BJR
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
British Journal of Radiology (2003) 76, S43-S49
© 2003 British Institute of Radiology
doi: 10.1259/bjr/86364648
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 Cosgrove, D
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cosgrove, D

Full Paper

Angiogenesis imaging – ultrasound

D Cosgrove

Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, UK


   Introduction
Top
 Introduction
Conventional B-mode and Doppler
 Functional methods
 Contrast enhancement
 Functional methods
 Targeted microbubbles
 Conclusion
 References
 
Ultrasound is an attractive modality for imaging angiogenesis because of the ease with which it can be repeated without exposing the patient or animal to any risk [1, 2]. Ultrasound imaging systems are also relatively inexpensive and mobile, a particular benefit for animal studies. However, small vessels cannot be detected with B-mode (grey-scale) scanning though flow in vessels down to arteriolar and venular size can often be detected and characterized with Doppler. The advent of microbubble contrast agents opens to way to detecting the microcirculation and they can also be deployed as tracers for functional studies.


   Conventional B-mode and Doppler
Top
 Introduction
 Conventional B-mode and Doppler
Functional methods
 Contrast enhancement
 Functional methods
 Targeted microbubbles
 Conclusion
 References
 
Although B-mode ultrasound cannot delineate vessels smaller than a few millimetres in diameter but, because of its sensitivity to motion, Doppler is able to detect signals from smaller vessels, though not from the microcirculation itself. In fact the earliest use of ultrasound for malignant neovasculature detection used spectral Doppler of the arteries feeding breast tumours (see below) [3]. Both these and vessels within tumours can be demonstrated with colour Doppler, power Doppler generally being the more appropriate implementation since the flow direction is not usually important in this application (Figure 1Go). Colour Doppler reveals the tortuous vascular anatomy as well as their abnormal branching pattern and even shunts and blind ending vessels [4, 5]. Visual scoring systems to quantify these have been developed [6] and have been applied to the breast [7], liver [8], kidneys [9], ovary [10], prostate [11], cervix [12] and in musculoskeletal tumours [13] where they help in the differential diagnosis benign versus malignant masses and can be used to target diagnostic biopsies. Correlation between the abundance of colour Doppler signals and histological microvessel density have been reported in the breast [14] though they do not always correspond closely, perhaps because of the different sized vessels detectable. Since the microvessel density acts as a predictor of the aggressivity of malignant tumours [15], it is to be anticipated that colour Doppler would also serve this purpose and it has been reported to predict response of cervical carcinoma to neo-adjuvant chemotherapy [12].



View larger version (97K):
[in this window]
[in a new window]
  		Figure 1. Power Doppler of a hepatocellular carcinoma. Power Doppler reveals the neovasculature of this large hepatocellular carcinoma. Note the complex, tortuous architecture of the tumour vessels, the smallest of which are around a millimetre in diameter.

 
Colour Doppler can also be used to assess the response of tumours to treatment by evaluating the anti-neovascular effects of both conventional chemotherapeutics and the specific anti-angiogenesis agents being developed [16, 17]. Here its ready repeatability is useful. Response to neoadjuvant treatment of breast carcinoma has been found to anticipate clinical response and vice versa, failure to suppress neovascularity provides early warning of unsuccessful chemotherapy in the breast and in the prostate [16, 18] (Figure 2Go). In animal models, quantitated power Doppler tracked the response of breast tumours to chemotherapy and radiotherapy [19].



View larger version (9K):
[in this window]
[in a new window]
  		Figure 2. Chart of colour Doppler signals from breast carcinomas undergoing chemotherapy. The clinical response, assessed by size measurements, lagged behind the quantitative change in colour Doppler signals which could be used as an early indicator of response (from Kedar et al [16]).

 
Doppler depicted vascularity can also be useful in highlighting recurrent tumour for example in the breast where post-operative scarring is confusing similar both clinically and on imaging [20]. Once the inflammatory reaction to surgery has subsided, i.e. after 6 months or so, vascular regions are suspicious and should be targeted for biopsy.


