Subharmonic aided pressure estimation for monitoring interstitial fluid pressure in tumours--in vitro and in vivo proof of concept

Abstract

The feasibility of using subharmonic aided pressure estimation (SHAPE) to noninvasively estimate interstitial fluid pressure (IFP) was studied. In vitro, radiofrequency signals, from 0.2 ml/l of Definity (Lantheus Medical Imaging, N Billerica, MA) were acquired within a water-tank with a Sonix RP ultrasound scanner (Analogic Ultrasound, Richmond, BC, Canada; fT/R=6.7/3.35 MHz and fT/R=10/5 MHz) and the subharmonic amplitudes of the signals were compared over 0-50 mmHg. In vivo, five swine with naturally occurring melanomas were studied. Subharmonic signals were acquired from tumours and surrounding tissue during infusion of Definity and compared to needle-based pressure measurements. Both in vitro and in vivo, an inverse linear relationship between hydrostatic pressure and subharmonic amplitude was observed with r(2)=0.63-0.95; p<0.05, maximum amplitude drop 11.36 dB at 10 MHz and -8 dB, and r(2) as high as 0.97; p<0.02 (10 MHz and -4/-8 dB most promising), respectively, indicating that SHAPE may be useful in monitoring IFP.

Keywords: Breast cancer; Contrast agents; Pressure estimation; Subharmonic signals; Ultrasound imaging.

Figure 1

a) – b) Water tank and acoustic setup with the L14-5 transducer. Notice the digital pressure gauge on the top of the tank and the syringe to alter the hydrostatic pressure. c) B-mode image of the water tank. The region of interest used for SHAPE is indicated with a red square.

Figure 2

An example B mode image from one of the swine melanomas. Tumour periphery is indicated by a blue dashed line, ROI for SHAPE with a green box and the location of the Stryker pressure monitor needle is indicated with a red circle

Figure 3

Subharmonic response to changes in acoustic power with the occurrence, growth and saturation phases. The relative subharmonic amplitude is scaled so that 0 dB refers to the lowest measured subharmonic amplitude and the remaining values are then scaled to that point as such: relative subharmonic amplitude = measured subharmonic amplitude – lowest measured subharmonic amplitude .

Figure 4

Decrease in subharmonic signal amplitude for Definity as a function of frequency and acoustic power (n = 3) when hydrostatic pressures were varied from 0 to 50 mmHg.

Figure 5

Inverse linear relationship between pressure and subharmonic signal amplitude for Definity at 10 MHz and −8 dB acoustic output power (n = 3).

Figure 6

Best fit in vivo measurements showing SHAPE results compared to the pressure monitor for 10 MHz. The difference between tissue and tumour IFP is clearly captured by SHAPE. Note that for a clearer comparison of best fit results, relative values for subharmonic amplitude (0 dB corresponding to the lowest dB value and then subharmonic amplitude difference relative to that value is reported) are used in the figure whereas actual values are used in table 1.