Ultrasound contrast agents (UCAs) play an important role in diagnosis and the imaging-guided treatment of liver tumor in clinical settings. However, most commercially available UCAs are micro-sized and fabricated through a chemical synthesis route. Here, we developed a new class of biosynthesized nanoscale contrast agent (PEG-GVs) and comprehensively compared its physicochemical characteristics and imaging performance with commercial Sonovue and Sonazoid. Our results revealed PEG-GVs may produce more stable and durable contrast signals, contributing to their penetration beyond blood vessels and long-time retention in liver. Interestingly, we found that PEG-GVs did not exhibit a continuously enhanced accumulation in the liver tumor due to the EPR effect, but displayed a rapid regression. The long-time retention of PEG-GVs in normal liver tissue and rapid regression from liver tumor lead to distinct display of liver tumor boundaries, enabling the early diagnosis of small liver metastases and presenting advantages in guiding radiofrequency ablation of liver tumor. Moreover, we have also verified that PEG-GVs exhibit excellent imaging performance and biosafety in macaques. Our study provides new insights into the roles of PEG-GVs in liver tumor diagnosis and ablation guidance.

Monodisperse phospholipid-coated microbubbles, with a size and resonance frequency tuned to the ultrasound driving frequency, have strong potential to enhance sensitivity, efficiency, and control in emerging diagnostic and therapeutic applications involving bubbles and ultrasound. A key requirement is that they retain their gas volume and shell material during physiologic pressure changes and withstand the overpressure during intravenous injection. The shell typically comprises a mixture of a phospholipid (e.g., DSPC) mixed with a PEGylated phospholipid (e.g., DPPE-PEG5000). We hypothesize that (i) lipid-coated microbubbles destabilize when shell buckling occurs under pressurization, (ii) the overpressure at which buckling occurs (buckling pressure) is linked to the molar fraction of PEGylated lipid in the shell, and (iii) PEGylated lipid can be selectively expelled from the shell by fluidizing it at elevated temperatures.

The buckling pressure was measured using ultrasound attenuation spectroscopy while the ambient pressure was varied. When the ambient pressure increased, the microbubble resonance frequency dropped sharply due to shell buckling and the associated loss of elasticity. The buckling pressure Pb was obtained for monodisperse microbubbles formed by microfluidic flow-focusing, with DPPE-PEG5000 mixed with DSPC at molar fractions from 1.5% to 10%. Additionally, Pb was quantified for microbubbles containing 10 mol% PEG after heating at temperatures ranging from 40∘C to 70∘C. The molar PEG content of the microbubbles was analyzed using high-performance liquid chromatography.

Quasi-static compression of a microbubble above its buckling pressure leads to its destabilization. Lowering the PEG molar fraction from 10 to 1.5% increased the buckling pressure from 3 kPa to 27 kPa. Similarly, heating the 10 mol% bubble suspension at 60∘C for one hour raised the buckling pressure by 20 kPa, due to the selective loss of PEGylated lipid from the shell, without affecting the monodispersity of the bubbles. The higher buckling pressure significantly improved microbubble stability, allowing them to withstand pressurization cycles of up to 45 kPa, nearly three times the systolic blood pressure in vivo.

This study aimed to evaluate the contrast-enhanced ultrasound with Sonazoid (Sonazoid-CEUS) features of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD).

In this retrospective study, patients who underwent surgical resection and were histopathologically diagnosed with NAFLD or cirrhosis-related HCC were included. All patients received Sonazoid-CEUS examinations within 1 week prior to hepatic surgery. The enhancement patterns of HCC lesions were evaluated and compared between the two groups according to the current World Federation for Ultrasound in Medicine and Biology guidelines. Multivariate logistic regression analysis was used to assess the correlations between Sonazoid-CEUS enhancement patterns and clinicopathologic characteristics.

From March 2022 to April 2023, a total of 151 patients with HCC were included, comprising 72 with NAFLD-related HCC and 79 with hepatitis B virus (HBV) cirrhosis-related HCC. On Sonazoid-CEUS, more than half of the NAFLD-related HCCs exhibited relatively early and mild washout within 60 seconds (54.2%, 39/72), whereas most HBV cirrhosis-related HCCs displayed washout between 60 and 120 seconds (46.8%, 37/79) or after 120 seconds (39.2%, 31/79) (P<0.001). In the patients with NAFLD-related HCC, multivariate analysis revealed that international normalized ratio (odds ratio [OR], 0.002; 95% confidence interval [CI], 0.000 to 0.899; P=0.046) and poor tumor differentiation (OR, 21.930; 95% CI, 1.960 to 245.319; P=0.012) were significantly associated with washout occurring within 60 seconds.

Characteristic Sonazoid-CEUS features are useful for diagnosing HCC in patients with NAFLD.

Hepatocellular carcinoma (HCC) is the most common form of hepatic malignancy, with high mortality rates recorded globally. Early detection through clinical biomarkers, medical imaging and histological assessment followed by rapid intervention are integral for positive patient outcomes. Although contrast-enhanced computed tomography scans and magnetic resonance imaging are recognised as the reference standard for the diagnosis and staging of HCC in international guidelines, ultrasound (US) examination is recommended as a screening tool for patients at risk. Contrast-enhanced US (CEUS) elevates the standard of an US examination using US contrast agents (UCAs), capable of diagnosing focal liver lesions with high efficacy. Most UCAs are purely intravascular, offering clinicians a dynamic representation of a lesions' arterial phase vascular kinetics, which is seldom seen in such detail during computed tomography or magnetic resonance imaging assessments. Despite its benefits, there is incongruity between international societies on the role of CEUS in the HCC clinical pathway. The transient nature of pure blood-pool agents is suggested to be insufficient to justify CEUS as a primary modality due to the inability to consistently perform whole liver imaging, alongside disputes regarding its capabilities to differentiate HCC from intrahepatic cholangiocarcinoma. A sinusoidal phase UCA affords clinicians the opportunity to perform whole liver imaging through Kupffer cell uptake in addition to visualising lesion vascular kinetics in the arterial and portal venous phases. Therefore, the purpose of this review was to examine the role of CEUS in the HCC clinical pathway in its current practice and observe how a Kupffer cell sinusoidal phase UCA may supplement contemporary diagnostic techniques through a multi-modality, multi-agent approach.

The aim of this paper is to highlight the combined role of ultrasound elastography and contrast-enhanced ultrasound in terms of diagnosis, staging, and follow-up of the post-treatment response. Contrast-enhanced ultrasound (CEUS) and ultrasound elastography are natural extensions of conventional USs that have created new opportunities, facilitating the implementation of multiparametric ultrasounds in the characterization of thyroid nodules, in risk stratification, and in the selection of nodules that request Fine Needle Aspiration (FNA), management, and follow-up of the nodules with indeterminate cytology, evaluation of pre-operative prognostic features, and treatment efficiency.

We aimed to evaluate the role of Contrast-enhanced intraoperative ultrasound (CE-IOUS) with perfluorobutane microbubbles (Sonazoid) in improving the prognosis of patients with unresectable colorectal cancer liver metastases (CRLM).

A total of 130 Patients with unresectable CRLM who underwent curative hepatic resection at our institute were retrospectively analyzed. Of these 130 enrolled patients, 67 underwent intraoperative ultrasound alone (IOUS group); 63 underwent additional CE-IOUS and IOUS (CE-IOUS group). Normalized inverse probability treatment weighting (IPTW) was employed to balance baseline characteristics between groups. Hepatic recurrence-free survival (HRFS) and overall survival (OS) were compared.