   Functional methods
Top
 Introduction
 Conventional B-mode and Doppler
 Functional methods
Contrast enhancement
 Functional methods
Targeted microbubbles
 Conclusion
 References
 
Spectral and colour Doppler signals provide a form of functional information on neovascularity, notably by indicating the maximal velocity in tumour supply vessels, e.g. those in breast carcinoma [3]. Analysis of the spectral waveforms supplies information on the resistance to flow of the supplied bed. In tumours this is complex because the low flow resistance that results from their lack of vasomotor control and their arteriovenous shunts may be counter balanced by high resistance to flow produced by the high interstitial (oncotic) pressure that is typical of tumours and results from the increased permeability of the microvasculature to osmotic compounds [21] (Figure 3Go). These effects may co-exist in a patchy form within the same tumour. Presumably this heterogeneity accounts for the contradictory reports of both high and low diastolic flows in malignancy [12, 22, 23]. However, some tumours consistently show low resistance indices, notably choriocarcinomas. A higher intratumoural resistance index (RI, which measures the resistance to flow of the microcirculation) than in the surrounding liver has been reported in liver metastases and hepatocellular carcinoma (HCC) [24]. In a study of 49 patients with carcinoma of the cervix, strong correlations were observed between the RI and histological features of aggressivity, which was associated with a lower RI [25]. In this study the microvascular density and the vascular endothelial growth factor-f (VEGF-f) were measured in biopsy specimens and they also correlated with reduced resistance (Figure 4Go).



View larger version (86K):
[in this window]
[in a new window]
  		Figure 3. Spectral Doppler signals from a tumour. Pancreatic carcinomas are relatively hypovascular but in this example a spectral Doppler trace could be obtained by using colour Doppler to guide positioning the sample volume. It shows continuing flow through diastole indicating a low resistance to flow consistent with failure of vasomotor regulation or perhaps, the presence of arteriovenous shunts.

 


View larger version (14K):
[in this window]
[in a new window]
  		Figure 4. Resistance index (RI) and vascular endothelial growth factor (VEGF). In these patients with cervical carcinoma, the resistance index was lower in tumours with increased VEGF with a regression index of –0.4 (p=0.004). This non-invasive index of flow resistance could be used as a marker of tumour aggressivity (from Lee [25]).

 

   Contrast enhancement
Top
 Introduction
 Conventional B-mode and Doppler
 Functional methods
 Contrast enhancement
Functional methods
 Targeted microbubbles
 Conclusion
 References
 
Microbubble enhanced colour Doppler allows smaller vessels to be demonstrated perhaps down to 70 µm in diameter, and this improves the detection of the same features as unenhanced Doppler can provide (Figure 5Go).



View larger version (43K):
[in this window]
[in a new window]
  		Figure 5. Enhanced colour Doppler in prostatic cancer. Colour Doppler has been advocated as a way to improve the well-known poor sensitivity of ultrasound for detecting prostatic cancer. Only weak colour signals could be obtained on the conventional scan (a) but after administration of the microbubble contrast agent SonoVue, there was marked enhancement in the left side of the prostate (b). Biopsy of this region demonstrated cancer.

 
Thus the neovascularity of breast and prostate tumours can be imaged and this has proved useful for differential diagnosis and to gauge response to treatment [26]. In the same way, enhanced colour Doppler helps direct biopsies for example in the prostate [27–29].

Adnexal masses pose a diagnostic problem especially as ultrasound is sometimes used for screening. The overlap of B-mode features between benign and malignant ovarian masses means that some for laparoscopic or surgical procedures are performed for each cancer detected. Contrast enhanced ultrasound may be able to improve on this and lead to a decision tree where abnormalities detected on conventional ultrasound are referred for contrast enhanced transvaginal ultrasound to decide whether surgery is necessary or whether surveillance is appropriate [30].

For the prostate contrast enhanced ultrasound has been shown to predict escape from response to treatment before a rise in prostate specific antigen (PSA) is noted and this could be useful to guide management [18] (Figure 6Go).



