AJR InPractice
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow VIDEO
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Wilson, S. R.
Right arrow Articles by Goldberg, B. B.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wilson, S. R.
Right arrow Articles by Goldberg, B. B.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Hotlight (NEW!)
Right arrow
What's Hotlight?
DOI:10.2214/AJR.09.2553
AJR 2009; 193:55-60
© American Roentgen Ray Society

Review

Contrast-Enhanced Ultrasound: What Is the Evidence and What Are the Obstacles?

Stephanie R. Wilson1, Lennard D. Greenbaum2 and Barry B. Goldberg3

1 Department of Diagnostic Imaging, Foothills Medical Centre, 1403 29 St., NW, Calgary, AB T2N 2T9, Canada.
2 The Hughes Center for Fetal Diagnostics, Winnie Palmer Hospital for Women & Babies, Orlando, FL.
3 Division of Ultrasound, Thomas Jefferson University Hospital, Philadelphia, PA.

Received February 9, 2009; accepted after revision March 23, 2009.

 
S. R. Wilson has an advisory role for ultrasound for Philips Healthcare and Siemens Medical Solutions and received a research grant from Lantheus Medical Imaging. L. D. Greenbaum performs premarket equipment evaluations for Philips Healthcare.

Address correspondence to S. R. Wilson (stephanie.wilson{at}albertahealthservices.ca).

FOR YOUR INFORMATION

A data supplement for this article can be viewed in the online version of the article at: www.ajronline.org.


Abstract
Top
 Abstract
Introduction
 The Evidence
 The Obstacles
 References
 
OBJECTIVE. Although ultrasound contrast agents (UCAs) are popular and widely used in Europe and Asia, the U.S. Food and Drug Administration (FDA) has not approved a microbubble agent for radiology imaging in the United States. Herein, we discuss the evidence for and the obstacles to using UCAs for contrast-enhanced ultrasound (CEUS).

CONCLUSION. Despite the obstacles to the use of UCAs for CEUS including regulatory and practice patterns, the evidence indicates that radiologists and patients will be missing an effectual imaging option if we do not encourage the use of CEUS and strongly support the approval of UCAs by the FDA. The evidence outweighs the obstacles: CEUS is cost-effective; can be performed at the bedside; uses no ionizing radiation; has no nephrotoxicity; and, most importantly, can provide accurate diagnostic information comparable to CT and MRI.

Keywords: contrast-enhanced ultrasound • contrast media • FDA approval • radiology practice guidelines • ultrasound contrast agents


Introduction
Top
 Abstract
 Introduction
The Evidence
 The Obstacles
 References
 
Contrast-enhanced ultrasound (CEUS) involves the use of microbubble contrast agents and specialized imaging techniques to show sensitive blood flow and tissue perfusion information. CEUS is a safe and easily performed technique with no requirement for ionizing radiation and no risk of nephrotoxicity. Although popular and widely used in Europe and Asia, the U.S. Food and Drug Administration (FDA) has not approved a microbubble agent for radiology imaging in the United States. Herein, we discuss the evidence and the obstacles.


The Evidence
Top
 Abstract
 Introduction
 The Evidence
The Obstacles
 References
 
The role of conventional ultrasound for imaging many organs of the body is limited by the capabilities of conventional color and spectral Doppler imaging. Although Doppler imaging may provide valuable directional blood flow information, it is most effective for evaluating large blood vessels with fast-flowing blood such as the carotid arteries; leg veins; and major visceral vessels of the abdomen, including the portal veins and hepatic arteries. The ability of Doppler imaging to detect blood flow at the perfusion level is limited.

The remedy for this problem is to add microbubble contrast agents and specialized ultrasound imaging techniques. The former enhances the Doppler signal from blood, whereas the latter serves to suppress the signals from the background tissue while enhancing the sensitivity to the Doppler signals from the microbubbles within the blood pool. These additions allow ultrasound imaging of blood flow at the tissue perfusion level, thus enabling ultrasound to play a competitive role relative to CT and MRI in the evaluation of the solid and hollow organs of the abdomen and pelvis.

Contrast-enhanced ultrasound (CEUS) shows tissue perfusion analogous to that shown on contrast-enhanced CT and MRI in which patterns of enhancement in the arterial and portal venous phases predict diagnoses of focal liver lesions (Figs. 1A, 1B, 1C, 1D, 1E, and 1F). After the injection of microbubbles, maximum-intensity-projection (MIP) techniques may add the information between ultrasound frames, thereby tracking the course of the microbubbles and allowing superior depiction of vessel morphology on CEUS as compared with either CT or MRI, when performed with a similar venous injection of contrast agent [1] (Figs. 2A, 2B, 2C, 2D, 2E, and 2F).