The treatment strategy was altered in 25 patients (25/63, 39.9%) due to the additional use of CE-IOUS. After applying IPTW, the CE-IOUS group exhibited a significantly lower rate of hepatic recurrence (hazard ratio [HR], 0.55; 95% confidence interval [CI] 0.32-0.95; P = 0.032). Subgroup analysis showed that CE-IOUS provided a significant benefit over IOUS in patients with bilobar liver metastases (P = 0.007), or with a number of live tumors < 3 (P = 0.021), or without DLM (P = 0.018), or with extrahepatic metastasis (P = 0.034), or with a minimum of 6 cycles of systemic therapy (P = 0.03).

CE-IOUS is necessary for unresectable CRLM after preoperative chemotherapy, as it enhances detection accuracy and improves the prognosis of unresectable CRLM patients.

This study aimed to explore whether cavitation generated by ultrasound-stimulated microbubbles (USMB) can enhance the therapeutic efficacy of colchicine and diminish its gastrointestinal side effects in rats with acute gouty arthritis (AGA).

The rat AGA model was established by injection of Monosodium urate (MSU) crystals. The rats were randomly divided into 6 groups (A: control group, B: model control group, C: cavitation group, D: high dose colchicine group, E: cavitation + low dose colchicine group, F: cavitation + high dose colchicine group) according to whether they were given cavitation and different doses of colchicine. The effect of cavitation on blood perfusion was analyzed by comparing contrast-enhanced ultrasound (CEUS) and the area under the curve (AUC) of CEUS with the ankle joint of right hind limb. The AGA symptoms were assessed by referring to the degree of ankle joint swelling within 24 h and the gait score. The infiltration of neutrophils was determined using the hematoxylin-eosin (HE) staining method. For the evaluation of vascular inflammation and dilation, plasma interleukin-1β (IL-1β) and endothelial nitric oxide synthase (eNOS) served as the key indicators. Besides, the severity of gastrointestinal adverse reactions is determined by analyzing the gastrointestinal reaction scores.

When compared with groups A, B, and D, the AUC was markedly higher in groups C, E, and F (all P < 0.05). In groups E and F, the degree of ankle swelling, gait scores, and the level of plasma IL-1β in AGA rats were lower, while the concentration of plasma eNOS was higher compared to the group D (all P < 0.05). HE staining findings demonstrated that the integration of cavitation and colchicine played a positive role in reducing neutrophil infiltration in the ankle joint synovium and mitigating the gastrointestinal reaction score in AGA rats. In contrast to groups D, E, and F that were given colchicine, group E had a substantially lower gastrointestinal reaction score, with statistically significant differences observed in pairwise comparisons (all P < 0.05).

In rats with AGA, cavitation generated by USMB exerted a remarkable effect on augmenting the blood perfusion of the ankle joint. This, in turn, not only amplified the anti-gout efficacy of colchicine but also reduced the dosage of colchicine. Concurrently, it effectively mitigated the associated gastrointestinal side effects.

To investigate Sonazoid contrast-enhanced ultrasound (CEUS) features of intrahepatic cholangiocarcinoma (ICC) based on liver backgrounds and tumor sizes.

A retrospective analysis was conducted on patients with histopathologically diagnosed ICC at two centers. Patients underwent Sonazoid CEUS examination at a dose of 0.0165 mL/kg before surgery or biopsy. Continuous imaging was recorded for the first 70 s, followed by intermittent scanning every 15-20 s for 5 min, with a Kupffer phase captured after an 8-min delay. Patients were categorized by liver backgrounds and tumor sizes. Two ultrasound experts evaluated the enhancement patterns of ICCAs during the arterial, portal, delayed, and Kupffer phases according to current guidelines.

From February 2019 to July 2022, a total of 85 ICC lesions were included. ICCs were categorized into normal liver (n = 24), chronic liver disease with fibrosis (n = 40), and cirrhosis (n = 21) groups based on different liver backgrounds, and into groups measuring ≤30 mm (n = 22), 31-50 mm (n = 32), and >50 mm (n = 31) based on tumor sizes. Most ICCs in liver fibrosis or liver cirrhosis tended to show non-rim enhancement in arterial phase (p = 0.022) and relatively later washout (39.9 ± 8.5 s vs. 39.7 ± 13.0 s) compared with those on a normal liver background (28.1 ± 5.6 s) (p < 0.001). Based on CEUS Liver Imaging Reporting and Data System, the diagnostic performance of LR-M criteria showed an accuracy of 100% in our high-risk populations. ICCs of ≤30 mm more commonly showed non-rim enhancement in arterial phase (p = 0.003) and relatively later washout (41.3 ± 12.5 s) compared with larger ICCs (p = 0.046). In the Kupffer phase, all ICCs showed marked washout with sharp margin delineation on Sonazoid CEUS, regardless of liver backgrounds and tumor sizes.

Sonazoid CEUS features of ICCs differ according to different liver backgrounds and tumor sizes. Arterial phase non-rim enhancement and relatively later washout were more commonly observed in ICCs on liver fibrosis or cirrhosis background or smaller ICCs (≤30 mm).

Sonazoid is a new ultrasound contrast agent with unique Kupffer phase imaging advantages and high mechanical index stability. This paper introduces the basic theories and advantages of Sonazoid ultrasound. Then, the application and latest advances of Sonazoid in the diagnosis and treatment of liver diseases are reviewed in detail. In addition, the advantages and disadvantages of Sonazoid ultrasound and its future directions are discussed. Sonazoid is expected to become an important tool for clinical ultrasound diagnosis and treatment.

We hypothesized that contrast-enhanced ultrasound (CEUS) using a microbubble technique to quantify microvascular changes and Nakagami imaging for tissue characterization would provide a new approach for diagnosing and differentiating benign and malignant choroidal lesions.

Five patients with choroidal melanoma (CM) and five patients with choroidal hemangioma (CH) were selected. Definity®, which contains perflutren microbubbles, was administered as a slow IV bolus (1 ml). CEUS was performed for 1 min postinjection of the contrast agent with ultrasound radiofrequency data acquired from 10 s to 60 s. The contrast value was calculated for the whole tumor region. A gradient magnitude method was used for each postcontrast frames with 1-second interval, and the time-averaged value in pixel intensity gradient of postinjection frames was estimated and reported. Based on the Nakagami statistical distribution model, two Nakagami parameters, m and Ω, where m (shape parameter), representing tissue heterogeneity, and Ω (scale parameter), representing the average energy of backscattered signals, were studied.

CEUS analysis showed that the time-averaged estimated contrast was significantly higher (p = 0.008) for CH compared to CM. Furthermore, the time-averaged contrast within the normal choroidal region was significantly higher than the choroidal tumor region for both CH and CM (p = 0.001 for CH cases and p < 0.0001 for CM cases). Nakagami analysis showed that the m estimates were significantly higher (p = 0.032) for CH (m = 0.61) than for CM (m = 0.28), indicating that CH is a more heterogeneous tumor than CM. The Ω estimates were significantly higher (p = 0.0019) for CH (Ω = 0.15) compared to CM (Ω = 0.03). These results may be due to the more vascular structures in CH compared to CM.

Quantitative intensity-based perfusion analysis using CEUS and backscattering tissue analysis using Nakagami imaging can provide valuable insights to differentiate benign and malignant choroidal lesions.

