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While mammography has high sensitivity in the detection of breast cancer, its low specificity results in a false-positive rate of roughly 80 %. Thus, a secondary tool for the characterization of breast masses would be highly beneficial. This ongoing study investigates the use of 4D harmonic and subharmonic imaging (HI and SHI) for the characterization of breast masses identified by mammography. Patients scheduled for an ultrasound guided biopsy of a mammographically-identified breast mass provided informed consent to undergo a contrast ultrasound study prior to biopsy. Scanning was performed using a modified Logiq 9 scanner with a 4D10L probe (GE Healthcare, Milwaukee, WI). Experimental software provided 4D HI (transmitting 2 cycle pulses at 5 MHz and receiving at 10 MHz) and 4D SHI (transmitting 4 cycle pulses at 5.8 MHz and receiving at 2.9 MHz). Subjects underwent 2D B-mode and power Doppler imaging (PDI), before receiving a 0.25 ml injection of the contrast agent Definity (Lantheus Medical Imaging, N. Billerica, MA) for 4D HI. After 30 minutes, subjects received a second injection of 20 µl/kg (up to 1.25 ml) for 4D SHI of the lesion. To date, 157 women have been enrolled and 149 have completed the study. Incomplete studies resulted from a failure to gain IV access (n=5), equipment malfunction (n=2), and a previously undisclosed contraindication to the contrast agent (n=1; unstable pulmonary status). 3D volume rates ranged from 1.7 Hz (for a 3.7×1.3×2.0 cm lesion) to 6.1 Hz (for a 6x4x6 mm lesion). SHI resulted in improved tissue suppression in 146 cases, equal tissue suppression in 2 cases, and inferior tissue suppression in 1 case relative to HI. Malignancy has been confirmed by pathology in 37 cases. Flow visualization (in all lesions) was evident in 82 cases on PDI, 8 cases on 4D HI, and 68 cases on 4D SHI. Thus, while the diagnostic value has yet to be determined by the radiologists, initial results indicate that 4D SHI provides improved tissue suppression and visualization of flow in breast masses.

The objective of this study was to compare coded harmonic imaging (HI) to pulse-inversion subharmonic imaging (SHI) in the characterization of renal masses. Twelve patients with 13 renal masses provided informed consent for an off-label CEUS exam prior to renal mass biopsy and cryoablation. All scanning was performed on a modified Logiq 9 ultrasound scanner with a 4C probe (GE Healthcare, Milwaukee, WI). Following baseline imaging, patients received a 2 ml bolus IV injection of the ultrasound contrast agent Optison (GE Healthcare, Princeton, NJ) and 10 ml flush during simultaneous 2D dual imaging in both grayscale (f = 4.0 MHz) and SHI (f transmit = 2.5 MHz, f recieve = 1.25 MHz). Following a 15 min wait, patients received a 1 ml contrast injection during imaging with the unit's HI package (f transmit = 2.0 MHz, f recieve = 4.0 MHz). A blinded radiologist with experience in CEUS evaluated the heterogeneity, intensity, and wash-in/wash-out kinetics of enhancement in the mass relative to the renal cortex. Additionally, contrast signal time intensity curves (TICs) were constructed from both the renal mass and cortex, fit to a contrast wash-in model, and used to calculate the time to peak, perfusion, maximum intensity, and area under the curve. Finally, the radiologist and TIC findings from each CEUS imaging mode were compared to pathology. Biopsy findings showed the 13 renal masses consisted of 9 renal cell carcinomas, 2 areas of benign renal parenchyma, 1 area of renal necrosis, and 1 oncocytoma. All masses showed heterogeneous enhancement with both SHI and HI. Increased enhancement of the mass relative to the renal cortex was observed during the early contrast wash-in phase in 2/9 malignant and 3/4 benign lesions on SHI, and 3/9 malignant and 1/4 benign lesions on HI. Early contrast wash out in the mass relative to the cortex was observed in 6/9 malignant and 0/4 benign lesions in SHI (sensitivity = 67%, specificity = 100%), and 8/9 malignant and 1/4 benign lesions in HI (sensitivity = 89%, specificity = 75%). Comparison of the TIC parameters obtained from the renal mass and cortex of malignant lesions showed no statistically significant differences when compared to benign lesions (p > 0.2). Thus, visualization of early contrast washout on HI or SHI appears to be a reliable indicator of renal carcinoma on CEUS; albeit based on a limited sample size.

