BJR
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
British Journal of Radiology (2006) 79, 188-194
© 2006 British Institute of Radiology
doi: 10.1259/bjr/17790547
This Article
Right arrow Figures Only
Right arrow Full Text (PDF)
Services
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
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stewart, V R
Right arrow Articles by Sidhu, P S
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stewart, V R
Right arrow Articles by Sidhu, P S

Commentary

New directions in ultrasound: microbubble contrast

V R Stewart, MRCP, FRCR and P S Sidhu, MRCP, FRCR

Department of Radiology, King's College Hospital, Denmark Hill, London SE5 9RS, UK

Correspondence: Dr Paul S Sidhu

Ultrasound is the most frequently performed "tomographic" imaging technique which befits the perception of ultrasound as being a low cost, safe and accessible imaging modality. Widely used as a "screening" tool, particularly in liver imaging, ultrasound is often perceived as inferior to other imaging modalities such as CT and MRI in diagnostically challenging clinical situations. Both CT and MR imaging techniques make use of well established contrast agents to improve the image and hence the diagnostic potential, but with the burden of increased radiation with CT and cost with both CT and MRI. With such widespread utilization of ultrasound, it remains an enigma that until recently ultrasound had no effective contrast agent to improve imaging. The advent of microbubble contrast has brought new possibilities and, not surprisingly, recent advancement of ultrasound has been driven by research into the properties and clinical application of microbubble contrast agents.

An overview of the physical properties of microbubble agents and the interaction of the microbubbles with sound waves that produce image contrast improvement is presented in this commentary. In addition, current established clinical use is detailed and areas of potential utilization are discussed.

Microbubble contrast properties

Ultrasound contrast as a concept was first observed in cardiology practice, rather fortuitously, when it was noted on echocardiography that small air bubbles surrounding a catheter tip placed in the left ventricle during cardiac catheterization produced transient high reflections [1]. Over the decades research into producing "bubbles" for use as an ultrasound contrast agent was hampered by the need to produce bubbles that were stable in the circulation, traversed the pulmonary circulation to allow recirculation and inert to the recipient. Technological advances over the last 20 years have allowed microbubbles with the necessary characteristics to be developed and, importantly, to be diagnostically useful [2].

In order to achieve transpulmonary recirculation and to be an effective contrast agent, the microbubbles need to pass through the smallest vascular component, the capillary system, intact. The ideal diameter for this to occur is between 2 µm and 8 µm, below that of red blood cells. Enhancement life-time of the microbubble, often several minutes in the circulation, is a manifestation of microbubble design. Microbubble stability is increased by external bubble encapsulation (galactose, phospholipids, denatured albumin or poly-butyl-cyanoacrylate) with or without surfactants and using gases with a low diffusion coefficient (perfluorocarbons) or a combination of both [3]. The gas components of the microbubbles are normally eliminated via the lungs whilst the stabilizing components are eliminated via the hepato-renal route [4].

Currently the agents in clinical use are Levovist® (Schering AG, Berlin, Germany; air with a galactose/palmitic acid surfactant), SonoVue® (Bracco SpA, Milan, Italy; sulphur hexachloride with a phospholipid shell), Optison® (Nycomed/Amersham, Oslo, Norway; octafluoropropane with an albumin shell), Imagent® (Alliance Pharmaceutical, CA; perflexane lipid microsphere) and Definity® (Bristol-Meyers-Squibb, NY; octafluoropropane with a lipid shell). A newer agent is CARDIOsphere® (Point Biomedical, CA; bilayer polymer/albumin shell containing nitrogen) developed for use in cardiology.