We have developed a non-invasive predictive nomogram model that combines image features from Sonazoid contrast-enhanced ultrasound (SCEUS) and Sound touch elastography (STE) with clinical features for accurate differentiation of malignant from benign focal liver lesions (FLLs). This study ultimately encompassed 262 patients with FLLs from the First Hospital of Shanxi Medical University, covering the period from March 2020 to April 2023, and divided them into training set (n = 183) and test set (n = 79). Logistic regression analysis was used to identify independent indicators and develop a predictive model based on image features from SCEUS, STE, and clinical features. The area under the receiver operating characteristic (AUC) curve was determined to estimate the diagnostic performance of the nomogram with CEUS LI-RADS, and STE values. The C-index, calibration curve, and decision curve analysis (DCA) were further used for validation. Multivariate and LASSO logistic regression analyses identified that age, ALT, arterial phase hyperenhancement (APHE), enhancement level in the Kupffer phase, and Emean by STE were valuable predictors to distinguish malignant from benign lesions. The nomogram achieved AUCs of 0.988 and 0.978 in the training and test sets, respectively, outperforming the CEUS LI-RADS (0.754 and 0.824) and STE (0.909 and 0.923) alone. The C-index and calibration curve demonstrated that the nomogram offers high diagnostic accuracy with predicted values consistent with actual values. DCA indicated that the nomogram could increase the net benefit for patients. The predictive nomogram innovatively combining SCEUS, STE, and clinical features can effectively improve the diagnostic performance for focal liver lesions, which may help with individualized diagnosis and treatment in clinical practice.

Accurate diagnosis of lymph node (LN) metastasis is vital for prognosis and treatment in patients with breast cancer. Imaging 1modalities such as ultrasound (US), MRI, CT, and 18F-FDG PET/CT are used for preoperative assessment. While conventional US is commonly recommended due to its resolution and sensitivity, it has limitations such as operator subjectivity and difficulty detecting small metastases. This review shows the microanatomy of axillary LNs to enhance accurate diagnosis and the characteristics of contrast-enhanced US (CE-US), which utilizes intravascular microbubble contrast agents, making it ideal for vascular imaging. A significant focus of this review is on distinguishing between two types of CE-US techniques for axillary LN evaluation: perfusion CE-US and lymphatic CE-US. Perfusion CE-US is used to assess LN metastasis via transvenous contrast agent administration, while lymphatic CE-US is used to identify sentinel LNs and diagnose LN metastasis through percutaneous contrast agent administration. This review also highlights the need for future research to clarify the distinction between studies involving "apparently enlarged LNs" and "clinical node-negative" cases in perfusion CE-US research. Such research standardization is essential to ensure accurate diagnostic performance in various clinical studies. Future studies should aim to standardize CE-US methods for improved LN metastasis diagnosis, not only in breast cancer but also across various malignancies.

Due to the intrinsic non-invasive nature, cost-effectiveness, high safety, and real-time capabilities, besides diagnostic imaging, ultrasound as a typical mechanical wave has been extensively developed as a physical tool for versatile biomedical applications. Especially, the prosperity of nanotechnology and nanomedicine invigorates the landscape of ultrasound-based medicine. The unprecedented surge in research enthusiasm and dedicated efforts have led to a mass of multifunctional micro-/nanosystems being applied in ultrasound biomedicine, facilitating precise diagnosis, effective treatment, and personalized theranostics. The effective deployment of versatile ultrasound-based micro-/nanosystems in biomedical applications is rooted in a profound understanding of the relationship among composition, structure, property, bioactivity, application, and performance. In this comprehensive review, we elaborate on the general principles regarding the design, synthesis, functionalization, and optimization of ultrasound-based micro-/nanosystems for abundant biomedical applications. In particular, recent advancements in ultrasound-based micro-/nanosystems for diagnostic imaging are meticulously summarized. Furthermore, we systematically elucidate state-of-the-art studies concerning recent progress in ultrasound-based micro-/nanosystems for therapeutic applications targeting various pathological abnormalities including cancer, bacterial infection, brain diseases, cardiovascular diseases, and metabolic diseases. Finally, we conclude and provide an outlook on this research field with an in-depth discussion of the challenges faced and future developments for further extensive clinical translation and application.

Focal liver lesions (FLLs) are a common form of liver disease, and identifying accurate pathological types is required to guide treatment and evaluate prognosis.

To compare and analyze the application effect of contrast-enhanced ultrasound (CEUS) and conventional ultrasound (US) in the clinical diagnosis of focal liver lesions.

A retrospective analysis was performed on 682 patients with space-occupying liver lesions admitted to our hospital between December 2015 and August 2021. Of these, 280 underwent CEUS-guided biopsies and 402 underwent conventional US biopsies, with the results of each biopsy subsequently compared between the two groups. The success rate and accuracy of the biopsies and their relationship with different pathological features were also analyzed.

The success rate, sensitivity, diagnostic accuracy, positive predictive value, and negative predictive value of the CEUS group were significantly higher than those of the US group (P < 0.05). Lesion size accuracy in the CEUS group was significantly higher than that in the US group (89.29% vs. 40.55%; P < 0.05). Lesion type accuracy in the CEUS group was significantly higher than that in the US group (86.49% vs. 43.59%), and the difference between the two groups was statistically significant (P < 0.05). The logistic regression analysis indicated that malignant lesions, lesions ≥5 cm, and lesions ≤1 cm were independent factors affecting the success rate of the puncture procedure (P < 0.05).

The sensitivity, specificity, and diagnostic accuracy of lesion size and type in the CEUS group were higher than those in the US group.

Purpose  This study aimed to compare contrast-enhanced ultrasound (CEUS) features of hepatic angiomyolipoma (HAML) and challenging cases of HCC, mainly those with no hepatitis infection but also with a low level of AFP (non-viral AFP- HCC). Materials and Methods  The study included pathologically confirmed HAMLs and non-viral AFP- HCCs undergoing CEUS from 2012 to 2023. Sonovue (SV) CEUS and Sonazoid (SZ) CEUS characteristics of the two groups were compared. Results  The study included 50 HAMLs (24% on SZ-CEUS) and 88 non-viral AFP- HCCs (21.6% on SZ-CEUS). The CEUS characteristics on SZ-CEUS were similar to those on SV-CEUS to a certain extent. HAMLs more frequently displayed no washout and partial washout with partial no washout, so-called PWNW, in the late phase and post-vascular phase, whereas HCCs more commonly exhibited mild washout. In the post-vascular phase, all non-viral AFP- HCCs exhibited washout, thereby facilitating differentiation from no-washoutHAMLs, superior to SV-CEUS, where some non-viral AFP- HCCs still exhibited no washout in late phase that could not be distinguished from HAMLs. It is noteworthy that PWNW was exclusively found in nodules exhibiting hyper- and hypoechoic separation of the nodules, and hyper- and hypoechoic separation of HAMLs in the post-vascular phase on SZ-CEUS demonstrated PWNW more frequently compared to the late phase, which can potentially help distinguish nodules with hyper- and hypoechoic separation as either HAML or non-viral AFP- HCC. Conclusion: This study highlighted the usefulness of SV- and SZ-CEUS for distinguishing HAML and non-viral AFP- HCC and filled in existing gaps regarding the SZ-CEUS features of HAML.

The aim of this study was to develop and prospectively validate a prediction model for superficial lymphadenopathy differentiation using Sonazoid contrast-enhanced ultrasound (CEUS) combined with ultrasound (US) and clinical data.

The training cohort comprised 260 retrospectively enrolled patients with 260 pathological lymph nodes imaged between January and December 2020. Two clinical US-CEUS models were created using multivariable logistic regression analysis and compared using receiver operating characteristic curve analysis: Model 1 included clinical and US characteristics; Model 2 included all confirmed predictors, including CEUS characteristics. Feature contributions were evaluated using the SHapley Additive exPlanations (SHAP) algorithm. Data from 172 patients were prospectively collected between January and May 2021 for model validation.

