Contrast-enhanced Ultrasound Research Articles

Contrast efficacy of novel phase convertible nanodroplets for safe CEUS imaging

Microbubble contrast agents in ultrasound/echocardiography are used to increase the echogenicity of the target tissues, thereby raising the contrast resolution of the resultant image. Recently, the trend has shifted toward the development of phase-convertible nanodroplets as ultrasound contrast agents due to their promising theragnostic potential by switching capability at the active site. Herein, we fabricated pre-PGS- perfluoropentane phase convertible nanodroplets and checked their in vitro and in vivo enhancement and safety profile. For this, we performed experiments on 20 male Wistar rats and 2 dogs. Biochemical assays of both rats and dogs included complete blood profiles, liver function tests, and renal function tests. For rat vitals, monitoring and histopathological analysis were also performed. Converted nanodroplets showed excellent contrast enhancement, better than Sonovue upon in vitro testing, with an enhancement time of up to 14 min. In vivo, experiments showed comparable opacification of the ventricles of both rats and dogs. All biochemical assays remained within the normal range during the study period. The histopathological analysis did not show any signs of drug-induced toxicity, showing the safety of these nanodroplets. Pre-PGS-PFP nanodroplets hold great potential for use in echocardiography and abdominal imaging in both human and veterinary applications after clinical trials.

3D-CEUS/MRI-CEUS fusion imaging vs 2D-CEUS after locoregional therapies for hepatocellular carcinoma: a multicenter prospective study of therapeutic responseevaluation.

To compare the diagnostic accuracy of 3D contrast-enhanced ultrasound (CEUS)/MRI-CEUS fusion imaging with 2D-CEUS in assessing the response of hepatocellular carcinoma (HCC) to locoregional therapies in a multicenter prospective study. A consecutive series of patients with HCC scheduled for locoregional treatment were enrolled between April 2021 and March 2023. Patients were randomly divided into 3D-CEUS/MRI-CEUS fusion imaging group (3D/fusion group) or 2D-CEUS group (2D group). CEUS was performed 1 week before and 4-6 weeks after locoregional treatment. Contrast-enhanced MRI (CE-MRI) 4-6 weeks after treatment was set as the reference standard. CEUS images were evaluated for the presence or absence of viable tumors. Diagnostic performance criteria, including sensitivity, specificity, accuracy, and area under the curve (AUC), were determined for each modality. A total of 140 patients were included, 70 patients in the 2D group (mean age, 60.2 ± 10.4 years) and 70 patients in the 3D/fusion group (mean age, 59.8 ± 10.6 years). The sensitivity of the 3D/fusion group was 100.0% (95% CI: 75.9, 100.0), higher than that of the 2D group (55.6%, 95% CI: 22.7, 84.7; p = 0.019). The specificity of the 3D/fusion group was 96.3% (95% CI: 86.2, 99.4), which was comparable to that of the 2D group (98.4%, 95% CI: 90.0, 99.9; p = 0.915). The AUC of the 3D/fusion group was 0.98 (95% CI: 0.95, 1.00), higher than that of the 2D group (0.77, 95% CI: 0.56, 0.98; p = 0.020). 3D-CEUS/MRI-CEUS fusion imaging exhibits superior diagnostic accuracy in evaluating the treatment response to locoregional therapies for HCC. 3D-CEUS/MRI-CEUS fusion imaging can be applied for post-treatment assessment of residual tumors in HCC undergoing locoregional treatment, offering potential benefits in terms of accurate diagnosis and clinical management. Evaluating for HCC recurrence following locoregional therapy is important. 3D-CEUS/MRI-CEUS fusion imaging achieved a higher sensitivity than 2D-CEUS in assessing residual tumors after locoregional therapies. 3D-CEUS/MRI-CEUS fusion imaging can help clinicians intervene early in residual HCC lesions after locoregional treatment.

The Current Role of Contrast-Enhanced Ultrasound (CEUS) in the Diagnosis and Staging of Bladder Cancer: A Review of the Available Literature.

