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Low delivery efficiency combined with systemic toxicity of traditional chemotherapy provides a need for improved chemotherapeutic delivery. Within our laboratory, we have developed polymer ultrasound contrast agents (1.2-1.8 μm in diameter) containing doxorubicin (Dox) within the shell (100-150 nm). In vivo this platform is expected to circulate through the vasculature until activated at the tumor site with external focused ultrasound (US). In vitro, the agent is responsive to US and when insonated at peak positive pressure amplitudes of 0.69 MPa and above, shows dramatic size reduction, eventually reaching a mean particle size of 350 nm, presumably due to fragmentation of, or gas release from the agent. The resulting Dox-polymer particles retain the drug and are small enough to pass through the leaky pores (350-400 nm) within the tumor vasculature, providing a sustained intratumoral release of chemotherapeutic as the polymer degrades. In vivo studies using a VX2 liver tumor model have shown that the combination of the agent and US results in nearly 50% less drug delivered to the nontargeted, healthy liver (p = 0.009) and a 110% increase (p = 0.004) in Dox delivery to the viable peripheral tissue of the tumor, relative to the uninsonated controls. This study shows how US-mediated destruction of drug-loaded polymer contrast agent can be used to deliver encapsulated drug for potential sustained release. Penetration mechanisms of these resulting particles and their ability to provide a sustained release from the tumor interstia will be explored in the future. [ABSTRACT FROM AUTHOR]

The article discusses contrast agents (CA) used in the ultrasound medical imaging modality, examining the effects of end capping and molecular weight on hollow CA's which are formed in the double emulsion process. A CA with 50:50 poly (lactic-co-glycolic-acid) (PLGA) is used in a double emulsion process, the authors state. Other topics include non-end capped PLGA which provides a maximum molecular weight enhancement of 18.5 dB and CA's tailored to particular applications by varying the choice of polymer.

Polymer microbubbles have garnered broad interest as potential theranostic agents. However, the capabilities of polymer MBs can be greatly enhanced, particularly regarding the imaging performance and functional versatility of the platform. This study investigates integrating fluorescent carbon nanodots within polylactic acid (PLA) microbubbles. First, the formulations are characterized by their size, microbubble counts, zeta potential, and resonance frequency. Then, the fluorescence capabilities, nanoparticle loading, and acoustic capabilities are examined. Unmodified (U-), carboxylated (C-), and aminated graphene quantum dots (A-GQDs) were separately suspended and synthesized at a 2% w/w ratio with PLA in the organic phase of the water/oil/water double emulsion process. The new microbubbles were characterized using an AccuSizer, Zetasizer, scanning electron microscopy, fluorescence microscopy and fluorimetry, a custom-built acoustic setup, and clinical ultrasound. The GQD microbubbles were sized between 1.4 and 1.9 µm (U = 1.90, C = 1.44, A = 1.72, Unloaded = 2.02 µm). The U-GQD microbubble exhibited a higher bubble concentration/mg PLA ( p  < .05) and the A-GQD microbubbles exhibited the greatest shift in zeta potential. Electron microscopy revealed smooth surfaces and a spherical shape, showing that the nanoparticle addition was not deleterious. The A-GQD microbubbles were specifically detectable using DAPI-filtering with fluorescence microscopy and had the highest TRITC-filtered fluorescence. The C-GQD microbubbles