Age, tumor history, long-axis diameter of lymph node, blood flow distribution, echogenic hilus, and the mean postvascular phase intensity (MPI) were identified as independent predictors for malignant lymphadenopathy. The area under the curve (AUC), sensitivity, specificity, and accuracy of MPI alone was 0.858 (95% confidence interval [CI], 0.817-0.891), 86.47%, 74.55%, and 81.2%, respectively. Model 2 had an AUC of 0.919 (95% CI, 0.879-0.949) and good calibration in training and validation cohorts. The incorporation of MPI significantly enhanced diagnostic capability (p < 0.0001 and p = 0.002 for training and validation cohorts, respectively). Decision curve analysis indicated Model 2 as the superior diagnostic tool. SHAP analysis highlighted MPI as the most pivotal feature in the diagnostic process.

The employment of our straightforward prediction model has the potential to enhance clinical decision-making and mitigate the need for unwarranted biopsies.

To assess whether the diagnostic performance of Sonazoid contrast-enhanced ultrasound (SZUS) is non-inferior to that of SonoVue contrast-enhanced ultrasound (SVUS) in diagnosing hepatocellular carcinoma (HCC) in individuals with high risk.

This prospective study was conducted from October 2020 to May 2022 and included participants with a high risk of HCC who underwent SZUS and SVUS. All lesions were confirmed by clinical or pathological diagnosis. Each nodule was classified according to the Contrast-Enhanced Ultrasound Liver Imaging Reporting and Data System version 2017 (CEUS LI-RADS v2017) for SVUS and SZUS and the modified CEUS LI-RADS (using Kupffer phase defect instead of late and mild washout) for SZUS. The diagnostic performance of both two modalities for all observations was compared. Analysis of the vascular phase and Kupffer phase imaging characteristics of CEUS was performed.

One hundred and fifteen focal liver lesions from 113 patients (94 HCCs, 12 non-HCC malignancies, and 9 benign lesions) were analysed. According to CEUS LI-RADS (v2017), SVUS and SZUS showed similar sensitivity (71.3% vs. 72.3%) and specificity (85.7% vs. 81.0%) in HCC diagnosis. However, the modified CEUS LI-RADS did not significantly improve the diagnostic efficacy of Sonazoid compared to CEUS LI-RADS v2017, having equivalent sensitivity (73.4% vs. 72.3%) and specificity (81.0% vs. 81.0%). The agreement between SVUS and SZUS for all observations was 0.610 (95% CI 0.475, 0.745), while for HCCs it was 0.452 (95% CI 0.257, 0.647).

Using LI-RADS v2017, SZUS and SVUS showed non-inferior efficacy in evaluating HCC lesions. In addition, adding Kupffer phase defects to SZUS does not notably improve its diagnostic efficacy.

Transvaginal 4-D hysterosalpingo-contrast sonography (TV 4-D HyCoSy) plays an important role in the detection and diagnosis of clinical female infertility. The purposes of this study were to analyze the influencing factors of TV 4murD HyCoSy complicated with contrast agent reflux and to provide evidence for clinical diagnosis and treatment. Female patients diagnosed as infertility by transvaginal hysterosalpingography from January 2021 to December 2022 were included. The characteristics of patients with and without contrast agent reflux were evaluated. Pearson correlation and logistic regression were conducted to analyze the related factors affecting the occurrence of contrast reflux. A total of 416 patients undergoing TV 4-D HyCoSy were included, and the incidence of contrast agent reflux in patients undergoing TV 4-D HyCoSy was 38.94%. Pearson correlation analysis results indicated that history of uterine cavity operation ( r = 0.556), adenomyosis of uterus ( r = 0.584), examination on less than 5 days after menstruation ( r = 0.602), endometrial thickness ( r = 0.566), and endometrial polyps ( r = 0.575) are all correlated with contrast agent reflux in patients undergoing 4-D HyCoSy (all P < 0.05). Logistic regression analysis showed that history of uterine cavity operation (odds ratio [OR], 1.109; 95% confidence interval [CI], 1.012-1.872), adenomyosis of uterus (OR, 2.026; 95% CI, 1.864-2.425), examination on less than 5 days after menstruation (OR, 2.465; 95% CI, 2.118-2.851), endometrial thickness less than 6 mm (OR, 2.866; 95% CI, 2.095-2.957), and endometrial polyps (OR, 1.587; 95% CI, 1.137-1.744) were the influencing factors of contrast agent reflux in patients undergoing (all P < 0.05). The incidence of contrast agent reflux in TV 4-D HyCoSy is high, and there are many influencing factors. Clinical medical workers should take early measures based on these influencing factors to reduce the contrast agent reflux.

Sonochemotherapy, which uses microbubble (MB)-assisted ultrasound (US) to deliver chemotherapeutic agents, has the potential to enhance tumour chemotherapy. The combination of US and MB has been demonstrated to prolong the survival of patients with pancreatic cancer. This phase 2 clinical trial aimed to determine the clinical efficacy and safety of sonochemotherapy for inoperable pancreatic ductal adenocarcinoma by using US and MB.

Eighty-two patients with stage III or IV pancreatic cancer were recruited from July 2018 to March 2021 and followed up until September 2022. US treatment was performed with a modified diagnostic US scanner for 30 min after chemotherapeutic infusion. The primary endpoint was overall survival (OS), and the secondary endpoints were Eastern Cooperative Oncology Group (ECOG) status < 2, progression-free survival (PFS), disease control rate (DCR), and adverse events.

Seventy-eight patients were randomly allocated (40 to chemotherapy and 38 to sonochemotherapy). The median OS was longer with sonochemotherapy than with chemotherapy (9.10 vs. 6.10 months; p = 0.037). The median PFS with sonochemotherapy was 5.50 months, compared with 3.50 months (p = 0.080) for chemotherapy. The time of ECOG status < 2 was longer with sonochemotherapy (7.20 months) than with chemotherapy (5.00 months; p = 0.029). The DCR was 73.68% for sonochemotherapy compared with 42.50% for the control (p = 0.005). The incidence of overall adverse events was balanced between the two groups.

The use of sonochemotherapy can extend the survival and well-being time of stage III or IV pancreatic cancer patients without any increase in serious adverse events.

ChineseClinicalTrials.gov ChiCTR2100044721 CLINICAL RELEVANCE STATEMENT: This multicentre, randomised, controlled trial has proven that sonochemotherapy, namely, the combination of diagnostic ultrasound, microbubbles, and chemotherapy, could extend the overall survival of patients with end-stage pancreatic ductal adenocarcinoma from 6.10 to 9.10 months without increasing any serious adverse events.

• This is the first multicentre, randomised, controlled trial of sonochemotherapy for clinical pancreatic cancer treatment using ultrasound and a commercial ultrasound contrast agent. • Sonochemotherapy extended the median overall survival from 6.10 (chemotherapy alone) to 9.10 months. • The disease control rate increased from 42.50% with chemotherapy to 73.68% with sonochemotherapy.

To compare contrast-enhanced ultrasound (CEUS) with microbubbles containing sulfur hexafluoride (SHF) and perfluorobutane (PFB) for the detection of colorectal liver metastasis (CRLM).

In this prospective study, conducted from September to November 2021, patients with colorectal cancer were consecutively recruited and underwent same-day ultrasound, SHF-CEUS, and PFB-CEUS. The reference standard was contrast-enhanced MRI and follow-up imaging. The size, depth, echogenicity, and calcification of each focal liver lesion were recorded. The number and conspicuity of CRLMs, based on washout appearance during the late phase (LP) (> 120 s)/Kupffer phase (KP), were evaluated offsite by two blinded readers.