Ultrasound techniques to exploit microbubble contrast properties

Microbubbles behave as echo enhancers, by expanding and contracting to create backscatter, on exposure to an ultrasound beam of any frequency. Microbubbles perform this task supremely well and increase the backscatter by >300 fold. Resonance of the microbubble will occur when there is a specific relationship between the bubble size and the ultrasound frequency (about 3 MHz). At low ultrasound beam power the expansion and contraction is symmetrical, therefore the bubbles oscillate in a "linear" fashion and the frequency of the scattered signal is unaltered. At higher power the microbubbles behave in "non-linear" fashion as they resist contraction under positive pressures more than expansion under negative pressures. The "non-linear" response results in emission of harmonics which are specific to the microbubbles. These harmonics occur within the range 1–20 MHz. The microbubble vibration may include both higher harmonics of the fundamental ultrasound frequency (2f, 3f, 4f etc.) and sub-harmonics (mostly f/2). The lower limit of 1 MHz relates to sub-harmonic generation when operating at 2 MHz. The upper limit is arbitrary, and could in principle extend much higher than 20 MHz. In practice the upper limit is constrained by the working bandwidth of the transducer. The bandwidth extends over a sufficient range of frequencies to enable the generated harmonics to be detected. This is typically not broad enough to detect more than the second harmonic (and sub-harmonics if needed), although other harmonics certainly exist in the backscattered signal. However, this will enable preferential imaging of microbubbles compared with the surrounding tissues.

Further increases in pressure cause the microbubbles to burst resulting in a strong non-linear echo, but this effect is transient and no further diagnostic information can be obtained until there is reperfusion of the area by intact microbubbles [2, 5, 6]. By imaging with a low mechanical index (MI) that allows for a non-linear response the amount of microbubble destruction is minimized, prolonging the effective period for diagnostic imaging. The MI (scaled by pulse amplitude and calculated from the peak rarefaction acoustic pressure and centre frequency) was conceived as a safety indicator of the potential for cavitation. It has been found useful as an approximate indicator to distinguish between high MI and low MI regimens of microbubble contrast use, although there are quantitative deficiencies for this application.

To process the resultant signal from the microbubbles, new techniques are necessary which selectively display the non-linear response from the contrast microbubbles preferentially. Pulse inversion harmonic imaging relies on the different behaviour of microbubbles exposed to consecutive pulses of inverted phase; linear signals from normal tissue cancel out whilst non-linear signals from microbubbles summate to produce an image [7]. Pulse inversion harmonic imaging requires the use of a broader transmit and receive bandwidth [8].

Another phenomenon observed with certain microbubble contrast agents (Levovist® and Sonazoid®, an agent not licensed) is the display of a late delayed phase in the liver, with signal displayed from stationary microbubbles. Uncertainty surrounds the exact reason for the persistence of microbubbles in the liver (and in the spleen, where SonoVue® also demonstrates this phenomenon [9]); speculation is that the microbubbles are trapped in the liver sinusoids [10] or actively taken up by the reticuloendothelial system [11]. This phase occurs at approximately 2 min and lasts for a variable period of time; about 3 further minutes with Levovist® and is best imaged with a "destructive" mode using high machine power with velocity 2D colour Doppler. This method, known as stimulated acoustic emission (or loss of correlation mode), results in a transient colour mosaic in liver tissue containing normal cells and a "black-hole" in malignant tissue containing no normal liver cells [12, 13]. This method of imaging microbubble contrast in the liver, excellent for detecting the presence of liver metastasis, is less favoured by radiologists in comparison with low mechanical MI techniques (Figure 1Go).


Figure 1
View larger version (37K):
[in this window]
[in a new window]
  		Figure 1. (a) A B-mode image of the right lobe of the liver obtained at 3 min 6 s following the administration of Levovist®. There is an indeterminate heterogeneous area (between arrows) that is poorly defined but suspicious of malignancy in a patient with a known primary tumour outside the liver. (b) Using a late-phase destructive mode (Agent Detection Imaging, ADI®; Siemens, Mountain View, CA), there is transient destruction of the microbubble contrast agent in normal liver tissue, but absence of microbubble contrast in the tumour appears as "two-black holes" (arrow).

 
Clinical applications of microbubble contrast

All the licensed microbubble agents are injected intravenously and do not cross cell membranes, remaining in the intravascular compartment, a distinct difference from other radiological contrast media. Microbubbles therefore give information on the vascularity and enhancement characteristics of a tissue rather than the functional properties; application is directed towards this unique feature. As microbubble contrast can be delivered under real time ultrasound observation it may provide additional information to CT and MRI.