had the highest loading efficiency at 59.4% ( p  < .05), and the lowest max acoustic enhancement at 5 MHz (U = 19.8, C = 17.6, A = 18.9, Unloaded = 18.5 dB; p  < .05). Additionally, all microbubbles were visible and susceptible to inertial cavitation utilizing clinical ultrasound. The A-GQDs showed promise toward improving the theranostic capabilities of the microbubble platform. They have imbued the most advantageous fluorescence capability and slightly improved backscatter enhancement while retaining all the necessary capabilities of an ultrasound contrast agent. Future studies will investigate the coloading potential of A-GQDs and drug within microbubbles., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Ultrasound's versatility and ease of use has expanded its application in many clinical settings. Technological advancements with contrast-enhanced ultrasound (CEUS) have allowed high quality imaging similar to CT or MRI with lower risk of contrast toxicity and radiation exposure. In this review article we examine the development of CEUS and its vast applications in the field of urology., Methods: A PubMed literature search was performed using keywords: contrast enhanced ultrasound, prostate cancer, renal cancer, and multiparametric ultrasound., Results: The development of CEUS has improved transrectal ultrasound imaging with increased detection of prostate cancer (PCa). Further enhancements of CEUS such as subharmonic imaging (SHI), flash replenishment imaging (FRI) and contrast ultrasound dispersion imaging (CUDI) allow improved PCa diagnosis. CEUS has also emerged as an important tool in characterizing suspicious renal mass without compromising renal function with contrast imaging., Conclusion: CEUS has modernized imaging and diagnosis of prostate and renal cancer. Future advancements and utilization of CEUS will allow its expansion into other urological subspecialties., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This work proposes an interpretable radiomics approach to differentiate between malignant and benign focal liver lesions (FLLs) on contrast-enhanced ultrasound (CEUS). Although CEUS has shown promise for differential FLLs diagnosis, current clinical assessment is performed only by qualitative analysis of the contrast enhancement patterns. Quantitative analysis is often hampered by the unavoidable presence of motion artifacts and by the complex, spatiotemporal nature of liver contrast enhancement, consisting of multiple, overlapping vascular phases. To fully exploit the wealth of information in CEUS, while coping with these challenges, here we propose combining features extracted by the temporal and spatiotemporal analysis in the arterial phase enhancement with spatial features extracted by texture analysis at different time points. Using the extracted features as input, several machine learning classifiers are optimized to achieve semiautomatic FLLs characterization, for which there is no need for motion compensation and the only manual input required is the location of a suspicious lesion. Clinical validation on 87 FLLs from 72 patients at risk for hepatocellular carcinoma (HCC) showed promising performance, achieving a balanced accuracy of 0.84 in the distinction between benign and malignant lesions. Analysis of feature relevance demonstrates that a combination of spatiotemporal and texture features is needed to achieve the best performance. Interpretation of the most relevant features suggests that aspects related to microvascular perfusion and the microvascular architecture, together with the spatial enhancement characteristics at wash-in and peak enhancement, are important to aid the accurate characterization of FLLs.

