Diagnostic Test Accuracy of Contrast-Enhanced Ultrasound With Sonazoid for Assessment of Focal Liver Lesions: A Systematic Review and Meta-Analysis.

This meta-analysis examined the diagnostic accuracy of Sonazoid-enhanced ultrasonography (SZ-CEUS) in discriminating malignant from benign focal liver lesions (FLLs) and HCC from non-HCC FLLs. Finding relevant studies required a rigorous PubMed, EMBASE, and other database search. To distinguish malignant from benign FLLs, SZ-CEUS had a pooled sensitivity of 94% (95% CI: 0.91-0.95) and specificity of 84% (95%: 0.78-0.89). HCC distinction had 83% sensitivity and 96% specificity (95% CI: 0.80-0.85 and 0.95-0.97). SZ-CEUS accurately distinguishes malignant from benign FLLs and HCC from non-HCC lesions, especially smaller HCC lesions.

Perfluorobutane-Enhanced CEUS in Intrahepatic Cholangiocarcinoma: Correlating Imaging Features With Liver Backgrounds and Tumor Sizes.

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

Evaluation of Renal Masses Using Contrast-Enhanced Ultrasound with Sonovue and Sonazoid.

OBJECTIVE: To explore the differences between SonoVue and Sonazoid contrast-enhanced ultrasound (CEUS) in evaluating enhancement features of renal masses and determine the diagnostic value of CEUS in clear cell renal cell carcinoma (ccRCC). METHODS: A total of 57 eligible patients were enrolled and divided into the ccRCC, papillary renal cell carcinoma (pRCC), non-ccRCC and non-pRCC malignancy groups, and benign mass groups based on their postsurgical histopathologic diagnosis. The enhancement features of renal masses following SonoVue and Sonazoid CEUS in each group were analyzed. Diagnostic efficiencies of SonoVue and Sonazoid CEUS for ccRCC and non-ccRCC were determined. RESULTS: There were no significant differences in the enhancement features of renal masses with SonoVue and Sonazoid imaging in the four groups (p > .05). Both SonoVue CEUS and Sonazoid CEUS showed good diagnostic performance for the differential diagnosis of ccRCC and non-ccRCC, with sensitivities of 88.6% and 85.7%, specificities of 76.5% and 88.2%, accuracies of 84.6% and 86.5%, positive predictive values of 88.6% and 93.8%, and negative predictive values of 76.5% and 75%, respectively. There were no statistically significant differences in any of the diagnostic performance indices between the two methods (p > .05). CONCLUSION: The CEUS features of SonoVue and Sonazoid in evaluating renal masses were similar in the vascular phase. Both SonoVue and Sonazoid CEUS showed good diagnostic performance for the differential diagnosis of ccRCC and non-ccRCC.

A non-invasive predictive model based on multimodality ultrasonography images to differentiate malignant from benign focal liver 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.

Prediction of microvascular invasion in hepatocellular carcinoma with conventional ultrasound, Sonazoid-enhanced ultrasound, and biochemical indicator: a multicenter study.

PURPOSE: To develop and validate a preoperative prediction model based on multimodal ultrasound and biochemical indicator for identifying microvascular invasion (MVI) in patients with a single hepatocellular carcinoma (HCC) ≤ 5 cm. METHODS: From May 2022 to November 2023, a total of 318 patients with pathologically confirmed single HCC ≤ 5 cm from three institutions were enrolled. All of them underwent preoperative biochemical, conventional ultrasound (US), and contrast-enhanced ultrasound (CEUS) (Sonazoid, 0.6 mL, bolus injection) examinations. Univariate and multivariate logistic regression analyses on clinical information, biochemical indicator, and US imaging features were performed in the training set to seek independent predictors for MVI-positive. The models were constructed and evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis in both validation and test sets. Subgroup analyses in patients with different liver background and tumor sizes were conducted to further investigate the model's performance. RESULTS: Logistic regression analyses showed that obscure tumor boundary in B-mode US, intra-tumoral artery in pulsed-wave Doppler US, complete Kupffer-phase agent clearance in Sonazoid-CEUS, and biomedical indicator PIVKA-II were independently correlated with MVI-positive. The combined model comprising all predictors showed the highest AUC, which were 0.937 and 0.893 in the validation and test sets. Good calibration and prominent net benefit were achieved in both sets. No significant difference was found in subgroup analyses. CONCLUSIONS: The combination of biochemical indicator, conventional US, and Sonazoid-CEUS features could help preoperative MVI prediction in patients with a single HCC ≤ 5 cm. CRITICAL RELEVANCE STATEMENT: Investigation of imaging features in conventional US, Sonazoid-CEUS, and biochemical indicators showed a significant relation with MVI-positivity in patients with a single HCC ≤ 5 cm, allowing the construction of a model for preoperative prediction of MVI status to help treatment decision making. KEY POINTS: MVI status is important for patients with a single HCC ≤ 5 cm. The model based on conventional US, Sonazoid-CEUS and PIVKA-II performs best for MVI prediction. The combined model has potential for preoperative prediction of MVI status.

