Influence of Phase Change Droplet Activation and Microbubble Cavitation on the Microenvironment of Hepatocellular Carcinoma.

OBJECTIVE: Both microbubble ultrasound contrast agents and acoustic phase change droplets (APCD) have been explored in hepatocellular carcinoma (HCC). This work aimed to evaluate changes to the HCC microenvironment following either microbubble or APCD destruction in a syngeneic pre-clinical model. METHODS: Mouse RIL-175 HCC tumors were grown in the right flank of 64 immunocompetent mice. Pre-treatment, photoacoustic volumetric tumor oxygenation, and power Doppler measurements were obtained using a Vevo 3100 system (VisualSonics, Toronto, Canada). The experimental groups received a 0.1 mL bolus injection of either Definity ultrasound contrast agent (Lantheus Medical Imaging) or APCD fabricated by condensing Definity. Following injection, ultrasound destruction was performed using flash-replenishment sequences on a Sequoia with a 10L4 probe (Siemens) for the duration of enhancement. Tumor oxygenation and power Doppler measurements were then repeated immediately post-ultrasound treatment. Twenty-four hours post-treatment, animals were euthanized, and tumors were harvested and stained for CD31, Cleaved Caspase 3 and CD45. RESULTS: Imaging biomarkers demonstrated a significant reduction in percent vascularity following either microbubble or APCD destruction in the tumor microenvironment ( p < 0.022) but no significant changes in tumor oxygenation (p = 0.12). Similarly, immunohistochemistry data demonstrated a significant decrease in CD31 expression (p < 0.042) and an increase in apoptosis (p < 0.014) in tumors treated with destroyed microbubbles or APCD relative to controls. Finally, a significant increase in CD45 expression was observed in tumors treated with APCD (p = 0.046), indicating an increase in tumor immune response. CONCLUSION: Ultrasound-triggered destruction of both microbubbles and APCD reduces vascularity, increases apoptosis, and may also increase immune response in this HCC model.

Evaluation of the Contrast-Enhanced Ultrasound Nonradiation Treatment Response Assessment LI-RADS v2024 Using Data From a Multi-Center Transarterial Chemoembolization Study.

RATIONALE AND OBJECTIVE: Hepatocellular carcinoma (HCC) locoregional treatment response is commonly evaluated using the Modified Response Evaluation Criteria in Solid Tumors and the American College of Radiology (ACR) Liver Reporting and Data System (LI-RADS) Treatment Response Assessment (TRA) for MRI/CT. This study aims to evaluate the diagnostic performance of the new ACR contrast-enhanced ultrasound (CEUS) Nonradiation TRA LI-RADS v2024 in HCC treated with transarterial chemoembolization (TACE). MATERIALS AND METHODS: This retrospective observational study included 87 patients treated with TACE from a previously reported cohort. At 15- and 30-days post-treatment, 68 and 72 HCC lesions were evaluated. Three blinded radiologists with different levels of CEUS experience interpreted the images independently. According to CEUS Nonradiation TRA LI-RADSv2024, both intralesional and perilesional tumor viability were evaluated and final TRA categories were as follows: TR-Nonviable, TR-Equivocal, and TR-Viable. The reference standard used was a composite of histology and imaging. RESULTS: 140 HCC lesions were analyzed. At 15 days post-treatment, the sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy of TR-Viable classification ranged from 72.5-94.3%, 72.2-86.4%, 86.8-91.4%, 65.6-86.7%, 76.9-86.8%, respectively. At 30 days post-treatment, the SN, PPV, and NPV of TR-Viable classification decreased, ranging from 65.9-84.2%, 85.7-90.6%, and 59.5-73.9%, respectively, while the SP increased, ranging from 80.0-88.0%. Kappa values ranged from 0.557-0.730, indicating moderate to substantial agreement. CONCLUSION: CEUS Nonradiation TRA LI-RADS is a reliable tool for the detection of viable tumors in lesions treated with TACE and demonstrates reproducibility across readers.

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.

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.

Diagnostic Performance of Quantitative Ultrasound Parameters in Non-alcoholic Fatty Liver Disease.

