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Background The current standard for assessing the severity of portal hypertension is the invasive acquisition of hepatic venous pressure gradient (HVPG). A noninvasive US-based technique called subharmonic-aided pressure estimation (SHAPE) could reduce risk and enable routine acquisition of these pressure estimates. Purpose To compare quantitative SHAPE to HVPG measurements to diagnose portal hypertension in participants undergoing a transjugular liver biopsy. Materials and Methods This was a prospective cross-sectional trial conducted at two hospitals between April 2015 and March 2019 (ClinicalTrials.gov identifier, NCT02489045). This trial enrolled participants who were scheduled for transjugular liver biopsy. After standard-of-care transjugular liver biopsy and HVPG pressure measurements, participants received an infusion of a US contrast agent and saline. During infusion, SHAPE data were collected from a portal vein and a hepatic vein, and the difference was compared with HVPG measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student t test. Receiver operating characteristic analysis was performed to determine the sensitivity and specificity of SHAPE. Results A total of 125 participants (mean age ± standard deviation, 59 years ± 12; 80 men) with complete data were included. Participants at increased risk for variceal hemorrhage (HVPG ≥12 mm Hg) had a higher mean SHAPE gradient compared with participants with lower HVPGs (0.79 dB ± 2.53 vs -4.95 dB ± 3.44; P < .001), which is equivalent to a sensitivity of 90% (13 of 14; 95% CI: 88, 94) and a specificity of 80% (79 of 99; 95% CI: 76, 84). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the HVPG measurements ( r = 0.68). Conclusion Subharmonic-aided pressure estimation is an accurate noninvasive technique for detecting clinically significant portal hypertension. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kiessling in this issue.

Transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) often requires retreatment and identification of feeding vessels supplying the residual/recurrent tumor is an important step in treatment planning. The objective of this study was to determine if contrast-enhanced ultrasound (CEUS) could correctly identify the vessel supplying the residual tumor. To date, 69 patients have undergone CEUS follow-up of HCC TACE therapy at our institution as part of an ongoing institutional review board approved trial (NCT02764801). The CEUS examinations were performed before HCC TACE as well as 1 to 2 weeks and 1 month after treatment using a Logiq E9 scanner with a C1-6 curved array transducer (GE Healthcare, Waukesha, WI). The CEUS images obtained 2 weeks after initial TACE treatment were reviewed, and any feeding vessels supplying the residual HCC were identified. Digital subtraction angiograms during the retreatment TACE were used as reference standard for feeding vessel identification. Thirteen patients with viable HCC post-TACE were included in this study. In these cases, the sonographer correctly identified 85% (11 of 13) of the feeding vessels later confirmed by angiography. Importantly, one of the false-negative cases involved a segment 8 tumor with parasitic blood supply from the medial left hepatic artery. In this case, CEUS identified a largely treated tumor with some residual internal flow, but was unable to visualize any major hepatic vascularity supplying the tumor. In conclusion, CEUS appears to be a valuable tool for planning retreatment of residual HCC post-TACE.

Objectives: This pilot study evaluated whether contrast-enhanced subharmonic imaging (SHI) could be used to characterize adnexal masses before surgical intervention., Methods: Ten women (with 12 lesions) scheduled for surgery of an ovarian mass underwent an SHI examination of their adnexal region using a modified LOGIQ E9 scanner (GE Healthcare, Waukesha, WI) with an endocavitary transducer, in which digital clips were acquired by pulse destruction-replenishment SHI across the lesions. Time-intensity curves were created offline to quantitatively evaluate SHI parameters (fractional tumor perfusion, peak contrast intensity, time to peak contrast enhancement, and area under the time-intensity curve), which were compared to pathologic characterizations of the lesions., Results: Of the 12 masses, 8 were benign, and 4 were malignant. A qualitative analysis of the SHI images by an experienced radiologist resulted in diagnostic accuracy of 70%, compared to 56% without contrast, whereas an inexperienced radiologist improved from 50% to 58% accuracy, demonstrating the benefit of SHI. A quantitative analysis of SHI parameters produced diagnostic accuracy as high as 81%. Peak contrast intensity was significantly greater in malignant than benign masses (mean ± SD, 0.109 ± 0.088 versus 0.046 ± 0.030 arbitrary units; P = .046). Malignant masses also showed significantly greater perfusion than benign masses (24.79% ± 25.34% versus 7.62% ± 6.50%; P = .045). When the radiologist reads were combined with the most predictive quantitative SHI parameter (percent perfusion), diagnostic accuracy improved to 84% for the experienced radiologist and 96% for the novice radiologist., Conclusions: Results indicate that SHI for presurgical characterization of adnexal masses may improve the determination of malignancy and diagnostic accuracy, albeit based on a small sample size., (© 2019 by the American Institute of Ultrasound in Medicine.)