Washout-parametric imaging with Sonazoid for enhanced differentiation of focal liver lesions.

PURPOSE: The study aimed to compare the diagnostic performance of washout-parametric imaging (WOPI) with that of conventional contrast-enhanced ultrasound (cCEUS) in differentiating focal liver lesions (FLLs). METHODS: A total of 181 FLLs were imaged with contrast-enhanced ultrasound using Sonazoid, and the recordings were captured for 10 minutes in a prospective setting. WOPI was constructed from three images, depicting the arterial phase (peak enhancement), the early portal venous phase (1-minute post-injection), and the vasculo-Kupffer phase (5 or 10 minutes post-injection). The intensity variations in these images were color-coded and superimposed to produce a single image representing the washout timing across the lesions. From the 181 FLLs, 30 hepatocellular carcinomas (HCCs), 30 non-HCC malignancies, and 30 benign lesions were randomly selected for an observer study. Both techniques (cCEUS and WOPI) were evaluated by four off-site readers. They classified each lesion as benign or malignant using a continuous rating scale, with the endpoints representing "definitely benign" and "definitely malignant." The diagnostic performance of cCEUS and WOPI was compared using the area under the receiver operating characteristic curve (AUC) with the DeLong test. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC). RESULTS: The difference in average AUC values between WOPI and cCEUS was 0.0062 (95% confidence interval, -0.0161 to 0.0285), indicating no significant difference between techniques. The interobserver agreement was higher for WOPI (ICC, 0.77) than cCEUS (ICC, 0.67). CONCLUSION: The diagnostic performance of WOPI is comparable to that of cCEUS in differentiating FLLs, with superior interobserver agreement.

Contrast-enhanced ultrasound features of hepatic angiomyolipoma: comparison with AFP-negative and non-viral hepatocellular carcinoma.

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.

A Comparative Study of SonoVue and Sonazoid for Contrast-Enhanced Ultrasound CT/MRI Fusion Guidance During Radiofrequency Ablation of Poorly Visualized Hepatic Malignancies: A Prospective Intra-Individual Analysis.

PURPOSE: This study aimed to evaluate the effectiveness of two contrast agents, SonoVue (SV) and Sonazoid (SZ), by comparing them intra-individually in contrast-enhanced ultrasound (CEUS)-CT/MRI fusion imaging (FI) to improve the visibility of inconspicuous liver malignancies on B-mode sonography for guiding percutaneous radiofrequency ablation (RFA). Additionally, the radiologists' preference between SonoVue- CT/MRI FI (SV-FI) and Sonazoid-CT/MRI FI (SZ-FI) was determined. METHODS: This prospective study enrolled 23 patients with inconspicuous hepatic malignancies (≤ 3 cm) on B-mode US who underwent both SV-FI and SZ-FI for RFA guidance. The patients underwent real-time CEUS FI with CT/MRI on the same day, utilizing both SV and SZ with at least 15-min intervals. Tumor visibility and radiologists' preferences were assessed and graded using a 4-point scale during the dynamic phases of both SV-FI and SZ-FI and the Kupffer phase of SZ-FI. RESULTS: The tumor visibility scores obtained from CEUS-CT/MRI FI were significantly better than those obtained from US-FI. Indeed, SV-FI and SZ-FI demonstrated comparable visibility scores when corresponding phases were compared (p > 0.05). However, the Kupffer phase images of SZ-FI displayed superior visibility scores (3.70 ± 0.56 vs. 2.96 ± 0.88; p = 0.002) than the late vascular phase images of SV-FI. The radiologists favored SZ-FI in many cases, exhibiting moderate inter-observer agreement (Kappa value = 0.587; 95% CI, 0.403-0.772). CONCLUSION: Although CEUS-CT/MRI FI with either SV or SZ substantially improved the visibility of inconspicuous tumors on US-CT/MRI FI, radiologists preferred SZ to SV to guide the RFA procedure.

