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Ultrasound Contrast Agents

 

Ultrasound - Microbubble Contrast Agents

Imaging Tumor Perfusion with Contrast Ultrasound:

Response to Therapy Assessment

Microbubble ultrasound contrast agents have been used for qualitative assessment of solid lesions in a clinical setting for several years. Recent work has described the use of these agents for measurement of the tumor vasculature, primarily as a quantitative endpoint for monitoring patient response to anti-cancer therapy. The size of the microbubble agent (1-8 um) renders them purely intravascular flow tracers, and early work confirmed that the kinetics of these agents in the blood are similar to that of erythrocytes (Wei et al, 1998). Agents are typically administered intravascularly as a bolus, and several quantitative parameters (such as the amplitude of the contrast enhancement and the time taken to peak enhancement  or clearance) have been shown to be reproducible measurements of tumor perfusion. Several recent studies have attempted to validate the use of contrast ultrasound for use in the context of drug validation in small and large experimental animals.

Response to Therapy in Small Animal Studies

Pollard (2006) and colleagues investigated the use of contrast ultrasound for monitoring response to anti-angiogenic therapy, using contrast enhanced CT and histology as gold standards. A rat model of breast cancer was used in this study, and the anti-angiogenic drug SU11657 was administered orally once tumors reached 0.5 cm in diameter. Contrast was administered as a continuous infusion via the tail vein, and three clips from each of two planes were acquired for each tumor at days 0, 7, and 14 post-treatment. A significant difference in blood flow was measured by contrast ultrasound on days 7 and 14. Tumor viability (percent of area) was determined by contrast ultrasound, contrast CT, and histology by blinded readers. The correlation between histology and ultrasound was slightly greater than that of histology to CT (R2=0.92 vs 0.86), and the correlation between ultrasound and CT was found to be 0.94. Contrast ultrasound was found to distinguish non-responsive and atypical responsive tumors with efficacy similar to contrast CT.
 
A similar study was performed by O’Connor et al (2009), in which the response of MH-7 colorectal tumors to treatment with an anti-VEGF mAb (clone G6-31; Genentech) was assessed with  contrast ultrasound and micro-CT in mice. Contrast enhancement within three parallel planes within the tumor was measured following IV administration of microbubble agents, and the relative blood flow and relative blood volume were calculated. Contrast ultrasound revealed a significant reduction in blood volume and a trend toward reduced blood flow at 48 hours post-treatment. Micro-CT casts showed a similar trend, with a reduction in vascular density at 48 h post treatment.
 
Figure 1. Contrast ultrasound imaging of subcutaneous tumors in mice. Leftmost panel shows B-mode scan of human bladder cancer tumor (MB49) on flank of mouse (tumor circled in blue). Subsequent panels are representative contrast scans of three tumors 15s after administration of Targestar®-P microbubble contrast agent. Regions of tumor that are not perfused (highlighted by red circle in second panel) are easily discriminated from those receiving blood flow. Images were acquired with Sequoia (Siemens) at 14 MHz.
 
Bagi (2009) and colleagues at Pfizer examined the use of contrast ultrasound to assess response of hepatocellular carcinoma (HCC) to Sunitinib or combination therapy. Nude rats were inoculated with Huh7.5 tumor cells subcutaneously, and treated with Sunitinib or Sunitinib + PF-562,271 (a FADk/Pyk2 inhibitor) on day 5 or 26. Contrast ultrasound imaging was able to show a distinct reduction in perfused area and necrotic area following combination treatment relative to Sunitinib alone, and contrast ultrasound correlated well to histology. Palmowski et al (2008) analyzed the response of epidermoid carcinoma tumors in mouse to Sunitinib using a Power Doppler based method. The use of microbubble contrast agents enables a more sensitive discrimination of blood flow in microvessels relative to Power Doppler imaging alone.
 
The effect of the anti-VEGF antibody Bevacizumab (Genentech) on tumor blood flow has been investigated by contrast ultrasound in several studies. Hoyt and colleagues (2010) showed that contrast ultrasound was able to detect response to therapy earlier than measurement of tumor volume. In this study, the area under the time-intensity curve and peak intensity correlated to treatment efficacy.
 
Guibal and colleagues (2010) examined the effect of discontinuation of Bevacizumab therapy in a mouse model of kidney cancer. This study showed that contrast ultrasound imaging detected a quantitative change in tumor perfusion between tumors that were continuously treated versus those in which treatment was interrupted. Moreover, contrast ultrasound was shown to be more sensitive than histological microvessel density measurements in detecting a response to therapy.
 
 
 
Figure 2. Regional analysis of perfusion in human prostate tumor (PC-3). Wash-in of Targestar-P over 15 s is shown in the panels at left. Three arbitrary regions of interest are selected, and time-intensity curve is plotted at left. Rapid and high-volume blood flow is observed for region 3, while regions 1 and 2 show delayed filling and lower blood flow.
 