Overall, 230 lesions (CRLMs, n = 219; benign lesions, n = 11) in 78 patients were evaluated. Lesion conspicuity (p = 0.344) and accuracy in the detection of CRLM were comparable for SHF- and PFB-CEUS (0.877 for SHF vs. 0.770 for PFB, p = 0.087). More CRLMs ≥ 10 mm were identified by LP contrast washout in SHF-CEUS than in KP PFB-CEUS (p < 0.001). More CRLMs < 10 mm were identified by KP washout in PFB-CEUS than in LP SHF-CEUS (p < 0.001). Conspicuity was better on PFB-CEUS than on SHF-CEUS (p = 0.027). In hyperechoic lesions, lesions located deeper than 80 mm, and calcified lesions, CRLM conspicuity on PFB-CEUS was inferior to that on SHF-CEUS (p < 0.05).

The overall accuracy of detection and conspicuity of washout in CRLMs were comparable between SHF and PFB-CEUS. PFB-CEUS has the advantage of identifying washout in small CRLMs. However, larger, hyperechogenic, deep-seated, or calcified lesions were better identified using SHF-CEUS.

Accuracy of detection and conspicuity of washout in CRLMs were comparable between SHF- and PFB-CEUS. PFB-CEUS has the advantage in detecting small CRLMs, whereas SHF-CEUS is better for detecting larger, hyperechogenic, deep-seated, or calcified lesions.

Contrast-enhanced ultrasound with sulfur hexafluoride in the late phase and perfluorobutane microbubbles in the Kupffer phase were comparable in terms of accuracy in the detection and conspicuity of colorectal liver metastases. Small colorectal liver metastases (< 10 mm) were more often identified in the Kupffer phase contrast-enhanced ultrasound imaging when using perfluorobutane microbubbles. Larger, hyperechogenic, deep-seated, or calcified lesions were better identified in the late phase contrast-enhanced ultrasound imaging (> 120 s) when using sulfur hexafluoride microbubbles.

No studies have been retrieved comparing perfluorobutane with sulfur hexafluoride for microwave ablation (MWA) in small hepatocellular carcinoma(sHCC).

To retrospective investigate the value of perfluorobutane ultrasonography contrast agent in ultrasonography (US)-guided MWA of sHCC.

We conducted a retrospective clinical controlled study about US-guided percutaneous MWA in patients with sHCC, and in patients undergoing intra-operative treatment with perfluorobutane or sulfur hexafluoride. In both groups, a contrast agent was injected to clear the tumor and then a needle was inserted. A 5-point needle prick difficulty score was developed to compare needle prick difficulty in the two groups of cases.

A total of 67 patients were included: 25 patients in group perfluorobutane, aged 41-82 (60.64±9.46), tumor size 1.1-2.8 (1.78±0.45) cm. 42 patients in group sulfur hexafluoride, aged 38-78 (62.26±9.27), with tumor size of 1.1-3.0 (1.89±0.49) cm. There was no significant difference in age or tumor size in both groups (P > 0.05). Puncture difficulty score (5-point): 2.0-2.7 (2.28±0.29) in group perfluorobutane, and 2.0-4.7 (2.95±0.85) in group sulfur hexafluoride, and the difference between the two groups was statistically significant (P < 0.05). Enhanced imaging results within 3 months after surgery: complete ablation rate was 100% (25/25) in the group perfluorobutane, 95.2% (40/42 in the group sulfur hexafluoride), with no significant difference between the two groups (P > 0.05).

Perfluorobutane kupffer phase can make the operator accurately deploy the ablation needle and reduce the difficulty of operation.

The aim of the work described here was to evaluate the impact of hepatocellular carcinoma (HCC) tumor size on Sonazoid contrast-enhanced ultrasound (CEUS) enhancement features, especially in tumors with diameters ≤30 mm and <10 mm.

In this retrospective study, we included patients with histopathologically confirmed HCC lesions and divided them into three groups on the basis of tumor size. All patients underwent Sonazoid-enhanced CEUS examinations before surgery. B-mode ultrasound (BMUS) features and CEUS enhancement patterns were evaluated according to current World Federation for Ultrasound in Medicine and Biology Guidelines criteria. The χ2- and Student t-tests were used to compare differences between groups.

We included 132 patients with histopathologically confirmed HCC lesions from November 2020 to September 2022. On the basis of tumor size, patients were divided into group 1 (<10 mm, n = 5), group 2 (10-30 mm, n = 54) and group 3 (>30 mm, n = 73). On BMUS, most HCCs appeared heterogeneous but predominantly hypo-echoic (61.4%, 81/132) with ill-defined margins and irregular shapes. Meanwhile, iso-echoic features were more common in small HCCs ≤30 mm (15.3%, 9/59), but a mixed hyper- and hypo-echoic appearance was more common in HCCs >30 mm (17.8%, 13/73) (p = 0.003). On Sonazoid-enhanced CEUS, all HCCs presented arterial phase hyperenhancement (APHE) (100.0%, 132/132). Most HCCs >30 mm exhibited heterogeneous hyperenhancement (86.3%, 63/73), whereas nearly one-third of small HCCs ≤30 mm exhibited homogeneous hyperenhancement (35.6%, 21/59) (p = 0.003). In the portal venous phase, there was a significantly higher proportion of washout in HCCs >30 mm (84.9%, 62/73) than in small HCCs ≤30 mm (64.4%, 38/59) (p = 0.006). During the Kupffer phase, 11 additional hypo-enhanced lesions (mean size: 14.1 ± 4.1 mm, iso-echoic on BMUS), which were also suspected to be HCC lesions, were detected in 5 patients with small HCCs ≤30 mm and 4 patients with HCCs >30 mm. All 5 cases of HCCs <10 mm exhibited APHE and late washout (>60 s). The majority (3/5, 60%) exhibited washout in the portal venous phase (70, 74 and 75 s), one case did so in the late phase (125 s) and another in the Kupffer phase (420 s).

Tumor size had a significant impact on the washout features of HCC lesions on Sonazoid-enhanced CEUS. Small HCC lesions ≤30 mm had a higher proportion of relatively late washout in comparison to larger lesions. Sonazoid-enhanced CEUS might be helpful in the detection and characterization of HCC lesions <10 mm.

Colorectal cancer (CRC) is a prevalent malignant tumor involving adenomas that develop into malignant lesions. Carcinoembryonic antigen (CEA) is a non-specific serum biomarker upregulated in CRC. The concentration of CEA is modulated by tumor stage and grade, tumor site in the colon, ploidy status, and patient smoking status. This study aimed to evaluate current evidence regarding the diagnostic power of CEA levels in the early detection of CRC recurrence in adults.

To evaluate current evidence regarding the diagnostic power of CEA levels in the early detection of CRC recurrence in adults.

A systematic search was performed using four databases: MEDLINE, Cochrane Trials, EMBASE, and the Web of Science. The inclusion criteria were as follows: Adult patients aged ≥ 18 years who had completed CRC curative treatment and were followed up postoperatively; reporting the number of CRC recurrences as an outcome; and randomized, clinical, cohort, and case-control study designs. Studies that were not published in English and animal studies were excluded. The following data were extracted by three independent reviewers: Study design, index tests, follow-up, patient characteristics, and primary outcomes. All statistical analyses were performed using the RevMan 5.4.1.