Contrast-enhanced ultrasound (CEUS) is an advanced imaging technique that integrates conventional US with the intravenous injection of specific US contrast agents (UCAs), combining the non-invasiveness of US with the higher accuracy of contrast-enhanced imaging. In contrast with magnetic resonance imaging (MRI), computed tomography (CT) and cystoscopy, CEUS has few contraindications, and UCAs are non-nephrotoxic agents that can be safely used in patients with kidney failure. CEUS is a well-established method for the detection of liver lesions and for echocardiography, and its indications are expanding. The updated 2018 WFUMB-EFSUMB guidelines have added the urinary bladder under non-hepatic applications of CEUS. The technique is able to distinguish between benign tissue, such as clots or hematoma, and malignant lesions by perfusing the mass with contrast agent. Thanks to the different perfusion rates of the various layers of the bladder wall, CEUS is also able to predict tumor invasion depth and stage. Despite that, current urological guidelines do not include CEUS as a plausible imaging technique for bladder urothelial carcinoma. The main reason for this omission might be the presence of scarce randomized evidence and the absence of large validated series. In this review, we describe the rationale behind the use of CEUS in bladder cancer and the added value of this imaging technique in the detection and staging of bladder lesions. In addition, we researched the available literature on the topic and then described the results of randomized clinical trials and a meta-analysis investigating the accuracy of CEUS in bladder cancer diagnosis and staging. The reported studies show that CEUS is a highly accurate diagnostic and staging tool for BC, reaching levels of specificity and sensitivity in differentiating between Ta-T1, or low-grade BC, and T2, or high-grade BC, that are comparable to those shown by the reference standard methods. Nonetheless, several limitations were found and are highlighted in this review. The aim of this study is to further validate and promote the use of CEUS as a quick, economic and effective diagnostic tool for this high-impact disease.

Ultrasound findings and clinical characteristics in differentiating renal urothelial carcinoma from endophytic clear cell renal cell carcinoma.

This study aimed to evaluate the clinical characteristics and features of conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) in differentiating between renal urothelial carcinomas (RUC) and endophytic clear cell renal cell carcinomas (EccRCC). A total of 72 RUCs and 120 EccRCCs confirmed by pathology were assessed retrospectively. Both CUS and CEUS were performed within 4 weeks before the surgery. Logistic regression analyses were used to select statistically significant variables of clinical, CUS, and CEUS features for the differentiation of RUC and EccRCC. Sensitivity (SEN), specificity (SPE), and the area under the receiver-operating characteristic curve (AUC) were assessed for diagnostic performance. Inter- and intra-observer agreements of CUS and CEUS features were evaluated using the intra-class correlation coefficient(ICC). Multiple logistic regression analysis demonstrated that clinical (age >50 years old and hematuria), CUS (size <4.0 cm, hypo-echogenicity, irregular shape, hydronephrosis) and CEUS (absence of non-enhancement area, iso- /hypo-enhancement in cortical phase and absence of rim-like enhancement) features were independent factors for RUC diagnosis. When combining clinical characters with CUS and CEUS features into an integrated diagnostic criterion, the AUC reached 0.917 (95% CI 0.873-0.961), with a sensitivity of 95.8% and specificity of 87.5%. ICC ranged from 0.756 to 0.907 for inter-observer agreement and 0.791 to 0.934 for intra-observer agreement for CUS and CEUSfeatures. The combination of clinical features of age and hematuria with imaging features of CUS and CEUS can be useful for the differentiation between RUC and EccRCC.

Directed Evolution of Acoustic Reporter Genes Using High-Throughput Acoustic Screening.

A major challenge in the fields of biological imaging and synthetic biology is noninvasively visualizing the functions of natural and engineered cells inside opaque samples such as living animals. One promising technology that addresses this limitation is ultrasound (US), with its penetration depth of several cm and spatial resolution on the order of 100 μm. Within the past decade, reporter genes for US have been introduced and engineered to link cellular functions to US signals via heterologous expression in commensal bacteria and mammalian cells. These acoustic reporter genes (ARGs) represent a novel class of genetically encoded US contrast agent, and are based on air-filled protein nanostructures called gas vesicles (GVs). Just as the discovery of fluorescent proteins was followed by the improvement and diversification of their optical properties through directed evolution, here we describe the evolution of GVs as acoustic reporters. To accomplish this task, we establish high-throughput, semiautomated acoustic screening of ARGs in bacterial cultures and use it to screen mutant libraries for variants with increased nonlinear US scattering. Starting with scanning site saturation libraries for two homologues of the primary GV structural protein, GvpA/B, two rounds of evolution resulted in GV variants with 5- and 14-fold stronger acoustic signals than the parent proteins. We anticipate that this and similar approaches will help high-throughput protein engineering play as large a role in the development of acoustic biomolecules as it has for their fluorescent counterparts.