View larger version (37K):
[in this window]
[in a new window]
  		Figure 6. Contrast-enhanced colour Doppler to predict response of prostatic cancer. In a group of patients undergoing androgen deprivation treatment for prostatic cancer, the area under the time–intensity curve (AUC) after injection of Levovist (upper graph) was compared with serum prostate specific antigen (PSA) levels (lower graph). Note the expanded time-scale of the vascularity index. Generally both indices showed similar time courses with a rapid fall and eventually a secondary rise. However, in two cases (orange and red traces) the vascularity either failed to fall or rose earlier than the PSA and these patients were subsequently found to have escaped from hormone control (from Eckerley et al [18]).

 
However, contrast specific modes are much more sensitive and less susceptible to motion artefact so that they can detect the distribution of the contrast agent even when the microbubbles are stationary. Thus microbubble-specific modes are able to demonstrate the microcirculation down to capillary level (although of course these vessels cannot be resolved as discrete structures). High mechanical index (MI) methods such as colour Doppler (and improved versions of it) were the first to be discovered and they offer exquisite sensitivity to the distribution of the microbubbles (a single microbubble can be detected) but the act of imaging destroys the microbubbles so an intermittent imaging technique must be used [31–33]. Despite the challenge of using a new scanning technique, several prospective studies have shown these high MI methods to be a useful approach especially with air containing microbubbles such as Levovist. It offers high sensitivity and specificity especially in the detection of liver metastases which appear as colour defects in the liver specific late phase at about 4 min after injection (Figure 7Go). Benign solid lesions mostly show at least some contrast signal and usually the intensity equals that of normal liver, so that they disappear in this phase. The sensitivity of this approach rivals that of 3 phase helical CT and may even improve on it, especially for subcentimetre lesions. Limitations are the depth to which the signals can be obtained (10–12 cm is usually the maximum) and the difficulty of access to some parts of the liver notably the lateral part of segment 8. Examination of the arterial phase is demanding and not easily achieved with the intermittent scanning that is required.



View larger version (40K):
[in this window]
[in a new window]
  		Figure 7. Agent detection imaging (ADI). The grey-scale scan in this patient with a known malignancy shows two areas suspicious for metastases (arrowheads in (a)). In the ADI mode, obtained several minutes after injection of a liver-specific contrast agent, these lesions are more clearly seen but additional lesions that were not apparent appear (arrows in (b)). The effect depends on the destruction of microbubbles that fill the microcirculation of the normal liver but rapidly wash out of the tumour's microcirculation.

 
The first method to improve the detection of microbubbles while retaining the spatial resolution of B-mode imaging was the phase inversion mode, the archetypical multipulse method which paved the way to high resolution, high sensitivity microbubble-specific scanning [34]. In this mode the returning echoes from a pair of pulses transmitted with opposite phase are added together. The linear signals from tissue are suppressed while non-linear signals from microbubbles are retained and used to form the image. (The non-linear signals from microbubbles result from their much greater compressibility than tissue allows.) In a five-centre multinational study phase inversion imaging was shown to improve benign malignant differentiation in the liver with results similar to contrast-enhanced CT [35]. The limitations are the same as those of the colour Doppler derived method.

Phase inversion imaging is also very effective at low mechanical indices when using the newer perfluoro gas filled agents such as SonoVue, Definity and Optison (Amersham, UK) and newer methods allow the signals from the contrast agent to be displayed separately from the B-mode image, either as a colour overlay or side-by-side in a split screen display [36] (Figure 8Go). The low power transmitted produces fewer tissue harmonics so the contrast agent information is scarcely contaminated by tissue signal while microbubble destruction is minimized so that real time imaging is possible. This allows the arterial phase to be interrogated so that the pattern of the vascular supply of tumours can be assessed [37, 38]. Hypervascular tumours such as renal cell carcinomas, hepatocellular carcinomas and vascular liver metastases are particularly well visualized with their supply arteries and tortuous intratumoural arteries depicted [39]. In addition, the low MI methods reveal the distribution of the microbubbles in the blood pool phase, which is especially prominent in the liver and spleen (the sinusoidal phase) and is analogous (or perhaps identical) to the liver-specific late phase of earlier microbubbles. Since malignancies have a lower blood volume than the liver, they appear as contrast defects against the bright liver background. Although not as well studied as the high MI modes, the phase inversion mode at low MI in the sinusoidal phase seems to offer the same diagnostic information as an agent such as Levovist for liver staging.