Established clinical applications
The first applications for the use of microbubble contrast were cardiac, where there are established clinical practices; these applications are outside the remit of the current review and will not be discussed. Microbubble contrast has been widely used in imaging of solid organs, particularly the liver where it has a number of established applications. The original application for these agents was in "Doppler rescue", with improvement in detection of colour Doppler signal from large vessels, particularly the portal vein and hepatic artery in transplantation [14–16] and in documentation of abnormal vessels in liver tumours [17]. With the advent of low MI imaging coupled with pulse inversion techniques, liver tumour imaging is now relatively sophisticated, precipitating a consensus publication of guidelines for identifying contrast enhancement patterns in various focal liver tumours [18].

In lesions where there are distinctive enhancement patterns, microbubble contrast enables accurate characterization of lesions so that more expensive, time-consuming examinations do not need to be performed. Recent studies have demonstrated characterization of liver lesions to be accurate in 85–96% of cases in distinguishing benign from malignant lesions [13, 19, 20]. Benign lesions tend to enhance in the arterial phase and retain microbubble contrast through the different vascular phases (arterial 10–35 s, early portal-venous 30–120 s and late portal-venous phases >120 s after administration) (Figure 2Go) [20].


Figure 2
View larger version (65K):
[in this window]
[in a new window]
  		Figure 2. (a) A well demarcated tumour in the right lobe of the liver (arrow) on B-mode imaging. (b) Image of the same tumour obtained at 18 s (arterial phase) following the administration of SonoVue®, and using a low mechanical index imaging technique (Cadence Contrast Pulse Sequencing, CPS®; Siemens, Mountain View, CA), demonstrates prominent arterial signal within the tumour. (c) Image of the same tumour at 60 s (portal-venous phase) demonstrating complete in-filling; the appearances are in keeping with a benign tumour and representative of an area of focal nodular hyperplasia.

 
Benign lesions often have characteristic enhancement patterns, such as peripheral nodular enhancement in haemangioma and homogeneous arterial enhancement with a central "spoke wheel" arterial pattern in focal nodular hyperplasia [20]. Metastases have variable enhancement patterns and may be hypovascular or hypervascular on the arterial phase following microbubble contrast administration, often displaying peripheral rim enhancement. On the portal-venous phase images, the enhancement fades and the metastases become of decreased reflectivity compared with normal hepatic parenchyma [19]. This appearance is accentuated by those microbubble contrast agents which display the late delayed phase of imaging in the liver when, at between 2 min and 5 min, increased conspicuity of focal lesions against the enhancing normal liver tissue is observed with a "destructive" mode using high machine power [13, 19]. However, confusion may arise if imaging is performed in the late delayed phase only. Multiple hepatic abscesses [21] or the rare biliary hamartomas [22] may present as focal areas of low reflectivity, mimicking metastases on a microbubble contrast ultrasound study; the only difference being a complete absence of vessels centrally in these two conditions if imaged with low MI techniques through all the vascular phases.

The application of intraoperative ultrasound during surgery for resection of metastases identifies metastases that were not seen on any form of pre-operative imaging, and changes management in 50% of cases [23]. Any further improvement on this would be useful; preliminary results suggest that microbubble contrast ultrasound demonstrates increased sensitivity and a capability of detecting lesions as small as 2–3 mm in diameter allowing improved outcome of patients undergoing "curative" metastasis resection [23, 24].

A number of ablation treatments (including ethanol, cryotherapy, high-intensity focused ultrasound and radiofrequency ablation) are employed in the management of malignant disease within the liver when the patient is not suitable for surgical resection or transplantation. Currently, radiofrequency ablation is receiving the most attention. In most situations ultrasound is the modality of choice for implementing this therapy, predominantly as it allows real time visualization of electrode placement. The outcome of radiofrequency ablation is dependent on attaining a successful "tumour-free" margin and complete necrosis of the tumour itself [25]. Performing biphasic CT or contrast enhanced MRI periprocedure is relatively impractical in delineating this margin, but microbubble contrast readily demonstrates residual tumour enhancement. Ablation therapy followed by imaging 10 min post-procedure will demonstrate residual tumour as an irregular margin that maintains the enhancement pattern seen prior to ablative therapy, different to the rim of enhancement seen post-ablation on CT thought to represent reactive hyperaemia [26]. If performed following ablation, microbubble contrast allows immediate further therapy if required, decreasing the number of treatment sessions.