Sonothrombolysis Before and After Percutaneous Coronary Intervention Provides the Largest Myocardial Salvage in ST Segment Elevation Myocardial Infarction

Sonothrombolysis is a therapeutic application of ultrasound with ultrasound contrast for patients with ST elevation myocardial infarction (STEMI). Recent trials demonstrated that sonothrombolysis, delivered before and after primary percutaneous coronary intervention (pPCI), increases infarct vessel patency, improves microvascular flow, reduces infarct size, and improves ejection fraction. However, it is unclear whether pre-pPCI sonothrombolysis is essential for therapeutic benefit. We designed a parallel 3-arm sham-controlled randomized controlled trial to address this. Patients presenting with first STEMI undergoing pPCI within 6 hours of symptom onset were randomized 1:1:1 into 3 arms: sonothrombolysis pre-/post-pPCI (group 1), sham pre- sonothrombolysis post-pPCI (group 2), and sham pre-/post-pPCI (group 3). Our primary end point was infarct size (percentage of left ventricular mass) assessed by cardiac magnetic resonance imaging at day 4±2. Secondary end points included myocardial salvage index (MSI) and echocardiographic parameters at day 4±2 and 6months. Our trial was ceased early due to the COVID pandemic. From 122 patients screened between September 2020 and June 2021, 51 patients (age 60, male 82%) were included postrandomization. Median sonothrombolysis took 5minutes pre-pPCI and 15minutes post-, without significant door-to-balloon delay. There was a trend toward reduction in median infarct size between group 1 (8% [interquartile range, 4,11]), group 2 (11% [7, 19]), or group 3 (15% [9, 22]). Similarly there was a trend toward improved MSI in group 1 (79% [64, 85]) compared to groups 2 (51% [45, 70]) and 3 (48% [37, 73]) No major adverse cardiac events occurred during hospitalization. Pre-pPCI sonothrombolysis may be key to improving MSI in STEMI. Multicenter trials and health economic analyses are required before clinical translation.

Evaluating the efficacy of percutaneous puncture biopsy guided by contrast-enhanced ultrasound for peripheral pulmonary lesions.

The incidence and mortality of lung cancer have increased annually. Accurate diagnosis can help improve therapeutic efficacy of interventions and prognosis. Percutaneous lung biopsy is a reliable method for the clinical diagnosis of lung cancer. Ultrasound-guided percutaneous lung biopsy technology has been widely promoted and applied in recent years. To investigate the diagnostic value of contrast-enhanced ultrasound (CEUS)-guided percutaneous biopsy in peripheral pulmonary lesions. We retrospectively collected data on 237 patients with peripheral thoracic focal lesions who underwent puncture biopsy at Wuxi People's Hospital. The patients were randomly divided into two groups: The CEUS-guided before lesion puncture group (contrast group) and conventional ultrasound-guided group (control group). Analyze the diagnostic efficacy of the puncture biopsy, impact of tumor size, and number of puncture needles and complications were analyzed and compared between the two groups. Accurate pathological results were obtained for 92.83% (220/237) of peripheral lung lesions during the first biopsy, with an accuracy rate of 95.8% (113/118) in the contrast group and 89.9% (107/119) in the control group. The difference in the area under the curve (AUC) between the contrast and the control groups was not statistically significant (0.952 vs 0.902, respectively; P > 0.05). However, when the lesion diameter ≥ 5 cm, the diagnostic AUC of the contrast group was higher than that of the control group (0.952 vs 0.902, respectively; P < 0.05). In addition, the average number of puncture needles in the contrast group was lower than that in the control group (2.58 ± 0.53 vs 2.90 ± 0.56, respectively; P < 0.05). CEUS guidance can enhance the efficiency of puncture biopsy of peripheral pulmonary lesions, especially for lesions with a diameter ≥ 5 cm. Therefore, CEUS guidance has high clinical diagnostic value in puncture biopsy of peripheral focal lung lesions.

Thermoablative Treatment of Papillary Microcarcinomas of Thyroid.