A total of 3232 studies were identified, with 73 remaining following the elimination of duplicates. After screening on predetermined criteria, 12 studies were included in the final analysis. At a reference standard of 5 mg/L, CEA detected only approximately half of recurrent CRCs, with a pooled sensitivity of 59% (range, 33%-83%) and sensitivity of 89% (range, 58%-97%).

CEA is a significant marker for CRC diagnosis. However, it has insufficient sensitivity and specificity to be used as a single biomarker of early CRC recurrence, with an essential proportion of false negatives.

The aim of this study was to develop a predictive model based on Sonazoid contrast-enhanced ultrasound (SCEUS) and clinical features to discriminate poorly differentiated hepatocellular carcinoma (P-HCC) from intrahepatic cholangiocarcinoma (ICC).

Forty-one ICC and forty-nine P-HCC patients were enrolled in this study. The CEUS LI-RADS category was assigned according to CEUS LI-RADS version 2017. Based on SCEUS and clinical features, a predicated model was established. Multivariate logistic regression analysis and LASSO logistic regression were used to identify the most valuable features, 400 times repeated 3-fold cross-validation was performed on the nomogram model and the model performance was determined by its discrimination, calibration, and clinical usefulness.

Multivariate logistic regression and LASSO logistic regression indicated that age (> 51 y), viral hepatitis (No), AFP level (≤  20 µg/L), washout time (≤  45 s), and enhancement level in the Kupffer phase (Defect) were valuable predictors related to ICC. The area under the receiver operating characteristic (AUC) of the nomogram was 0.930 (95% CI: 0.856-0.973), much higher than the subjective assessment by the sonographers and CEUS LI-RADS categories. The calibration curve showed that the predicted incidence was more consistent with the actual incidence of ICC, and 400 times repeated 3-fold cross-validation revealed good discrimination with a mean AUC of 0.851. Decision curve analysis showed that the nomogram could increase the net benefit for patients.

The nomogram based on SCEUS and clinical features can effectively differentiate P-HCC from ICC.

Contrast-enhanced ultrasound (CEUS) is a dependable modality for the diagnosis of various clinical conditions. A judicious selection of ultrasound contrast agent (UCA) is imperative for optimizing imaging and improving diagnosis. Approved UCAs for imaging the majority of organs include SonoVue, a pure blood agent, and Sonazoid, which exhibits an additional Kupffer phase. Despite the fact that the two UCAs are increasingly being employed, there is a lack of comparative reviews between the two agents in different organs diseases. This review represents the first attempt to compare the two UCAs in non-hepatic organs, primarily including breast, thyroid, pancreas, and spleen diseases. Through comparative analysis, this review provides a comprehensive and objective evaluation of the performance characteristics of SonoVue and Sonazoid, with the aim of offering valuable guidance for the clinical application of CEUS. Overall, further clinical evidences are required to compare and contrast the dissimilarities between the two UCAs in non-hepatic organs, enabling clinicians to make an appropriate selection based on actual clinical applications.

Contrast-enhanced ultrasonography (CEUS) is a noninvasive imaging modality used to diagnose hepatocellular carcinoma (HCC) based on specific imaging features, without the need for pathologic confirmation. Two types of ultrasound contrast agents are commercially available: pure intravascular agents (such as SonoVue) and Kupffer agents (such as Sonazoid). Major guidelines recognize CEUS as a reliable imaging method for HCC diagnosis, although they differ depending on the contrast agents used. The Korean Liver Cancer Association-National Cancer Center guideline includes CEUS with either SonoVue or Sonazoid as a second-line diagnostic technique. However, Sonazoid-enhanced ultrasound is associated with several unresolved issues. This review provides a comparative overview of these contrast agents regarding pharmacokinetic features, examination protocols, diagnostic criteria for HCC, and potential applications in the HCC diagnostic algorithm.

The aim of the work described here was to evaluate the diagnostic performance of perfluorobutane (PFB)-enhanced ultrasound in differentiating hepatocellular carcinoma (HCC) from non-HCC malignancies and other benign lesions using different acquisition methods.

This prospective study included 69 patients with solid liver lesions larger than 1 cm who were scheduled for biopsy or radiofrequency ablation between September 2020 and March 2021. Lesion diagnosis was designated by three blinded radiologists after reviewing three different sets of acquired images selected according to the following presumed acquisition methods: (i) method A, acquisition up to 5 min after contrast injection; (ii) method B, acquisition up to 1 min after contrast injection with additional Kupffer phase; and (iii) method C, acquisition up to 5 min after contrast injection with additional Kupffer phase.

After excluding 7 technical failures, 62 patients with liver lesions (mean size: 24.2 ± 14.8 mm), which consisted of 7 benign lesions, 37 non-HCC malignancies and 18 HCCs. For the HCC diagnosis, method C had the highest sensitivity (75.9%), followed by method B (72.2%) and method A (68.5%), but failed to exhibit statistical significance (p = 0.12). There was no significant difference with respect to the pooled specificity between the three methods (p = 0.28). Diagnostic accuracy was the highest with method C (87.1%) but failed to exhibit statistical significance (p = 0.24).

Image acquisition up to 5 min after contrast injection with additional Kupffer phase could potentially result in high accuracy and sensitivity without loss of specificity in diagnosing HCC with PFB-enhanced ultrasound.

Over the past decade, super-resolution ultrasound localization microscopy (SR-ULM) has revolutionized ultrasound imaging with its capability to resolve the microvascular structures below the ultrasound diffraction limit. The introduction of this imaging technique enables the visualization, quantification, and characterization of tissue microvasculature. The early implementations of SR-ULM utilize microbubbles (MBs) that require a long image acquisition time due to the requirement of capturing sparsely isolated microbubble signals. The next-generation SR-ULM employs nanodroplets that have the potential to significantly reduce the image acquisition time without sacrificing the resolution. This review discusses various nanodroplet-based ultrasound localization microscopy techniques and their corresponding imaging mechanisms. A summary is given on the preclinical applications of SR-ULM with nanodroplets, and the challenges in the clinical translation of nanodroplet-based SR-ULM are presented while discussing the future perspectives. In conclusion, ultrasound localization microscopy is a promising microvasculature imaging technology that can provide new diagnostic and prognostic information for a wide range of pathologies, such as cancer, heart conditions, and autoimmune diseases, and enable personalized treatment monitoring at a microlevel.

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer therapy combining NIR-light irradiation with an antibody and IR700DX, a light-sensitive substance, to destroy tumours. However, homogeneous irradiation is difficult because the light varies depending on the distance and tissue environment. Therefore, markers that indicate sufficient irradiation are necessary. Nanoparticles sized 10∼200 nm show enhanced permeation and retention within tumours, which is further enhanced via NIR-PIT (super enhanced permeability and retention, SUPR). We aimed to monitor the effectiveness of NIR-PIT by measuring SUPR.

A xenograft mouse tumour model was established by inoculating human cancer cells in both buttocks of Balb/C-nu/nu mice, and NIR-PIT was performed on only one side. To evaluate SUPR, fluorescent signal examination was performed using QD800-fluorescent nanoparticles and NIR-fluorescent poly (d,l-lactide-co-glycolic acid) (NIR-PLGA) microparticles. Harmonic signals were evaluated using micro-bubbles of the contrast agent Sonazoid and contrast-enhanced ultrasound (CEUS) imaging. The correlation between SUPR immediately after treatment and NIR-PIT effectiveness on the day after treatment was evaluated.

QD800 fluorescent signals persisted only in the treated tumours, and the intensity of remaining signals showed high positive correlation with the therapeutic effect. NIR-PLGA fluorescent signals and Sonazoid-derived harmonic signals remained for a longer time in the treated tumours than in the controls, and the kE value of the two-compartment model correlated with NIR-PIT effectiveness.