Microbubble contrast originally developed for Doppler rescue remains invaluable in demonstrating vessel patency, firmly established in such diverse areas as transcranial Doppler, echocardiography, liver transplantation and in the diagnosis of renal artery stenosis [5, 6, 16, 27, 28].

Microbubble contrast has also found a niche outside the vascular compartment in the setting of vesico-ureteric reflux in children where a high sensitivity and specificity compared with conventional micturating cystourography (MCUG) has been demonstrated [29]. In a study comparing conventional MCUG with a microbubble contrast examination, a significant number of children were up-graded from a grade 1 reflux on MCUG to a grade 2; with management and prognostic implications [30]. The advantage of avoiding ionizing radiation is obvious, although the procedure remains invasive.

Potential clinical applications
Whilst most applications for ultrasound contrast are established in the liver, further uses are developing in other areas.

A number of groups have investigated the utility of microbubble contrast as an adjuvant to the FAST scan (Focused Assessment Sonography in Trauma) in blunt abdominal trauma [31–34]. Non-enhanced FAST scanning is able to "triage" patients with blunt abdominal trauma accurately; patients with negative imaging virtually never need surgical intervention [35]. The addition of microbubble contrast to the examination would increase the confidence of the operator in the face of a negative examination. The most likely role of microbubble contrast in blunt abdominal trauma would be the ability to assess patients more accurately in order to expedite the most appropriate management whether this is surgery, further imaging with CT or observation alone.

The role of ultrasound, colour Doppler ultrasound and microbubble contrast ultrasound in detecting breast carcinomas is yet to be fully established. There is a suggested role for colour Doppler ultrasound in the differential diagnosis of breast disease [36, 37]. Studies have demonstrated an increased sensitivity in vascularity with microbubble contrast, but with conflicting views on the specificity of differentiating benign and malignant lesions [38, 39]. These studies were performed with conventional machine settings, but as the newer harmonic and phase inversion techniques develop, analysis of breast masses with microbubble contrast may become a useful tool. A study used microbubble contrast in the evaluation of radiofrequency ablation in breast tumours with some success, a similar use as with radiofrequency ablation of liver tumours [40].

One of the goals of treatment of any cancer is the identification of disease involvement of the sentinel node – the first node to drain a tumour into the lymphatic system. This predicts the need to remove the regional lymph nodes. Microbubble contrast may play a role in this scenario; sentinel nodes in swine models with melanoma demonstrated sentinel node enhancement in 28 of 31 sentinel lymph nodes, some within seconds of peritumour injection of microbubble contrast. The authors, using low MI greyscale pulse-inversion imaging, also demonstrated signal voids within the lymph nodes representative of intranodal metastasis with 95% sensitivity [41]. This method of sentinel node detection is as good as alternative techniques without the adverse effects of these established techniques; blue dye is invasive, has a relatively high rate of allergic reaction and a technical failure rate of 20%, whereas technetium 99m scintigraphy has a reported failure rate of 12% [42]. Both these techniques may detect non-sentinel nodes (false-positive), leading to unnecessarily extensive nodal dissection. Another group have successfully developed a specific microbubble that targets lymph nodes, using the stimulated acoustic emission ultrasound imaging method [43]. Further studies are required to fully evaluate these techniques with application, particularly within the axilla of breast cancer patients, an important potential clinical use [44].

Another interesting area for clinical use of microbubble contrast is in musculoskeletal ultrasound for the demonstration of synovitis. MRI of joints, although informative and accurate, is not readily accessible to provide an "on-demand" clinical service that patients with inflammatory synovitis require for rapid diagnosis and disease management. More pertinent is the better resolution capability of ultrasound in comparison with MRI especially in the smaller joints. Ultrasound can accurately differentiate between joint fluid and synovium, except in the presence of echogenic joint fluid, when the addition of microbubble contrast may help [45]. The addition of microbubble contrast to the ultrasound examination of the synovium will demonstrate ongoing or recurrence of inflammation by assessing the increase of vascular enhancement; which may be of promise in the small joints of the hand [46].