Ultrasound imaging studies of tumor angiogenesis are often conducted with pathological markers as the reference standard. There is, however, no established standard for how to analyze specimen markers and compare them to imaging parameters. Hence, this study compared different methods for obtaining tumor neovascularity parameters based on immunohistochemical markers to contrast-enhanced subharmonic ultrasound imaging (SHI). Breast cancer cells (MDA-MB-231) were implanted into the mammary fat pad of 85 athymic, nude, female rats. An ultrasound contrast agent was injected and SHI was performed using a Sonix RP scanner (Analogic Ultrasound, Richmond, BC, Canada) transmitting and receiving at 8 and 4 MHz, respectively. Tumor specimens were sliced corresponding to the imaging planes and stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2). Tumor neovascularity was assessed in 4 different ways 1) over the entire tumor, 2) in small sub-ROIs, 3) in the tumor periphery and centrally, and 4) in regions of maximum marker expression (so called hotspots). Of the 85 rats implanted 54 (64 %) exhibited tumor growth and 38 were successfully imaged. SHI depicted the tortuous morphology of tumor neovessels and delineated small areas of necrosis. SHI measures of tumor vascularity did not correlate with the immunohistochemical markers when assessed over the entire tumor area or over small sub-ROIs (p gt; 0.18). However, when the specimens were sub-dived into a central and a peripheral region, COX-2 and VEGF correlated with SHI in the periphery (r = −0.42; p = 0.005 and r = −0.32; p = 0.049, respectively). In conclusion, when comparing quantitative contrast measures of tumor neovascularity to immunohistochemical markers of angiogenesis in xenograft models it appears that sub-ROIs corresponding to the biologically active region (i.e., the tumor periphery) should be used to account for tumor heterogeneity and development.

Ability to visualize breast lesion vascularity and quantify the vascular heterogeneity using contrast-enhanced three-dimensional (3D) harmonic (HI) and subharmonic (SHI) ultrasound imaging was investigated in a clinical population. Patients (n = 134) identified with breast lesions on mammography were scanned using power Doppler imaging (PDI), contrast-enhanced 3D HI and 3D SHI on a modified Logiq 9 scanner (GE Healthcare). Ultrasound contrast agent (UCA) flow was identified in 4D View™ (GE Medical Systems) and used to generate a map of time-intensity curves for each lesion volume. Time-points corresponding to baseline, peak intensity and washout of UCA were identified to develop vascular heterogeneity plots. Vascularity was observed with PDI in 82 lesions (61 benign and 21 malignant). 3D HI showed flow in 8 lesions (5 benign and 3 malignant), while 3D SHI visualized flow in 68 (49 benign and 19 malignant). Analysis of vascular heterogeneity in the 3D SHI volumes found benign lesions having a significant difference in vascularity between central and peripheral sections (1.71 ± 0.96 vs. 1.13 ± 0.79 dB, p < 0.001, respectively) whereas malignant lesions showed no difference (1.66 ± 1.39 vs. 1.24 ± 1.14 dB, p = 0.24), indicative of more vascular coverage. These preliminary results suggest quantitative evaluation of vascular heterogeneity in breast lesions using contrast-enhanced 3D SHI is feasible and able to detect variations in vascularity between central and peripheral sections for benign and malignant lesions. Finally, 3D parametric volumes were produced for perfusion (PER) and area under the curve (AUC).

Nodules in the thyroid are present in 13–76 % of ultrasound (US) imaging evaluations; although only 4–15 % are malignant. A better understanding of thyroid nodule vascularity might be clinically helpful and the purpose of this study was thus to determine the flow imaging capabilities of a new prototype US image processing technique (SMI; Toshiba Medical Systems, Tokyo, Japan) for the depiction of microvascular flow in normal thyroid tissue and thyroid nodules compared to standard color and power Doppler imaging (CDI and PDI). SMI is a novel, microvascular flow imaging mode implemented on the Aplio 500 scanner (Toshiba). By analyzing clutter motion and using a new adaptive algorithm to identify and remove tissue motion SMI is designed to improve the visualization of microvascular blood flow. SMI depicts this information as a color overlay or as a monochrome map of flow. Ten healthy volunteers and 22 patients, with 25 thyroid nodules, were studied. Subjects underwent a thyroid US examination consisting of grayscale US, CDI and PDI followed by color and monochrome SMI. In the volunteers, pulsed Doppler guided by the 4 flow modes determined the lowest velocity measurable within the normal thyroid. For the patient data, 2 radiologists independently scored overall flow detection, vessel branching and noise on a visual analog scale of 1 (worst) to 10 (best). In the volunteers color and monochrome SMI captured microvasculature with lower velocities than CDI and PDI (2.2 ± 0.35 and 2.1 ± 0.32 cm/s vs. 2.6 ± 0.44 and 2.8 ± 0.77 cm/s; p < 0.012). For all 25 nodules both readers found that color and monochrome SMI showed more microvascular flow and provided better depiction of the vessel branching compared to CDI and PDI (p < 0.0001). Clutter noise was significantly higher in the monochrome SMI mode than in the other 3 modes (p < 0.001). Consequently, initial results indicate that SMI can depict more detailed peri- and intra-nodular thyroid microvascular flow than CDI and PDI.