SUPR measurement using Sonazoid and CEUS imaging could be easily adapted for clinical use as a therapeutic image-based biomarker for monitoring and confirming of NIR-PIT efficacy.

This research was supported by ARIM JAPAN of MEXT, the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, 21K07217) (JSPS), CREST (JPMJCR19H2, JST), and FOREST-Souhatsu (JST). Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takeda Science Foundation; The Japan Health Foundation; and Princess Takamatsu Cancer Research Fund. Funders only provided financial support and had no role in the study design, data collection, data analysis, interpretation, and writing of the report.

Abnormal tumor vasculature is reported to severely hinder the therapeutic potency of diverse cancer therapeutics by restricting their intratumoral accumulation and/or causing therapeutic resistance. Herein, a microbubble-assisted ultrasonication technology (MAUT) of systemic administration of octafluoropropane-filled microbubbles together with tumor localized ultrasound (US) exposure is developed to generally promote intratumoral accumulation efficacy of three kinds of anti-tumor drugs with varying sizes through the cavitation effect-induced disruption of tumor blood vessels. MAUT was further shown to enable selective tumor hypoxia attenuation by filling microbubbles with high-purity oxygen and thus reducing the production of immunosuppressive lactic acids by suppressing glycolysis in cancer cells. Resultantly, MAUT markedly enhanced the therapeutic outcome of systemically administered anti-programmed death-1 (anti-PD-1) and chemotherapeutic doxorubicin (DOX) with and without using nanoscale liposomes as delivery vehicles. This work highlights that MAUT is a biocompatible yet versatile strategy to effectively reinforce the therapeutic potency of a broad range of cancer therapeutics, promising for future clinical usage.

Contrast enhanced ultrasound (CEUS) has been widely implemented in clinical practice because of the enormous quantity of information it provides, along with its low cost, reproducibility, minimal invasiveness, and safety of the second-generation ultrasound contrast agents. To overcome the limitation of CEUS given by the subjective evaluation of the contrast enhancement behaviour, quantitative analysis of contrast kinetics with generation of time-intensity curves has been introduced in recent years. The quantification of perfusion parameters [named as dynamic-CEUS (D-CEUS)] has several applications in gastrointestinal neoplastic and inflammatory disorders. However, the limited availability of large studies and the heterogeneity of the technologies employed have precluded the standardisation of D-CEUS, which potentially represents a valuable tool for clinical practice in management of gastrointestinal diseases. In this article, we reviewed the evidence exploring the application of D-CEUS in gastrointestinal diseases, with a special focus on liver, pancreas, and inflammatory bowel diseases.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare type of primary liver cancer. It is a complex "biphenotypic" tumor type consisting of bipotential hepatic progenitor cells that can differentiate into cholangiocytes subtype and hepatocytes subtype. The prognosis of patients with cHCC-CC is quite poor with its specific and more aggressive nature. Furthermore, there are no definite demographic or clinical features of cHCC-CC, thus a clear preoperative identification and accurate non-invasive imaging diagnostic analysis of cHCC-CC are of great value. In this review, we first summarized the epidemiological features, pathological findings, molecular biological information and serological indicators of cHCC-CC disease. Then we reviewed the important applications of non-invasive imaging modalities-particularly ultrasound (US)-in cHCC-CC, covering both diagnostic and prognostic assessment of patients with cHCC-CC. Finally, we presented the shortcomings and potential outlooks for imaging studies in cHCC-CC.

Collapse of lipidic ultrasound contrast agents under high-frequency compressive load has been historically interpreted by the vanishing of surface tension. By contrast, buckling of elastic shells is known to occur when costly compressible stress is released through bending. Through quasi-static compression experiments on lipidic shells, we analyse the buckling events in the framework of classical elastic buckling theory and deduce the mechanical characteristics of these shells. They are then compared with that obtained through acoustic characterization. This article is part of the theme issue 'Probing and dynamics of shock sensitive shells'.

Radiation therapy (RT) has been the standard of care for treating a multitude of cancer types. However, ionizing radiation has adverse short and long-term side effects which have resulted in treatment complications for decades. Thus, advances in enhancing the effects of RT have been the primary focus of research in radiation oncology. To avoid the usage of high radiation doses, treatment modalities such as high-intensity focused ultrasound can be implemented to reduce the radiation doses required to destroy cancer cells. In the past few years, the use of focused ultrasound (FUS) has demonstrated immense success in a number of applications as it capitalizes on spatial specificity. It allows ultrasound energy to be delivered to a targeted focal area without harming the surrounding tissue. FUS combined with RT has specifically demonstrated experimental evidence in its application resulting in enhanced cell death and tumor cure. Ultrasound-stimulated microbubbles have recently proved to be a novel way of enhancing RT as a radioenhancing agent on its own, or as a delivery vector for radiosensitizing agents such as oxygen. In this mini-review article, we discuss the bio-effects of FUS and RT in various preclinical models and highlight the applicability of this combined therapy in clinical settings.

Objective: To assess the value of microbubble contrast agent SonoVue in the thorough preoperative lymphatic mapping of patients with thyroid carcinoma, including the lymphatic drainage region, the detection of sentinel lymph node (SLN), and the diagnosis of lymph node metastasis (LNM). Materials and methods: 55 patients with 62 thyroid malignancies proved by surgical pathology (59 papillary thyroid carcinomas and three medullary thyroid carcinomas) who underwent preoperative lymphatic contrast-enhanced ultrasound (LCEUS) with microbubble contrast agent SonoVue were enrolled. All LNM were confirmed by pathology. The location of thyroid lesions, ultrasonic features of lymph nodes, lymphatic drainage region, and detection of SLN were assessed. The diagnostic performance (sensitivity, specificity, positive predictive value, negative predictive value and accuracy) of different parameters for the LNM diagnosis was calculated. Results: SonoVue effectively demonstrated the lymphatic drainage region for all enrolled thyroid carcinomas. The most common lymphatic drainage region for thyroid carcinomas was region VI (93.55%), followed by region III (62.90%), region IV (48.39%) and region II (4.84%). When divided by the lesion location, the most common lymphatic drainage regions for the nodule in isthmus, superior lobe and inferior lobe of the thyroid were region VI, region III, and region VI respectively. SLN was detected in 96.77% (60/62) of cases. The two cases without SLN demonstration had pathologically proven LNM. The most common sonographic sign of LNM was perfusion defect (54.17%). The diagnostic accuracy of SonoVue in central and lateral compartment LNM was 86.67% and 91.67%, respectively. Conclusion: Microbubble contrast agent SonoVue is a valuable imaging contrast medium for thorough preoperative lymphatic mapping in patients with thyroid carcinoma, including the lymphatic drainage region, the detection of SLN, and the diagnosis of LNM. LCEUS with SonoVue alone has limitations of false negatives when there is lymphatic vessel obstruction and may need to be combined with other ultrasound modalities.

To determine whether Sonazoid-enhanced ultrasound (SZUS) was noninferior to SonoVue-enhanced ultrasound (SVUS) in diagnosing hepatocellular carcinoma (HCC) using the same diagnostic criteria.