A further important clinical use for microbubble contrast is in vascular ultrasound, applicable in particular to the carotid circulation in the management of cerebrovascular disease. Numerous studies have established the importance of assessing the degree of narrowing of the internal carotid artery in relation to symptoms in order to ascertain the need for surgical or increasingly radiological intervention [47, 48]. Ultrasound is highly accurate in assessing the degree of stenosis of the internal carotid artery, far more cost-effective than other imaging modalities and much more "patient-friendly". However, there remain instances of ultrasound limitation. Ordinary colour Doppler microbubble contrast enhanced examinations are problematic as a consequence of artefacts, most notably "blooming" [49]. Technical advances with high frequency linear transducers, coupled with the newer harmonic imaging techniques, has allowed improvements in lumen delineation without the need to use colour Doppler ultrasound. The images produced are likened to "ultrasound angiograms" as they clearly display the outer and inner luminal margins of the vessel allowing precise assessment of intima-media thickening, atheromatous plaques, ulceration and areas of marked stenosis [50].

The use of microbubble contrast in gene therapy and targeted delivery of drugs is an area of active research, where microbubbles are engineered to carry antibodies or DNA to target tissues [51]. With gene therapy, a particular area that shows promise is skeletal muscle [52, 53]. Ultrasound enhances gene transfer by increasing cell permeability, termed "sonoporation" a process enabled by microbubble contrast, believed to occur by lowering the threshold for ultrasound bioeffects [54]. Interestingly the type of microbubble may influence the rate of gene transfection, with the perfluorocarbon microbubbles (Optison® in this study) the most efficient [55]. There is even a suggestion that perfluorocarbon microbubbles may promote gene transfection without the need for ultrasound [56].

Safety

Microbubble contrast agents approved for clinical use are well tolerated with serious side-effects rarely observed, predominantly minor in nature (headache, nausea) which are invariably self limiting [57]. Generalized allergy-like reactions occur rarely [58]. There is the possibility of bioeffects arising from the use of microbubble agents; microvascular rupture can occur where gas bodies are insonated [18]. This may be problematic in areas of sensitivity such as the retina and the brain when imaged through the open fontanelle. A further concern is the development of premature ventricular contractions when high MI end systolic triggering is specifically used in echocardiography but not with other applications [59].

Conclusion

Ultrasound microbubble contrast already has established uses in the liver as a Doppler rescue agent and further applications are constantly being developed. It is likely that administration will eventually become routine in day to day practice as is the situation in a number of European countries (Italy, Germany and Spain) and Japan (soon to be followed by China) where the microbubble agents are licensed and there is enthusiasm among the "imagers". The UK has been slower in the uptake of using microbubble contrast for a number of reasons [60]. However, the imagers in the USA can only admire from a distance the advances made in the clinical application of microbubble contrast agents by their European and Asian counterparts; only limited off-licence use of these agents for abdominal imaging is endorsed.

Received for publication July 19, 2005. Revision received September 23, 2005. Accepted for publication October 5, 2005.

