The capacity of contrast-enhanced ultrasound (CEUS) to detect microvessel perfusion has received much attention in cancer imaging since it can be used to evaluate the enhancement patterns of the ...lesions during all vascular phases in real time, with higher temporal resolution as compared other imaging modalities. A rich body of literature has demonstrated the potential usefulness of CEUS in the assessment of HCC in response to both locoregional and systemic therapies. It is useful to evaluate the efficacy of ablation immediately after treatment to provide guidance for the retreatment of residual unablated tumors. In patients treated with transarterial chemoembolization (TACE), CEUS showed a high degree of concordance with computed tomography and magnetic resonance for the differentiation of responders from non-responders. Dynamic CEUS (D-CEUS) has emerged as a promising tool for the depicting changes in tumor perfusion during anti-angiogenetic treatment that can be associated with tumor response and clinical outcome. This article provides a general review of the current literature regarding the usefulness of CEUS in monitoring HCC response to therapy, highlighting the role of the procedure in different stages of the disease.
The aim of this article is to provide an inventory of the use of contrast-enhanced ultrasound (CEUS) in relation to percutaneous interventional procedures. The article is structured into a systematic ...literature review followed by a clinical part relating to percutaneous CEUS-guided procedures. A literature search identified 3109 records. After abstract screening, 55 articles were analyzed and supplemented with pictorial material to explain the techniques. In conclusion, the best-evidenced indications for CEUS-guided interventions are biopsy and ablation of inconspicuous or B-mode-invisible tumors, intraprocedural ablation control and follow-up, as well as percutaneous transhepatic cholangiography and drainage procedures.
Shell‐stabilized gas microbubbles (MB) and nanobubbles (NB) are frequently used for biomedical ultrasound imaging and therapeutic applications. While it is widely recognized that monodisperse bubbles ...can be more effective in these applications, the efficient formulation of uniform bubbles at high concentrations is difficult to achieve. Here, it is demonstrated that a standard mini‐extruder setup, commonly used to make vesicles or liposomes, can be used to quickly and efficiently generate monodisperse NBs with high yield. In this highly reproducible technique, the NBs obtained have an average diameter of 0.16 ± 0.05 µm and concentration of 6.2 ± 1.8 × 1010 NBs mL−1 compared to 0.32 ± 0.1 µm and 3.2 ± 0.7 × 1011 mL−1 for NBs made using mechanical agitation. Parameters affecting the extrusion and NB generation process including the temperature, concentration of the lipid solution, and the number of passages through the extruder are also examined. Moreover, it is demonstrated that extruded NBs show a strong acoustic response in vitro and a strong and persistent US signal enhancement under nonlinear contrast enhanced ultrasound imaging in mice. The extrusion process is a new, efficient, and scalable technique that can be used to easily produce high yield smaller monodispersed nanobubbles.
Shell‐stabilized, gas nanobubbles are used in a variety of biomedical and industrial applications, but are difficult to make. Here a high yield, scalable method for direct production of monodisperse lipid‐shelled C3F8 nanobubbles for biomedical applications via a simple extrusion process is presented. Compared to self‐assembly via mechanical agitation, the process is efficient, and requires no postprocessing for size isolation.
Purpose
Contrast‐enhanced ultrasound (CEUS) by injection of microbubbles (MBs) has shown promise as a cost‐effective imaging modality for prostate cancer (PCa) detection. More recently, nanobubbles ...(NBs) have been proposed as novel ultrasound contrast agents. Unlike MBs, which are intravascular ultrasound contrast agents, the smaller diameter of NBs allows them to cross the vessel wall and target specific receptors on cancer cells such as the prostate‐specific membrane antigen (PSMA). It has been demonstrated that PSMA‐targeted NBs can bind to the receptors of PCa cells and show a prolonged retention effect in dual‐tumor mice models. However, the analysis of the prolonged retention effect has so far been limited to qualitative or semi‐quantitative approaches.
Methods
This work introduces two pharmacokinetics models for quantitative analysis of time–intensity curves (TICs) obtained from the CEUS loops. The first model is based on describing the vascular input by the modified local density random walk (mLDRW) model and independently interprets TICs from each tumor lesion. Differently, the second model is based on the reference‐tissue model, previously proposed in the context of nuclear imaging, and describes the binding kinetics of an indicator in a target tissue by using a reference tissue where binding does not occur.
Results
Our results show that four estimated parameters, β, β/λ$\beta /\lambda $, β+/β−${\beta }_ + /{\beta }_ - $, for the mLDRW‐input model, and γ for the reference‐based model, were significantly different (p‐value <0.05) between free NBs and PSMA‐NBs. These parameters estimated by the two models demonstrate different behaviors between PSMA‐targeted and free NBs.
Conclusions
These promising results encourage further quantitative analysis of targeted NBs for improved cancer diagnostics and characterization.
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•The LR-5 CEUS class is an optimal diagnostic tool for HCC.•The other LR classes (LR-3, LR-4 and LR-M) require histological confirmation.•These data could change the diagnostic ...algorithm of HCC.
The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned because of the risk of a false positive diagnosis in cases of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS Liver Imaging Reporting and Data System LI-RADS®) to classify lesions at risk of HCC investigated by CEUS. The aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC.
A total of 1,006 nodules from 848 patients with chronic liver disease at risk of HCC were collected in five Italian centers and retrospectively analyzed. Nodules were classified as LR-5, (HCC) if ≥1 cm with arterial phase hyperenhancement, and late washout (onset ≥60 s after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (n = 506) or histology (n = 500).