Figure 1
View larger version (105K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 1A —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Baseline transverse ultrasound image shows mixed echogenic mass in cirrhotic liver.

 

Figure 2
View larger version (85K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 1B —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Arterial phase CEUS image shows hypervascular mass.

 

Figure 3
View larger version (109K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 1C —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Portal venous phase CEUS image obtained at 150 seconds shows washout of lesion such that it is now less enhanced than adjacent liver.

 

Figure 4
View larger version (158K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 1D —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Unenhanced CT image shows lesion is hypoattenuating.

 

Figure 5
View larger version (179K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 1E —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Contrast-enhanced arterial phase CT image shows lesion is hypervascular.

 

Figure 6
View larger version (174K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 1F —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Portal venous phase image shows lesion has washed out. Both CT and CEUS suggest hepatocellular carcinoma.

 

Figure 7
View larger version (127K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2A —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Baseline sagittal image shows bulbous expansion of tip of left lobe of liver.

 

Figure 8
View larger version (80K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2B —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Sequential images obtained in arterial phase of CEUS show stellate vascularity, centrifugal filling, and homogeneous hypervascularity at peak enhancement (E).

 

Figure 9
View larger version (94K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2C —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Sequential images obtained in arterial phase of CEUS show stellate vascularity, centrifugal filling, and homogeneous hypervascularity at peak enhancement (E).

 

Figure 10
View larger version (109K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2D —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Sequential images obtained in arterial phase of CEUS show stellate vascularity, centrifugal filling, and homogeneous hypervascularity at peak enhancement (E).

 

Figure 11
View larger version (119K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2E —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Sequential images obtained in arterial phase of CEUS show stellate vascularity, centrifugal filling, and homogeneous hypervascularity at peak enhancement (E).

 

Figure 12
View larger version (112K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2F —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Image in portal venous phase at 3 minutes shows sustained contrast enhancement and central nonenhancing scar (arrow).

 
Microbubble contrast agents are composed of tiny bubbles of an injectable gas in a supporting shell. The compelling evidence for the introduction of such agents to the United States environment includes their ease of use, contribution to positive patient care, and favorable safety profile [2]. Piscaglia and Bolondi [3], in a retrospective review of European experience with the use of microbubble contrast agents in more than 23,000 patients, reported only two serious adverse events and no deaths. Microbubble contrast agents are not nephrotoxic and may be used in patients with any level of renal function. Further, their use is not associated with ionizing radiation, an important factor in this era of increasing awareness about the risks associated with excess exposure to CT [4].

The actual performance of CEUS requires contrast-specific software on the ultrasound equipment that suppresses the signal from the background tissue leaving only the signal from the microbubbles. This is accomplished by various techniques, the most common of which is pulse inversion whereby two signals are sent down a single scan line and the second is a mirror image of the first. Echoes from both pulses are collected by the transducer and summed. Linear reflectors, such as normal tissue, produce no net signal. However, nonlinear reflectors, such as microbubbles, produce echoes that are asymmetric and do not sum to zero. The result is that echoes from bubbles are detected preferentially using this method, improving image contrast between tissue and microbubbles. If the sound is transmitted at a low mechanical index (MI), the microbubble population is preserved and long periods—up to several minutes—of observation are possible. Low-MI techniques comprise the standard imaging methods used today for CEUS. Conversely, if the sound is transmitted at a high MI, the bubbles may be destroyed in a single pulse. This facilitates a flash replenishment technique whereby the bubbles can be visualized refilling the liver or tumor after their destruction, which is optimal for visualization of vessel morphology in characterization studies.

Liver mass characterization is the most established and successful indication for the performance of CEUS [5-8]. Investigators have shown that simple algorithms allow diagnosis of most liver masses [9]. Reflective of many published studies reporting the success of CEUS for this indication, Ding et al. [6], in a study of 147 tumors using established and familiar diagnostic criteria, reported a high sensitivity of 96.3% and 97.5% specificity for the diagnosis of hemangioma and a very credible low of 92% sensitivity and 86.7% specificity for hepatocellular carcinoma. Therefore, CEUS can rapidly characterize incidentally detected masses found on conventional ultrasound or other techniques. Further, CEUS is valuable for the evaluation of nodules in the patient at risk for hepatocellular carcinoma [10, 11] and for the often-difficult differentiation between adenoma and focal nodular hyperplasia in asymptomatic young women [12-15].