RATIONALE AND OBJECTIVES: Marked liver steatosis, steatohepatitis, and significant fibrosis are risk factors for unfavorable outcomes in non-alcoholic fatty liver disease (NAFLD). In this study, the diagnostic performance of attenuation coefficient (AC), liver stiffness (LS), and dispersion slope (DS) was evaluated separately and combined in the diagnosis of liver steatosis and fibrosis in NAFLD suspects using biopsy or magnetic resonance imaging (MRI) as a reference standard. MATERIALS AND METHODS: Seventy-four NAFLD suspects were prospectively imaged with an Aplio i800 ultrasound scanner (Canon Medical Systems, Tustin, CA). AC, LS, and DS measurements were obtained from the right liver lobe. RESULTS: Thirty-four patients underwent liver biopsy, and 40 had MRI. There were 32 patients (43%) with liver steatosis and fibrosis (S + F), 22 (30%) with steatosis (S), 5 (7%) with fibrosis (F), and 15 (20%) with normal liver (N). Mean ACs were significantly higher in steatotic livers (n = 54) than in non-steatotic livers (n = 20) (P < 0.0001). LS and DS were significantly higher in patients with liver fibrosis (n = 37) compared to non-fibrotic livers (n = 37) (P = 0.0004 and P = 0.0002, respectively). In detecting (S + F), the area under the receiver operating characteristic curve (AUROCC) was 0.87 for combined ultrasound parameters of LS and AC (negative predictive value [NPV]: 75%, positive predictive value [PPV]: 77%, P < 0.0001). In detecting patients with liver steatosis and fibrosis stage ≥2, LS had an AUROCC of 0.93 (NPV: 87%, PPV: 82%, P < 0.0001). In the biopsy group, 32% (11/34) were diagnosed with non-alcoholic steatohepatitis (NASH). DS values showed a significant difference among patients with (n = 23) or without (n = 11) hepatocellular ballooning (P = 0.02). AUROCC was 0.87 for combined ultrasound parameters of AC, LS, and DS with body mass index (BMI) in detecting NASH (NPV: 80%, PPV: 87%, P = 0.0006). CONCLUSION: AC and LS showed high diagnostic value in detecting liver steatosis and fibrosis, respectively. The combined AC and LS values further improved the diagnostic accuracy in detecting NAFLD and high-risk NAFLD patients.

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.

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.

Comparison of Magnetic Resonance-Based Elastography and Ultrasound Shear Wave Elastography in Patients With Suspicion of Nonalcoholic Fatty Liver Disease.

ABSTRACT: This study investigated the correlation between magnetic resonance elastography (MRE) and shear wave ultrasound elastography (SWE) in patients with clinically diagnosed or suspected nonalcoholic fatty liver disease (NAFLD). Subjects with or at risk of NAFLD identified by magnetic resonance imaging (MRI) proton density fat fraction (PDFF) were prospectively enrolled. For each patient, 6 valid 2-dimensional SWE measurements were acquired using a Logiq E10 scanner (GE HealthCare, Waukesha, WI). A reliability criterion of an interquartile range to median ratio of ≤15% was used for SWE to indicate quality dataset. Magnetic resonance elastography, and MR-fat quantification data were collected the same day as part of the patient's clinical standard of care. Magnetic resonance imaging PDFF was used as a reference to quantify fat with >6.4% indicating NAFLD. Pearson correlation and t-test were performed for statistical analyses. A total of 140 patients were enrolled, 112 of which met SWE reliability measurement criteria. Magnetic resonance elastography and 2-dimensional SWE showed a positive correlation across all study subjects ( r = 0.27; P = 0.004). When patients were grouped according to steatosis and fibrosis state, a positive correlation was observed between MRE and SWE in patients with fibrosis ( r = 0.30; P = 0.03), without fibrosis ( r = 0.27; P = 0.03), and with NAFLD ( r = 0.28; P = 0.02). No elastography technique correlated with liver fat quantification ( P > 0.52). Magnetic resonance elastography was significantly different between patients with and without fibrosis ( P < 0.0001). However, this difference was not apparent with SWE ( P = 0.09). In patients with suspected or known NAFLD, MRE, and SWE demonstrated a positive correlation. In addition, these noninvasive imaging modalities may be useful adjunct techniques for monitoring NAFLD.