The median nodule size was 2 cm. Of 1,006 nodules, 820 (81%) were HCC, 40 (4%) were cholangiocarcinoma, 116 (11%) regenerative nodules (±dysplastic). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96 47%) and the LR-4 202 (HCC 173 87%).
The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non-invasive diagnosis.
This is a retrospective study of approximately 1,000 focal lesions at risk for hepatocellular carcinoma (HCC). Herein, we demonstrate that the refined definition of the typical contrast enhanced ultrasound pattern of HCC introduced by the Liver Imaging Reporting and Data System (LI-RADS®) practically abolishes the risk of misdiagnosis of other malignant entities (e.g. cholangiocarcinoma) for HCC with negligible reduction in sensitivity. These data support the use of contrast enhanced ultrasound to diagnose HCC in cirrhosis.
Purpose
Microvascular processes play key roles in many diseases including diabetes. Improved understanding of the microvascular changes involved in disease development could offer crucial insight ...into the relationship of these changes to disease pathogenesis. Super‐resolution ultrasound (SR‐US) imaging has showed the potential to visualize microvascular detail down to the capillary level (i.e., subwavelength resolution), but optimization is still necessary. The purpose of this study was to investigate in vivo SR‐US imaging of skeletal muscle microvascularity using microbubble (MB) contrast agents of various size and concentration while evaluating different ultrasound (US) system level parameters such as imaging frame rate and image acquisition length.
Methods
An US system equipped with a linear array transducer was used in a harmonic imaging mode at low transmit power. C57BL/6J mice fed a normal diet were used in this study. An assortment of size‐selected MB contrast agents (1–2 μm, 3–4 μm, and 5–8 μm in diameter) were slowly infused in the tail vein at various doses (1.25 × 107, 2.5 × 107, or 5 × 107 MBs). US image data were collected before MB injection and thereafter for 10 min at 30 frames per s (fps). The US transducer was fixed throughout and between each imaging period to help capture microvascular patterns along the same image plane. An adaptive SR‐US image processing technique was implemented using custom Matlab software.
Results
Experimental findings illustrate the use of larger MB results in better SR‐US images in terms of skeletal muscle microvascular detail. A dose of 2.5 × 107 MBs resulted in SR‐US images with optimal spatial resolution. An US imaging rate of at least 20 fps and image acquisition length of at least 8 min also resulted in SR‐US images with pronounced microvascular detail.
Conclusions
This study indicates that MB size and dose and US system imaging rate and data acquisition length have significant impact on the quality of in vivo SR‐US images of skeletal muscle microvascularity.
BACKGROUNDContrast-enhanced ultrasound (CEUS) is considered a secondary examination compared to computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of hepatocellular ...carcinoma (HCC), due to the risk of misdiagnosing intrahepatic cholangiocarcinoma (ICC). The introduction of CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS) might overcome this limitation. Even though data from the literature seems promising, its reliability in real-life context has not been well-established yet. AIMTo test the accuracy of CEUS LI-RADS for correctly diagnosing HCC and ICC in cirrhosis. METHODSCEUS LI-RADS class was retrospectively assigned to 511 nodules identified in 269 patients suffering from liver cirrhosis. The diagnostic standard for all nodules was either biopsy (102 nodules) or CT/MRI (409 nodules). Common diagnostic accuracy indexes such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed for the following associations: CEUS LR-5 and HCC; CEUS LR-4 and 5 merged class and HCC; CEUS LR-M and ICC; and CEUS LR-3 and malignancy. The frequency of malignant lesions in CEUS LR-3 subgroups with different CEUS patterns was also determined. Inter-rater agreement for CEUS LI-RADS class assignment and for major CEUS pattern identification was evaluated. RESULTSCEUS LR-5 predicted HCC with a 67.6% sensitivity, 97.7% specificity, and 99.3% PPV (P < 0.001). The merging of LR-4 and 5 offered an improved 93.9% sensitivity in HCC diagnosis with a 94.3% specificity and 98.8% PPV (P < 0.001). CEUS LR-M predicted ICC with a 91.3% sensitivity, 96.7% specificity, and 99.6% NPV (P < 0.001). CEUS LR-3 predominantly included benign lesions (only 28.8% of malignancies). In this class, the hypo-hypo pattern showed a much higher rate of malignant lesions (73.3%) than the iso-iso pattern (2.6%). Inter-rater agreement between internal raters for CEUS-LR class assignment was almost perfect (n = 511, k = 0.94, P < 0.001), while the agreement among raters from separate centres was substantial (n = 50, k = 0.67, P < 0.001). Agreement was stronger for arterial phase hyperenhancement (internal k = 0.86, P < 2.7 × 10-214; external k = 0.8, P < 0.001) than washout (internal k = 0.79, P < 1.6 × 10-202; external k = 0.71, P < 0.001). CONCLUSIONCEUS LI-RADS is effective but can be improved by merging LR-4 and 5 to diagnose HCC and by splitting LR-3 into two subgroups to differentiate iso-iso nodules from other patterns.
The field of medical ultrasound has undergone a significant evolution since the development of microbubbles as contrast agents. However, because of their size, microbubbles remain in the vasculature ...and therefore have limited clinical applications. Building a better—and smaller—bubble can expand the applications of contrast-enhanced ultrasound by allowing bubbles to extravasate from blood vessels—creating new opportunities. In this review, we summarize recent research on the formulation and use of nanobubbles (NBs) as imaging agents and as therapeutic vehicles. We discuss the ongoing debates in the field and reluctance to accepting NBs as an acoustically active construct and a potentially impactful clinical tool that can help shape the future of medical ultrasound. We hope that the overview of key experimental and theoretical findings in the NB field presented in this article provides a fundamental framework that will help clarify NB–ultrasound interactions and inspire engagement in the field.
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