Washout of contrast agent in the portal venous phase of liver mass evaluation with CEUS has been shown to have a high association with malignant histology [9], although benign lesions may also show washout. The timing of washout on CEUS adds further specificity in that metastases of any cell type generally show complete and rapid washout in the conventional time frame defined as the arterial phase [16, 17], whereas hepatocellular carcinoma often shows incomplete and slow washout [10].

Detection of liver masses is also greatly improved with CEUS in that more masses and smaller masses may be shown than can be seen on conventional ultrasound scans [18, 19] (Figs. 3A, 3B, and 3C). Albrecht et al. [19], in a description of 123 patients, showed the addition of CEUS improved sensitivity for the detection of individual metastases from 71% to 87% (p < 0.001). On a per-patient basis, sensitivity improved from 94% to 98% (p = 0.44) and specificity improved from 60% to 88% (p < 0.01).


Figure 13
View larger version (110K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 3A —Advantage of contrast-enhanced ultrasound (CEUS) for detection of liver metastases is shown in 72-year-old man with metastatic colon cancer. Baseline transverse sonogram shows gross steatosis and focal superficial mass in segment IV. Second tiny mass (arrow) may be present.

 

Figure 14
View larger version (100K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 3B —Advantage of contrast-enhanced ultrasound (CEUS) for detection of liver metastases is shown in 72-year-old man with metastatic colon cancer. Portal venous phase CEUS image of known mass shows typical complete washout so that mass is now more conspicuous, appearing black, relative to enhanced parenchyma. Second smaller mass (arrow) is confirmed.

 

Figure 15
View larger version (46K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 3C —Advantage of contrast-enhanced ultrasound (CEUS) for detection of liver metastases is shown in 72-year-old man with metastatic colon cancer. Sweep through liver shows two additional metastases in segment VI that are obvious here but were unsuspected on baseline scan (A).

 
CEUS applications continue to grow [20] for the evaluation of focal pathology in the kidney [21, 22], pancreas, spleen, breast, ovary [23], and prostate. CEUS evaluation of the vasa vasorum in carotid plaque reflects the inflammation and degeneration associated with atherosclerosis [24, 25]. Research pursuits offer promise of future lymphatic mapping with detection of tumor deposits in sentinel lymph nodes [26]. Pure vascular applications include monitoring of aortic stentgrafts [27] and also determination of major blood vessel patency, such as the hepatic artery after liver transplantation.

The impact of the introduction of CEUS on an ultrasound practice is addressed in two retrospective reviews of more than 1,000 patients each in which CEUS was performed for liver mass characterization using two different second-generation contrast agents [28, 29]. In both studies, the accuracy of diagnosis of CEUS in patients with pathology confirmation was identical at 89%. Both also document a similar reduction in time to diagnosis; reduction in referral for CT, MRI, or both; and a positive contribution to patient management in 17.5% and 15.6%, respectively. The negative impact from CEUS was very low in both studies at 0.8% and 1.7%, respectively.


The Obstacles
Top
 Abstract
 Introduction
 The Evidence
 The Obstacles
References
 
With such compelling evidence of the efficacy of CEUS and with the extensive use of microbubble contrast agents throughout Europe and Asia, why are ultrasound contrast agents (UCAs) rarely used for body imaging in the United States? The answers fall into two categories: regulatory and practice patterns. The regulatory issues involve the FDA.

There are three major manufacturers of UCAs: Bracco Imaging (Milano, Italy), GE Healthcare (Little Chalfont, United Kingdom), and Lantheus Medical Imaging (North Billerica, MA). Two second-generation perfluorocarbon contrast agents, perflutren protein-type A microspheres for injection (Optison, GE Healthcare) and perflutren lipid microsphere injectable suspension (Definity, Lantheus Medical Imaging), have been approved by the FDA for left ventricular opacification. However, no agent has been approved for a noncardiac use in the United States. By 2005, this approval process had come to a standstill because of safety concerns of the FDA and the extent and type of information requested by the FDA in the design of suggested clinical trials (Greenbaum L, personal communication with FDA, Bracco Imaging, GE Healthcare, and Bristol-Myers Squibb). The safety issue was primarily with one agent; during its after-marketing surveillance, three deaths were reported.