Purpose: Contrast-enhanced ultrasound (CEUS) is a useful tool to assess treatment response after percutaneous ablation or transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). Here, we performed a systematic review and meta-analysis to evaluate the usefulness of CEUS in identifying residual tumor after locoregional therapy., Methods: PubMed, Scopus, and Cochrane library databases were searched from their inception until March 8, 2021, for diagnostic test accuracy studies comparing CEUS to a reference standard for identifying residual tumors after locoregional therapy of HCC. The pooled sensitivity, specificity, accuracy, and diagnostic odds ratio (DOR) were obtained using a bivariate random effects model. Subgroup analyses were performed by stratifying the studies based on study design, type of locoregional therapy, CEUS criteria for residual tumor, timing of CEUS follow up, and type of standard reference., Results: Two reviewers independently evaluated 1479 publications. After full-text review, 142 studies were found to be relevant, and 43 publications (50 cohorts) were finally included. The overall sensitivity of CEUS in detection of residual disease estimated from the bivariate random effects model was 0.85 (95% CI 0.80-0.89). Similarly, the overall specificity was 0.94 (95% CI 0.91-0.96). The diagnostic accuracy was 93.5%. The DOR was 70.1 (95% CI 62.2-148), and the AUROC was 0.95. Importantly, subgroup analysis showed no apparent differences in the diagnostic performance between locoregional therapy (TACE vs. ablation) and criteria used to define residual enhancement, timing of performing CEUS, study design, or type of reference standard., Conclusion: CEUS is a highly accurate method to identify HCC residual tumor after TACE or percutaneous ablation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale and Objectives: Contrast-enhanced ultrasound (CEUS) has increasingly gained acceptance in the postoperative evaluation of kidney-transplantation recipients. Our meta-analysis aims to evaluate the diagnostic accuracy of CEUS in identifying post-transplantation complications., Materials and Methods: PubMed, Scopus, Ovid Medline, and Cochrane databases were searched from their inception until February 28, 2020, for diagnostic test accuracy studies comparing CEUS to a reference standard for monitoring complications after kidney transplantation. A meta-analysis was conducted to calculate the pooled sensitivity, specificity, accuracy, and diagnostic odds ratio using a bivariate random effects model. Sensitivity analysis was performed using R software by stratifying the studies based on study design, sample size, age, and origin of the study to evaluate the influence of these factors on the overall effect., Results: Two independent reviewers analyzed 285 publications, out of which 29 were determined directly relevant and 12 (with a total of 542 cases) contained all required data for the meta-analysis. The overall sensitivity of included studies was estimated to be 0.86 (95% confidential interval (CI); 0.78--0.92). Similarly, the overall specificity was estimated to be 0.90 (95% CI; 0.82-0.94). Log diagnostic odds ratio was 4.25 (95% CI; 3.43-5.07), and the area under the curve of the pooled receiver operating characteristic was 0.94. Stratified sensitivity analyses showed study design, sample size, age group, and origin of the study had no significant impact on the overall diagnostic value of CEUS., Conclusion: Evidence suggests that CEUS is a potentially effective and accurate method to evaluate a variety of complications such as rejection, vascular complications, and malignancies after kidney transplantation., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Importance: Thyroid nodules are common incidental findings. Ultrasonography and molecular testing can be used to assess risk of malignant neoplasm., Objective: To examine whether a model developed through automated machine learning can stratify thyroid nodules as high or low genetic risk by ultrasonography imaging alone compared with stratification by molecular testing for high- and low-risk mutations., Design, Setting, and Participants: This diagnostic study was conducted at a single tertiary care urban academic institution and included patients (n = 121) who underwent ultrasonography and molecular testing for thyroid nodules from January 1, 2017, through August 1, 2018. Nodules were classified as high risk or low risk on the basis of results of an institutional molecular testing panel for thyroid risk genes. All thyroid nodules that underwent genetic sequencing for cytological results with Bethesda System categories III and IV were reviewed. Patients without diagnostic ultrasonographic images within 6 months of fine-needle aspiration or who received definitive treatment at an outside medical center were excluded., Main Outcomes and Measures: Thyroid nodules were categorized by the model as high risk or low risk using ultrasonographic images. Results were compared using genetic testing., Results: Among the 134 lesions identified in 121 patients (mean [SD] age, 55.7 [14.2] years; 102 women [84.3%]), 683 diagnostic ultrasonographic images were selected. Of the 683 images, 556 (81.4%) were used for training the model, 74 (10.8%) for validation, and 53 (7.8%) for testing. Most nodules had no mutation (75 [56.0%]), whereas 43 nodules (32.1%) had a high-risk mutation and 16 (11.9%) had an unknown or a low-risk mutation (χ2 = 39.060; P < .001). In total, 228 images (33.4%) were of nodules classified as genetically high risk (n = 43), and 455 (66.6%) were of low-risk nodules (n = 91). The model performed with a sensitivity of 45% (95% CI, 23.1%-68.5%), a specificity of 97% (95% CI, 84.2%-99.9%), a positive predictive value of 90% (95% CI, 55.2%-98.5%), a negative predictive value of 74.4% (95% CI, 66.1%-81.3%), and an overall accuracy of 77.4% (95% CI, 63.8%-97.7%)., Conclusions and Relevance: The study found that the model developed through automated machine learning could produce high specificity for identifying nodules with high-risk mutations on molecular testing. This finding shows promise for the diagnostic applications of machine learning interpretation of sonographic imaging of indeterminate thyroid nodules.