View larger version (39K):
[in this window]
[in a new window]
  		Figure 8. Vascular recognition imaging. A subtle lesion (arrowhead in (a)) suggests a metastasis in this patient with a known colorectal carcinoma. Using a low power (MI ~ 0.1) microbubble-specific mode in which the contrast information is shown in the colour overlay, a peripheral feeding vessel (arrowhead in (b)) is seen the arterial phase at 17 s. Later ((c), 41 s) the contrast medium has washed out of the tumour but is continuing to accumulate in the large vascular volume of the liver so that the metastasis now appears as a prominent colour defect, leaving no doubt as to its presence. (In this mode motion of contrast medium in large vessels is shown as red or blue, according to their flow direction relative to the transducer, while stationary blood (i.e. the microcirculation) is depicted in green.) (SonoVue kindly supplied by Bracco, Milan.)

 
The arterial phase is helpful for lesion characterization since many benign lesions have characteristic spatial and temporal patterns (Table 1Go). For example, haemangiomas often show a pathognomonic pattern of clumpy filling at the periphery of the lesion in the arterial phase with subsequent slow percolation to fill the lesion from its periphery, although for large haemangiomas this filling may not be complete. When this pattern is observed, the reliability is equivalent to that of contrast enhanced CT or MR, though a proportion of haemangiomas are atypical and do not fill in this way on any imaging technique. Focal nodular hyperplasia (FNH) also has typical appearances with a central supply artery (corresponding with the central scar) which fills the lesion in a centrifugal fashion, often giving a transient spoke-wheel pattern that is very characteristic. In the sinusoidal phase the lesion takes up contrast to the same extent to the surrounding liver and so disappears. FNH may even retain more contrast than the liver and shows strong signals in this phase. Often the central scar becomes very obvious as a small filling defect. Lesions that consist of normal liver tissue such as regenerating nodules in cirrhosis and irregular fat deposition (focal fatty change and focal fatty sparing), not surprisingly behave in the same way as normal liver in both the arterial and sinusoidal phases.


View this table:
[in this window]
[in a new window]
  		Table 1. Vascular patterns of liver masses in low mechanical index contrast imaging

 
HCCs generally have a rich arterial supply that is visualized in the arterial phase as tortuous, irregular vessels penetrating into the tumour from its supply arteries. Thereafter, the contrast washes out rapidly, reflecting the lower vascular volume of tumours compared with normal liver, so that they appear as a defect against the enhanced liver background in scans after the first 60 s or so. However, some HCCs (probably those that are better differentiated) do retain significant contrast and therefore are not obvious in the sinusoidal phase.

The amount of arterial supply to metastases varies; those that are hypervascular such as some thyroid, renal and melanoma metastases have temporal spatial patterns identifiable to those of HCCs. The majority of metastases are not hypervascular and do not show arterial filling although peripheral arteries may be obvious in this early phase. Regardless of their arterial supply, metastases consistently have a low fractional vascular volume and so, like HCCs, contrast washes out rapidly and they are seen as defects in the sinusoidal phase.

Similar features are noted in other malignancies, for example in the spleen, but most tissue beds have lower fractional vascular volumes than the liver and spleen so that there is no equivalent to the late (sinusoidal) phase. Renal cell carcinomas typically show pronounced tortuous and irregular vessels that appear around 20 s after injection and then rapidly washout. Some but not all prostate carcinomas show the same pattern [40, 41] and anecdotes of the same spatial and temporal patterns in the testis and thyroid have been presented.