The information issues include a requirement in previous clinical trials conducted in the United States to use contrast-enhanced CT, contrast-enhanced MRI, or both as the reference standard. Furthermore, there are also cross-platform problems because previous clinical trials performed in the hope of gaining a radiology approval have shown great inconsistencies in the performance of CEUS depending on the type of ultrasound equipment used. The American Institute of Ultrasound in Medicine (AIUM) was concerned about this standstill and formed a task force to address the problem in 2005.

As a result of efforts from the AIUM task force, there were several meetings with the FDA during 2005 and 2006, including an extensive educational session presented by the AIUM to the FDA staff in March 2006. At that time, the FDA asked the AIUM to write a protocol for the performance of a clinical trial using UCAs to image the liver. This protocol was accepted by the FDA later that year and was subsequently published [30]. Key issues addressed were appropriate end points, examination procedures, equipment criteria, safety, and training. Perhaps the most significant recommendation for a possible trial was that the comparison should be CEUS versus non-CEUS and not CEUS versus contrast-enhanced CT or MRI.

Unfortunately, as the AIUM initiative was moving forward, all progress came to an abrupt halt on October 10, 2007, when the FDA issued a "black box warning" on the labeling for the two approved UCAs in the United States, Definity and Optison [31]. The warning greatly expanded the list of contraindications for using these agents and also mandated a 30-minute monitoring period after their use in all patients. This significantly affected the cardiology community because the new contraindications for use restricted cardiologists from using Definity or Optison on the very patients who benefited most from contrast-enhanced echocardiography [32, 33]. Further, the warning was another impediment to the use of UCAs by radiologists who were already burdened by the lack of an approved radiology indication.

A grassroots action started in response with a letter to the FDA signed by 161 physicians from the United States and the international community. Many radiologists in the United States participated. A group of cardiologists subsequently met with the FDA in December 2007 to present their objections to the black box warning, present additional safety information, and request the convening of an advisory panel (Feinstein SB, personal communication). Based on the new safety information, on May 13, 2008, the FDA modified the black box warning by rescinding the new contraindications and requiring monitoring only in patients with pulmonary hypertension or unstable cardiopulmonary conditions [34].

There have been ongoing interactions with the FDA, including testimony on June 24, 2008, at the FDA Cardiovascular and Renal Drugs Advisory Committee meeting titled "Safety Considerations in the Development of Ultrasound Contrast Agents." However, there still is no FDA-approved radiology indication for the use of UCAs. Although there has been off-label use by radiologists, there is no reimbursement for the use of UCAs. Despite this obstacle, the future looks promising. In September 2008, Bracco announced that it would initiate an American clinical trial based on the AIUM protocol for the characterization of focal liver lesions using CEUS (Bokor D, Bracco, personal communication). In addition, in response to the actions of the FDA, a group of radiologists and cardiologists joined forces to form the International Contrast Ultrasound Society to promote the use of UCAs, respond to regulatory agencies, and educate the medical community and public about the benefits of UCAs.

The other obstacle for radiologists using CEUS has to do with practice patterns. For the purposes of this discussion, we will limit the use of CEUS to imaging of the liver, the most common noncardiac use worldwide. Liver imaging in the United States is performed almost exclusively by radiologists, and they primarily use CT and MRI. Obtaining CT or MR studies is dependent on radiologic technologists following established protocols for all examinations. These technologists are highly skilled but little, if any, "art" is required. Although performing occasional examinations may require specialized imaging, for the most part, the radiologist can sit at his or her PACS station and wait for the examination to be placed on the work list. By comparison, CEUS is a dynamic examination that depends on the skill of the sonographer and requires the active participation of the sonologist. Therefore, it cannot compete with CT or MRI from an efficiency and productivity point of view. Add to this the differences in reimbursement based on relative value units between ultrasound and CT or MRI (Encoder Pro, Ingenix) and the fact that CEUS is currently not reimbursable. Therefore, radiologists have little incentive to use CEUS other than intellectual curiosity. However, recent concerns about excess ionizing radiation from CT and renal toxicity from MRI contrast agents have opened a window of opportunity for CEUS.

Despite all these obstacles, radiologists and patients will be missing an effectual imaging option if we do not encourage the use of CEUS and strongly support the approval of UCAs by the FDA. CEUS is cost-effective; can be performed at the bedside; uses no ionizing radiation; has no nephrotoxicity; and, most importantly, can provide accurate diagnostic information comparable to CT and MRI: The evidence outweighs the obstacles.