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.)

"How to perform contrast-enhanced ultrasound (CEUS)" provides general advice on the use of ultrasound contrast agents (UCAs) for clinical decision-making and reviews technical parameters for optimal CEUS performance. CEUS techniques vary between centers, therefore, experts from EFSUMB, WFUMB and from the CEUS LI-RADS working group created a discussion forum to standardize the CEUS examination technique according to published evidence and best personal experience. The goal is to standardise the use and administration of UCAs to facilitate correct diagnoses and ultimately to improve the management and outcomes of patients.

Aim: To assess the insulating effect of a poloxamer 407 (P407)-based gel during microwave ablation of liver adjacent to the diaphragm., Methods: We prepared serial dilutions of P407, and 22.5% (w/w) concentration was identified as suitable for ablation procedures. Subsequently, microwave ablations were performed on the livers of 24 rabbits (gel, saline, control groups, n = 8 in each). The P407 solution and 0.9% normal saline were injected into the potential space between the diaphragm and liver in experimental groups. No barriers were applied to the controls. After microwave ablations, the frequency, size and degree of thermal injury were compared histologically among the three groups. Subsequently, another 8 rabbits were injected with the P407 solution and microwave ablation was performed. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine (Cr) in serum were tested at 1 d before microwave ablation and 3 and 7 d after operation., Results: In vivo ablation thermal injury to the adjacent diaphragm was evaluated in the control, saline and 22.5% P407 gel groups ( P = 0.001-0.040). However, there was no significant difference in the volume of ablation zone among the three groups ( P > 0.05). Moreover, there were no statistical differences among the preoperative and postoperative gel groups according to the levels of ALT, AST, BUN and Cr in serum (all P > 0.05)., Conclusion: Twenty-two point five percent P407 gel could be a more effective choice during microwave ablation of hepatic tumors adjacent to the diaphragm. Further studies for clinical translation are warranted., Competing Interests: Conflict-of-interest statement: The authors alone are responsible for the paper. The authors declare no conflicts of interest.

Objectives: Subharmonic imaging (SHI) is a technique that uses the nonlinear oscillations of microbubbles when exposed to ultrasound at high pressures transmitting at the fundamental frequency ie, f o and receiving at half the transmit frequency (ie, f o /2). Subharmonic aided pressure estimation (SHAPE) is based on the inverse relationship between the subharmonic amplitude of the microbubbles and the ambient pressure change., Methods: Eight waveforms with different envelopes were optimized with respect to acoustic power at which the SHAPE study is most sensitive. The study was run with four input transmit cycles, first in vitro and then in vivo in three canines to select the waveform that achieved the best sensitivity for detecting changes in portal pressures using SHAPE. A Logiq 9 scanner with a 4C curvi-linear array was used to acquire 2.5 MHz radio-frequency data. Scanning was performed in dual imaging mode with B-mode imaging at 4 MHz and a SHI contrast mode transmitting at 2.5 MHz and receiving at 1.25 MHz. Sonazoid, which is a lipid stabilized gas filled bubble of perfluorobutane, was used as the contrast agent in this study., Results: A linear decrease in subharmonic amplitude with increased pressure was observed for all waveforms (r from -0.77 to -0.93; P < .001) in vitro. There was a significantly higher correlation of the SHAPE gradient with changing pressures for the broadband pulses as compared to the narrowband pulses in both in vitro and in vivo results. The highest correlation was achieved with a Gaussian windowed binomial filtered square wave with an r-value of -0.95. One of the three canines was eliminated for technical reasons, while the other two produced very similar results to those obtained in vitro (r from -0.72 to -0.98; P <.01). The most consistent in vivo results were achieved with the Gaussian windowed binomial filtered square wave (r = -0.95 and -0.96)., Conclusions: Using this waveform is an improvement to the existing SHAPE technique (where a square wave was used) and should make SHAPE more sensitive for noninvasively determining portal hypertension., (© 2016 by the American Institute of Ultrasound in Medicine.)

A polymer ultrasound contrast agent (UCA) developed in our lab has been shown to greatly reduce in size when exposed to ultrasound, resulting in nanoparticles less than 400 nm in diameter capable of escaping the leaky vasculature of a tumor to provide a sustained release of drug. Previous studies with the hydrophilic drug doxorubicin (DOX) demonstrated enhanced drug delivery to tumors when triggered with ultrasound. However the therapeutic potential has been limited due to the relatively low payload of DOX. This study compares the effects of loading the hydrophobic drug paclitaxel (PTX) on the agent's acoustic properties, drug payload, tumoricidal activity, and the ability to deliver drugs through 400 nm pores. A maximum payload of 129.46 ± 1.80 μg PTX/mg UCA (encapsulation efficiency 71.92 ± 0.99%) was achieved, 20 times greater than the maximum payload of DOX (6.2 μg/mg), while maintaining the acoustic properties. In vitro, the tumoricidal activity of paclitaxel loaded UCA exposed to ultrasound was significantly greater than controls not exposed to ultrasound (p<0.0016). This study has shown that PTX loaded UCA triggered with focused ultrasound have the potential to provide a targeted and sustained delivery of drug to tumors., (Copyright © 2011 Elsevier B.V. All rights reserved.)