Longitudinal ultrasound imaging and network modeling in rats reveal sex-dependent suppression of liver regeneration after resection in alcoholic liver disease.

Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial hepatectomy (PHx) in male and female rats fed via Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5-7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow rates were seen in most animals, with ethanol-fed males showing higher peak portal flow than any other experimental group. A computational model of liver regeneration was used to evaluate the contribution of physiological stimuli and estimate the animal-specific parameter intervals. The results implicate lower metabolic load, over a wide range of cell death sensitivity, in matching the model simulations to experimental data of ethanol-fed male rats. However, in the ethanol-fed female rats and controls of both sexes, metabolic load was higher and in combination with cell death sensitivity matched the observed volume recovery dynamics. We conclude that adaptation to chronic ethanol intake has a sex-dependent impact on liver volume recovery following liver resection, likely mediated by differences in the physiological stimuli or cell death responses that govern the regeneration process. Immunohistochemical analysis of pre- and post-resection liver tissue validated the results of computational modeling by associating lack of sensitivity to cell death with lower rates of cell death in ethanol-fed male rats. Our results illustrate the potential for non-invasive ultrasound imaging to assess liver volume recovery towards supporting development of clinically relevant computational models of liver regeneration.

Ultrasound-Based Machine Learning Approach for Detection of Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Current diagnosis of nonalcoholic fatty liver disease (NAFLD) relies on biopsy or MR-based fat quantification. This prospective study explored the use of ultrasound with artificial intelligence for the detection of NAFLD. METHODS: One hundred and twenty subjects with clinical suspicion of NAFLD and 10 healthy volunteers consented to participate in this institutional review board-approved study. Subjects were categorized as NAFLD and non-NAFLD according to MR proton density fat fraction (PDFF) findings. Ultrasound images from 10 different locations in the right and left hepatic lobes were collected following a standard protocol. MRI-based liver fat quantification was used as the reference standard with >6.4% indicative of NAFLD. A supervised machine learning model was developed for assessment of NAFLD. To validate model performance, a balanced testing dataset of 24 subjects was used. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy with 95% confidence interval were calculated. RESULTS: A total of 1119 images from 106 participants was used for model development. The internal evaluation achieved an average precision of 0.941, recall of 88.2%, and precision of 89.0%. In the testing set AutoML achieved a sensitivity of 72.2% (63.1%-80.1%), specificity of 94.6% (88.7%-98.0%), positive predictive value (PPV) of 93.1% (86.0%-96.7%), negative predictive value of 77.3% (71.6%-82.1%), and accuracy of 83.4% (77.9%-88.0%). The average agreement for an individual subject was 92%. CONCLUSIONS: An ultrasound-based machine learning model for identification of NAFLD showed high specificity and PPV in this prospective trial. This approach may in the future be used as an inexpensive and noninvasive screening tool for identifying NAFLD in high-risk patients.

Ultrasound quantitative assessment of ventral finger microvasculopathy in systemic sclerosis with Raynaud's phenomena: a comparative study.

OBJECTIVE: To assess the finger vascularity of systemic sclerosis patients with Raynaud's phenomenon (RP-SSc) using various ultrasound techniques. METHODS: All fingers (except thumbs) of 18 RP-SSc patients and 18 controls were imaged at room temperature using four ultrasound vascular imaging techniques. The percent vascular area was quantified by counting blood flow pixels in a 25 mm2 square centred at the nail fold for the dorsal side and in 25 mm2 and 100 mm2 square from the fingertip for the ventral side. The mean vascular intensity was calculated from the corresponding areas for dorsal and ventral sides. RESULTS: The percent vascular areas and mean vascular intensities in RP-SSc were significantly lower than those in controls for both dorsal and ventral sides (p<0.01). The mean vascular intensities showed slightly higher area under the curve (AUC) than the percent vascular areas (0.53-0.91 vs 0.53-0.90) regardless of imaging technique and assessment side. For each imaging technique, the ventral side vascularity showed a higher AUC (0.74-0.91) compared with the dorsal side (0.53-0.81). Moreover, ventral side abnormalities were associated with a history of digital ulcers. CONCLUSIONS: Ultrasound demonstrated potential to quantify finger vascularity of RP-SSc. The ventral side of the fingers showed a higher accuracy in detecting RP-SSc than the dorsal side.