This prospective, single-center, noninferiority study (NCT04847726) enrolled 105 at-risk participants (71 male; mean age ± standard deviation, 63 ± 11 years; range, 26-86 years) with treatment-naïve solid hepatic nodules (≥ 1 cm). All participants underwent same-day SZUS (experimental method) and SVUS (control method) for one representative nodule per participant. Images were interpreted by three readers (the operator and two independent readers). All malignancies were diagnosed histopathologically, while the benignity of other lesions was confirmed by follow-up stability or pathology. The primary endpoint was per-lesion diagnostic accuracy for HCC pooled across three readers using the conventional contrast-enhanced ultrasound diagnostic criteria, including arterial phase hyperenhancement followed by mild (assessed within 2 minutes after contrast injection) and late (≥ 60 seconds with a delay of 5 minutes) washout. The noninferiority delta was -10%p. Furthermore, different time delays were compared as washout criteria in SZUS, including delays of 2, 5, and > 10 minutes.

A total of 105 lesions (HCCs [n = 61], non-HCC malignancies [n = 19], and benign [n = 25]) were evaluated. Using the 5-minutes washout criterion, per-lesion accuracy of SZUS pooled across the three readers (72.4%; 95% confidence interval [CI], 64.1%-79.3%) was noninferior to that of SVUS (71.4%; 95% CI, 63.1%-78.6%), meeting the statistical criterion for non-inferiority (difference of 0.95%p; 95% CI, -3.8%p-5.7%p). The arterial phase hyperenhancement combined with the 5-minutes washout criterion showed the same sensitivity as that of the > 10-minutes criterion (59.0% vs. 59.0%, p = 0.989), and the specificities were not significantly different (90.9% vs. 86.4%, p = 0.072).

SZUS was noninferior to SVUS for diagnosing HCC in at-risk patients using the same diagnostic criteria. No significant improvement in HCC diagnosis was observed by extending the washout time delay from 5 to 10 minutes.

We assessed the diagnostic value of Sonazoid-enhanced ultrasound (SEUS) in determining the macroscopic classification of hepatocellular carcinoma (HCC) because of its strong relevance to the poor prognosis of the non-simple nodular (non-SN) type. The PubMed, EMBASE, Web of Science and Cochrane Library databases were searched for studies investigating patients who underwent surgery for HCC after undergoing SEUS pre-operatively. Five studies involving a total of 334 patients met the inclusion criteria. The summary sensitivity and specificity were 0.74 (95% confidence interval [CI]: 0.63-0.83) and 0.92 (95% CI: 0.82-0.97), respectively. The positive and negative likelihood ratios of SEUS for determining the macroscopic classification of HCC in Kupffer phase were 9.21 (95% CI: 4.02-21.13) and 0.28 (95% CI: 0.19-0.41), respectively. The diagnostic odds ratio of SEUS for determining the macroscopic classification of HCC was 34.2 (95% CI: 11.64-100.51), and the area under the summary receiver operating characteristic curve was 0.87 (95% CI: 0.84-0.90). Subgroup analysis suggested that small HCCs (≤30 mm) and studies including fewer than 70 patients may be associated with a higher diagnostic odds ratio than the corresponding subsets. SEUS had moderate diagnostic value for determining the macroscopic classification of HCC in the Kupffer phase.

To investigate the Sonazoid-enhanced contrast-enhanced ultrasound (CEUS) features of hepatocellular carcinoma (HCC) in a non-cirrhosis liver background, in comparison to those in liver cirrhosis.

In this retrospective study, 19 patients with surgery and histopathologically proven HCC lesions in non-cirrhosis liver background were included regarding Sonazoid-enhanced CEUS characteristics. Two radiologists evaluated the CEUS features of HCC lesions according to the WFUMB (World Federation of Societies for Ultrasound in Medicine and Biology) guidelines criteria. Thirty-six patients with HCC lesions in liver cirrhosis were included as a control group. Final diagnoses were confirmed by surgery and histopathological results.

Liver background of the non-cirrhosis group including normal liver (n = 7), liver fibrosis (n = 11), and alcoholic liver disease (n = 1). The mean size of non-cirrhosis HCC lesions was 60.8 ± 46.8 mm (ranging from 25 to 219 mm). During the arterial phase of Sonazoid-enhanced CEUS, most HCCs in non-cirrhotic liver (94.7%, 18/19) and in cirrhotic liver (83.3%, 30/36) presented non-rim hyperenhancement. During the portal venous phase, HCC lesions in the non-cirrhosis liver group showed relatively early washout (68.4%, 13/19) (p = 0.090). Meanwhile, HCC lesions in liver cirrhosis background showed isoenhancement (55.6%, 20/36). All lesions in the non-cirrhotic liver group showed hypoenhancement in the late phase and the Kupffer phase (100%, 19/19). Five cases of HCC lesions in liver cirrhosis showed isoenhancement during the late phase and hypoenhancement during the Kupffer phase (13.9%, 5/36). The rest of the cirrhotic HCC lesions showed hypoenhancement during the late phase and the Kupffer phase (86.1%, 31/36). Additional hypoenhanced lesions were detected in three patients in the non-cirrhosis liver group and eight patients in the liver cirrhosis group (mean size: 13.0 ± 5.6 mm), which were also suspected to be HCC lesions.

Heterogeneous hyperenhancement during the arterial phase as well as relatively early washout are characteristic features of HCC in the non-cirrhotic liver on Sonazoid-enhanced CEUS.

Current literature on the role of contrast-enhanced ultrasound (CEUS) in the diagnosis of hepatocellular carcinoma (HCC) in non-cirrhotic patients is limited. The aim of this retrospective multicenter study was to analyze CEUS features of histologically proven HCC in patients with non-cirrhotic liver. In this multicenter study, 96 patients from eight medical institutions with histologically proven HCC lesions in non-cirrhotic liver were retrospectively reviewed regarding SonoVue-enhanced CEUS features. Two ultrasound experts assessed the CEUS enhancement pattern and came to a consensus using the World Federation of Societies for Ultrasound in Medicine and Biology guideline criteria. The mean size of HCC lesions included was 60.3 ± 37.8 mm (mean ± standard deviation). Most of the lesions were heterogeneous but predominantly hypo-echoic on B-mode ultrasound (64.5%, 62/96), with ill-defined margins and irregular shapes. During the arterial phase of CEUS, most of the HCC lesions in non-cirrhotic liver exhibited heterogeneous hyperenhancement (78.1%, 75/96) compared with the surrounding liver parenchyma. Almost 30% of HCC lesions (28.1%, 27/96) exhibited early wash-out (<60 s). All lesions exhibited wash-out and hypo-enhancement in the late phase. CEUS features of HCC lesions in non-cirrhotic patients typically include hyperenhancement in the arterial phase and relatively rapid wash-out in the portal venous phase, which is different from HCC in cirrhotic livers and more similar to liver metastasis.

Contrast-enhanced ultrasound (CEUS) is used in various medical specialties as a diagnostic imaging tool and for procedural guidance. Experience in the procedure is currently attained via supervised clinical practice that is challenged by patient availability and risks. Prior simulation-based training and subsequent assessment could improve and ensure competence before performance on patients, but no simulator currently exists. Immersive virtual reality (IVR) is a new promising simulation tool that can replicate complex interactions and environments that are unfeasible to achieve by traditional simulators. This study was aimed at developing an IVR simulation-based test for core CEUS competencies and gathering validity evidence for the test in accordance with Messick's framework. The test was developed by IVR software specialists and clinical experts in CEUS and medical education and imitated a CEUS examination of a patient with a focal liver lesion with emphasis on the pre-contrast preparations. Twenty-five medical doctors with varying CEUS experience were recruited as test participants, and their results were used to analyze test quality and to establish a pass/fail standard. The final test of 23 test items had good internal reliability (Cronbach's α = 0.85) and discriminatory abilities. The risks of false positives and negatives (9.1% and 23.6%, respectively) were acceptable for the test to be used as a certification tool prior to supervised clinical training in CEUS.