   Functional methods
Top
 Introduction
 Conventional B-mode and Doppler
 Functional methods
Contrast enhancement
 Functional methods
Targeted microbubbles
 Conclusion
 References
 
In a sense these three phase studies are an example of functional imaging but a more formal approach with quantification of the wash-in, wash-out phases is possible. Many commercial scanners now offer built-in quantification packages; alternatively data can be transferred to a computer for off-line quantification using general or bespoke software. The robustness of this approach hinges on the premise that signal intensity is proportional to microbubble concentration, and this has been validated for many situations [42, 43].

An example of the clinical value of functional assessment is in the characterization of adnexal masses: in a study of 70 gynaecological patients, the transit dynamics of Levovist was studied with colour Doppler and compared with the surgical findings [44]. The best criteria for distinguishing benign from malignant masses were the slopes of the rising and falling time intensity curves, which gave accuracies as high as 92%. This method could be used to determine which patients could be spared surgery and managed by follow-up observation.

A potentially important way to study the microvasculature relies on the fragility of microbubble contrast agents. If they are inactivated using a high power frame then the refill of the cleared slice can be followed with non-destructive low power monitoring frames [45]. The rate of refill follows an exponential curve whose initial upslope relates to the speed of blood flow while its maximum value relates to the fractional vascular volume. The product of these two is a measure of the true tissue perfusion. In effect, this is a negative bolus technique and the method is unique to ultrasound since other contrast media are not easily inactivated. Refill kinetics was developed for the myocardium but can be used in other vascular beds. In an animal study of implanted mammary tumours studied with Definity (Bristol-Meyers Squibb), the time required for replenishment shortened with tumour progression in the control group [46]. However, in animals treated with a novel antiangiogenesis drug, this increased and the time-integral of the curve decreased. Features such as these were incorporated into functional (parametric) images, which showed good correlation with tumour necrosis demonstrated on histology [47]. The heterogeneous vasculature of tumours should be revealed using this method but there are no reports of its use to date. Features calculated from the refill curve could be used to form functional (parametric) images which could allow visualization of the heterogeneous flow in tumours.


   Targeted microbubbles
Top
 Introduction
 Conventional B-mode and Doppler
 Functional methods
 Contrast enhancement
 Functional methods
 Targeted microbubbles
Conclusion
 References
 
Active compounds, even large molecules such as DNA, can be attached to microbubbles. While the main focus of interest in these agents is as drug/gene delivery vehicles [48], they are also promising as diagnostic tools, including the neovascularization of tumours. In an experimental study, microbubbles to which integrins had been attached, were found to collect preferentially in new blood vessels on intravital microscopy [49]. An increased ultrasound signal was obtained from matrigel plugs within which neovascularization had been stimulated by impregnating them with fibroblast growth factor.


   Conclusion
Top
 Introduction
 Conventional B-mode and Doppler
 Functional methods
 Contrast enhancement
 Functional methods
 Targeted microbubbles
 Conclusion
References
 
Depiction and detection of tumour vascularity with ultrasound has advanced progressively from Doppler studies of large and medium-sized vessels to the use of microbubble contrast agents which can detect the microcirculation. The unique ability to inactivate microbubbles with ultrasound allows very sharp negative boluses to be tracked for functional studies of the microvasculature. The ready repeatability of ultrasound is proving useful in following tumour response to conventional and novel anti-tumour drugs. Targeted microbubbles are being developed that may allow selective imaging of neovascularization.


   References
Top
 Introduction
 Conventional B-mode and Doppler
 Functional methods
 Contrast enhancement
 Functional methods
 Targeted microbubbles
 Conclusion
 References
 