Clinical Applications

Several recent studies have highlighted the use of contrast ultrasound imaging for monitoring the response to anti-cancer therapy in a clinical setting. Lamuraglia et al (2006) performed a prospective study in renal cell carcinoma patients, and showed that contrast ultrasound imaging was able to predict progression-free survival in patients responding to sorafenib therapy. A subsequent study by Lassau and colleagues (2010) demonstrated that contrast ultrasound imaging parameters were predictive of response by traditional measurements, including overall survival and the RECIST criteria.
Escudier and colleagues (2007) similarly utilized contrast ultrasound imaging as a surrogate endpoint in a small phase I trial for combination therapy (sorafenib + IFN alpha-2a) in advanced renal cell carcinoma. The use of contrast ultrasound to monitor response to Imatinib in gastrointestinal stromal tumors was demonstrated by Lassau (2006). In the context of liver cancer, Averkiou and colleagues (2010) showed that contrast ultrasound imaging was able to monitor the response to combination therapy in patients with colorectal metastases in the liver. In this study, the contrast agent wash-in time within the lesions was shown to predict response to treatment in 80% of patients after the first treatment, and 100% of patients by the final treatment.
 

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References

  1. Averkiou M, Lampaskis M, Kyriakopoulou K, Skarlos D, Klouvas G, Strouthos C, Leen E. Quantification of tumor microvascularity with respiratory gated contrast enhanced ultrasound for monitoring therapy. Ultrasound Med Biol. 2010 Jan;36(1):68-77
  2. Bagi CM, Christensen J, Cohen DP, Roberts WG, Wilkie D, Swanson T, Tuthill T, Andresen CJ. Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block growth and recovery of human hepatocellular carcinoma in a rat xenograft model. Cancer Biol Ther. 2009 May;8(9):856-65.
  3. Escudier B, Lassau N, Angevin E, Soria JC, Chami L, Lamuraglia M, Zafarana E, Landreau V, Schwartz B, Brendel E, Armand JP, Robert C. Phase I trial of sorafenib in combination with IFN alpha- 2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma. Clin Cancer Res. 2007 Mar 15;13(6):1801-9.
  4. Guibal A, Taillade L, Mulé S, Comperat E, Badachi Y, Golmard JL, Le Guillou-Buffello D, Rixe O, Bridal SL, Lucidarme O. Noninvasive contrast-enhanced US quantitative assessment of tumor microcirculation in a murine model: effect of discontinuing anti-VEGF therapy. Radiology. 2010 Feb;254(2):420-9.
  5. Hoyt K, Warram JM, Umphrey H, Belt L, Lockhart ME, Robbin ML, Zinn KR. Determination of breast cancer response to bevacizumab therapy using contrast-enhanced ultrasound and artificial neural networks. J Ultrasound Med. 2010 Apr;29(4):577-85.
  6. Lamuraglia M, Escudier B, Chami L, Schwartz B, Leclère J, Roche A, Lassau N. To predict progression- free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer. 2006 Oct;42(15):2472-9. Epub 2006 Sep11. Erratum in: Eur J Cancer. 2007 May;43(8):1336.
  7. Lassau N, Lamuraglia M, Chami L, Leclère J, Bonvalot S, Terrier P, Roche A, Le Cesne A. Gastrointestinal stromal tumors treated with imatinib: monitoring response with contrast-enhanced sonography. AJR Am J Roentgenol. 2006 Nov;187(5):1267-73.
  8. Lassau N, Koscielny S, Albiges L, Chami L, Benatsou B, Chebil M, Roche A, Escudier BJ. Metastatic renal cell carcinoma treated with sunitinib: early evaluation of treatment response using dynamic contrast- enhanced ultrasonography. Clin Cancer Res. 2010 Feb 15;16(4):1216-25.
  9. O'Connor JP, Carano RA, Clamp AR, Ross J, Ho CC, Jackson A, Parker GJ, Rose CJ, Peale FV, Friesenhahn M, Mitchell CL, Watson Y, Roberts C, Hope L, Cheung S, Reslan HB, Go MA, Pacheco GJ, Wu X, Cao TC, Ross S, Buonaccorsi GA, Davies K, Hasan J, Thornton P, del Puerto O, Ferrara N, van Bruggen N, Jayson GC. Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging. Clin Cancer Res. 2009 Nov 1;15(21):6674-82.
  10. Palmowski M, Huppert J, Hauff P, Reinhardt M, Schreiner K, Socher MA, Hallscheidt P, Kauffmann GW, Semmler W, Kiessling F. Vessel fractions in tumor xenografts depicted by flow- or contrast sensitive three-dimensional high-frequency Doppler ultrasound respond differently to antiangiogenic treatment. Cancer Res. 2008 Sep 1;68(17):7042-9.
  11. Pollard RE, Broumas AR, Wisner ER, Vekich SV, Ferrara KW. Quantitative contrast enhanced ultrasound and CT assessment of tumor response to antiangiogenic therapy in rats. Ultrasound Med Biol. 2007 Feb;33(2):235-45.
  12. Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation. 1998 Feb 10;97(5):473-83.

Comments

It is now possible to

Muhammad usman (not verified) - 01/10/2011 - 11:46

It is now possible to download the code for 000-649 PMON2000 R3.x from CVS. Note that you should grab pmon2000 instead of pmon to get the new version. This version currently have 000-816 no code for powerpc. If you want to contribute to change that please feel free to do so. This code is 000-928 mainly provided for system integrators and there is not many targets supported 'out of the box'. BSPs exist for a couple of PMC-Sierra evaluation boards and for the Linksys NSS4000 and cissp certification NSS6000." Thanks for the information 70-271 \ 117-201 \ 642-072 \ 646-223 \ 650-575 \ SK0-002 \ 117-202 \ 646-046 \ E20-611 \ HP0-S23 \ HP2-E31 \ HP2-K03 \ HP2-T19 \ 000-025 \ 000-032 \ 000-037 \ 000-530



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