Recently, locoregional treatment with ultrasound-guided radiofrequency has been proposed as a new, effective, and safe procedure for low-risk papillary thyroid microcarcinoma (PTC < 1 cm), not eligible or recruitable for surgery. Until now, the gold standard has been the surgery and then the active surveillance. The aim of the study is to present our experience of ultrasound-guidedthermoablation, a procedure performed before demolitive surgery and post-active surveillance. It is a non-invasive treatment that does not require general anesthesia, with a low risk of complications, hypothyroidism, and hypoparathyroidism. All nodules described on ultrasound showed a volumetric increase (follow-up from 12 to 36 months). The cytological examination in all cases showed TIR 4b and TIR 5 papillary microcarcinoma. All the patients were offered the possibility of radiofrequency thermoablation; they were all informed and gave their consent. 18G active tip electrode needles 7 or 10 mm (Amica Gen HS) were used with the moving shot method under local anesthesia in a day hospital setting. No severe complications were reported. Contrast-Enhanced Ultrasonography (CEUS) with SonoVue (CEUS Sonovue) was performed post-procedure and then at 1, 3, 6, and 12 months, which documented complete revascularization and progressive volumetric reduction of the treated area. Our experience has confirmed that radiofrequency ablation can effectively eliminate small papillary thyroid carcinomas with fewer complications. In our opinion, it is a valid alternative for the treatment of low-risk and indolent papillary thyroid microcarcinomas, even in the absence of surgical contraindications.

Pathological Intraplaque Hemorrhage as the Gold Standard to Assess the Efficacy of Ultrasound in Predicting Vulnerable Carotid Plaque Rupture.

To assess the clinical utility of ultrasound in predicting the risk of carotid vulnerable plaque rupture using pathological intraplaque hemorrhage as the gold standard. A total of 118 patients who underwent endarterectomy due to symptomatic carotid artery stenosis were enrolled. Conventional ultrasound assessed the plaque thickness, area stenosis rate, echo, and surface morphology. Neovascularization were assessed by contrast-enhanced ultrasound (CEUS) and tracing intraplaque nonenhanced areas. According to neovascularization grade (0-4), plaques were classified as low-, intermediate-, and high risk. Fresh intraplaque hemorrhage within the pathology was adopted as the gold standard for diagnosing plaque rupture risk. Thus, we divided patients into ruptured risk and nonruptured risk groups to assess the value of crucial factors for plaque rupture risk using ultrasound. Of the 118 patients, hypertension accounted for 71.2%, hyperlipidemia 68.6%, diabetes 52.5%, and statin history 64.4%. In the rupture risk group, diabetes, smoking, and stenosis rate were significantly higher than the nonrupture risk group (P < .001); plaque thickness ≥4 mm (P > .05); and mainly hypoechoic with irregular surface morphology (P < .001), nonenhanced areas in the plaques (P < .001), and neovascularization >grade 2 (P < .001). Compared with the low-risk group, plaque rupture risk was 7.219 times higher in the medium-risk group and 18.333 times higher in the high-risk group. The kappa value of the interobserver consistency of crucial ultrasound parameters was >0.75, and the intraclass correlation coefficient was 0.919 (P < .01). Both conventional ultrasound and CEUS have significant clinical importance in the prediction of rupture risk in vulnerable carotid plaques, thereby enabling stroke risk stratification and the assessment of plaque rupture risk.

Diagnostic value of contrast-enhanced ultrasound and shear-wave elastography for small breast nodules.

The study aims to evaluate the diagnostic efficacy of contrast-enhanced ultrasound (CEUS) and shear-wave elastography (SWE) in detecting small malignant breast nodules in an effort to inform further refinements of the Breast Imaging Reporting and Data System (BI-RADS) classification system. This study retrospectively analyzed patients with breast nodules who underwent conventional ultrasound, CEUS, and SWE at Gongli Hospital from November 2015 to December 2019. The inclusion criteria were nodules ≤ 2 cm in diameter with pathological outcomes determined by biopsy, no prior treatments, and solid or predominantly solid nodules. The exclusion criteria included pregnancy or lactation and low-quality images. Imaging features were detailed and classified per BI-RADS. Diagnostic accuracy was assessed using receiver operating characteristic curves. The study included 302 patients with 305 breast nodules, 113 of which were malignant. The diagnostic accuracy was significantly improved by combining the BI-RADS classification with CEUS and SWE. The combined approach yielded a sensitivity of 88.5%, specificity of 87.0%, positive predictive value of 80.0%, negative predictive value of 92.8%, and accuracy of 87.5% with an area under the curve of 0.877. Notably, 55.8% of BI-RADS 4A nodules were downgraded to BI-RADS 3 and confirmed as benign after pathological examination, suggesting the potential to avoid unnecessary biopsies. The integrated use of the BI-RADS classification, CEUS, and SWE enhances the accuracy of differentiating benign and malignant small breast nodule, potentially reducing the need for unnecessary biopsies.