  1. Yang X. Imaging vascular gene therapy. Radiology 2003;228:37–49.
  2. McDonald DM, Choyke PL. Imaging of angiogenesis: from microscope to clinic. Nat Med 2003;9:713–25.[CrossRef][Medline]
  3. Burns PN, Halliwell M, Wells PN, Webb AJ. Ultrasonic Doppler studies of the breast. Ultrasound Med Biol 1982;8:127–43.[CrossRef][Medline]
  4. Cherrington JM, Strawn LM, Shawver LK. New paradigms for the treatment of cancer: the role of anti-angiogenesis agents. Adv Cancer Res 2000;79:1–38.[Medline]
  5. Cosgrove D, Bamber J, Davey J, McKinna J, Sinnett H. Color Doppler signals from breast tumors. Radiology 1990;176:175–80.[Abstract]
  6. Cosgrove DO, Kedar RP, Bamber JC, al-Murrani B, Davey JB, Fisher C, et al. Breast diseases: color Doppler US in differential diagnosis. Radiology 1993;189:99–104.[Abstract]
  7. Cosgrove D, Kedar R, Bamber J, al-Murrani B, Davey J, Fisher C, et al. Breast diseases: color Doppler US in differential diagnosis. Radiology 1993;189:99–104.
  8. Tanaka S, Kitamura T, Fujita M, Nakanishi K, Okuda S. Color Doppler flow imaging of liver tumours. AJR 1990;154:509–14.[Abstract/Free Full Text]
  9. Escudier B, Lassau N, Couanet D, Angevin E, Mesrati F, Leborgne S, et al. Phase II trial of thalidomide in renal-cell carcinoma. Ann Oncol 2002;13:1029–35.[Abstract/Free Full Text]
  10. Emoto M, Iwasaki H, Mimura K, Kawarabayashi T, Kikuchi M. Differences in the angiogenesis of benign and malignant ovarian tumors, demonstrated by analyses of color Doppler ultrasound, immunohistochemistry, and microvessel density. Cancer 1997;80:899–907.[CrossRef][Medline]
  11. Guercini F, Solivetti FM, Dimitri M, D'Ascenzo R, Micali F. Color Doppler in the diagnosis of malignant prostatic neoplasia. Preliminary results. Arch Ital Urol Nefrol Androl 1991;63 Suppl 2:29–33.
  12. Alcazar JL, Jurado M. Transvaginal color Doppler for predicting pathological response to preoperative chemoradiation in locally advanced cervical carcinoma: a preliminary study. Ultrasound Med Biol 1999;25:1041–5.[CrossRef][Medline]
  13. Belli P, Constantini M, Mirk P, Maresca G, Prioli F, Marano P. Role of color Doppler sonography in the assessment of musculoskeletal soft tissue masses. J Ultrasound Med 2000;19:823–30.[Abstract]
  14. Yang WT, Tse GM, Lam PK, Metreweli C, Chang J. Correlation between color power Doppler sonographic measurement of breast tumor vasculature and immunohistochemical analysis of microvessel density for the quantitation of angiogenesis. J Ultrasound Med 2002;21:1227–35.[Abstract/Free Full Text]
  15. Lassau N, Koscielny S, Avril MF, Margulis A, Duvillard P, De Baere T, et al. Prognostic value of angiogenesis evaluated with high-frequency and color Doppler sonography for preoperative assessment of melanomas. AJR Am J Roentgenol 2002;178:1547–51.[Abstract/Free Full Text]
  16. Kedar RP, Cosgrove DO, Smith IE, Mansi JL, Bamber JC. Breast carcinoma: measurement of tumor response to primary medical therapy with color Doppler flow imaging. Radiology 1994;190:825–30.[Abstract]
  17. Merritt CR. Imaging the results of antiangiogenesis therapy. Acad Radiol 2001;8:119–20.[CrossRef][Medline]
  18. Eckersley RJ, Sedelaar JP, Blomley MJ, Wijkstra H, deSouza NM, Cosgrove DO, et al. Quantitative microbubble enhanced transrectal ultrasound as a tool for monitoring hormonal treatment of prostate carcinoma. Prostate 2002;51:256–67.[CrossRef][Medline]
  19. Denis F, Bougnoux P, de Poncheville L, Prat M, Catroux R, Tranquart F. In vivo quantitation of tumour vascularisation assessed by Doppler sonography in rat mammary tumours. Ultrasound Med Biol 2002;28:431–7.[CrossRef][Medline]