References

  1. Gramiak R, Shah PM. Echocardiography of the aortic root. Invest Radiol 1968;3:356–66.[Medline]
  2. Harvey CJ, Blomley MJK, Eckersley RJ, Cosgrove DO. Developments in ultrasound contrast media. Eur Radiol 2001;11:675–89.[CrossRef][Medline]
  3. Correas JM, Bridal L, Lesavre A, Mejean A, Claudon M, Helenon O. Ultrasound contrast agents: properties, principles of action, tolerance, and artifacts. Eur Radiol 2001;11:1316–28.[CrossRef][Medline]
  4. Greis C. Technology overview: SonoVue. Eur Radiol Suppl 2004;14:P11–P15.[CrossRef]
  5. Blomley MJK, Cooke JC, Unger EC, Monaghan MJ, Cosgrove DO. Microbubble contrast agents; a new era in ultrasound. BMJ 2001;322:1222–5.[Free Full Text]
  6. Leen E. Ultrasound contrast harmonic imaging of abdominal organs. Semin Ultrasound CT MRI 2001;22:11–24.[CrossRef][Medline]
  7. Simpson DH, Chin CT, Burns PN. Pulse inversion Doppler: a new method for detecting nonlinear echoes from microbubble contrast agents. IEEE Trans Biomed Engin 1999;46:372–82.
  8. Whittingham TA. Broadband transducers. Eur Radiol 1999;9:S298–S303.
  9. Lim AKP, Patel N, Eckersley RJ, Taylor-Robinson SD, Cosgrove DO, Blomley MJK. Evidence for spleen-specific uptake of a microbubble contrast agent: a quantitative study in healthy volunteers. Radiology 2004;231:785–8.[Abstract/Free Full Text]
  10. Hauff P, Fritzsch T, Reinhardt M, Weitschies W, Luders F, Uhlendorf V, et al. Delineation of experimental liver tumors in rabbits by a new ultrasound contrast agent and stimulated acoustic emission. Invest Radiol 1997;32:95–9.
  11. Forsberg F, Goldberg BB, Liu JB, Merton DA, Rawool NM, Shi WT. Tissue-specific US contrast agent for evaluation of hepatic and splenic parenchyma. Radiology 1999;210:125–32.[Abstract/Free Full Text]
  12. Blomley MJK, Sidhu PS, Cosgrove DO, Albrecht T, Harvey CJ, Heckemann RA, et al. Different types of liver lesions differ in their uptake of the microbubble contrast agent SH U 508A in the late liver phase? Early experience. Radiology 2001;220:661–7.[Abstract/Free Full Text]
  13. Bryant TH, Blomley MJK, Albrecht T, Sidhu PS, Leen E, Basilico R, et al. Liver phase uptake of a liver specific microbubble improves characterization of liver lesions: a prospective multi-center study. Radiology 2004;232:392–9.
  14. Marshall MM, Beese RC, Muiesan P, Sarma DI, O'Grady J, Sidhu PS. Assessment of portal venous patency in the liver transplant candidate: a prospective study comparing ultrasound, microbubble-enhanced colour Doppler ultrasound with arteriography and surgery. Clin Radiol 2002;57:377–83.[CrossRef][Medline]
  15. Gebel M, Caselitz M, Bowen-Davies PE, Weber S. A multicenter, prospective, open label, randomized, controlled phase IIIb study of SH U 508A (Levovist) for Doppler signal enhancement in the portal vascular system. Ultraschall Med 1998;19:148–56.[Medline]
  16. Sidhu PS, Shaw AS, Ellis SM, Karani JB, Ryan SM. Microbubble ultrasound contrast in the assessment of hepatic artery patency following liver transplantation: role in reducing frequency of hepatic artery arteriography. Eur Radiol 2004;14:21–30.[CrossRef][Medline]
  17. Tano S, Ueno N, Tomiyama T, Kimura K. Possibility of differentiating small hyperechoic liver tumours using contrast-enhanced colour Doppler ultrasonography: a preliminary study. Clin Radiol 1997;52:41–5.[CrossRef][Medline]
  18. Albrecht T, Blomley MJK, Bolondi L, Claudon M, Correas JM, Cosgrove DO, et al. Guidelines for the use of contrast agents in ultrasound. January 2004. Ultraschall Med 2004;25:249–56.[CrossRef][Medline]
  19. Albrecht T, Hohmann J, Oldenburg A, Skork J, Wolf KJ. Detection and characterisation of liver metastases. Eur Radiol Suppl 2004;14:P25–P33.[CrossRef]
  20. Bleuzen A, Tranquart F. Incidental liver lesions: diagnostic value of cadence contrast pulse sequencing (CPS) and SonoVue. Eur Radiol Suppl 2004;14:P53–P62.[CrossRef]