The Value of CEUS LI-RADS combined with AFP in early diagnosis of hepatocellular carcinoma in low- and high-risk patients.

We found that the occurrence of hepatocellular carcinoma (HCC) has increased significantly in non-cirrhotic individuals, with HCC being frequently overlooked or misdiagnosed. Contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) is known to have a high diagnostic quality in high-risk HCC patients. Therefore, we aimed to compare the detection accuracy of CEUS LI-RADS for HCC between low- and high-risk individuals, to confirm its value in low-risk patients at increased risk of HCC, but not yet included in the high-risk groups of LI-RADS. In addition, since CEUS LR-4 and LR-M categories contain a relatively high proportion of HCC, and serum alpha-fetoprotein (AFP) is the most commonly used biomarker for HCC, and the clinically valid, we attempted to further improve the early diagnostic capability of CEUS LI-RADS for HCC in the low-risk and high-risk patients by combining CEUS LR-4 and LR-M categories with AFP. We defined high-risk groups (HR)-included in the high-risk patients of LI-RADS, low-risk groups (LR)-not included in the high-risk patients of LI-RADS and enrolled 189 HCC patients with LR and HR settings in a retrospective study. All lesions were confirmed histopathologically. The CEUS LI-RADS accuracy for detecting HCC in these two patients was compared. In addition, the diagnostic algorithm in our study was proposed (for CEUS LR-4 and LR-M patients with AFP>20 ng/ml). we analyzed the ability of CEUS LI-RADS as a valid method of establishing the early diagnosis of HCC in LR and HR patients by combining LR-4 and LR-M categories with AFP. Through comparative analysis, the specificity of the CEUS LR-5 category for HCC in the HR group was 78.4%, whereas in the LR group, it was 94.2%. Meanwhile, the sensitivity (63.2% vs. 63.0%) and positive predictive value (PPV) (75.0% vs. 88.7%) did not differ between the LR and HR groups ( P = 0.990, P = 0.299). It is noteworthy that there were the high proportion of HCC in CEUS LR-4 and LR-M categories in our cases and when we combined CEUS LR-4 and LR-M categories with AFP significantly improved the sensitivity by 21.0% (84.2%) in the LR group, and by 16.0% (79.0%) in the HR group, with statistically difference in sensitivity after combination in the HR group ( P = 0.014). The CEUS LR-5 category has real meaningful utility in the diagnosis of HCC in both LR and HR patients. The early detection power of the CEUS LI-RADS category for HCC patients was further increased when the CEUS LR-4 and LR-M categories were combined with elevated AFP.

Bioactive Nanotherapeutic Ultrasound Contrast Agent for Concurrent Breast Cancer Ultrasound Imaging and Treatment.

Contrast-enhanced ultrasound (CEUS) plays a crucial role in cancer diagnosis. The use of ultrasound contrast agents (UCAs) is inevitable in CEUS. However, current applications of UCAs primarily focus on enhancing imaging quality of ultrasound contrast rather than serving as integrated platforms for both diagnosis and treatment in clinical settings. In this study, a novel UCA, termed NPs-DPPA(C3F8), is innovatively prepared using a combination of nanoprecipitation and ultrasound vibration methods. The DPPA lipid possesses inherent antiangiogenic and antitumor activities, and when combined with C3F8, it functions as a theranostic agent. Notably, the preparation of NPs-DPPA(C3F8) is straightforward, requiring only one hour from raw materials to the final product due to the use of a single material, DPPA. NPs-DPPA(C3F8) exhibits inherent antiangiogenic and biotherapeutic activities, effectively inhibiting triple-negative breast cancer (TNBC) angiogenesis and reducing VEGFA expression both in vitro and in vivo. Clinically, NPs-DPPA(C3F8) enables simultaneous real-time imaging, tumor assessment, and antitumor activity. Additionally, through ultrasound cavitation, NPs-DPPA(C3F8) can overcome the dense vascular walls to increase accumulation at the tumor site and facilitate internalization by tumor cells. The successful preparation of NPs-DPPA(C3F8) offers a novel approach for integrating clinical diagnosis and treatment of TNBC.

Conventional and Contrast-enhanced US of the Lung: From Performance to Diagnosis.