  20. Baz E, Madjar H, Reuss C, Vetter M, Hackeloer B, Holz K. The role of enhanced Doppler ultrasound in differentiation of benign vs. malignant scar lesion after breast surgery for malignancy [In Process Citation]. Ultrasound Obstet Gynecol 2000;15:377–82.[CrossRef][Medline]
  21. Vaupel P. Blood flow, oxygenation, tissue pH distribution and bioenergetic state of tumors. Ernst Schering Research Foundation No 23. Berlin, Germany: Schering AG, 1994.
  22. Peters-Engl C, Medl M, Mirau M, Wanner C, Bilgi S, Sevelda P, et al. Color-coded and spectral Doppler flow in breast carcinomas--relationship with the tumor microvasculature. Breast Cancer Res Treat 1998;47:83–9.[CrossRef][Medline]
  23. Mehta TS, Raza S, Baum JK. Use of Doppler ultrasound in the evaluation of breast carcinoma. Semin Ultrasound CT MR 2000;21:297–307.[CrossRef][Medline]
  24. De Gaetano AM, Barbaro B, Chiarla C, De Franco A, Maresca G, Marano P. The tissue characterization of focal liver lesions by color Doppler echography. Radiol Med (Torino) 1995;89:453–63.
  25. Lee CN, Cheng WF, Chen CA, Chu JS, Hsieh CY, Hsieh FJ. Angiogenesis of endometrial carcinomas assessed by measurement of intratumoral blood flow, microvessel density, and vascular endothelial growth factor levels. Obstet Gynecol 2000;96:615–21.[Abstract/Free Full Text]
  26. Kedar RP, Cosgrove D, 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]
  27. Strohmeyer D, Frauscher F, Klauser A, Recheis W, Eibl G, Horninger W, et al. Contrast-enhanced transrectal color doppler ultrasonography (TRCDUS) for assessment of angiogenesis in prostate cancer. Anticancer Res 2001;21:2907–13.[Medline]
  28. Lagalla R, Caruso G, Urso R, Bizzini G, Marasa L, Miceli V. [The correlations between color Doppler using a contrast medium and the neoangiogenesis of small prostatic carcinomas.] Radiol Med (Torino) 2000;99:270–5.
  29. Ragde H, Kenny GM, Murphy GP, Landin K. Transrectal ultrasound microbubble contrast angiography of the prostate. Prostate 1997;32:279–83.[CrossRef][Medline]
  30. D'Arcy T, Jayaram V, Lynch M, Soutter W, Cosgrove D, Harvey C, et al. Ovarian cancer detected non-invasively by contrast-enhanced power Doppler ultrasound. Br J Obstet Gynecol 2004;111:619–22.
  31. Blomley MJ, Albrecht T, Cosgrove DO, Eckersley RJ, Butler-Barnes J, Jayaram V, et al. Stimulated acoustic emission to image a late liver and spleen-specific phase of Levovist in normal volunteers and patients with and without liver disease. Ultrasound Med Biol 1999;25:1341–52.[CrossRef][Medline]
  32. Blomley MJ, Albrecht T, Cosgrove DO, Patel N, Jayaram V, Butler-Barnes J, et al. Improved imaging of liver metastases with stimulated acoustic emission in the late phase of enhancement with the US contrast agent SH U 508A: early experience. Radiology 1999;210:409–16.[Abstract/Free Full Text]
  33. Bryant T, Blomley M, Albrecht T, Sidhu P, 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 2003: in press.
  34. Hope-Simpson D, Chin C, Burns P. Pulse inversion Doppler: a new method for detecting non-linear echoes from microbubble contrast agent. IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, 1999.
  35. Albrecht T, Blomley MJ, Burns PN, Wilson S, Harvey CJ, Leen E, et al. Improved detection of hepatic metastases with pulse-inversion US during the liver-specific phase of SHU 508A: multicenter study. Radiology 2003;227:361–70.[Abstract/Free Full Text]
  36. Phillips P. Contrast pulse sequences (CPS): imaging of non-linear microbubbles. In: IEE Ultrasonics Symposium 2001;2:1739–45.
  37. Leen E, Angerson WJ, Yarmenitis S, Bongartz G, Blomley M, Del Maschio A, et al. Multi-centre clinical study evaluating the efficacy of SonoVue (BR1), a new ultrasound contrast agent in Doppler investigation of focal hepatic lesions. Eur J Radiol 2002;41:200–6.[CrossRef][Medline]