Current status and future perspectives of contrast-enhanced ultrasound diagnosis of breast lesions.

Advances in various imaging modalities for breast lesions have improved diagnostic capabilities not only for tumors but also for non-tumorous lesions. Contrast-enhanced ultrasound (CEUS) plays a crucial role not only in the differential diagnosis of breast lesions, identification of sentinel lymph nodes, and diagnosis of lymph node metastasis but also in assessing the therapeutic effects of neoadjuvant chemotherapy (NAC). In CEUS, two image interpretation approaches, i.e., qualitative analysis and quantitative analysis, are employed and applied in various clinical settings. In this paper, we review CEUS for breast lesions, including its various applications.

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.

Background: 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. Methods: 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. Results: 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. Conclusions: 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).

Principle of contrast-enhanced ultrasonography.

Sonazoid, an ultrasound contrast agent, has been covered by insurance in Japan since January 2007 for the diagnosis of hepatic mass lesions and is widely used for diagnosing not only primary liver cancer but also liver metastases such as those from breast cancer and colorectal cancer. Contrast-enhanced ultrasound for breast mass lesions has been covered by insurance since August 2012 after phase II and phase III clinical trials showed that the diagnostic performance was significantly superior to that of B-mode and contrast-enhanced magnetic resonance imaging. This paper describes the principles of imaging techniques in contrast-enhanced ultrasonography including the filter, pulse inversion, amplitude modulation, and amplitude-modulated pulse inversion methods. The pulse inversion method, which visualizes the second-harmonic component using the nonlinear scattering characteristics of the contrast agent, is widely used regardless of the contrast agent and target organ because of its high resolution. Sonazoid has a stiffer shell and requires a higher acoustic amplitude than Sonovue to generate nonlinear vibrations. The higher transmitted sound pressure generates more tissue harmonic components. Since pulse inversion allows visualization of the tissue harmonic components, amplitude modulation and amplitude-modulated pulse inversion, which include few tissue harmonic components, are primarily used. Amplitude modulation methods detect nonlinear signals from the contrast agent in the fundamental band. The mechanism of the amplitude modulation is considered to be changes in the echo signal's phase depending on the sound pressure. Since the tissue-derived component is minor in amplitude modulation methods, good contrast sensitivity can be obtained.

A combined model based on radiomics features of Sonazoid contrast-enhanced ultrasound in the Kupffer phase for the diagnosis of well-differentiated hepatocellular carcinoma and atypical focal liver lesions: a prospective, multicenter study.

OBJECTIVE: The objective of this study was to develop a combined model based on radiomics features of Sonazoid contrast-enhanced ultrasound (CEUS) during the Kupffer phase and to evaluate its value in differentiating well-differentiated hepatocellular carcinoma (w-HCC) from atypical benign focal liver lesions (FLLs). METHODS: A total of 116 patients with preoperatively Sonazoid-CEUS confirmed w-HCC or benign FLL were selected from a prospective multiple study on the clinical application of Sonazoid in FLLs conducted from August 2020 to March 2021. According to the randomization principle, the patients were divided into a training cohort and a test cohort in a 7:3 ratio. Seventy-nine patients were used for establishing and training the radiomics model and combined model. In comparison, 37 patients were used for validating and comparing the performance of the models. The diagnostic efficacy of the models for w-HCC and atypical benign FLLs was evaluated using ROCs curves and decision curves. A combined model nomogram was created to assess its value in reducing unnecessary biopsies. RESULTS: Among the patients, there were 55 cases of w-HCC and 61 cases of atypical benign FLLs, including 28 cases of early liver abscess, 16 cases of atypical hepatic hemangioma, 8 cases of hepatocellular dysplastic nodules (DN), and 9 cases of focal nodular hyperplasia (FNH). The radiomics model and combined model we established had AUCs of 0.905 and 0.951, respectively, in the training cohort, and the AUCs of the two models in the test cohort were 0.826 and 0.912, respectively. The combined model outperformed the radiomics feature model significantly. Decision curve analysis demonstrated that the combined model achieved a higher net benefit within a specific threshold probability range (0.25 to 1.00). A nomogram of the combined model was developed. CONCLUSION: The combined model based on the radiomics features of Sonazoid-CEUS in the Kupffer phase showed satisfactory performance in diagnosing w-HCC and atypical benign FLLs. It can assist clinicians in timely detecting malignant FLLs and reducing unnecessary biopsies for benign diseases.