In recent years, lung US has evolved from a marginal tool to an integral component of diagnostic chest imaging. Contrast-enhanced US (CEUS) can improve routine gray-scale imaging of the lung and chest, particularly in diagnosis of peripheral lung diseases (PLDs). Although an underused tool in many centers, and despite inherent limitations in evaluation of central lung disease caused by high acoustic impedance between air and soft tissues, lung CEUS has emerged as a valuable tool in diagnosis of PLDs. Owing to the dual arterial supply to the lungs via pulmonary and bronchial (systemic) arteries, different enhancement patterns can be observed at lung CEUS, thereby enabling accurate differential diagnoses in various PLDs. Lung CEUS also assists in identifying patients who may benefit from complementary diagnostic tests, including image-guided percutaneous biopsy. Moreover, lung CEUS-guided percutaneous biopsy has shown feasibility in accessible subpleural lesions, enabling higher histopathologic performance without significantly increasing either imaging time or expenses compared with conventional US. The authors discuss the technique of and basic normal and pathologic findings at conventional lung US, followed by a more detailed discussion of lung CEUS applications, emphasizing specific aspects of pulmonary physiology, basic concepts in lung US enhancement, and the most commonly encountered enhancement patterns of different PLDs. Finally, they discuss the benefits of lung CEUS in planning and guidance of US-guided lung biopsy. ©RSNA, 2024 Supplemental material is available for this article.

Intraplaque neovascularization combined with plaque elasticity for predicting ipsilateral stroke in patients with asymptomatic mild carotid stenosis.

Intraplaque neovascularization (IPN) is a biomarker for vulnerable atherosclerotic plaques and can be effectively visualized via contrast-enhanced ultrasound (CEUS). Plaque elasticity is influenced by elements such as lipid core and fibrosis and can be quantitatively assessed on shear wave elastography (SWE). Studies combining the use of CEUS and SWE for the assessment of stroke risk are currently lacking. Our study thus aimed to determine the predictive value of IPN combined with plaque elasticity among patients with asymptomatic carotid plaque. Consecutive patients with mild carotid stenosis who underwent CEUS and SWE were retrospectively analyzed. IPN was graded according to the presence and location of microbubbles within the plaque, while plaque elasticity was measured in terms of mean shear wave velocity (SWV). All patients were followed up for 6 months to monitor the development of ischemic stroke. The predictive values of IPN and SWV, individually and in combination, were assessed. A total of 121 patients were included, of whom 95 (78.5%) were male. The mean age was 63.1±10.7 years. Both grade 2 IPN [hazard ratio (HR) =2.37, 95% confidence interval (CI): 1.58-9.65; P=0.039] and SWV (HR =0.43, 95% CI: 0.20-0.95; P=0.038) were independently associated with future ischemic stroke events. The combined model demonstrated a significantly better predictive performance (HR =3.243, 95% CI: 1.87-6.17; P=0.027). The combination of IPN and SWV demonstrated significantly better predictive value for the risk of stroke. Our combined model thereby has the potential to guide the clinical stratification and management of patients with asymptomatic mild carotid stenosis.

Exploring the Theranostic Applications and Prospects of Nanobubbles.

Anticancer medications as well as additional therapeutic compounds, have poor clinical effectiveness due to their diverse distribution, non-selectivity for malignant cells, and undesirable off-target side effects. As a result, ultrasound-based targeted delivery of therapeutic compounds carried in sophisticated nanocarriers has grown in favor of cancer therapy and control. Nanobubbles are nanoscale bubbles that exhibit unique physiochemical properties in both their inner core and outer shell. Manufacturing nanobubbles primarily aims to enhance therapeutic agents' bioavailability, stability, and targeted delivery. The small size of nanobubbles allows for their extravasation from blood vessels into surrounding tissues and site-specific release through ultrasound targeting. Ultrasound technology is widely utilized for therapy due to its speed, safety, and cost-effectiveness, and micro/nanobubbles, as ultrasound contrast agents, have numerous potential applications in disease treatment. Thus, combining ultrasound applications with NBs has recently demonstrated increased localization of anticancer molecules in tumor tissues with triggered release behavior. Consequently, an effective therapeutic concentration of drugs/genes is achieved in target tumor tissues with ultimately increased therapeutic efficacy and minimal side effects on other non-cancerous tissues. This paper provides a brief overview of the production processes for nanobubbles, along with their key characteristics and potential therapeutic uses.