  21. Kim KW, Choi BI, Park SH, Kim AY, Koh YH, Lee HJ, et al. Pyogenic hepatic abscesses: distinctive features from hypovascular hepatic malignancies on contrast-enhanced ultrasound with SH U 508A; early experience. Ultrasound Med Biol 2004;30:725–33.[CrossRef][Medline]
  22. Berry JD, Boxer ME, Rashid HI, Sidhu PS. Microbubble contrast enhanced ultrasound characteristics of multiple biliary hamartomas (von Meyenberg complexes). Ultrasound 2004;12:95–7.[CrossRef]
  23. Leen E, Moug S, Horgan P. Potential impact and utilization of ultrasound contrast media. Eur Radiol Suppl 2004;14:P16–P24.[CrossRef]
  24. Siosteen AK, Elvin A. Intra-operative uses of contrast-enhanced ultrasound. Eur Radiol Suppl 2004;14:P87–P95.[CrossRef]
  25. Solbiati L, Tonolini M, Cova L. Monitoring RF ablation. Eur Radiol Suppl 2004;14:P34–P42.[CrossRef]
  26. Wen YL, Kudo M, Zheng RQ, Minami Y, Chung H, Suetomi Y, et al. Radiofrequency ablation of hepatocellular carcinoma: therapeutic response using contrast-enhanced coded phase-inversion harmonic sonography. AJR Am J Roentgenol 2003;181:57–63.[Abstract/Free Full Text]
  27. Grant EG. Sonographic contrast agents in vascular imaging. Semin Ultrasound CT MRI 2001;22:25–41.[CrossRef][Medline]
  28. Satchithananda K, Sellars MEK, Ryan SM, Sidhu PS. Microbubble ultrasound contrast agents in the visualization of peripheral vasculature in 'Doppler rescue': a review. Ultrasound 2004;12:176–84.[CrossRef]
  29. Darge K, Troeger J, Duetting T, Zieger B, Rohrschneider W, Moehring K, et al. Reflux in young patients: comparison of voiding US of the bladder and retrovesical space with echo enhancement versus voiding cystourethrography for diagnosis. Radiology 1999;210:201–7.[Abstract/Free Full Text]
  30. Darge K, Troeger J. Vesicoureteral reflux grading in contrast-enhanced voiding urosonography. Eur J Radiol 2002;43:122–8.[Medline]
  31. Catalano O, Lobianco R, Raso MM, Siani A. Blunt hepatic trauma: evaluation with contrast-enhanced sonography. J Ultrasound Med 2005;24:299–310.[Abstract/Free Full Text]
  32. Catalano O, Lobianco R, Sandomenico F, Siani A. Splenic trauma: evaluation with contrast-specific sonography and a second generation contrast medium. J Ultrasound Med 2003;22:467–77.[Abstract/Free Full Text]
  33. Oldenburg A, Hohmann J, Skork J, Albrecht T. Imaging of pediatric splenic injury with contrast-enhanced ultrasonography. Pediatr Radiol 2004;34:351–4.[CrossRef][Medline]
  34. Poletti PA, Platon A, Becker CD, Mentha G, Vermeulen B, Buhler LH, et al. Blunt abdominal trauma: does the use of a second-generation sonographic contrast agent help to detect solid organ injuries? AJR Am J Roentgenol 2004;183:1293–301.[Abstract/Free Full Text]
  35. Farahmand N, Sirlin CB, Brown MA, Shragg GP, Fortlage D, Hoyt DB, et al. Hypotensive patients with blunt abdominal trauma: performance of screening US. Radiology 2005;235:436–43.[Abstract/Free Full Text]
  36. Cosgrove DO, Kedar RP, Bamber JC, Al-Murrani B, Davey JBN, Fisher C, et al. Breast disease: color Doppler US in differential diagnosis. Radiology 1993;189:99–104.[Abstract/Free Full Text]
  37. Cosgrove DO, Bamber JC, Davey JB, McKinna JA, Sinnett HD. Color Doppler signals from breast tumors. Work in progress. Radiology 1990;176:175–80.[Abstract/Free Full Text]
  38. Kedar RP, Cosgrove DO, McCready VR, Bamber JC, Carter ER. Microbubble contrast agent for color Doppler US: effect on breast masses - work in progress. Radiology 1996;198:679–86.[Abstract/Free Full Text]
  39. Kook SH, Kwag HJ. Value of contrast-enhanced power Doppler sonography using a microbubble echo-enhancing agent in evaluation of small breast lesions. J Clin Ultrasound 2003;31:227–38.[Medline]
  40. Lamuraglia M, Lassau N, Garbay JR, Mathieu MC, Rouzier R, Jaziri S, et al. Doppler US with perfusion software and contrast medium injection in the early evaluation of radiofrequency in breast cancer recurrences: a prospective phase II study. Eur J Radiol 2005;6
  41. Goldberg BB, Merton DA, Liu JB, Thakur M, Murphy GF, Needleman L, et al. Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US. Radiology 2004;230:727–34.[Abstract/Free Full Text]
