Analysis of Sonazoid contrast-enhanced ultrasound for predicting the risk of microvascular invasion in hepatocellular carcinoma: a prospective multicenter study.

OBJECTIVES: The aim of this study was to evaluate the potential of Sonazoid contrast-enhanced ultrasound (SNZ-CEUS) as an imaging biomarker for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). METHODS: From August 2020 to March 2021, we conducted a prospective multicenter study on the clinical application of Sonazoid in liver tumor; a MVI prediction model was developed and validated by integrating clinical and imaging variables. Multivariate logistic regression analysis was used to establish the MVI prediction model; three models were developed: a clinical model, a SNZ-CEUS model, and a combined model and conduct external validation. We conducted subgroup analysis to investigate the performance of the SNZ-CEUS model in non-invasive prediction of MVI. RESULTS: Overall, 211 patients were evaluated. All patients were split into derivation (n = 170) and external validation (n = 41) cohorts. Patients who had MVI accounted for 89 of 211 (42.2%) patients. Multivariate analysis revealed that tumor size (> 49.2 mm), pathology differentiation, arterial phase heterogeneous enhancement pattern, non-single nodular gross morphology, washout time (< 90 s), and gray value ratio (≤ 0.50) were significantly associated with MVI. Combining these factors, the area under the receiver operating characteristic (AUROC) of the combined model in the derivation and external validation cohorts was 0.859 (95% confidence interval (CI): 0.803-0.914) and 0.812 (95% CI: 0.691-0.915), respectively. In subgroup analysis, the AUROC of the SNZ-CEUS model in diameter ≤ 30 mm and ˃ 30 mm cohorts were 0.819 (95% CI: 0.698-0.941) and 0.747 (95% CI: 0.670-0.824). CONCLUSIONS: Our model predicted the risk of MVI in HCC patients with high accuracy preoperatively. CLINICAL RELEVANCE STATEMENT: Sonazoid, a novel second-generation ultrasound contrast agent, can accumulate in the endothelial network and form a unique Kupffer phase in liver imaging. The preoperative non-invasive prediction model based on Sonazoid for MVI is helpful for clinicians to make individualized treatment decisions. KEY POINTS: • This is the first prospective multicenter study to analyze the possibility of SNZ-CEUS preoperatively predicting MVI. • The model established by combining SNZ-CEUS image features and clinical features has high predictive performance in both derivation cohort and external validation cohort. • The findings can help clinicians predict MVI in HCC patients before surgery and provide a basis for optimizing surgical management and monitoring strategies for HCC patients.

Long-term efficacy and safety of microwave ablation for hepatocellular carcinoma adjacent to the gallbladder with a diameter ≤ 5 cm: a multicenter, propensity score matching study.

OBJECTIVE: To compare the long-term efficacy and safety of microwave ablation (MWA) as first-line therapy for hepatocellular carcinoma (HCC) adjacent versus nonadjacent to the gallbladder. MATERIALS AND METHODS: From 2006 to 2018, 657 patients with ≤5 cm HCC who underwent percutaneous ultrasound-guided MWA as first-line therapy from 5 hospitals were enrolled in this retrospective study. Patients were grouped into the adjacent group (n = 49) and the nonadjacent group (n = 608) according to whether the tumor was adjacent to the gallbladder. Propensity score matching (PSM) was used to balance baseline variables between the two groups. RESULTS: Forty-eight patient pairs were matched after PSM. For the PSM cohort, during a median follow-up time of 60 months, there were no differences in PFS (hazard ratio [HR], 1.011; 95% confidence interval [CI], 0.647-1.578; p = 0.963) or OS (HR 0.925; 95% CI 0.522-1.639; p = 0.789) between the adjacent and nonadjacent groups. Univariate and multivariate analyses revealed that the tumor adjacent to the gallbladder was not an independent risk factor for PFS or OS (all p > 0.05). Subgroup analysis showed comparable PFS and OS between the two groups in the <3 cm subgroup and the 3-5 cm subgroups (all p > 0.05). In addition to more use of assistive technology (p < 0.05), the adjacent group shared comparable local tumor progression, complications, technical success rate, and hospital stay (all p > 0.05) to the nonadjacent group. CONCLUSION: There were comparable long-term efficacy and complications between patients with HCC adjacent and nonadjacent to the gallbladder treated with MWA.