The American College of Radiology contrast-enhanced ultrasound Liver Imaging Reporting and Data System and its modified version in diagnosing hepatocellular carcinoma via Sonazoid: a meta-analysis.

The American College of Radiology (ACR) developed the contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) for pure blood contrast agents, but Sonazoid was not included. Modifications to LI-RADS have been proposed for Sonazoid. The purpose of this meta-analysis was to identify and compare the diagnostic efficacy of the two LI-RADS algorithms of Sonazoid. We searched the PubMed, MEDLINE, Web of Science, Embase, and Cochrane Library databases from databases inception to August 31, 2023, to find original studies on the ACR LI-RADS and/or modified LI-RADS algorithm with Sonazoid used as the contrast agent in patients with high-risk hepatocellular carcinoma (HCC). A bivariate random-effects model was used. Data pooling, meta-regression, and sensitivity analysis were performed for meta-analysis. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool was used to assess the methodological quality, and the Deeks funnel plot asymmetry test was used to evaluate the publication bias. A meta-analysis of 10 studies with 1,611 observations was conducted. The pooled data for ACR LI-RADS category 5 (LR-5) and modified LR-5 were respectively as follows: pooled sensitivity, 0.70 [95% confidence interval (CI): 0.64-0.75] and 0.81 (95% CI: 0.76-0.86) (P<0.05); pooled specificity, 0.90 (95% CI: 0.82-0.94) and 0.87 (95% CI: 0.81-0.91) (P>0.05); and pooled area under the summary receiver operating characteristic curve, 0.84 and 0.91. The diagnostic performance of LI-RADS category M (LR-M) of the two algorithms was comparable. Study heterogeneity was observed. The results indicated that modified LR-5 algorithm demonstrated improved diagnostic sensitivity compared with the ACR LR-5 algorithm of Sonazoid, with differences observed between the different versions. Further research is needed to validate and explore the optimal diagnostic criteria for HCC using Sonazoid. Before the database search was conducted, this study was registered on PROSPERO (International Prospective Register of Systematic Reviews; CRD42023455220).

Dual-Drug Loaded Nanobubbles Combined with Sonodynamic and Chemotherapy for Hepatocellular Carcinoma Therapy.

Chemotherapy remains the primary therapeutic approach for advanced Hepatocellular Carcinoma (HCC). The therapeutic effect of chemotherapy is limited and the toxic side effects are serious. The aim of this study is to develop a nanobubble that is ultrasonically responsive to reduce the toxic side effects of direct chemotherapy. We developed curcumin/doxorubicin-cis-aconitic anhydride-polyethylene glycol nanobubble (C/DCNB) surface modified with acid-sensitive polyethylene glycol (PEG). And it is loaded with curcumin (CUR) and doxorubicin (DOX), as liposomes at the nanoscale for diagnosis and therapy of tumors. In this study, the acid-sensitive PEG on the surface layer of nanobubbles serves to stabilize them in the blood circulatory system and in normal tissues, while peeling off in the acidic tumor microenvironment (pH 6.8). C/DCNB can identify tumor sites through contrast-enhanced ultrasound (CEUS). And ultrasound-mediated nanobubbles promote permeability of the tumor vascular, thus improving the enhanced permeability and retention (EPR) effects in the tumor, leading to the accumulation of nanobubbles in the tumor. After endocytosis of nanobubbles, drugs are released and curcumin generates reactive oxygen species (ROS) under ultrasound conditions. CUR can enhance the sensitivity of tumor cells to DOX by inhibiting the expression of P-glycoprotein. In vitro and vivo experiments demonstrate that C/DCNB can facilitate contrast-enhanced ultrasound imaging while simultaneously delivering drugs, enabling both imaging and treatment. The combination of C/DCNB and ultrasound provides an effective strategy for improving the efficiency of HCC therapy and imaging.

Randomized Feasibility Study Evaluating Multiple FDA-approved Microbubbles for CEUS Lymphography.