Improving diagnostic accuracy of ultrasound texture features in detecting and quantifying hepatic steatosis using various beamforming sound speeds.

Objective.While ultrasound image texture has been utilized to detect and quantify hepatic steatosis, the texture features extracted using a single (conventionally 1540 m s-1) beamforming speed of sound (SoS) failed to achieve reliable diagnostic performance. This study aimed to investigate if the texture features extracted using various beamforming SoSs can improve the accuracy of hepatic steatosis detection and quantification.Approach.Patients with suspected non-alcoholic fatty liver disease underwent liver biopsy or MRI proton density fat fraction (PDFF) as part of standard of care, were prospectively enrolled. The radio-frequency data from subjects' right and left liver lobes were collected using 6 beamforming SoSs: 1300, 1350, 1400, 1450, 1500 and 1540 m s-1and analyzed offline. The texture features, i.e. Contrast, Correlation, Energy and Homogeneity from gray-level co-occurrence matrix of normalized envelope were obtained from a region of interest in the liver parenchyma.Main results.Forty-three subjects (67.2%) were diagnosed with steatosis while 21 had no steatosis. Homogeneity showed the area under the curve (AUC) of 0.75-0.82 and 0.58-0.81 for left and right lobes, respectively with varying beamforming SoSs. The combined Homogeneity value over 1300-1540 m s-1from left and right lobes showed the AUC of 0.90 and 0.81, respectively. Furthermore, the combined Homogeneity values from left and right lobes over 1300-1540 m s-1improved the AUC to 0.94. The correlation between texture features and steatosis severity was improved by using the images from various beamforming SoSs. The combined Contrast values over 1300-1540 m s-1from left and right lobes demonstrated the highest correlation (r= 0.90) with the MRI PDFF while the combined Homogeneity values over 1300-1540 m s-1from left and right lobes showed the highest correlation with the biopsy grades (r= -0.81).Significance.The diagnostic accuracy of ultrasound texture features in detecting and quantifying hepatic steatosis was improved by combining its values extracted using various beamforming SoSs.

Diagnostic Performance Comparison Between Ultrasound Attenuation Measurements From Right and Left Hepatic Lobes for Steatosis Detection in Non-alcoholic Fatty Liver Disease.

RATIONALE AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is currently diagnosed by liver biopsy or MRI proton density fat fraction (MRI-PDFF) from left hepatic lobe (LTHL) and/or right hepatic lobe (RTHL). The objective of this study was to compare the diagnostic value of ultrasound attenuation coefficients (ACs) from RTHL and LTHL in detecting hepatic steatosis using biopsy or MRI-PDFF as a reference standard. MATERIALS AND METHODS: Sixty-six patients with suspected NAFLD were imaged with an Aplio i800 ultrasound scanner (Canon Medical Systems, Tustin, CA). Five AC measurements from RTHL and LTHL were averaged separately and together to be compared with the reference standard. RESULTS: Forty-seven patients (71%) were diagnosed with NAFLD. Mean ACs were significantly higher in fatty livers than non-fatty livers (RTHL: 0.73 ± 0.10 vs. 0.63 ± 0.07 dB/cm/MHZ; p < 0.0001, LTHL: 0.78 ± 0.11 vs. 0.63 ± 0.06 dB/cm/MHz; p < 0.0001, RTHL & LTHL: 0.76 ± 0.09 vs. 0.63 ± 0.05 dB/cm/MHz; p < 0.0001). Biopsy steatosis grades (n =31) were better correlated with the mean ACs of RTHL & LTHL (r = 0.72) compared to LTHL (r = 0.67) or RTHL (r = 0.61). Correlation between MRI-PDFF (n = 35) and mean ACs was better for LTHL (r = 0.69) compared to the RTHL & LTHL (r = 0.66) or RTHL (r = 0.45). Higher diagnostic accuracy was shown for the mean ACs of RTHL & LTHL (AUC 0.89, specificity 94%, sensitivity 78%) compared to LTHL (AUC 0.89, specificity 88%, sensitivity 82%) or RTHL (AUC 0.81, specificity 89%, sensitivity 68%). CONCLUSION: Ultrasound ACs from RTHL and LTHL showed comparable diagnostic values in detection of hepatic steatosis with the highest diagnostic accuracy when they were averaged together.