Intra-individual comparison of Sonazoid contrast-enhanced ultrasound and SonoVue contrast-enhanced ultrasound in diagnosing hepatocellular carcinoma.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Noninvasive Visualization of Tumor Blood Vessels within Hepatocellular Carcinoma by Application of Superb Microvascular Imaging to Contrast-Enhanced Ultrasonography.

The combination or sequential use of systemic therapies, such as lenvatinib and locoregional therapies, can improve the curability rate of hepatocellular carcinoma. This is based on the notion that lenvatinib remodels abnormal tumor vessels into normal vessels, potentially enhancing the efficacy of locoregional therapies. In this case report, we achieved noninvasive visualization of tumor blood vessels by applying superb microvascular imaging (SMI) to contrast-enhanced ultrasonography (CEUS). A man in his 80s with a borderline resectable hepatocellular carcinoma received preoperative therapy using lenvatinib. The patient achieved a complete response after lenvatinib therapy, underwent hepatectomy, and maintained a cancer-free status. CEUS and SMI revealed a decrease in tumor blood vessels at 1 week after lenvatinib administration and a decrease in tumor perfusion at 2 weeks. Although CEUS alone is adequate for noninvasive real-time evaluation of tumor perfusion, it is not sufficient to achieve accurate assessments of tumor blood vessels. We performed a noninvasive time-course evaluation of vascular normalization after lenvatinib administration by applying SMI. The evaluation of vascular normalization with lenvatinib therapy using CEUS and SMI can support the decision to proceed to conversion therapies.

Compared with SonoVue® LR-5, Sonazoid® modified LR-5 has better diagnostic sensitivity for hepatocellular carcinoma: a systematic review and meta-analysis.

Background: The contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI-RADS) is a standardized system for reporting liver nodules in patients at risk of developing hepatocellular carcinoma (HCC) and is only recommended for pure blood pool agents such as SonoVue®. A modified LI-RADS was proposed for Sonazoid®, a Kupffer cell-specific contrast agent. This meta-analysis was conducted to compare the diagnostic efficiency of the CEUS LI-RADS for SonoVue® and the modified LI-RADS for Sonazoid®. Methods: The PubMed, Medline, Web of Science, Embase, and Cochrane Library databases were systematically searched to retrieve studies on the diagnostic efficiency of the CEUS LI-RADS algorithms in diagnosing HCC using SonoVue® and/or Sonazoid® from January 2016 to June 2023. Histopathology or imaging follow-up served as the reference standards. Only articles published in English on retrospective or prospective studies with full reports were included in the meta-analysis. A bivariate random-effects model was used. Data pooling, meta-regression, and sensitivity analysis were performed for the meta-analysis. Deeks' funnel plot asymmetry test was used to evaluate publication bias, and the QUADAS-2 tool was used to assess the methodological quality of eligible studies. Results: In total, 26 studies comprising 8,495 patients with 9,244 lesions were included in the meta-analysis. The pooled data results for SonoVue® LI-RADS category 5 (LR-5) and Sonazoid® modified LR-5 were as follows: pooled sensitivity: 0.68 [95% confidence interval (CI): 0.64-0.73, I2=89.20%; P<0.01] and 0.82 (95% CI: 0.74-0.87, I2=85.39%; P<0.01) (P<0.05); pooled specificity: 0.93 (95% CI: 0.90-0.96, I2=86.52%; P<0.01) and 0.86 (95% CI: 0.79-0.91, I2=59.91%; P=0.01) (P<0.05); pooled area under the curve (AUC): 0.86 (95% CI: 0.82-0.89) and 0.91 (95% CI: 0.88-0.93) (P<0.05), respectively. The meta-regression analysis revealed that the study design, subject enrollment method, and reference standard contributed to the heterogeneity of SonoVue® LR-5, and the number of lesions was a source of heterogeneity for Sonazoid® modified LR-5. The diagnostic performance of the LI-RADS category M (LR-M) algorithms of SonoVue® and Sonazoid® was comparable. Conclusions: The Sonazoid® modified LR-5 algorithm had a higher diagnostic sensitivity, lower specificity, and higher AUC than SonoVue® LR-5.

