Quantification of Microvascular Tortuosity during Tumor Evolution Using Acoustic Angiography

Shelton, Sarah E.; Lee, Yueh Z.; Lee, Mike; Chérin, Emmanuel; Foster, F. Stuart; Aylward, Stephen; Dayton, Paul A.

doi:10.1016/j.ultrasmedbio.2015.02.012

Cited by 102 publications

(92 citation statements)

References 41 publications

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“…Recent acoustic angiography studies have characterized the tortuosity of tumor vasculature and found it to be significantly higher than that of control tissue [5, 6]. However the presence of a tumor and its effect on the 3-D morphology and spatial variability of surrounding vasculature has not yet been characterized quantitatively using ultrasound.…”

Section: Introductionmentioning

confidence: 99%

The “Fingerprint” of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach

Rao

Shelton

2016

IEEE Trans. Biomed. Eng.

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Goal Abnormalities of microvascular morphology have been associated with tumor angiogenesis for more than a decade, and are believed to be intimately related to both tumor malignancy and response to treatment. However, the study of these vascular changes in-vivo has been challenged due to the lack of imaging approaches which can assess the microvasculature in 3-D volumes non-invasively. Here, we use contrast-enhanced “acoustic angiography” ultrasound imaging to observe and quantify heterogeneity in vascular morphology around solid tumors. Methods Acoustic angiography, a recent advance in contrast-enhanced ultrasound imaging, generates high resolution microvascular images unlike anything possible with standard ultrasound imaging techniques. Acoustic angiography images of a genetically engineered mouse breast cancer model were acquired to develop an image acquisition and processing routine that isolated radially expanding regions of a 3-D image from the tumor boundary to the edge of the imaging field for assessment of vascular morphology of tumor and surrounding vessels. Results Quantitative analysis of vessel tortuosity for the tissue surrounding tumors 3 to 7 mm in diameter revealed that tortuosity decreased in a region 6 to 10 mm from the tumor boundary, but was still significantly elevated when compared to control vasculature. Conclusion Our analysis of angiogenesis-induced changes in the vasculature outside the tumor margin reveals that the extent of abnormal tortuosity extends significantly beyond the primary tumor mass. Significance Visualization of abnormal vascular tortuosity may make acoustic angiography an invaluable tool for early tumor detection based on quantifying the vascular footprint of small tumors and a sensitive method for understanding changes in the vascular microenvironment during tumor progression.

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Section: Introductionmentioning

confidence: 99%

The “Fingerprint” of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach

Rao

Shelton

2016

IEEE Trans. Biomed. Eng.

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“…By mechanically scanning this dual-frequency transducer, it is possible to acquire high resolution images of vasculature (Fig. 1) and differentiate healthy tissue from tumor-bearing tissue based on visualizing angiogenesis (Gessner et al 2012; Shelton et al In review). However, the exact mechanism by which broadband harmonic energy is produced is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

On the Relationship Between Microbubble Fragmentation, Deflation and Broadband Superharmonic Signal Production

Lindsey¹,

Rojas²,

Dayton³

2015

Ultrasound in Medicine & Biology

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Acoustic angiography imaging of microbubble contrast agents utilizes the superharmonic energy produced from excited microbubbles, and enables high-contrast, high-resolution imaging. However, the exact mechanism by which broadband harmonic energy is produced is not fully understood. In order to elucidate the role of microbubble shell fragmentation in superharmonic signal production, simultaneous optical and acoustic measurements were performed on individual microbubbles at transmit frequencies from 1.75 to 3.75 MHz and pressures near the shell fragmentation threshold for microbubbles of varying diameter. High-amplitude, broadband superharmonic signals were produced with shell fragmentation, while weaker signals (approximately 25% of peak amplitude) were observed in the presence of shrinking bubbles. Furthermore, when imaging populations of stationary microbubbles with a dual-frequency ultrasound imaging system, a sharper decline in image intensity with respect to frame number was observed for 1 μm bubbles than for 4 μm bubbles. Finally, in a study of two rodents, increasing frame rate from 4 to 7 Hz resulted in a decrease in mean steady-state image intensity of 27% at 1000 kPa and 29% at 1300 kPa. While the existence of superharmonic signals when bubbles shrink has the potential to prolong the imaging efficacy of microbubbles, parameters such as frame rate and peak pressure must be balanced with expected re-perfusion rate in order to maintain adequate contrast during in vivo imaging.

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“…Utilization of a lower transmit frequency allows for excitation of microbubbles closer to their resonance frequencies and provides better penetration relative to high frequency imaging. Using this approach, which we refer to as “acoustic angiography,” we have demonstrated the ability to differentiate healthy from tumor-bearing tissue based on quantitative, image-based metrics of angiogenesis (Gessner et al 2012; Shelton et al 2015). Figure 1 shows example acoustic angiography maximum intensity projections of tortuous vasculature associated with a subcutaneous tumor model, along with anatomical B-mode images of the same tissue volume.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Contrast-to-Tissue Ratio Through Pulse Windowing in Dual-Frequency “Acoustic Angiography” Imaging

Lindsey

Shelton

Dayton

2015

Ultrasound in Medicine & Biology

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Early-stage tumors in many cancers are characterized by vascular remodeling, indicative of transformations in cell function. We have previously presented a high-resolution ultrasound imaging approach for detecting these changes which is based on microbubble contrast agents. In this technique, images are formed from only the higher harmonics of microbubble contrast agents, producing images of vasculature alone with 100–200 μm resolution. In this article, shaped transmit pulses are applied to imaging the higher broadband harmonic echoes of microbubble contrast agents, and the effects of varying pulse window and phasing on microbubble and tissue harmonic echoes are evaluated using a dual-frequency transducer in vitro and in vivo. An increase in contrast-to-tissue ratio of 6.8 ± 2.3 dB was observed in vitro by using an inverted pulse with a cosine window relative to a non-inverted pulse with a rectangular window. The increase in mean image intensity due to contrast enhancement in vivo in five rodents was 13.9 ± 3.0 dB greater for an inverted cosine-windowed pulse and 17.8 ± 3.6 dB greater for a non-inverted Gaussian-windowed relative to a non-inverted pulse with a rectangular window. Implications for pre-clinical and diagnostic imaging are also discussed.

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Quantification of Microvascular Tortuosity during Tumor Evolution Using Acoustic Angiography

Cited by 102 publications

References 41 publications

The “Fingerprint” of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach

The “Fingerprint” of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach

On the Relationship Between Microbubble Fragmentation, Deflation and Broadband Superharmonic Signal Production

Optimization of Contrast-to-Tissue Ratio Through Pulse Windowing in Dual-Frequency “Acoustic Angiography” Imaging

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