Volumetric Quantitative Contrast-enhanced Ultrasonography Evaluation of Complex Renal Cysts: An Adjunctive Metric to the Bosniak Classification System to Predict Malignancy.

BACKGROUND: Management of complex renal cysts is guided by the Bosniak classification system, which may be inadequate for risk stratification of patients for intervention. Fractional tumor vascularity (FV) calculated from volumetric contrast-enhanced ultrasound (CEUS) images may provide additional useful information. OBJECTIVE: To evaluate CEUS and FV calculation for risk stratification of patients with complex renal cysts. DESIGN, SETTING, AND PARTICIPANTS: This was a pilot prospective study with institutional review board approval involving patients undergoing surgery for Bosniak IIF-IV complex renal cysts. CEUS was performed preoperatively on the day of surgery with two-dimensional (2D) and three-dimensional (3D) imaging and sulfur hexafluoride lipid-type A microspheres as the ultrasound contrast agent. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A custom MATLAB program was used to select regions of interest on CEUS scans. FV was calculated according to FV = 1 - (total nonenhancing area/total lesion area). We assessed the ability of 2D- and 3D-derived percentage FV (2DFV%, and 3DFV%) and Bosniak classification schemes (pre-2019 [P2019B] and post-2019 [B2019]) to predict malignancy, aggressive histology, and upstaging on surgical pathology. Performance was assessed as area under the receiver operating characteristic curve (AUC). RESULTS AND LIMITATIONS: Twenty eligible patients were included in final analysis, of whom 85% (n = 17) had Bosniak IV cysts and 85% (n = 17) had malignant disease on final pathology. Four (24%) of the malignant lesions were International Society of Urological Pathology grade 3-4. The AUC for predicting malignancy was 0.980, 0.824, 0.863, and 0.824 with P2019B, B2019, 2DFV%, and 3DFV%, respectively. When the Bosniak classification was combined with FV%, three models had an AUC of 1, while the combined 2DFV% + B2019 model had AUC of 0.980. CONCLUSIONS: FV is a novel metric for evaluating complex cystic renal masses and enhances the ability of the Bosniak classification system to predict malignancy. This metric may serve as an adjunct in risk stratification for surgical intervention. Further prospective evaluation is warranted. PATIENT SUMMARY: Cysts in the kidney are currently classified using a scheme called the Bosniak system. We assessed measurement of the percentage of vascular tissue (called fractional vascularity) in cysts on a special type of ultrasound scan. This promising test adds information when combined with the Bosniak system and can help in guiding appropriate treatment.

A Comprehensive Motion Compensation Method for In-Plane and Out-of-Plane Motion in Dynamic Contrast-Enhanced Ultrasound of Focal Liver Lesions.

Contrast-enhanced ultrasound (CEUS) acquisitions of focal liver lesions are affected by motion, which has an impact on contrast signal quantification. We therefore developed and tested, in a large patient cohort, a motion compensation algorithm called the Iterative Local Search Algorithm (ILSA), which can correct for both periodic and non-periodic in-plane motion and can reject frames with out-of-plane motion. CEUS cines of 183 focal liver lesions in 155 patients from three hospitals were used to develop and test ILSA. Performance was evaluated through quantitative metrics, including the root mean square error and R2 in fitting time-intensity curves and standard deviation value of B-mode intensities, computed across cine frames), and qualitative evaluation, including B-mode mean intensity projection images and parametric perfusion imaging. The median root mean square error significantly decreased from 0.032 to 0.024 (p < 0.001). Median R2 significantly increased from 0.88 to 0.93 (p < 0.001). The median standard deviation value of B-mode intensities significantly decreased from 6.2 to 5.0 (p < 0.001). B-Mode mean intensity projection images revealed improved spatial resolution. Parametric perfusion imaging also exhibited improved spatial detail and better differentiation between lesion and background liver parenchyma. ILSA can compensate for all types of motion encountered during liver CEUS, potentially improving contrast signal quantification of focal liver lesions.