The efficacy of modified contrast-enhanced ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) using Sonazoid in diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis.

Background: The contrast-enhanced ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) is an algorithm for the diagnosis of hepatocellular carcinoma (HCC) in high-risk populations. Previous studies have shown the algorithm to have high specificity and moderate sensitivity. Nevertheless, it is designated for utilization solely with blood pool contrast agents. Sonazoid, a contrast agent that combines blood pools and Kupffer cells properties, has recently gained approval for marketing in an increased number of countries. Enhanced sensitivity in diagnosing HCC may be achieved through the distinctive Kupffer phase (KP) exhibited by Sonazoid. Certain academics have suggested the modified CEUS LI-RADS using Sonazoid. The main criteria of mild and late (≥60 seconds) washout in CEUS LI-RADS LR-5 were replaced by KP (>10 minutes) defects as the primary criteria. The purpose of this research was to evaluate the effectiveness of the modified CEUS LI-RADS using Sonazoid in diagnosing HCC. Methods: Original studies on Sonazoid and CEUS LI-RADS were searched in the PubMed, Embase, Cochrane Library, and Web of Science databases until 13 July 2023, with no restrictions on language. We enrolled studies that applied Sonazoid for CEUS in patients at high risk of HCC and modified CEUS LI-RADS for the diagnosis of intrahepatic nodules. Meta-analyses, evaluations, case studies, correspondences, remarks, and summaries of conferences were excluded. Additionally, studies that fell outside the scope of this study and contained data on the same patients were also excluded. We evaluated the quality of research by employing the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. A bivariate mixed effects model was utilized to conduct a meta-analysis, summarizing the sensitivity and specificity in the diagnosis of HCC. The investigation of potential factors contributing to study heterogeneity was conducted using meta-regression analysis. Results: Out of the 103 studies screened, 6 studies (835 lesions) were included in the final results. Modified CEUS LR-5 exhibited a sensitivity of 0.77 [95% confidence interval (CI): 0.70-0.82; I2=71.98%; P=0.00] and a specificity of 0.88 (95% CI: 0.83-0.92; I2=0.00; P=0.47) for HCC diagnosis, with heterogeneity in sensitivity. The presence of heterogeneity in the study was found to have a significant association with factors such as the study design, the number of image reviewers, the proportion of cirrhosis, the proportion of other non-HCC malignancies (OM) cases, and the type of reference standard (P≤0.05). Conclusions: The modified CEUS LI-RADS LR-5 categorization demonstrates a reasonable level of sensitivity 0.77, but an insufficient level of specificity 0.88 when diagnosing HCC. KP defects cannot be used as a primary feature in the diagnosis of HCC by CEUS LI-RADS, perhaps as an ancillary feature.

Perfluorobutane application value in microwave ablation of small hepatocellular carcinoma (<3 cm).

BACKGROUND: No studies have been retrieved comparing perfluorobutane with sulfur hexafluoride for microwave ablation (MWA) in small hepatocellular carcinoma(sHCC). OBJECTIVE: To retrospective investigate the value of perfluorobutane ultrasonography contrast agent in ultrasonography (US)-guided MWA of sHCC. METHODS: 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. RESULTS: 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). CONCLUSION: Perfluorobutane kupffer phase can make the operator accurately deploy the ablation needle and reduce the difficulty of operation.

Impact of Hepatocellular Carcinoma Tumor Size on Sonazoid Contrast-Enhanced Ultrasound Enhancement Features.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Development and Comparison of Prediction Models Based on Sonovue- and Sonazoid-Enhanced Ultrasound for Pathologic Grade and Microvascular Invasion in Hepatocellular Carcinoma.