  38. Wilson SR, Burns PN. Liver mass evaluation with ultrasound: the impact of microbubble contrast agents and pulse inversion imaging. Semin Liver Dis 2001;21:147–59.[CrossRef][Medline]
  39. Jakobsen JA, Correas JM. Ultrasound contrast agents and their use in urogenital radiology: status and prospects. Eur Radiol 2001;11:2082–91.[CrossRef][Medline]
  40. Shigeno K, Igawa M, Shiina H, Kishi H, Urakami S. Transrectal colour Doppler ultrasonography for quantifying angiogenesis in prostate cancer. BJU Int 2003;91:223–6.[CrossRef][Medline]
  41. Roy C, Buy X, Lang H, Saussine C, Jacqmin D. Contrast enhanced color Doppler endorectal sonography of prostate: efficiency for detecting peripheral zone tumors and role for biopsy procedure. J Urol 2003;170:69–72.[CrossRef][Medline]
  42. Albrecht T, Urbank A, Mahler M, Bauer A, Dore CJ, Blomley MJ, et al. Prolongation and optimization of Doppler enhancement with a microbubble US contrast agent by using continuous infusion: preliminary experience. Radiology 1998;207:339–47.[Abstract]
  43. Blomley MJ, Albrecht T, Cosgrove DO, Bamber JC. Can relative contrast agent concentration be measured in vivo with color Doppler US? Radiology 1997;204:279–81.[Medline]
  44. Orden M-J, Jurvelin J, Kirkenin P. Kinetics of a US contrast agent in benign and malignant adnexal tumors. Radiology 2003;226:405–10.[Abstract/Free Full Text]
  45. Wei K, Jayaweera A, Firoozan S. Quantification of myocardial blood flow with ultrasound induced destruction of microbubbles administered as a constant venous infusion. Circulation 1998;97:473–83.[Medline]
  46. Pollard R, Sadlowski A, Bloch S, Murray L, Wisner E, Griffey S, et al. Contrast-assisted destruction-replenishment ultrasound for the assessment of tumor microvasculature in a rat model. Technol Cancer Res Treat 2002;1:459–70.[Medline]
  47. Eckersley R, Cosgrove D, Blomley M, Hashimoto H. Functional imaging of tissue response to bolus injection of ultrasound contrast agent. Proc IEEE Ultrasonics Symposium 1988;2:1779–82.
  48. Lu Q, Liang H-D, Partridge T, Blomley M. Microbubble ultrasound improves the efficiency of gene transduction in skeletal muscle in vivo with reduced tissue damage. Gene Therapy 2003;10:396–405.[CrossRef][Medline]
  49. Leong-Poi H, Christiansen J, Klibanov AL, Kaul S, Lindner JR. Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins. Circulation 2003;107:455–60.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 J Ultrasound MedHome page
J. Murphy-Lavallee, H.-J. Jang, T. K. Kim, P. N. Burns, and S. R. Wilson
Are Metastases Really Hypovascular in the Arterial Phase?: The Perspective Based on Contrast-Enhanced Ultrasonography
J. Ultrasound Med., November 1, 2007; 26(11): 1545 - 1556.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Roentgenol.Home page
J. M. Provenzale
Imaging of Angiogenesis: Clinical Techniques and Novel Imaging Methods
Am. J. Roentgenol., January 1, 2007; 188(1): 11 - 23.
[Abstract] [Full Text] [PDF]

Home page
 J Ultrasound MedHome page
T. E. Yankeelov, K. J. Niermann, J. Huamani, D. W. Kim, C. C. Quarles, A. C. Fleischer, D. E. Hallahan, R. R. Price, and J. C. Gore
Correlation Between Estimates of Tumor Perfusion From Microbubble Contrast-Enhanced Sonography and Dynamic Contrast-Enhanced Magnetic Resonance Imaging
J. Ultrasound Med., April 1, 2006; 25(4): 487 - 497.
[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 Cosgrove, D
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cosgrove, D

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