Prior studies on contrast-enhanced ultrasound (CEUS) lymphography for preoperative mapping before lymphaticovenous anastomosis surgery in patients with extremity lymphedema have been limited to using only Lumason and Sonazoid as microbubble contrast agents. The purpose of this study was to determine the feasibility of using two other Food & Drug Administration-approved microbubble agents, Optison and Definity, for imaging lymphatic vessels in the upper extremities. Nine female adults with unilateral upper extremity lymphedema anticipating lymphaticovenous anastomosis surgery underwent CEUS lymphography of the unaffected upper extremity randomized to either Lumason, Definity, or Optison. Lymphatic vessels were visualized in all but one case when undilated Definity was used. In the eight upper extremities where lymphatic vessels were visualized, an average of eight intradermal injections of microbubbles were performed in the extremity. Lymphatic vessels could be identified in 57% (36 of 63) of the injections. The effective dilution for each of the microbubble agents is provided. This was the first successful demonstration of lymphatic vessel visualization using either Definity or Optison. Broadening the range of available microbubble agents for CEUS lymphography could improve accessibility to the procedure and provide potentially safer alternatives.

Comparison of Contrast-Enhanced Voiding Urosonography with Standard Fluoroscopic Voiding Cystography for the Diagnosis of Vesicoureteral Reflux: A single-Institute of Children

Abstract Contrast-enhanced voiding urosonography (ce-VUS) is widely used in Europe to diagnose vesicoureteric reflux (VUR) in children. It is highly sensitive and avoids exposure to ionizing radiation. We compared the sensitivity and specificity of ce-VUS to those of VCUG performed on patients in Saudi Arabia and the Middle East to emphasize the agreement between the two modalities in detecting VUR in children with urinary tract infections (UTIs). Aims: To evaluate the diagnostic performance of ce-VUS using a second-generation ultrasound contrast agent for diagnosing VUR and to compare its performance with that of the standard VCUG. Settings and Design: Twenty-eight consecutive children who underwent ce-VUS and VCUG from September to December 2023 were enrolled. Methods and Material: ce-VUS and VCUG were performed simultaneously by two operators using an intravesical infusion of a mixture of ultrasound contrast medium, iodinated contrast medium, and water. Three pediatric radiologists independently reviewed the ce-VUS and VCUG images and reported the presence and degree of VUR (grades I–V). Statistical Analysis Used: This prospective study involved the consecutive recruitment of pediatric patients with suspected VUR. 28 patients (14 boys and 14 girls; 14 years ± 1 month) met the selection criteria. Results: Twenty-three patients yielded similar positive and negative results of VUR on both left and right sides in VCUG and ce-VUS. Only five patients showed discordant results. The diagnostic sensitivities of VCUG and ce-vus for the left VUR were 90% and 91%, respectively, whereas those for the right VUR were both 100%. The specificities of VCUG and ce-vus for the right VUR were 94.44% and 94.74%, respectively, whereas those for the right VUR were both 100%. Conclusions: Considering that radiation exposure among infants and children should be minimized, ce-VUS can potentially replace VCUG as an alternative diagnostic modality for detecting VUR.

Using four-point subcutaneous injection of lymphatic contrast-enhanced ultrasound to diagnose lymphedema of lower extremity.

The diagnosis of lymphedema primarily relies on the clinical symptoms, signs, medical history and imaging. Objective lymphatic imaging helps improving the diagnosis of lymphedema. This study aimed to develop an effective imaging tool to diagnose lymphedema. This is a single-center retrospective study. From September 2022 to November 2023, we enrolled thirty-two patients, involving 40 lower extremities who underwent lymphatic contrast-enhanced ultrasound (CEUS) following a subcutaneous injection of contrast agent at four points in the First Affiliated Hospital of Sun Yat-sen University. Cohen's kappa value, sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. Lymphoscintigraphy was the reference standard. Successful lymphatic-CEUS detection was defined as the situation that lymphatic drainage of medial or lateral lower limbs were observed. The successful detection rate was 100% (40 of 40). The diagnosis of lymphedema was based on the presence of either medial or lateral lymphatic obstructions, or subcutaneous lymphatic enhancement. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for diagnosing lymphedema by lymphatic-CEUS were as follows: 91.2% (31 of 34), 100% (6 of 6), 100% (31 of 31), 66.7% (6 of 9) and 92.5% (37 of 40), respectively. The Cohen's Kappa value was 0.756. The area under the receiver operating characteristic curve (AUC) for the subcutaneous injection of four-point lymphatic-CEUS was 0.956. This study put forward a novel four-point lymphatic-CEUS method to detect the functions of the lymphatics of lower extremities and established a lymphatic-CEUS standard for diagnosing lymphedema of lower extremities. Four-point lymphatic-CEUS is a considerable option for diagnosing lymphedema of lower extremities.