reduction in blood flow occurring within the postischemic microcirculation was accurately detected by MCE. This approach has potential application in the evaluation and management of postischemic reperfusion in humans.