The application of MWA to HCC adjacent and nonadjacent to the gallbladder resulted in comparable PFS and OS and complications.For both cohorts, MWA shared comparable complications (immediate and delayed), LTP, hospitalization, and operative time.MWA might be a first-line alternative for ≤5 cm HCC adjacent to the gallbladder with the use of assistive technologies and advances in technology.

Long-term efficacy of microwave ablation in the treatment of subcapsular hepatocellular carcinomas of ≤3 cm in diameter: a multicenter, propensity score-matched study.

OBJECTIVE: To compare the long-term efficacy of microwave ablation (MWA) for subcapsular and non-subcapsular hepatocellular carcinomas (HCCs) using propensity score matching (PSM). MATERIALS AND METHODS: Using a multicenter database, we enrolled 430 patients (347 men, 83 women; age range, 15-71 years) with HCCs who received percutaneous ultrasound-guided MWA, between January 2012 and December 2018. The patients were grouped as follows, based on whether the tumor was adjacent to the capsule: subcapsular group (n = 142) and non-subcapsular group (n = 142). To evaluate the correlation between subcapsular position and efficacy of MWA, a Cox proportional hazards model was used to calculate disease-free survival (DFS) and overall survival (OS) based on PSM data. RESULTS: In total, 142 pairs of patients were matched. In the PSM cohort, the 1-year, 3-year, and 5-year DFS rates of the subcapsular and non-subcapsular groups were 84%, 61%, and 47%, respectively, and 85%, 67%, and 58%, respectively, while the 1-year, 3-year, and 5-year OS rates were 98%, 90%, and 84%, respectively, and 98%, 90%, and 88%, respectively. In the PSM cohort, subcapsular position was not an independent risk factor for DFS (hazard ratio [HR] = 1.291, p = 0.196) or OS (HR = 0.926, p = 0.866). Additionally, there were no significant differences in the incidence of local tumor progression, major complications, technical success rate, number of puncture needles, and postoperative hospital stay between the two groups (p > 0.05). CONCLUSION: There were no significant differences in DFS, OS, incidence of local tumor progression, and major complications between patients with subcapsular and non-subcapsular HCCs treated with MWA.

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.

Restoration of Sinusoid Fenestrae Followed by Targeted Nanoassembly Delivery of an Anti-Fibrotic Agent Improves Treatment Efficacy in Liver Fibrosis.

During the onset of liver fibrosis, capillarized liver sinusoidal endothelial cells (LSECs) limit substance exchange between the blood and the Disse space, further accelerating hepatic stellate cell (HSCs) activation and fibrosis progression. Limited accessibility of therapeutics to the Disse space is often overlooked and remains a major bottleneck for HSCs-targeted therapy in liver fibrosis. Here, an integrated systemic strategy for liver fibrosis treatment is reported, utilizing pretreatment with the soluble guanylate cyclase stimulator, riociguat, followed by insulin growth factor 2 receptor-mediated targeted delivery of the anti-fibrosis agent, JQ1, via peptide-nanoparticles (IGNP-JQ1). The riociguat reversed the liver sinusoid capillarization to maintain a relatively normal LSECs porosity, thus facilitating the transport of IGNP-JQ1 through the liver sinusoid endothelium wall and enhancing the accumulation of IGNP-JQ1 in the Disse space. IGNP-JQ1 is then selectively taken up by activated HSCs, inhibiting their proliferation and decreasing collagen deposition in the liver. The combined strategy results in significant fibrosis resolution in carbon tetrachloride-induced fibrotic mice as well as methionine-choline-deficient-diet-induced nonalcoholic steatohepatitis (NASH) mice. The work highlights the key role of LSECs in therapeutics transport through the liver sinusoid. The strategy of restoring LSECs fenestrae by riociguat represents a promising approach for liver fibrosis treatment.

Radiomics Based on Contrast-Enhanced Ultrasound Images for Diagnosis of Pancreatic Serous Cystadenoma.