References
Top
 Abstract
 Introduction
 The Evidence
 The Obstacles
 References
 

  1. Wilson SR, Jang HJ, Kim TK, Iijima H, Kamiyama N, Burns PN. Real-time temporal maximumintensity-projection imaging of hepatic lesions with contrast-enhanced sonography. AJR 2008;190 : 691-695[Abstract/Free Full Text]
  2. Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients). Am J Cardiol2008; 102:1742 -1746[CrossRef][Medline]
  3. Piscaglia F, Bolondi L. The safety of SonoVue in abdominal applications: retrospective analysis of 23,188 investigations. Ultrasound Med Biol 2006;32 : 1369-1375[CrossRef][Medline]
  4. Brenner DJ, Hall EJ. Computed tomography: an increasing source of radiation exposure. N Engl J Med 2007;357 : 2277-2284[Free Full Text]
  5. Leen E, Ceccotti P, Kalogeropoulou C, Angerson WJ, Moug SJ, Horgan PG. Prospective multicenter trial evaluating a novel method of characterizing focal liver lesions using contrast-enhanced sonography. AJR 2006; 186:1551 -1559[Abstract/Free Full Text]
  6. Ding H, Wang WP, Huang BJ. Imaging of focal liver lesions low-mechanical-index real-time ultrasonography with SonoVue. J Ultrasound Med 2005; 24:285 -297[Abstract/Free Full Text]
  7. Quaia E, Degobbis F, Tona G, Mosconi E, Bertolotto M, Pozzi Mucelli R. Differential patterns of contrast enhancement in different focal liver lesions after injection of the microbubble US contrast agent SonoVue [in English and Italian]. Radiol Med 2004;107 : 155-165[Medline]
  8. Wilson SR, Jang HJ, Kim TK, Burns PN. Diagnosis of focal liver masses on ultrasonography: comparison of unenhanced and contrast-enhanced scans. J Ultrasound Med 2007;26 : 775-787; quiz, 788-790[Abstract/Free Full Text]
  9. Wilson SR, Burns PN. An algorithm for the diagnosis of focal liver masses using microbubble contrast-enhanced pulse-inversion sonography. AJR 2006; 186:1401 -1412[Abstract/Free Full Text]
  10. Jang HJ, Kim TK, Burns PN, Wilson SR. Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation. Radiology 2007;244 : 898-906[Abstract/Free Full Text]
  11. Nicolau C, Catala V, Vilana R, et al. Evaluation of hepatocellular carcinoma using SonoVue, a second generation ultrasound contrast agent: correlation with cellular differentiation. Eur Radiol2004; 14:1092 -1099[CrossRef][Medline]
  12. Kim TK, Jang HJ, Burns PN, Murphy-Lavallee J, Wilson SR. Focal nodular hyperplasia and hepatic adenoma: differentiation with low-mechanical-index contrast-enhanced sonography. AJR2008; 190:58 -66[Abstract/Free Full Text]
  13. Ungermann L, Elias P, Zizka J, Ryska P, Klzo L. Focal nodular hyperplasia: spoke-wheel arterial pattern and other signs on dynamic contrast-enhanced ultrasonography. Eur J Radiol2007; 63:290 -294[CrossRef][Medline]
  14. Yen YH, Wang JH, Lu SN, et al. Contrast-enhanced ultrasonographic spoke-wheel sign in hepatic focal nodular hyperplasia. Eur J Radiol 2006; 60:439 -444[CrossRef][Medline]
  15. Dietrich CF, Schuessler G, Trojan J, Fellbaum C, Ignee A. Differentiation of focal nodular hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound. Br J Radiol2005; 78:704 -707[Abstract/Free Full Text]
  16. Murphy-Lavallee J, Jang HJ, Kim TK, Burns PN, Wilson SR. Are metastases really hypovascular in the arterial phase? The perspective based on contrast-enhanced ultrasonography. J Ultrasound Med2007; 26:1545 -1556[Abstract/Free Full Text]
  17. Quaia E, D'Onofrio M, Palumbo A, Rossi S, Bruni S, Cova M. Comparison of contrast-enhanced ultrasonography versus baseline ultrasound and contrast-enhanced computed tomography in metastatic disease of the liver: diagnostic performance and confidence. Eur Radiol2006; 16:1599 -1609[CrossRef][Medline]
  18. Leen E, Ceccotti P, Moug SJ, et al. Potential value of contrast-enhanced intraoperative ultrasonography during partial hepatectomy for metastases: an essential investigation before resection? Ann Surg 2006; 243:236 -240[CrossRef][Medline]