Tumoral oxygenation and biodistribution of Lonidamine oxygen microbubbles following localized ultrasound-triggered delivery.

Prior work has shown that microbubble-assisted delivery of oxygen improves tumor oxygenation and radiosensitivity, albeit over a limited duration. Lonidamine (LND) has been investigated because of its ability to stimulate glycolysis, lactate production, inhibit mitochondrial respiration, and inhibit oxygen consumption rates in tumors but suffers from poor bioavailability. The goal of this work was to characterize LND-loaded oxygen microbubbles and assess their ability to oxygenate a human head and neck squamous cell carcinoma (HNSCC) tumor model, while also assessing LND biodistribution. In tumors treated with surfactant-shelled microbubbles with oxygen core (SE61O2) and ultrasound, pO2 levels increased to a peak 19.5 ± 9.7 mmHg, 50 s after injection and returning to baseline after 120 s. In comparison, in tumors treated with SE61O2/LND and ultrasound, pO2 levels showed a peak increase of 29.0 ± 8.3 mmHg, which was achieved 70 s after injection returning to baseline after 300 s (p < 0.001). The co-delivery of O2andLNDvia SE61 also showed an improvement of LND biodistribution in both plasma and tumor tissues (p < 0.001). In summary, ultrasound-sensitive microbubbles loaded with O2 and LND provided prolonged oxygenation relative to oxygenated microbubbles alone, as well as provided an ability to locally deliver LND, making them more appropriate for clinical translation.

Evaluation of Suspected Small Bowel Ischemia Using Contrast-Enhanced Ultrasound with Computed Tomography Fusion.

Small bowel ischemia can lead to fatal complications such as necrosis, perforation, and sepsis. Clinical examinations and laboratory tests are usually inconclusive in critically ill patients. The need for surgical exploration is decided based on imaging, examination, and clinical judgment. The decision to operate is time-critical and can be lifesaving, but surgical intervention has the potential to cause additional morbidity, especially in unstable patients. Contrast-enhanced computed tomography (CECT) is the study of choice in suspected small bowel ischemia but has poor specificity. Contrast-enhanced ultrasound (CEUS) provides real-time visualization of the bowel wall vascularity. In this case report, we used a CEUS with CT fusion examination to rule out small bowel ischemia in a critically ill patient with suspected closed loop small bowel obstruction on CECT and in whom surgical exploration would have not been well tolerated. The patient's condition later improved, and an abdominal CT showed no evidence of obstruction.

Development of a Dual Drug-Loaded, Surfactant-Stabilized Contrast Agent Containing Oxygen.

Co-delivery of cancer therapeutics improves efficacy and encourages synergy, but delivery faces challenges, including multidrug resistance and spatiotemporal distribution of therapeutics. To address these, we added paclitaxel to previously developed acoustically labile, oxygen-core, surfactant-stabilized microbubbles encapsulating lonidamine, with the aim of developing an agent containing both a therapeutic gas and two drugs acting in combination. Upon comparison of unloaded, single-loaded, and dual-loaded microbubbles, size (~1.7 µm) and yield (~2 × 109 microbubbles/mL) (~1.7) were not statistically different, nor were acoustic properties (maximum in vitro enhancements roughly 18 dB, in vitro enhancements roughly 18 dB). Both drugs encapsulated above required doses calculated for head and neck squamous cell carcinoma, the cancer of choice. Interestingly, paclitaxel encapsulation efficiency increased from 1.66% to 3.48% when lonidamine was included. During preparation, the combination of single drug-loaded micelles gave higher encapsulation (µg drug/g microbubbles) than micelles loaded with either drug alone (lonidamine, 104.85 ± 22.87 vs. 87.54 ± 16.41), paclitaxel (187.35 ± 8.38 vs. 136.51 ± 30.66). In vivo intravenous microbubbles produced prompt ultrasound enhancement within tumors lasting 3-5 min, indicating penetration into tumor vasculature. The ability to locally destroy the microbubble within the tumor vasculature was confirmed using a series of higher intensity ultrasound pulses. This ability to locally destroy microbubbles shows therapeutic promise that warrants further investigation.