Rationale and Objectives: To explore the influence of data parsing (either selection of frames at set time intervals or by an experienced sonographer) of contrast-enhanced ultrasound (CEUS) exams on physician diagnoses and confidence levels., Materials and Methods: Forty consecutive CEUS exams consisting of 10 cases each of indeterminate liver lesions, indeterminate renal lesions, renal cell carcinoma postablation follow-up, and hepatocellular carcinoma postchemoembolization follow-up were selected for analysis. Exams were parsed into sets consisting of five images selected by the performing sonographer and sets containing systematically stored frames every 10, 30, and 60 seconds. Three blinded physicians then reviewed the cine loop and each set of images in randomized order and provided a diagnosis and confidence level., Results: For all clinical applications investigated, no statistically significant differences in diagnostic performance measures or reader confidence were observed between review of the entire cine loop and images selected by the performing sonographer (p > 0.42). Diagnostic performance at 10-second intervals did not show statically significant changes compared to the full cine loop review for all applications (p > 0.18), although reader confidence decreased. At 30-60-second intervals, both diagnostic performance and reader confidence showed statistically significant reduction compared to review of the full cine loop (p < 0.045)., Conclusions: Transfer and review of large cine loops from CEUS exams represent a potential barrier to adoption within the United States workflows. This study demonstrates that images selected by a performing trained sonographer may provide the same value without the review time and data storage costs needed for full cine loop review. Parsing by time points reduced reader confidence and diagnostic performance., (Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Subharmonic-aided pressure estimation (SHAPE) estimates hydrostatic pressure using the inverse relationship with subharmonic amplitude variations of ultrasound contrast agents (UCAs). We studied the impact of varying incident acoustic outputs (IAO), UCA concentration, and hematocrit on SHAPE. A Logiq 9 scanner with a 4C curvilinear probe (GE, Milwaukee, Wisconsin) was used with Sonazoid (GE Healthcare, Oslo, Norway) transmitting at 2.5 MHz and receiving at 1.25 MHz. An improved IAO selection algorithm provided improved correlations ( r from -0.85 to -0.95 vs. -0.39 to -0.98). There was no significant change in SHAPE gradient as the pressure increased from 10 to 40 mmHg and hematocrit concentration was tripled from 1.8 to 4.5 mL/L (Δ0.00-0.01 dB, p = 0.18), and as UCA concentration was increased from 0.2 to 1.2 mL/L (Δ0.02-0.05 dB, p = 0.75). The results for the correlation between the SHAPE gradient and hematocrit values for patients ( N = 100) in an ongoing clinical trial were also calculated showing a poor correlation value of 0.14. Overall, the SHAPE gradient is independent of hematocrit and UCA concentration. An improved algorithm for IAO selection will make SHAPE more accurate.

Objective: To evaluate efficacy of using 2D and 3D contrast enhanced ultrasound (CEUS) for surveillance of RCC recurrence in patients post-ablation and identify imaging hallmarks of recurrence., Methods: 53 patients >8 months post ablation of RCC provided informed consent for this IRB approved study. Patients received 2D and 3D CEUS examinations with Optison (GE Healthcare). Three radiologists of varying CEUS experience described enhancement characteristics, made a diagnosis of recurrence/no-recurrence, and quantified their diagnostic confidence levels., Results: Cases of RCC recurrence showed full ablation cavity enhancement with equal arrival times and intensity compared to the renal cortex. Lack of recurrence was characterized as a complete lack of enhancement within the cavity, or delayed enhancement stemming from the periphery of the ablation cavity. Sensitivity for detecting RCC recurrence was 100% for all readers and specificity was 90%-94%. Reader agreement ranged from 88% to 96%. No significant improvements were achieved with the addition of 3D CEUS, and its inclusion resulted in decreased reader confidence., Conclusion: Contrast-enhanced ultrasound successfully identified all cases of RCC recurrence in this study. Importantly, some patients with complete response to treatment developed delayed enhancement at the periphery of the ablation cavity over time, corresponding to fat necrosis, scarring or granulation tissue within the ablation cavity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Mapping of the lymphatic chain for identification of the sentinel lymph node (SLN) is an important aspect of predicting outcomes for patients with breast cancer, and it is usually performed as an intraoperative procedure using blue dye and/or radiopharmaceutical agents. Recently, the use of contrast-enhanced ultrasound (CEUS) has been proposed as an alternative imaging technique for this mapping. The objective of this study was to evaluate the use of subdermal administration of the ultrasound (US) contrast agent Sonazoid (GE Healthcare, Oslo, Norway) in terms of patient safety and to select the dose to be used for lymphatic applications in humans., Methods: This study was performed in 12 female volunteers who received bilateral subdermal injections of Sonazoid (1 or 2 mL dose) in the mid-upper outer quadrant of their breasts at 2 different time points. Contrast-enhanced US examinations were performed 0, 0.25, 0.5, 1, 2, 4, 6, and 24 hours after injection to identify SLNs., Results: Sentinel lymph nodes were identified within the first hour after injection as enhanced structures, and there was no significant difference by dose in the number of SLNs identified (P = .74). The volunteers only had minor adverse experiences (AEs) that resolved completely without intervention by study completion., Conclusions: The subdermal use of Sonazoid in this study showed only minor local and nonsignificant AEs that were completely resolved without any intervention. Two different doses were compared with no significant differences observed between them. Hence, the lower dose studied (1 mL) was selected for use in future clinical studies., (© 2017 by the American Institute of Ultrasound in Medicine.)

Objectives: To use subharmonic imaging (SHI) to depict the vascularity of pancreatic masses compared to contrast-enhanced endoscopic ultrasound (EUS) and pathologic results., Methods: Sixteen patients scheduled for biopsy of a pancreatic mass were enrolled in an Institutional Review Board-approved study. Pulse-inversion SHI (transmitting/receiving at 2.5/1.25 MHz) was performed on a LOGIQ 9 system (GE Healthcare, Milwaukee, WI) with a 4C transducer, whereas contrast harmonic EUS (transmitting/receiving at 4.7/9.4 MHz) was performed with a radial endoscope (GF-UTC180; Olympus Corporation, Tokyo, Japan) connected to a ProSound SSD α-10 scanner (Hitachi Aloka, Tokyo, Japan). Two injections of the contrast agent Definity (Lantheus Medical Imaging, North Billerica, MA) were administrated (0.3-0.4 and 0.6-0.8 mL for EUS and SHI, respectively). Contrast-to-tissue ratios (CTRs) in the mass and an adjacent vessel were calculated. Four physicians independently scored the images (benign to malignant) for diagnostic accuracy and inter-reader agreement., Results: One patient dropped out before imaging, leaving 11 adenocarcinomas, 1 gastrointestinal stromal tumor with pancreatic infiltration, and 3 benign masses. Marked subharmonic signals were obtained in all patients, with intratumoral blood flow clearly visualized with SHI. Significantly greater CTRs were obtained in the masses with SHI than with EUS (mean ± SD, 1.71 ± 1.63 versus 0.63 ± 0.89; P = .016). There were no differences in the CTR in the surrounding vessels or when grouped by pathologic results (P > .60). The accuracies for contrast EUS and SHI were low (<53%), albeit with a greater κ value for SHI (0.34) than for EUS (0.13)., Conclusions: Diagnostic accuracy of contrast EUS and transabdominal SHI for assessment of pancreatic masses was quite low in this pilot study. However, SHI had improved tumoral CTRs relative to contrast EUS., (© 2017 by the American Institute of Ultrasound in Medicine.)

This study evaluated the feasibility of employing non-invasive intra-cardiac pressure estimation using subharmonic signals from ultrasound contrast agents in humans. This institutional review board-approved proof-of-concept study included 15 consenting patients scheduled for left and right heart catheterization. During the catheterization procedure, Definity was infused intra-venously at 4-10 mL/min. Ultrasound scanning was performed with a Sonix RP using pulse inversion, three incident acoustic output levels and 2.5-MHz transmit frequency. Radiofrequency data were processed and subharmonic amplitudes were compared with the pressure catheter data. The correlation coefficient between subharmonic signals and pressure catheter data ranged from -0.3 to -0.9. For acquisitions with optimum acoustic output, pressure errors between the subharmonic technique and catheter were as low as 2.6 mmHg. However, automatically determining optimum acoustic output during scanning for each patient remains to be addressed before clinical applicability can be decided., (Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objectives: Different methods for obtaining tumor neovascularity parameters based on immunohistochemical markers were compared to contrast-enhanced subharmonic imaging (SHI)., Methods: Eighty-five athymic nude female rats were implanted with 5 × 10(6) breast cancer cells (MDA-MB-231) in the mammary fat pad. The contrast agent Definity (Lantheus Medical Imaging, North Billerica, MA) was injected, and SHI was performed using a modified Sonix RP scanner (Analogic Ultrasound, Richmond, British Columbia, Canada) with a L9-4 linear array (transmitting/receiving frequencies, 8/4 MHz). Afterward, specimens were stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF), and cyclooxygenase 2 (COX-2). Tumor neovascularity was assessed in 4 different ways using a histomorphometry system (×100 magnification: (1) over the entire tumor; (2) in small sub-regions of interest (ROIs); (3) in the tumor periphery and centrally; and (4) in 3 regions of maximum marker expression (so-called hot spots). Results from specimens and from SHI were compared by linear regression., Results: Fifty-four rats (64%) showed tumor growth, and 38 were successfully imaged. Subharmonic imaging depicted the tortuous morphologic characteristics of tumor neovessels and delineated small areas of necrosis. The immunohistochemical markers did not correlate with SHI measures over the entire tumor area or over small sub-ROIs (P > .18). However, when the specimens were subdivided into central and peripheral regions, COX-2 and VEGF correlated with SHI in the periphery (r = -0.42; P = .005; and r = -0.32; P = .049, respectively)., Conclusions: When comparing quantitative contrast measures of tumor neovascularity to immunohistochemical markers of angiogenesis in xenograft models, ROIs corresponding to the biologically active region should be used to account for tumor heterogeneity.

Tissue harmonic imaging (THI) is a routinely used component of diagnostic ultrasonography (US). In this method, higher-frequency harmonic waves produced by nonlinear fundamental US wave propagation are used to generate images that contain fewer artifacts than those seen on conventional fundamental wave US tissue imaging. Harmonic frequencies are integer multiples of the fundamental frequency. The majority of current clinical US systems use second harmonic echoes for THI image formation. Image processing techniques (ie, bandwidth receive filtering, pulse inversion, side-by-side phase cancellation, and pulse-coded harmonics) are used to eliminate the fundamental frequency echoes, and the remaining harmonic frequency data are used to generate the diagnostic image. Advantages of THI include improved signal-to-noise ratio and reduced artifacts produced by side lobes, grating lobes, and reverberation. THI has been accepted in US practice, and variations of the technology are available on most US systems typically used for diagnostic imaging in radiologic practice. Differential THI is a further improvement that combines the advantages of THI, including superior tissue definition and reduced speckle artifact, with the greater penetration of lower frequency US, which permits high-quality harmonic imaging at greater depth than could previously be performed with conventional THI., ((©)RSNA, 2015.)

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide., (Copyright © 2013 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: Although contrast-enhanced ultrasound imaging techniques such as harmonic imaging (HI) have evolved to reduce tissue signals using the nonlinear properties of the contrast agent, levels of background suppression have been mixed. Subharmonic imaging (SHI) offers near complete tissue suppression by centering the receive bandwidth at half the transmitting frequency. The aims of this study were to demonstrate the feasibility of three-dimensional (3D) SHI and to compare it to 3D HI., Materials and Methods: Three-dimensional HI and SHI were implemented on a Logiq 9 ultrasound scanner with a 4D10L probe. Four-cycle SHI was implemented to transmit at 5.8 MHz and receive at 2.9 MHz, while two-cycle HI was implemented to transmit at 5 MHz and receive at 10 MHz. The ultrasound contrast agent Definity was imaged within a flow phantom and the lower pole of two canine kidneys in both HI and SHI modes. Contrast-to-tissue ratios and rendered images were compared offline., Results: SHI resulted in significant improvement in contrast-to-tissue ratios relative to HI both in vitro (12.11 ± 0.52 vs 2.67 ± 0.77, P< .001) and in vivo (5.74 ± 1.92 vs 2.40 ± 0.48, P = .04). Rendered 3D subharmonic images provided better tissue suppression and a greater overall view of vessels in a flow phantom and canine renal vasculature., Conclusions: The successful implementation of SHI in 3D allows imaging of vascular networks over a heterogeneous sample volume and should improve future diagnostic accuracy. Additionally, 3D SHI provides improved contrast-to-tissue ratios relative to 3D HI., (Copyright © 2012 AUR. Published by Elsevier Inc. All rights reserved.)

Subharmonic-aided pressure estimation (SHAPE) is a technique that utilizes the subharmonic emissions, occurring at half the insonation frequency, from ultrasound contrast agents to estimate ambient pressures. The purpose of this work was to compare the performance of different processing techniques for the raw radiofrequency (rf) data acquired for SHAPE. A closed loop flow system was implemented circulating reconstituted Sonazoid (GE Healthcare, Oslo, Norway; 0.2 ml for 750 ml diluent) and the beam-formed unprocessed rf data were obtained from a 4 mm diameter lumen of a Doppler flow phantom (ATS Laboratories, Inc., Bridgeport, CT) using a SonixRP scanner (Ultrasonix, Richmond, BC, Canada). The transmit frequency and incident acoustic pressures were set to 2.5 MHz and 0.22 MPa, respectively, in order to elicit Sonazoid subharmonic emissions that are ambient-pressure sensitive. The time-varying ambient pressures within the flow phantom were recorded by a Millar pressure catheter. Four techniques for extracting the subharmonic amplitude from the rf data were tested along with two noise filtering techniques to process this data. Five filter orders were tested for the noise removing filters. The performance was evaluated based on the least root-mean-square errors reported after linear least-square regression analyses of the subharmonic data and the pressure catheter data and compared using a repeated ANOVA. When the subharmonic amplitudes were extracted as the mean value within a 0.2 MHz bandwidth about 1.25 MHz and when the resulting temporally-varying subharmonic signal was median filtered with an order of 500, the filtered subharmonic signal significantly predicted the ambient pressures (r2 = 0.90; p < 0.001) with the least error. The resulting root mean square and mean absolute errors were 8.16 +/- 0.26 mmHg and 6.70 +/- 0.17 mmHg, respectively. Thus, median processing the subharmonic data extracted as the mean value within a 0.2 MHz bandwidth about the theoretical subharmonic frequency turned out to be the best technique to process acoustic data for SHAPE. The implementation of this technique on ultrasound scanners may permit real-time SHAPE applications.

Parametric maps showing perfusion of contrast media can be useful tools for characterizing lesions in breast tissue. In this study we show the feasibility of parametric subharmonic imaging (SHI), which allows imaging of a vascular marker (the ultrasound contrast agent) while providing near complete tissue suppression. Digital SHI clips of 16 breast lesions from 14 women were acquired. Patients were scanned using a modified LOGIQ 9 scanner (GE Healthcare, Waukesha, WI) transmitting/receiving at 4.4/2.2 MHz. Using motion-compensated cumulative maximum intensity (CMI) sequences, parametric maps were generated for each lesion showing the time to peak (TTP), estimated perfusion (EP), and area under the time-intensity curve (AUC). Findings were grouped and compared according to biopsy results as benign lesions (n = 12, including 5 fibroadenomas and 3 cysts) and carcinomas (n = 4). For each lesion CMI, TTP, EP, and AUC parametric images were generated. No significant variations were detected with CMI (P = .80), TTP (P = .35), or AUC (P = .65). A statistically significant variation was detected for the average pixel EP (P = .002). Especially, differences were seen between carcinoma and benign lesions (mean ± SD, 0.10 ± 0.03 versus 0.05 ± 0.02 intensity units [IU]/s; P = .0014) and between carcinoma and fibroadenoma (0.10 ± 0.03 versus 0.04 ± 0.01 IU/s; P = .0044), whereas differences between carcinomas and cysts were found to be nonsignificant. In conclusion, a parametric imaging method for characterization of breast lesions using the high contrast to tissue signal provided by SHI has been developed. While the preliminary sample size was limited, results show potential for breast lesion characterization based on perfusion flow parameters.

The potential for noninvasive monitoring and quantification of tumor angiogenesis with contrast-enhanced ultrasound imaging has been investigated in a murine cancer model. Seventy athymic nude mice were implanted with the human melanoma cell line DB-1 but only 30 of these were available for the final study. The 30 mice were divided into three groups (10 mice/group), which were studied with contrast-enhanced ultrasound imaging 4, 5 or 6 weeks post-implantation. Power Doppler and pulse inversion harmonic imaging (PIHI) were performed (in real time and intermittently) with a Sonoline Elegra scanner (Siemens Medical Solutions, Issaquah, WA) following injection of Optison (dose: 0.4-0.6 ml/kg; GE Healthcare, Princeton, NJ). Ultrasound results were compared to immunohistochemical stains for endothelial cells (CD31), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Linear regression analysis indicated statistically significant correlations between the percent area stained with VEGF and ultrasound measures of tumor neovascularity obtained with all three techniques (p < 0.01). Contrast-enhanced ultrasound imaging of tumor neovascularity appears to provide a noninvasive marker of angiogenesis corresponding to the expression of VEGF in the DB-1 model and may become a useful tool for monitoring clinical anti-angiogenic therapies.

This study was conducted to compare quantifiable measures of vascularity obtained from contrast-enhanced color flow images of breast lesions to pathologic vascularity measurements. Nineteen patients with solid breast masses received Levovist Injection (10 mL at 300 mg/mL; Berlex Laboratories, Montville, NJ, USA). Color flow images of the mass pre and post contrast were obtained using an HDI 3000 scanner (Philips Medical Systems, Bothell, WA, USA) optimized for clinical scanning on an individual basis. After surgical removal, specimens were sectioned in the same planes as the ultrasound images and stained with an endothelial cell marker (CD31). Microvessel area (MVA) and intratumoral microvessel density (MVD) were determined for vessels 10-19 microm, 20-29 microm, 30-39 microm, 40-49 microm and > or =50 microm in diameter using a microscope and image processing software. From the ultrasound images, the number of color pixels before and after contrast administration relative to the total area of the breast mass was calculated as a first-order measure of fractional tumor vascularity. Vascularity measures were compared using reverse stepwise multiple linear regression analysis. In total, 58 pathology slides (with 8,106 frames) and 185 ultrasound images were analyzed. There was a significant increase in flow visualization pre to post Levovist injection (p = 0.001), but no differences were found between the 11 benign and the eight malignant lesions (p > 0.35). Ultrasound vascularity measurements post contrast correlated significantly with pathology (0.15 < or = r2 < or = 0.46; p < 0.03). The 30-39 microm vessel range contributed most significantly to the MVD relationship (p < 0.001), whereas the MVA was mainly influenced by vessels 20-29 microm (p < 0.004). Precontrast ultrasound only correlated with pathology for relative MVA (r2 = 0.16; p = 0.01). In conclusion, contrast-enhanced color flow imaging provides a noninvasive measure of breast tumor neovascularity, corresponding mainly to vessels 20-39 microm in diameter, when used in a typical clinical setting.

In this study, the destruction of the contrast agent Sonazoid (GE Healthcare, Oslo, Norway) was measured in vitro as a function of centre frequency (2-3 MHz), acoustic amplitude (0.66-1.6 MPa), pulse length (2-16 cycles) and PRF (0.5-8.0 kHz). Up to 82% of microbubbles were destroyed after exposure to a single 1.6 MPa acoustic pulse (16 cycles, 2.5 MHz and PRF of 1.0 kHz), while at a low amplitude of 0.66 MPa, fractional destruction increased gradually from 0 to 40% after exposure to 9 (identical) pulses. Fractional destruction increased from approximately 8 to 66% as pulse length was changed from 2 to 16 cycles following exposure to a single 2.5 MHz, 1.3 MPa pulse. As the PRF was increased from 0.5 to 8.0 kHz, shorter exposure time intervals (from 4.8 to 1.2 ms) were needed to achieve the same fractional destruction of 80%. Conversely, as the transmit frequency was increased from 2 to 3 MHz the fractional destruction decreased (by more than half within the first 3 pulses). The influence of changes in acoustic pressure and duty cycle on the destruction of Sonazoid microbubbles was highly statistically significant (p < or = 0.01) with a threshold around 0.67 MPa for a duty cycle of 0.0064. In conclusion, the fractional destruction increases with the duty cycle and the acoustic pressure amplitude and decreases with ultrasonic transmit frequency. Better understanding of the influence of the ultrasound transmit parameters on the destruction of contrast microbubbles should help improve existing contrast-assisted imaging modalities and may help develop new techniques for better use of contrast agents.

Objective: The purpose of this study was to determine whether lymphatic channels (LCs) and sentinel lymph nodes (SLNs) could be detected on sonographic imaging after subcutaneous, submucosal, or parenchymal injections of a sonographic contrast agent (ie, lymphosonography) in a variety of anatomic locations in several animal models., Methods: Eight swine, 7 canines, 4 rabbits, and a monkey were used for these evaluations. Gray scale pulse inversion harmonic imaging of the LCs and the SLNs was performed after subcutaneous (n = 58), submucosal (n = 14), or parenchymal (n = 8) injections of a tissue-specific sonographic contrast agent (Sonazoid; GE Healthcare, Oslo, Norway). In many instances, blue dye was injected into the same locations as Sonazoid, and surgical dissection of the SLNs and LCs was performed for comparison. Scanning electron microscopy (SEM) of contrast-enhanced and control lymph nodes from 2 rabbits was performed to determine the mechanism of contrast agent uptake and retention within SLNs., Results: After subcutaneous, submucosal, or parenchymal contrast agent injections, gray scale pulse inversion harmonic imaging could be used to identify the number and location(s) of LCs and SLNs. After subcutaneous, submucosal, or parenchymal contrast agent injections, Sonazoid was confined to the SLNs (ie, contrast enhancement was not detected in the second-echelon nodes). There was good agreement between the results of lymphosonography and blue dye with surgical dissection in identifying the regional LCs and SLNs. Scanning electron microscopy identified vacuoles representing intact contrast microbubbles within contrast-enhanced SLN macrophages, which were not present in the control lymph nodes., Conclusions: Lymphosonography can be used to detect lymphatic drainage pathways and SLNs in a variety of animal models.

A new nonlinear contrast specific imaging modality, excitation-enhanced imaging (EEI) has been implemented on commercially-available scanners for real-time imaging. This novel technique employs two acoustic fields: a low-frequency, high-intensity ultrasound field (the excitation field) to actively condition contrast microbubbles, and a second lower-intensity regular imaging field applied shortly afterwards to detect enhanced contrast scattering. A Logiq 9 scanner (GE Healthcare, Milwaukee, WI) with a 3.5C curved linear array and an AN2300 digital ultrasound engine (Analogic Corporation, Peabody, MA) with a P4-2 phased array transducer (Philips Medical Systems, Bothell, WA) were modified to perform EEI on a vector-by-vector basis in fundamental and pulse inversion harmonic grayscale modes. Ultrasound contrast microbubbles within an 8 mm vessel embedded in a tissue-mimicking flow phantom (ATS Laboratories, Bridgeport, CT) were imaged in vitro. While video intensities of scattered signals from the surrounding tissue were unchanged, video intensities of echoes from contrast bubbles within the vessel were markedly enhanced. The maximum enhancement achieved was 10.4 dB in harmonic mode (mean enhancement: 6.3 dB; p = 0.0007). In conclusion, EEI may improve the sensitivity of ultrasound contrast imaging, but further work is required to assess the in vivo potential of this new technique.

Purpose: To determine if lymphatic channels and sentinel lymph nodes (SLNs) with and without metastases can be detected with lymphatic ultrasonography (US) after peritumoral injection of a US contrast agent and to determine if lymphatic US can be used to assess SLNs for the presence of metastatic infiltration., Materials and Methods: Six swine with 17 melanomas were evaluated. Conventional gray-scale, color flow, and gray-scale phase-inversion harmonic US examinations were performed. A US contrast agent was administered in four sites around each melanoma (1-mL total dose). Lymphoscintigraphy was followed by injection of a blue dye and then dissection. SLNs identified at lymphatic US were characterized by two readers in consensus as normal or as having metastases; results were compared with histologic findings. Statistical analyses included the sign test and the kappa statistic., Results: Lymphatic US depicted 28 SLNs, while lymphoscintigraphy depicted 27 "hot spots" suspected of representing SLNs (including two false-positive findings). Dissection after blue dye injection helped identify 31 SLNs. There were no false-positive US findings for SLN detection. Five of six nodes not seen with lymphoscintigraphy were detected with lymphatic US. The accuracy of SLN detection was 90% (28 of 31) for lymphatic US and 81% (25 of 31) for lymphoscintigraphy (P =.29). Lymphatic US correctly depicted metastases in 19 of 20 SLNs, and five of the eight normal SLNs were correctly characterized, with an accuracy of 86% (kappa = 0.62)., Conclusion: Detection of SLNs with lymphatic US compared favorably with that at lymphoscintigraphy. Lymphatic US can depict metastases within the SLN, which was not possible with lymphoscintigraphy., (Copyright RSNA, 2004)

A novel contrast imaging technique has been developed for use with microbubble contrast agents. It employs two acoustic fields: there is an excitation field for conditioning microbubbles and an imaging field for detecting microbubbles. The maximum increases (due to microbubble conditioning) in scattered first and second harmonic signals were 14.5 and 16 dB, respectively. This technique is unique for effectively enhancing the blood-to-tissue image contrast.

Breast cancer diagnosis through ultrasound tissue characterization was studied using receiver operating characteristic (ROC) analysis of combinations of acoustic features, patient age, and radiological findings. A feature fusion method was devised that operates even if only partial diagnostic data are available. The ROC methodology uses ordinal dominance theory and bootstrap resampling to evaluate A(z) and confidence intervals in simple as well as paired data analyses. The combined diagnostic feature had an A(z) of 0.96 with a confidence interval of at a significance level of 0.05. The combined features show statistically significant improvement over prebiopsy radiological findings. These results indicate that ultrasound tissue characterization, in combination with patient record and clinical findings, may greatly reduce the need to perform biopsies of benign breast lesions.

Objective: This study evaluated the utility of a new animal model for prostate cancer imaging using a new ultrasonographic contrast agent (Sonazoid [NC100100]; Amersham Health, Oslo, Norway), for prostate cancer detection., Methods: Twenty-four dogs had a canine transmissible venereal sarcoma cell line injected (50 million cells/mL) directly into the prostate, producing a neoplasm in 15 to 40 days. Transrectal ultrasonography was performed in power Doppler mode on 8 dogs (phase I) and in gray scale phase inversion harmonic imaging mode on 16 animals (including control animals without tumors; phase II). Evaluations were repeated after intravenous injections of the contrast agent (dose, 0.00625-0.20 microL/kg). Histopathologic examination was performed after each study. For the phase II experiments, sensitivity, specificity, and accuracy were calculated., Results: The contrast agent improved visualization of the prostate cancer vascularity and delineation of tumor size and shape in both power Doppler and phase inversion harmonic imaging modes. Canine transmissible venereal sarcoma tumors ranging from 3 x 5 to 40 x 50 mm were detected. The accuracy for detecting the number of prostate tumors increased (in phase II) from 67% to 87% with the addition of the contrast agent. Histopathologic examination confirmed the ultrasonographic findings and revealed typical canine transmissible venereal sarcoma cells infiltrating the prostate with moderate neovascularity., Conclusions: The novel canine tumor model was useful for evaluating ultrasonographic prostate imaging techniques. Improved detection of prostate tumors in dogs was possible with gray scale phase inversion harmonic imaging of the contrast agent. The accuracy of lesion detection increased from 67% to 87%.

Frequency compounding was recently investigated for computer aided classification of masses in ultrasonic B-mode images as benign or malignant. The classification was performed using the normalized parameters of the Nakagami distribution at a single region of interest at the site of the mass. A combination of normalized Nakagami parameters from two different images of a mass was undertaken to improve the performance of classification. Receiver operating characteristic (ROC) analysis showed that such an approach resulted in an area of 0.83 under the ROC curve. The aim of the work described in this paper is to see whether a feature describing the characteristic of the boundary can be extracted and combined with the Nakagami parameter to further improve the performance of classification. The combination of the features has been performed using a weighted summation. Results indicate a 10% improvement in specificity at a sensitivity of 96% after combining the information at the site and at the boundary. Moreover, the technique requires minimal clinical intervention and has a performance that reaches that of the trained radiologist. It is hence suggested that this technique may be utilized in practice to characterize breast masses.

Objective: To assess the feasibility and usefulness of contrast-enhanced sonography for tumor detection and guidance of liver VX2 tumor ablation and to evaluate post radiofrequency ablation effectiveness., Methods: VX2 tumors were implanted into the livers of 6 rabbits. Both conventional and harmonic gray scale and power Doppler imaging were performed with a commercially available scanner to evaluate the liver tumors before and after intravenous injection of a sonographic contrast agent before and after radiofrequency ablation. Contrast-enhanced imaging was used to detect the tumors before ablation, to guide needle insertion, and to measure the ablation sites after radiofrequency ablation. Pathologic examination was performed for comparison., Results: Three tumors were seen without contrast enhancement, whereas 10 tumors (<1 cm) were detected with contrast enhancement. Intentionally, 2 tumors were completely ablated and 5 tumors were partially ablated. In 3 cases, incompletely ablated tumors could only be identified on contrast-enhanced Doppler imaging by enhancing the detection of residual tumor vascularity. There was excellent concordance between sonographic imaging and gross pathologic findings., Conclusions: Contrast-enhanced sonographic imaging appears useful for detection of liver tumors and for guiding and monitoring tumor ablation therapies.

This study evaluates a new reticuloendothelium specific sonographic contrast agent NC100100 (Sonazoid) for detection of liver VX-2 tumors in rabbits. Gray scale imaging of five groups of three rabbits, with hepatic VX-2 tumors implanted 7, 10, 12, 14, and 18 days previously, was performed prior to injection of Sonazoid (dosages, 0.01-0.5 ml/kg). Sonazoid produces induced acoustic emission after uptake in the liver. Therefore, harmonic gray scale images were obtained immediately after injection as well as delayed (by up to 2(1/2) h). Five rabbits (one from each group) also had angiography performed, while all animals were evaluated by pathologic examination. Non-contrast enhanced sonography detected 17 of 61 tumors (29%), as well as three false-positives, while the addition of Sonazoid detected 57 tumors (93%) and one false-positive (P<0.001). Acoustic emission made 2 x 2 mm tumors (invisible in conventional B-mode sonography) clearly perceivable in harmonic gray scale. In the subgroup that received angiography, 12 of 36 tumors (33%) were detected with conventional sonography compared to 22 tumors (61%) seen with angiography (P = 0.002). After injection of Sonazoid the ultrasonographic detection rate increased to 97% (35 of 36 tumors), which was a significant improvement over angiography (P = 0.00024). Improved detection of hepatic VX-2 tumors with second harmonic gray scale imaging of Sonazoid is possible because of this agent's acoustic emission capabilities.

The purpose of this study was to determine the feasibility and usefulness of using an ultrasonographic contrast agent to enhance the sonographic detection of bleeding sites in a canine model. SH U 563, an ultrasound contrast agent that elicits acoustic emission (i.e., random transient Doppler shifts produced by contrast particle rupture) even when stationary, was used. Acoustic emission is identified as a mosaic pattern on color Doppler imaging. A total of 13 active bleeding sites were created within intraabdominal organs (kidney and spleen, n = 3), the urinary tract (n = 3), and the gastrointestinal tract (n = 7) in three canine models. Gray scale and color Doppler imaging studies were performed prior to and after each of 13 individual intravenous contrast agent administrations. Imaging results were compared to gross pathologic findings. After contrast agent administration, pooling of contrast medium-containing blood in the regions adjacent to bleeding sites could be detected with color Doppler imaging as regions with the characteristic acoustic emission color display. After injection gray scale imaging failed to demonstrate the location or extent of hemorrhaging adequately. A linear relationship existed between the blood loss due to gastrointestinal tract bleeding and the amount of acoustic emission detected (r2 = 0.81). SH U 563 combined with color Doppler imaging improves the detection of bleeding sites in a variety of locations throughout the body.

Harmonic imaging is a new contrast-specific imaging modality, which utilizes the nonlinear properties of microbubble-based sonographic contrast agents by transmitting at the fundamental frequency but receiving at the second harmonic frequency. The feasibility of improving the detection of slow, small-volume blood flow using real-time harmonic imaging has been investigated in vivo. Proteinaceous microspheres (FS069) were administrated to four dogs, two woodchucks (with multiple hepatomas), and one rabbit. Three different scanners were used to obtain real-time images of kidneys and liver (including vessels) in harmonic and conventional gray scale and color flow modes. The duration of contrast enhancement lasted significantly longer in harmonic than in conventional modes (on average 87 s; P = 0.008). Harmonic images were less susceptible to artifacts, such as acoustic shadowing, and a clear increase in the (flow) signal-to-noise ratio was observed. These preliminary in vivo results demonstrate the feasibility of performing real-time, contrast-enhanced harmonic imaging, but further studies are required to establish clinical efficacy.

Conventional (mean Doppler frequency shift) color Doppler imaging and a new method of displaying blood flow in color that uses the amplitude of the Doppler signal were utilized to evaluate three vascular sonographic contrast agents. To compare the two color flow detection modalities, a total of 20 pairs of contrast agent injections were performed while imaging a variety of abdominal organs and tumors in experimental animal models. The 20 paired injections were scored independently to indicate whether color amplitude imaging better demonstrated the effects of contrast enhancement (n = 14), both techniques were equivalent in demonstrating the effects of contrast enhancement (n = 4), or color Doppler imaging better demonstrated the effects of contrast enhancement (n = 2). These results indicate that compared to color Doppler imaging, color amplitude imaging improved visualization of both normal and abnormal blood flow in 70% of these cases (P < 0.0001). Specifically, with contrast enhancement of the Doppler signals, organ vascularity and regional differences in parenchymal blood flow were better demonstrated with color amplitude imaging than with color Doppler imaging. In addition, since color amplitude imaging is nondirectional and less angle dependent than color Doppler imaging, it was possible to visualize vessel continuity more completely and to demonstrate vessel branching more clearly with this modality. However, owing to the lack of directivity and poor temporal resolution, information obtained with color amplitude imaging appears to be complementary to that of color Doppler imaging. In conclusion, color amplitude imaging is a reliable method of determining the effectiveness of vascular sonographic contrast agents and should be considered one of the primary flow imaging modalities used for the assessment of these agents.

The purpose of this study was to assess the ability of a sonographic contrast agent to increase parenchymal echogenicity and improve tumor visibility. The agent is an emulsion that changes at body temperature from nonechogenic submicrometer liquid droplets to echogenic 1 to 5 microns microbubbles, capable of transversing the pulmonary and capillary circulations. Peripheral venous injections (dosages of 0.05 to 0.8 ml/kg) were administered to five woodchucks (three with multiple hepatomas), 12 rabbits (with renal VX-2 tumors), and four dogs. Ultrasonograms were acquired from kidney, liver, tumors (including tumor vessels) and normal vessels. Uptake and washout curves were generated via videodensitometry. Finally, Doppler shifts from a cuff transducer around the celiac trunk were analyzed to provide an in vivo dose-response curve. Vascular enhancement, including hepatoma and VX-2 tumor vessels, was seen for 2 to 3 min. Maximum enhancement was 18.7 dB for a 0.6 ml/kg dose. Enhancement of normal liver and kidney parenchyma was observed in all three species for up to 20 min. Small hepatomas became more echogenic centrally, but larger tumors showed no increase in central echogenicity. In conclusion, improved tumor visibility and parenchymal enhancement was demonstrated in animals.