  42. Bostick PJ, Guiliano AE. Vital dyes in sentinel node localization. Semin Nucl Med 2000;30:18–24.[CrossRef][Medline]
  43. Hauff P, Reinhardt M, Briel A, Debus N, Schirner M. Molecular targeting of lymph nodes with l-selectin ligand-specific US contrast agent: a feasibility study in mice and dogs. Radiology 2004;231:667–73.[Abstract/Free Full Text]
  44. 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;24:953–65.[Abstract/Free Full Text]
  45. Magarelli N, Guglielmi G, Di Matteo L, Tartaro A, Mattei PA, Bonomo L. Diagnostic utility of an echo-contrast agent in patients with synovitis using power Doppler ultrasound: a preliminary study with comparison to contrast-enhanced MRI. Eur Radiol 2001;11:1039–46.[CrossRef][Medline]
  46. Szkudlarek M, Court-Payen M, Strandberg C, Klarlund M, Klausen T, Oÿstergaard M. Contrast-enhanced power Doppler ultrasonography of the metacarpophalangeal joints in rheumatoid arthritis. Eur Radiol 2003;13:163–8.[Medline]
  47. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445–53.[Abstract]
  48. European Carotid Surgery Trialists' Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379–87.[CrossRef][Medline]
  49. Ferrer JME, Samso JJ, Serrando JR, Valenzuela VF, Montoya SB, Docampo MM. Use of ultrasound contrast in the diagnosis of carotid artery occlusion. J Vasc Surg 2000;31:736–41.[CrossRef][Medline]
  50. Kono Y, Pinnell SP, Sirlin CB, Sparks SR, Georgy B, Wong W, et al. Carotid arteries: contrast-enhanced US angiography--preliminary clinical experience. Radiology 2004;230:561–8.[Abstract/Free Full Text]
  51. Miller MW. Gene transfection and drug delivery. Ultrasound Med Biol 2000;26:S59–S62.
  52. Taniyama Y, Tachibana K, Hiraoka K, Aoki M, Yamamoto S, Matsumoto K, et al. Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle. Gene Ther 2002;9:372–80.[CrossRef][Medline]
  53. Lu QL, Liang HD, Partridge T, Blomley MJ. Microbubble ultrasound improves the efficiency of gene transduction in skeletal muscle in vivo with reduced tissue damage. Gene Ther 2003;10:396–405.[CrossRef][Medline]
  54. Tachibana K, Uchida T, Ogawa K, Yamashita N, Tamura K. Induction of cell-membrane porosity by ultrasound. Lancet 1999;353:1409[Medline]
  55. Li T, Tachibana K, Kuroki M, Kuroki M. Gene transfer with echo-enhanced contrast agents: comparison between albunex, optison, and levovist in mice--initial results. Radiology 2003;229:423–8.[Abstract/Free Full Text]
  56. Blomley M. Which US microbubble contrast agent is best for gene therapy? Radiology 2003;229:297–8.[Free Full Text]
  57. Jakobsen JA, Oyen R, Thomsen HS, Morcos SK. Safety of ultrasound contrast agents. Eur Radiol 2005;15:941–5.[CrossRef][Medline]
  58. Crucinio N, Nacchiero MC, Panella C, Ierardi E. A case of adverse reaction potentially related to a microbubble contrast agent for ultrasonography. Eur J Radiol (Extra) 2004;52:25–6.[CrossRef]
  59. van der Wouw P, Brauns A, Bailey S, Powers J, Wilde A. Premature ventricular contractions during triggered imaging with ultrasound contrast. J Am Soc Echocardiogr 2000;13:288–94.[CrossRef][Medline]
  60. Sidhu PS. Microbubbles are here to be burst! Radiology Now 2003;20:2–3.



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
G. Korpanty, J. G. Carbon, P. A. Grayburn, J. B. Fleming, and R. A. Brekken
Monitoring Response to Anticancer Therapy by Targeting Microbubbles to Tumor Vasculature
Clin. Cancer Res., January 1, 2007; 13(1): 323 - 330.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Figures Only
Right arrow Full Text (PDF)
Services
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
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stewart, V R
Right arrow Articles by Sidhu, P S
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stewart, V R
Right arrow Articles by Sidhu, P S

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
BJR DMFR IMAGING  ALL BIR JOURNALS