OBJECTIVE: This study was aimed at developing and comparing prediction models based on Sonovue and Sonazoid contrast-enhanced ultrasound (CEUS) in predicting pathologic grade and microvascular invasion (MVI) of hepatocellular carcinoma (HCC). Also investigated was whether Kupffer phase images have additional predictive value for the above pathologic features. METHODS: Ninety patients diagnosed with primary HCC who had undergone curative hepatectomy were prospectively enrolled. All patients underwent conventional ultrasound (CUS), Sonovue-CEUS and Sonazoid-CEUS examinations pre-operatively. Clinical, radiologic and pathologic features including pathologic grade, MVI and CD68 expression were collected. We developed prediction models comprising clinical, CUS and CEUS (Sonovue and Sonazoid, respectively) features for pathologic grade and MVI with both the logistic regression and machine learning (ML) methods. RESULTS: Forty-one patients (45.6%) had poorly differentiated HCC (p-HCC) and 37 (41.1%) were MVI positive. For pathologic grade, the logistic model based on Sonazoid-CEUS had significantly better performance than that based on Sonovue-CEUS (area under the curve [AUC], 0.929 vs. 0.848, p = 0.035), whereas for MVI, these two models had similar accuracy (AUC, 0.810 vs. 0.786, p = 0.068). Meanwhile, we found that well-differentiated HCC tended to have a higher enhancement ratio in 6-12 min during the Kupffer phase of Sonazoid-CEUS, as well as higher CD68 expression compared with p-HCC. In addition, all of these models can effectively predict the risk of recurrence (p < 0.05). CONCLUSION: Sonovue-CEUS and Sonazoid-CEUS were comparably excellent in predicting MVI, while Sonazoid-CEUS was superior to Sonovue-CEUS in predicting pathologic grade because of the Kupffer phase. The enhancement ratio in the Kupffer phase has additional predictive value for pathologic grade prediction.

Assessment of arterial-phase hyperenhancement and late-phase washout of hepatocellular carcinoma-a meta-analysis of contrast-enhanced ultrasound (CEUS) with SonoVue® and Sonazoid®.

OBJECTIVES: The recognition of arterial phase hyperenhancement (APHE) and washout during the late phase is key for correct diagnosis of hepatocellular carcinoma (HCC) with contrast-enhanced ultrasound (CEUS). This meta-analysis was conducted to compare SonoVue®-enhanced and Sonazoid®-enhanced ultrasound in the assessment of HCC enhancement and diagnosis. METHODS: Studies were included in the analysis if they reported data for HCC enhancement in the arterial phase and late phase for SonoVue® or in the arterial phase and Kupffer phase (KP) for Sonazoid®. Forty-two studies (7502 patients) with use of SonoVue® and 30 studies (2391 patients) with use of Sonazoid® were identified. In a pooled analysis, the comparison between SonoVue® and Sonazoid® CEUS was performed using chi-square test. An inverse variance weighted random-effect model was used to estimate proportion, sensitivity, and specificity along with 95% confidence interval (CI). RESULTS: In the meta-analysis, the proportion of HCC showing APHE with SonoVue®, 93% (95% CI 91-95%), was significantly higher than the proportion of HCC showing APHE with Sonazoid®, 77% (71-83%) (p < 0.0001); similarly, the proportion of HCC showing washout at late phase/KP was significantly higher with SonoVue®, 86% (83-89%), than with Sonazoid®, 76% (70-82%) (p < 0.0001). The sensitivity and specificity for the detection of APHE plus late-phase/KP washout detection in HCC were also higher with SonoVue® than with Sonazoid® (sensitivity 80% vs 52%; specificity 80% vs 73% in studies within unselected patient populations). CONCLUSION: APHE and late washout in HCC are more frequently observed with SonoVue® than with Sonazoid®. This may affect the diagnostic performance of CEUS in the diagnosis of HCCs. CLINICAL RELEVANCE STATEMENT: Meta-analysis data show the presence of key enhancement features for diagnosis of hepatocellular carcinoma is different between ultrasound contrast agents, and arterial hyperenhancement and late washout are more frequently observed at contrast-enhanced ultrasound with SonoVue® than with Sonazoid®. KEY POINTS: • Dynamic enhancement features are key for imaging-based diagnosis of HCC. • Arterial hyperenhancement and late washout are more often observed in HCCs using SonoVue®-enhanced US than with Sonazoid®. • The existing evidence for contrast-enhanced US may need to be considered being specific to the individual contrast agent.