  19. Albrecht T, Blomley MJ, Burns PN, et al. Improved detection of hepatic metastases with pulse-inversion US during the liver-specific phase of SHU 508A: multicenter study. Radiology2003; 227:361 -370[Abstract/Free Full Text]
  20. Weskott HP. Emerging roles for contrast-enhanced ultrasound. Clin Hemorheol Microcirc 2008;40 : 51-71[Medline]
  21. Robbin ML, Lockhart ME, Barr RG. Renal imaging with ultrasound contrast: current status. Radiol Clin North Am2003; 41:963 -978[CrossRef][Medline]
  22. Correas JM, Claudon M, Tranquart F, Hélénon O. Contrast-enhanced ultrasonography: renal applications [in French]. J Radiol 2003;84 (12 Pt 2):2041 -2054[Medline]
  23. Fleischer AC, Lyshchik A, Jones HW Jr, et al. Contrast-enhanced transvaginal sonography of benign versus malignant ovarian masses: preliminary findings. J Ultrasound Med 2008;27 : 1011-1018; quiz, 1019-1021[Abstract/Free Full Text]
  24. Granada JF, Feinstein SB. Imaging of the vasa vasorum. Nat Clin Pract Cardiovasc Med 2008;5 [suppl 2]:S18 -S25[CrossRef][Medline]
  25. Coli S, Magnoni M, Sangiorgi G, et al. Contrast-enhanced ultrasound imaging of intraplaque neovascularization in carotid arteries: correlation with histology and plaque echogenicity. J Am Coll Cardiol 2008; 52:223 -230[Abstract/Free Full Text]
  26. Goldberg BB, Merton DA, Liu JB, Murphy G, Forsberg F. Contrast-enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes. J Ultrasound Med 2005;24 : 953-965[Abstract/Free Full Text]
  27. Dill-Macky MJ, Wilson SR, Sternbach Y, Kachura J, Lindsay T. Detecting endoleaks in aortic endografts using contrast-enhanced sonography. AJR 2007; 188:830; [web]W262-W268
  28. Tombesi P, Catellani M, Abbasciano V, Sartori S, Tassinari D. Impact of contrast-enhanced ultrasonography in a tertiary clinical practice. J Ultrasound Med 2008;27 : 991-992[Free Full Text]
  29. Lanka B, Jang HJ, Kim TK, Burns PN, Wilson SR. Impact of contrast-enhanced ultrasonography in a tertiary clinical practice. J Ultrasound Med 2007;26 : 1703-1714[Abstract/Free Full Text]
  30. Greenbaum L, Burns P, Copel J, et al.; American Institute of Ultrasound in Medicine. American Institute of Ultrasound in Medicine recommendations for contrast-enhanced liver ultrasound imaging clinical trials. J Ultrasound Med 2007;26 : 705-716[Free Full Text]
  31. U.S. Food and Drug Administration Website. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research. www.fda.gov/medwatch/safety/2007/oct07.htm#Definity. Published October 2007. Revised July 31, 2008. Accessed April 16, 2009
  32. Main ML, Goldman JH, Grayburn PA. Thinking outside the "box": the ultrasound contrast controversy. J Am Coll Cardiol 2007; 50:2434 -2437[Abstract/Free Full Text]
  33. Keen CE. Ultrasound contrast advocates take aim at FDA black box warning. www.auntminnie.com/index.asp?Sec=sup&Sub=ult&Pag=dis&ItemId=79499&d=1. Published January 3, 2008. Updated March 7, 2008. Accessed April 16, 2009
  34. U.S. Food and Drug Administration Website. FDA alert: information for healthcare professionals—Micro-bubble contrast agents (marketed as Definity [perflutren lipid microsphere] injectable suspension and Optison [perflutren protein-type A microspheres for injection]). www.fda.gov/cder/drug/InfoSheets/HCP/microbubbleHCP.htm. Published October 12, 2007. Updated July 17, 2008. Accessed April 16, 2009
  35. Kim TY, Jang HJ, Wilson SR. Microbubble contrast agents for ultrasound imaging: safety and efficacy in abdominal and vascular imaging. US Radiol 2008; 1:54 -57

Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow VIDEO
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Wilson, S. R.
Right arrow Articles by Goldberg, B. B.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wilson, S. R.
Right arrow Articles by Goldberg, B. B.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Hotlight (NEW!)
Right arrow
What's Hotlight?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS