Characterization of Indeterminate Breast Lesions Based on Pressure Estimates by Noninvasive 3D Contrast-Enhanced Ultrasound.

OBJECTIVE: To assess the ability of the pressure gradient between breast lesions and adjacent normal tissue estimated by 3D subharmonic-aided pressure estimation (SHAPE) to characterize indeterminate breast lesions. METHODS: This prospective study enrolled patients scheduled for ultrasound-guided needle biopsies of a breast lesion. Before the biopsy, 3D SHAPE data were collected from the breast lesion during the infusion of an ultrasound contrast agent (Definity) as well as after clearance of the agent. Direct, invasive pressure measurements in the lesion and adjacent normal tissue were then obtained using an intracompartmental pressure monitoring system (C2DX) before tissue sampling as part of the biopsy procedure. The mean SHAPE gradient and invasive measurement gradient between the lesion and adjacent normal tissue were compared to the biopsy results. The SHAPE gradients were also compared to the invasive pressure gradients. RESULTS: There were 8 malignant and 13 benign lesions studied. The SHAPE gradients and invasive pressure gradients were significantly different between the benign and malignant lesions (2.86 ± 3.24 vs. -0.03 ± 1.72 a.u.; p = 0.03 and 9.9 ± 8.5 vs. 20.9 ± 8.0 mmHg; p = 0.008, respectively). The area under the curves, specificities, and sensitivities for detecting malignancy by SHAPE gradients and invasive pressure gradients were 0.79 and 0.88, 77% and 92%, and 88% and 50%, respectively. A weak negative correlation was found between the SHAPE and invasive pressure gradients (r = -0.2). CONCLUSION: The pressure gradient between a breast lesion and adjacent normal tissue estimated by 3D SHAPE shows potential for characterizing indeterminate breast lesions.

Macrophage uptake rate of Sonazoid in breast lymphosonography is highly conserved in healthy controls.

Subcutaneous microbubble administration in connection with contrast enhanced ultrasound (CEUS) imaging is showing promise as a noninvasive and sensitive way to detect tumor draining sentinel lymph nodes (SLNs) in patients with breast cancer. Moreover, there is potential to harness the results from these approaches to directly estimate cancer burden, since some microbubble formulas, such as the Sonazoid used in this study, are rapidly phagocytosed by macrophages, and the macrophage concentration in a lymph node is inversely related to the cancer burden. This work presents a mathematical model that can approximate a rate constant governing macrophage uptake of Sonazoid, ki, given dynamic CEUS Sonazoid imaging data. Twelve healthy women were injected with 1.0 ml of Sonazoid in an upper-outer quadrant of one of their breasts and SLNs were imaged in each patient immediately after injection, and then at 0.25, 0.5, 1, 2, 4, 6, and 24 h after injection. The mathematical model developed was fit to the dynamic CEUS data from each subject resulting in a mean ± sd of 0.006 ± 0.005 h-1 and 0.4 ± 0.1 h-1 for relative lymphatic flow (EFl) and ki, respectively. Furthermore, the roughly 25% sd of the ki measurement was similar to the sd that would be expected from realistic noise simulations for a stable 0.4 h-1 value of ki, suggesting that macrophage concentration is highly consistent among cancer-free SLNs. These results, along with the significantly smaller variance in ki measurement observed compared to relative lymphatic flow suggest that ki may be a more precise and promising approach of estimating macrophage abundance, and inversely cancer burden, for future efforts to establish a noninvasive CEUS SLN biopsy. .

Investigation Into the Subharmonic Response of Three Contrast Agents in Static and Dynamic Flow Environments Using a Commercially Available Diagnostic Ultrasound Scanner.

OBJECTIVE: The objective of this study was to investigate the subharmonic response of Lumason (also known as SonoVue; Bracco, Milan, Italy) to static and dynamic ambient pressures, with a direct comparison to Sonazoid (GE HealthCare, Oslo, Norway) and Definity (Lantheus Medical Imaging, MA, USA). The subharmonic responses of contrast agents can be exploited to perform subharmonic-aided pressure estimation. METHODS: The subharmonic response of each ultrasound contrast agent was evaluated in both a static and dynamic tank using a commercially available Logiq E10 clinical ultrasound scanner (GE HealthCare) equipped with subharmonic imaging (SHI) and an acoustic power-optimization algorithm. A C1-6 curvilinear array that transmits at 2.5 MHz and receives at 1.25 MHz in SHI mode was used to acquire the subharmonic signals. Data was transferred offline into MATLAB (MathWorks) to perform linear regression analysis and statistical testing for significance of the slopes (i.e., agent sensitivity). RESULTS: Sonazoid and Definity showed an inverse linear dependency between subharmonic signal and hydrostatic pressure at all pressure ranges (static and dynamic) tested, with maximum sensitivity under 50 mmHg in the static tank (-0.190 and -0.194 dB/mmHg for Sonazoid and Definity, respectively). Lumason exhibited a tri-phasic subharmonic behavior, beginning with a linear trend from 0 to 90 mmHg (sensitivity = 0.069 dB/mmHg), followed by a plateau from 100 to 130 mmHg, and an inverse linear trend from 140 to 200 mmHg (sensitivity = -0.137 dB/mmHg). CONCLUSION: The subharmonic response of Lumason is tri-phasic and differs from Sonazoid and Definity. Further investigation is needed to solidify understanding of the subharmonic behavior of Lumason to identify its usefulness for subharmonic-aided pressure estimation.

Characterizing Sentinel Lymph Node Status in Breast Cancer Patients Using a Deep-Learning Model Compared With Radiologists' Analysis of Grayscale Ultrasound and Lymphosonography.

ABSTRACT: The objective of the study was to use a deep learning model to differentiate between benign and malignant sentinel lymph nodes (SLNs) in patients with breast cancer compared to radiologists' assessments.Seventy-nine women with breast cancer were enrolled and underwent lymphosonography and contrast-enhanced ultrasound (CEUS) examination after subcutaneous injection of ultrasound contrast agent around their tumor to identify SLNs. Google AutoML was used to develop image classification model. Grayscale and CEUS images acquired during the ultrasound examination were uploaded with a data distribution of 80% for training/20% for testing. The performance metric used was area under precision/recall curve (AuPRC). In addition, 3 radiologists assessed SLNs as normal or abnormal based on a clinical established classification. Two-hundred seventeen SLNs were divided in 2 for model development; model 1 included all SLNs and model 2 had an equal number of benign and malignant SLNs. Validation results model 1 AuPRC 0.84 (grayscale)/0.91 (CEUS) and model 2 AuPRC 0.91 (grayscale)/0.87 (CEUS). The comparison between artificial intelligence (AI) and readers' showed statistical significant differences between all models and ultrasound modes; model 1 grayscale AI versus readers, P = 0.047, and model 1 CEUS AI versus readers, P < 0.001. Model 2 r grayscale AI versus readers, P = 0.032, and model 2 CEUS AI versus readers, P = 0.041.The interreader agreement overall result showed κ values of 0.20 for grayscale and 0.17 for CEUS.In conclusion, AutoML showed improved diagnostic performance in balance volume datasets. Radiologist performance was not influenced by the dataset's distribution.

Development of a contrast-enhanced ultrasound guided high intensity focused ultrasound system for coagulation of liver parenchyma.

BACKGROUND: The liver is the most common organ injured in blunt abdominal trauma and makes up roughly 5% of all trauma admissions. Current treatments are invasive and resource-intensive, which may delay care. We aim to develop and validate a contrast-enhanced ultrasound (CEUS)guided noninvasive tool to treat liver lacerations at the bedside. METHODS: Two 1.8 MHz high-intensity focused ultrasound (HIFU) elements were coupled to a C1-6 diagnostic ultrasound probe and a Logiq E10 scanner (GE HealthCare) utilizing a custom enclosure for co-registered imaging and ablation. A phantom was created from polyacrylamide gel combined with thermochromic ink whose color changes above biological ablative temperatures (60 °C). The HIFU wave was focused approximately 0.5 cm below the surface utilizing a 50% duty cycle generating 11.9 MPa for 20, 30, 40, 50, and 60s. Experiments were repeated on ex vivo chicken livers in a water bath. Finally, the livers of 4 live swine underwent up to 6 CEUS-guided treatments using parameters optimized from in vitro work. RESULTS: Treatment of the phantom between 20-60s, produced ablation sizes from 0.016 to 0.4 cm 3 . The relationship between time and size was exponential (R 2 = 0.992). Ablation areas were also well visualized on with ultrasound imaging. The ex vivo liver ablation size at 20s was 0.37 cm 3 , at 30s was 0.66 cm 3 , and at 100 s was 5.0 cm 3 . For the in-vivo swine experiments, the average ablation area measured 2.0x0.75 cm with a maximum of 3.5x1.5 cm. CEUS was utilized with the contrast agent Definity (Lantheus) for identification of lacerations as well as immediate post operative evaluation of therapy. CONCLUSION: These experiments demonstrate the feasibility of CEUS guided transdermal HIFU ablation and the time-dependent size of ablation. This work warrants future investigations into using ultrasound to detect active bleeding and HIFU to coagulate grade III and IV liver laceration. STUDY TYPE: Therapeutic/care management.

Acoustic response and ambient pressure sensitivity characterization of SonoVue for noninvasive pressure estimation.

Subharmonic aided pressure estimation (SHAPE) is a noninvasive pressure measurement technique based on the pressure dependent subharmonic signal from contrast microbubbles. Here, SonoVue microbubble with a sulfur hexafluoride (SF6) core, was investigated for use in SHAPE. The study uses excitations of 25-700 kPa peak negative pressure (PNP) and 3 MHz frequency over eight pressurization cycles between atmospheric pressure and overpressures, ranging from 0 to 25 kPa (0 to 186 mm Hg). The SonoVue subharmonic response was characterized into two types. Unlike other microbubbles, SonoVue showed significant subharmonic signals at low excitations (PNPs, 25-400 kPa), denoted here as type I subharmonic. It linearly decreased with increasing overpressure (-0.52 dB/kPa at 100 kPa PNP). However, over multiple pressurization-depressurization cycles, type I subharmonic changed; its value at atmospheric pressure decreased over multiple cycles, and at later cycles, it recorded an increase in amplitude with overpressure (highest, +13 dB at 50 kPa PNP and 10 kPa overpressure). The subharmonic at higher excitations (PNP > 400 kPa), denoted here as type II subharmonic, showed a consistent decrease with the ambient pressure increase with strongest sensitivity of -0.4 dB/kPa at 500 kPa PNP.

Addressing the need for preclinical study of penile prosthesis infection: a new animal model and narrative review.

Background and Objective: Erectile dysfunction (ED) is a common condition in men, and many patients refractory to conservative treatment may undergo penile prostheses (PPs) placement. The primary concern following PP implantation is device infection. Although antibiotic and hydrophilic coatings have reduced the incidence of inflatable PP (IPP) infections, there remains room for improvement. Optimization of PP outcomes requires a practical in vivo model to better understand mechanisms of infection and to test new infection control strategies. We aimed to describe a new rabbit model which contains a functional IPP and review previously reported animal PP models. Methods: An IPP was placed into rabbit flanks and cycled for functionality testing. Rabbits were evaluated for signs of pain and distress over 14 days. Separately, narrative review methodology was utilized to search the PubMed and Scopus databases for all publications through March 21, 2023, which studied PP within an in vivo setting. Three independent reviewers ultimately selected 12 papers from 1992-2021 for inclusion. Key Content and Findings: Several animal studies highlighted the initial functionality or feasibility of devices for ED before their introduction in the clinical setting. There are several subsequent studies aimed at optimizing the type of antibiotic use or coating material using segments of PP material in an in vivo setting. However, the literature lacks a contemporary animal model containing a functional IPP. Our novel rabbit model offers a safe, practical way to implant a functioning IPP and investigate new perioperative infection prevention and treatment strategies before trials in the clinical setting. Conclusions: Animal models have played a key role in testing medical devices, including PPs, prior to their clinical introduction. Our review uncovered no modern animal studies involving placement of a functional PP. A new animal model can facilitate study of evolving microorganism profiles, novel methods to enhance antibiotic delivery, and proposed treatment options.

Evaluation of Intracardiac Pressures Using Subharmonic-aided Pressure Estimation with Sonazoid Microbubbles.

Purpose To investigate if the right ventricular (RV) systolic and left ventricular (LV) diastolic pressures can be obtained noninvasively using the subharmonic-aided pressure estimation (SHAPE) technique with Sonazoid microbubbles. Materials and Methods Individuals scheduled for a left and/or right heart catheterization were prospectively enrolled in this institutional review board-approved clinical trial from 2017 to 2020. A standard-of-care catheterization procedure was performed by advancing fluid-filled pressure catheters into the LV and aorta (n = 25) or RV (n = 22), and solid-state high-fidelity pressure catheters into the LV and aorta in a subset of participants (n = 18). Study participants received an infusion of Sonazoid microbubbles (GE HealthCare), and SHAPE data were acquired using a validated interface developed on a SonixTablet (BK Medical) US scanner, synchronously with the pressure catheter data. A conversion factor, derived using cuff-based pressure measurements with a SphygmoCor XCEL PWA (ATCOR) and subharmonic signal from the aorta, was used to convert the subharmonic signal into pressure values. Errors between the pressure measurements obtained using the SHAPE technique and pressure catheter were compared. Results The mean errors in pressure measurements obtained with the SHAPE technique relative to those of the fluid-filled pressure catheter were 1.6 mm Hg ± 1.5 [SD] (P = .85), 8.4 mm Hg ± 6.2 (P = .04), and 7.4 mm Hg ± 5.7 (P = .09) for RV systolic, LV minimum diastolic, and LV end-diastolic pressures, respectively. Relative to the measurements with the solid-state high-fidelity pressure catheter, the mean errors in LV minimum diastolic and LV end-diastolic pressures were 7.2 mm Hg ± 4.5 and 6.8 mm Hg ± 3.3 (P ≥ .44), respectively. Conclusion These results indicate that SHAPE with Sonazoid may have the potential to provide clinically relevant RV systolic and LV diastolic pressures. Keywords: Ultrasound-Contrast, Cardiac, Aorta, Left Ventricle, Right Ventricle ClinicalTrials.gov registration no.: NCT03245255 © RSNA, 2024.

The Effect of Mixing Iodinated Contrast Media and Ultrasound Contrast Agents on Subharmonic Signals.

Subharmonic aided pressure estimation (SHAPE) is a technique that utilizes subharmonic signals from microbubble contrast agents for pressure estimation. Validation of the SHAPE technique relies on synchronous measurements of in vivo pressures using contrast microbubbles and a pressure catheter (reference standard). For the guidance and placement of pressure catheter in vivo, iodinated contrast is used with fluoroscopy. Therefore, during data acquisition for validation studies of the SHAPE technique, both contrast microbubbles and iodinated contrast are present simultaneously within the vasculature. This study aims to elucidate the effects of iodinated contrast (Visipaque, GE HealthCare) on subharmonic signal amplitude from contrast microbubbles (Definity, Lantheus Medical Imaging, Inc.). In an acrylic water tank, 0.06 mL of Definity and varied amounts of Visipaque (0.14, 0.43, 0.85, and 1.70 mL) were added to 425 mL of deionized water. Ultrasound scanning was performed with a SonixTablet scanner (BK Medical Systems) using optimized parameters for SHAPE with Definity (ftransmit/receive = 3.0/1.5 MHz; chirp down pulse). Subharmonic data was acquired and analyzed at 9 different incident acoustic outputs (n = 3). Results showed an increase in subharmonic signal amplitude from Definity microbubbles in the presence of 0.14 mL Visipaque by 2.8 ± 1.3 dB (p < .001), no change with 0.85 mL Visipaque (0.7 ± 1.2 dB; p = .09) and a decrease in subharmonic amplitude in the presence of 1.70 mL Visipaque by 1.9 ± 0.7 dB (p < .001). While statistically significant effect on subharmonic signal amplitude of Definity microbubbles was noted due to the mixture, the magnitude of the effect was minimal (~2.8 dB) and unlikely to impact in vivo SHAPE measurements.

Contrast-enhanced ultrasound liver imaging reporting and data system: clinical validation in a prospective multinational study in North America and Europe.

BACKGROUND AND AIMS: The objective of this study is to determine the diagnostic accuracy of the American College of Radiology Contrast-Enhanced Ultrasound (CEUS) Liver Imaging Reporting and Data System LR-5 characterization for HCC diagnosis in North American or European patients. APPROACH AND RESULTS: A prospective multinational cohort study was performed from January 2018 through November 2022 at 11 academic and nonacademic centers in North America and Europe. Patients at risk for HCC with at least 1 liver observation not previously treated, identified on ultrasound (US), or multiphase CT or MRI performed as a part of standard clinical care were eligible for the study. All participants were examined with CEUS of the liver within 4 weeks of CT/MRI or tissue diagnosis to characterize up to 2 liver nodules per participant using ACR CEUS Liver Imaging Reporting and Data System. Definite HCC diagnosis on the initial CT/MRI, imaging follow-up, or histology for CT/MRI-indeterminate nodules were used as reference standards. A total of 545 nodules had confirmed reference standards in 480 patients, 73.8% were HCC, 5.5% were other malignancies, and 20.7% were nonmalignant. The specificity of CEUS LR-5 for HCC was 95.1% (95% CI 90.1%-97.7%), sensitivity 62.9% (95% CI 57.9%-67.7%), positive predictive value 97.3% (95% CI 94.5%-98.7%), and negative predictive value 47.7% (95% CI 41.7%-53.8%). In addition, benign CEUS characterization (LR-1 or LR-2) had 100% specificity and 100% positive predictive value for nonmalignant liver nodules. CONCLUSIONS: CEUS Liver Imaging Reporting and Data System provides an accurate categorization of liver nodules in participants at risk for HCC.

Evaluation of Uterine Fibroid Vascularity Using Contrast-Enhanced Ultrasound in Comparison with Contrast-Enhanced Magnetic Resonance Imaging.

OBJECTIVE: The aim of the work described here was to assess uterine fibroid vascularity using contrast-enhanced ultrasound (CEUS) as compared with magnetic resonance imaging (MRI). METHODS: Forty women diagnosed with symptomatic uterine fibroids scheduled for uterine artery embolization (UAE) were enrolled in this institutional review board-approved study. Before UAE, participants underwent CEUS examination with an Aplio i800 scanner (Canon Medical Systems, Tustin, CA, USA) with curvilinear array (8C1). CEUS was performed using 2.0 mL of the ultrasound contrast agent Lumason (Bracco, Milan, Italy) administered intravenously. Digital CEUS clips were acquired and randomized offline, and fibroids were characterized as hyper- or hypovascular. MRI was used as reference standard for fibroid vascularity and compared with CEUS. Results were analyzed using McNemar's test. RESULTS: Forty participants were enrolled in the trial. One patient did not proceed with the UAE procedure and one patient refused pre-procedure MRI because of claustrophobia. Therefore, 38 participants underwent CEUS and MRI examinations before UAE. Hypervascular fibroids were seen on MRI and CEUS in 24 and 26 participants, respectively. Hypovascular fibroids were seen with MRI and CEUS in 14 and 12 participants, respectively. Fibroids characterized as hypovascular in two participants by MRI were characterized as hypervascular by CEUS. CEUS and MRI findings were similar in 36 of 38 participants, corresponding to an accuracy of 95% (p = 0.62). CONCLUSION: Contrast-enhanced ultrasound can accurately assess uterine fibroid vascularity, serving as a potential alternative to MRI in determination of the vascularity of uterine fibroids.

Identification of sentinel lymph nodes in esophageal cancer patients using contrast-enhanced EUS with peritumoral injections.

Objectives: The objective of this pilot study was to compare the performance of contrast-enhanced EUS (CE-EUS)-guided fine-needle aspiration (FNA) with EUS-FNA for lymph node (LN) staging in esophageal cancer. Methods: Thirty-seven subjects with esophageal cancer undergoing EUS staging were enrolled, and 30 completed this institutional review board-approved study. A Prosound F75 US system (Hitachi Medical Systems, Tokyo, Japan) with harmonic contrast imaging software and GF-UCT180 curvilinear endoscope (Olympus, Tokyo, Japan) was utilized. All LNs identified by standard EUS were first noted. Sonazoid (dose: 1 mL; GE Healthcare, Oslo, Norway) was administered peritumorally, and all enhanced LNs were recorded. Fine-needle aspiration was performed on LNs considered suspicious by EUS alone, as well as LNs enhanced on CE-EUS. Performance of each modality was compared using FNA cytology as reference standard. Results: A total of 132 LNs were detected with EUS, of which 59 showed enhancement on CE-EUS. Fifty-three LNs underwent FNA, and 22 LNs were determined to be malignant. Among the latter, 10 were considered suspicious by EUS, whereas the other 12 LNs underwent FNA only because of CE-EUS enhancement. Contrast-enhanced EUS showed enhancement in 19 of the 22 malignant LNs. The rate of metastatic node identification from EUS was 45% (10/22), and it was 86% (19/22; P = 0.008) for CE-EUS. Eight subjects (8/30 [27% of study total]) had nodal status upgraded by the addition of CE-EUS, which influenced LN staging and clinical management. Conclusions: Fine-needle aspiration of LNs identified by CE-EUS may increase metastasis positive rate by ruling out LNs not associated with the tumor drainage pattern. In addition, CE-EUS seems to identify more metastatic LNs that would not be biopsied under the standard EUS criteria.

Contrast-enhanced US Evaluation of Hepatocellular Carcinoma Response to Chemoembolization: A Prospective Multicenter Trial.

Background Contrast-enhanced (CE) US has been studied for use in the detection of residual viable hepatocellular carcinoma (HCC) after locoregional therapy, but multicenter data are lacking. Purpose To compare two-dimensional (2D) and three-dimensional (3D) CE US diagnostic performance with that of CE MRI or CT, the current clinical standard, in the detection of residual viable HCC after transarterial chemoembolization (TACE) in a prospective multicenter trial. Materials and Methods Participants aged at least 21 years with US-visible HCC scheduled for TACE were consecutively enrolled at one of three participating academic medical centers from May 2016 to March 2022. Each underwent baseline 2D and 3D CE US before TACE, 2D and 3D CE US 1-2 weeks and/or 4-6 weeks after TACE, and CE MRI or CT 4-6 weeks after TACE. CE US and CE MRI or CT were evaluated by three fellowship-trained radiologists for the presence or absence of viable tumors and were compared with reference standards of pathology (18%), angiography on re-treatment after identification of residual disease at 1-2-month follow-up imaging (31%), 4-8-month CE MRI or CT (42%), or short-term (approximately 1-2 months) CE MRI or CT if clinically decompensated and estimated viability was greater than 50% at imaging (9%). Diagnostic performance criteria, including sensitivity and specificity, were obtained for each modality and time point with generalized estimating equation analysis. Results A total of 132 participants were included (mean age, 64 years ± 7 [SD], 87 male). Sensitivity of 2D CE US 4-6 weeks after TACE was 91% (95% CI: 84, 95), which was higher than that of CE MRI or CT (68%; 95% CI: 58, 76; P < .001). Sensitivity of 3D CE US 4-6 weeks after TACE was 89% (95% CI: 81, 94), which was higher than that of CE MRI or CT (P < .001), with no evidence of a difference from 2D CE US (P = .22). CE MRI or CT had 85% (95% CI: 76, 91) specificity, higher than that of 4-6-week 2D and 3D CE US (70% [95% CI: 56, 80] and 67% [95% CI: 53, 78], respectively; P = .046 and P = .023, respectively). No evidence of differences in any diagnostic criteria were observed between 1-2-week and 4-6-week 2D CE US (P > .21). Conclusion The 2D and 3D CE US examinations 4-6 weeks after TACE revealed higher sensitivity in the detection of residual HCC than CE MRI or CT, albeit with lower specificity. Importantly, CE US performance was independent of follow-up time. Clinical trial registration no. NCT02764801 © RSNA, 2023 Supplemental material is available for this article.

Contrast-Enhanced Ultrasound and High Sensitive Doppler for Monitoring Outcomes of Uterine Artery Embolization.

RATIONALE AND OBJECTIVES: To monitor fibroid microvascularity using contrast-enhanced ultrasound (CEUS) and a new high-sensitive Doppler mode (SMI) for assessment of uterine artery embolization (UAE) outcomes. MATERIALS AND METHODS: Forty women with symptomatic uterine fibroids scheduled for UAE were enrolled in this Institutional Review Board-approved study. Subjects underwent three examinations (day 0, 15, and 90 post-UAE) with Color Doppler (CDI), power Doppler (PDI), color and monochrome SMI (cSMI and mSMI), and CEUS imaging of the fibroids. Clips were assessed by two radiologists classifying fibroids based on their vascularity. Fibroid fractional vascularity (FV; % of enhanced pixels within the fibroid) and flow intensity (as mean brightness level of the enhanced pixels) were quantified. Results were analyzed using repeated measures ANOVA and nonparametric Wilcoxon sign rank tests. Inter-reader agreement was assessed with κ-values. RESULTS: There was overall agreement between readers for all imaging modalities and examination times (P = .25; κ = 0.70). The FV analysis showed statistically significant differences between CEUS and the Doppler imaging modes (CDI, PDI, cSMI, and mSMI) for the three examination times were compared (P < .0001). The comparison using CDI, PDI, and cSMI showed no statistically significant difference (P = .53). The flow intensity analysis comparison between the Doppler imaging modes (CDI, PDI, cSMI and mSMI) and examination times showed statistically significant differences between all the Doppler imaging modalities (P = .02), except for the 90days post-UAE (P = .34). When the comparison was made for CDI, PDI, and cSMI there was no statistically significant differences (P < .47). CONCLUSION: CEUS and SMI can accurately evaluate fibroid microvascularity, and therefore, can be a noninvasive and accurate method for monitoring outcomes following UAE treatment.

Anatomy Versus Physiology: Is Breast Lymphatic Drainage to the Internal Thoracic (Internal Mammary) Lymphatic System Clinically Relevant?

Approximately 15%-25% of breast lymphatic drainage passes through the internal thoracic (internal mammary) lymphatic system, draining the inner quadrants of the breast. This study aimed to use lymphosonography to identify sentinel lymph nodes (SLNs) in the axillary and internal thoracic lymphatic systems in patients with breast cancer. Seventy-nine patients received subcutaneous ultrasound contrast agent injections around the tumor. Lymphosonography was used to identify SLNs. In 14 of the 79 patients (17.7%), the tumor was located in the inner quadrant of the breast. Lymphosonography identified 217 SLNs in 79 patients, averaging 2.7 SLNs per patient. The 217 identified SLNs in the 79 patients were located in the axillary lymphatic system; none were located in the internal thoracic (internal mammary) lymphatic system, although it was expected in two to four patients (i.e., 4-11 SLNs). These results implied that SLNs associated with breast cancer are predominantly located in the axillary lymphatic system.

In Vitro and In Vivo Evaluation of Ultrasound-Triggered Release From Novel Spinal Device.

OBJECTIVES: Bacterial infection following spinal fusion is a major clinical concern with up to 20% incidence. An ultrasound-triggered bulk-release system to combat postsurgical bacterial survival was designed and evaluated. METHODS: Polylactic acid (PLA) clips were loaded with vancomycin (VAN) and microbubbles (Sonazoid, GE HealthCare) in vitro. Stability was determined over 14 days. VAN-loaded clips were submerged in water and insonated using a Logiq E10 scanner (GE HealthCare) with a curvilinear C6 probe. Doppler-induced VAN release was quantified using spectrophotometry. For in vivo testing, clips were loaded with methylene blue (MeB) solution and Sonazoid. These clips were implanted into a rabbit along the spine at L2 and L5, as well as a pig at L1 and L3, then insonated in Doppler mode using the C6 probe. RESULTS: Sonazoid microbubbles were better preserved when incubated in VAN compared with distilled water at 4°C, 25°C, and 37°C incubation temperatures (P = .0131). Contrast enhancement was observed from both solutions when incubated at 4°C storage conditions. Insonated clips achieved average cumulative VAN release of 101.8 ± 2.8% (81.4 ± 2.8 mg) after 72 hours. Uninsonated clips had only 0.3 ± 0.1% (0.3 ± 0.1 mg) average cumulative VAN release (P < .0001). Clips retrieved from the rabbit did not rupture with insonation nor produce MeB staining of surrounding tissues. In the pig, the PLA film was visibly ruptured and MeB tissue was observed following insonation, whereas the uninsonated clip was intact. CONCLUSION: These results demonstrate ultrasound-triggered release of an encapsulated prophylactic solution and provide an important proof-of-concept for continuing large animal evaluations for translational merit.

Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer.

Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O2 and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O2 and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls (p < 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation.

Contrast-enhanced subharmonic aided pressure estimation for assessment of intracranial pressure in vivo.

BACKGROUND: Intracranial pressure (ICP) monitoring in children currently requires invasive techniques. Subharmonic aided pressure estimation (SHAPE) uses contrast-enhanced ultrasound (CEUS) to measure intravascular and interstitial pressure, but utility in ICP measurements has yet to be explored. OBJECTIVE: The objective of this study was to investigate SHAPE as a novel tool for noninvasive ICP measurements in fetal lambs. MATERIALS AND METHODS: Eighteen fetal lambs at 107-139 days gestational age (term = 145 days) underwent subdural ICP catheter placement. The brain was imaged in the coronal plane in CEUS mode optimized for SHAPE, while infusing an US contrast agent into the fetal circulation. After SHAPE calibration, saline was infused via the subdural catheter to increase ICP. Five-second SHAPE cine clips were obtained at various ICPs. Subharmonic intensity values of the whole brain and thalami were correlated with ICP values using mixed effects linear regression analyses and the strength of the relationship was evaluated by Spearman's rank-order correlation. RESULTS: Forty-nine experiments produced 723 datapoints, including SHAPE intensity values and mean ICP measurements. There was a statistically significant inverse relationship between SHAPE intensity values and ICP measurements in the whole brain and thalami (median rho value - 0.58 and - 0.56, respectively). CONCLUSION: SHAPE intensity values of the brain demonstrate an inverse and statistically significant correlation with in vivo ICP measurements in an animal model.