OBJECTIVE: The purpose of the study was to develop and validate a radiomics model by using contrast-enhanced ultrasound (CEUS) data for pre-operative differential diagnosis of pancreatic cystic neoplasms (PCNs), especially pancreatic serous cystadenoma (SCA). METHODS: Patients with pathologically confirmed PCNs who underwent CEUS examination at Chinese PLA hospital from May 2015 to August 2022 were retrospectively collected. Radiomic features were extracted from the regions of interest, which were obtained based on CEUS images. A support vector machine algorithm was used to construct a radiomics model. Moreover, based on the CEUS image features, the CEUS and the combined models were constructed using logistic regression. The performance and clinical utility of the optimal model were evaluated by area under the receiver operating characteristic curve (AUC), sensitivity, specificity and decision curve analysis. RESULTS: A total of 113 patients were randomly split into the training (n = 79) and test cohorts (n = 34). These patients were pathologically diagnosed with SCA, mucinous cystadenoma, intraductal papillary mucinous neoplasm and solid-pseudopapillary tumor. The radiomics model achieved an AUC of 0.875 and 0.862 in the training and test cohorts, respectively. The sensitivity and specificity of the radiomics model were 81.5% and 86.5% in the training cohort and 81.8% and 91.3% in the test cohort, respectively, which were higher than or comparable with that of the CEUS model and the combined model. CONCLUSION: The radiomics model based on CEUS images had a favorable differential diagnostic performance in distinguishing SCA from other PCNs, which may be beneficial for the exploration of personalized management strategies.

Nomogram based on Sonazoid contrast-enhanced ultrasound to differentiate intrahepatic cholangiocarcinoma and poorly differentiated hepatocellular carcinoma: a prospective multicenter study.

OBJECTIVES: 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). PATIENTS AND METHOD: 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. RESULTS: 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. CONCLUSIONS: The nomogram based on SCEUS and clinical features can effectively differentiate P-HCC from ICC.

Contrast-enhanced ultrasound features predict the prognosis of percutaneous microwave ablation of intrahepatic cholangiocarcinoma.

OBJECTIVE: To evaluate the prognostic effect of pre-operative contrast-enhanced ultrasound (CEUS) features on intrahepatic cholangiocarcinoma (ICC) after percutaneous microwave ablation (MWA). METHODS: A total of ICC 29 patients (average age 56.34 ± 9.78 years old, 33~75 years old) underwent MWA from March 2012 to December 2020, with a total of 58 lesions (0.5-8.1 cm, mean diameter, 2.68 ± 1.59 cm), and their pre-operative CEUS images and clinical data were collected and reviewed. Survival rate, local progression rate, intra- and extrahepatic metastasis rate were evaluated. Uni- and multivariate analysis were used to analyze the prognostic factors affecting the survival of ICC patients with pre-operative CEUS features. RESULTS: The median follow-up time after MWA was 18.43 months (4.17-93.13 months). 1-, 2-, and 3-year OS rates were 64.4%, 48.1% and 48.1%; 6-, 12-, 18-, 24-, 36-, 48-, and 60-month local progress and extrahepatic metastasis rates were 0.0%, 4.0%, 17.7%, 17.7%, 17.7%, 17.7%, 17.7% and 3.4%, 21.5%, 32.7%, 45.6%, 55.2%, 55.2% and 77.6%, respectively. Uni- and multivariate analysis showed that post-operative extrahepatic metastasis was an important factor for long-term survival of ICC patients after MWA (p = 0.006, 0.01), and Rim-enhancement feature of pre-operative CEUS was identified as an independent predictor of post-operative extrahepatic metastasis and long-term survival (p = 0.02, 0.02). CONCLUSION: Rim-enhancement feature of pre-operative CEUS is a predictor high post-operative extrahepatic metastasis and poor prognosis through distant microvascular metastasis after MWA of ICC patients. ADVANCES IN KNOWLEDGE: This study determined the important CEUS features of ICC and analyzed their impact on the prognosis of ICC patients after MWA, providing scientific guidance for better clinical treatment in the future.