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Objectives: Contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) is used to definitively diagnose hepatocellular carcinoma (HCC) in patients at risk. However, the user variability associated with CEUS LI-RADS has not been validated in North American and European patients. This study aims to evaluate the inter-reader agreements of CEUS LI-RADS features for, and final categorization of, HCC in patients at risk., Methods: This retrospective multicenter clinical study used the database of a previous prospective multinational study, evaluating the accuracy of CEUS LI-RADS for HCC diagnosis in patients at risk. All cases were first evaluated by a site physician performing/supervising the CEUS examination. Randomly selected cases were re-evaluated by a blinded central reader. Final diagnosis was confirmed with the reference standard, which was a composite of imaging tests and histology. Cohen's kappa test was used to evaluate inter-reader agreement., Results: This study included 150 liver nodules and 58.0% (87/150) were confirmed as HCC, 4.7% (7/150) non-HCC malignancies, 22.7% (34/150) had no confirmed final diagnosis, and 14.7% (22/150) were nonmalignant. Inter-reader agreements were substantial for CEUS LI-RADS categorization (κ = 0.61; 95% confidence interval [CI]: 0.51-0.71) and major features assessment (ranged κ = 0.64-0.78), LR-5 (κ = 0.65; 95% CI: 0.52-0.77), and LR-M (κ = 0.67; 95% CI: 0.44-0.90), while for LR-1 and LR-2 categorization was almost perfect (κ = 0.85; 95% CI: 0.65-1.00)., Conclusion: Our study reported a substantial inter-reader agreement for overall CEUS LI-RADS categorization, especially for LR-5 and LR-M, and major imaging features of HCC, further confirming CEUS LI-RADS as a valuable and reliable tool for diagnosis of HCC., (© 2024 The Author(s). Journal of Ultrasound in Medicine published by Wiley Periodicals LLC on behalf of American Institute of Ultrasound in Medicine.)

Background Indeterminate focal liver observations in patients at risk for hepatocellular carcinoma (HCC) may require invasive biopsy or follow-up, which could lead to delays in definitive categorization and to postponement of treatment. Purpose To examine clinical effect of contrast-enhanced US (CEUS) in participants with high-risk indeterminate liver observations categorized as Liver Imaging Reporting and Data System (LI-RADS) category LR-4 (probably HCC) or LI-RADS category LR-M (probably or definitely malignant but not HCC specific) at CT or MRI. Materials and Methods This was a secondary analysis of a prospective international multicenter validation study for CEUS LI-RADS (January 2018 to August 2021). CEUS was performed within 4 weeks of CT or MRI. Tissue histologic and CT or MRI follow-up data were used as reference standards. Clinical effect of CEUS for HCC was evaluated in observations 10 mm or larger categorized as CT/MRI LR-4 and LR-M. Results Included were 109 participants (mean age, 64.3 years ± 8.3 [SD]; 68.8% [75 of 109] male participants) with 113 observations (≥10 mm) categorized as CT/MRI LR-4 (53.1%; 60 of 113) or LR-M (46.9%; 53 of 113). CEUS resulted in management recommendation changes in 33.6% (95% CI: 25, 43; 38 of 113) of observations; among these, 95% (95% CI: 82, 99; 36 of 38) were correct. A total of 30.1% (34 of 113) of CT/MRI LR-4 and LR-M observations were categorized at CEUS as LI-RADS category LR-5 (definite HCC), making biopsy unnecessary; 94% (32 of 34) of these categorizations were correct. Of CT/MRI LR-4 observations, 7% (four of 60) were categorized as CEUS LR-M; subsequent biopsy confirmed non-HCC malignancy in all participants. Clinical impact of CEUS was more substantial for observations 20 mm or larger ( n = 68); CEUS helped appropriately categorize both LR-5 and LR-M lesions as HCC and non-HCC malignancies, respectively, and resulted in management recommendation changes in 40% (27 of 68) of observations with 100% accuracy. Conclusion CEUS resolved some high-risk indeterminate liver observations (categorized as LR-4 and LR-M at CT or MRI), with particularly high clinical impact for observations measuring at least 20 mm. Clinical trial registration no. NCT03318380 © RSNA, 2025 Supplemental material is available for this article.

Purpose: To determine the diagnostic accuracy of combining CEUS and CT/MRI LI-RADS major imaging features for the improved categorization of liver observations indeterminate on both CT/MRI and CEUS., Materials and Methods: A retrospective analysis using a database from a prospective study conducted at 11 centers in North America and Europe from 2018 to 2022 included a total of 109 participants at risk for HCC who had liver observations with indeterminate characterization (LR3, LR-4, and LR-M) on both CEUS and CT/MRI. The individual CEUS and CT/MRI LI-RADS major features were extracted from the original study and analyzed in various combinations. Reference standards included biopsy, explant histology, and follow-up CT/MRI. The diagnostic performance of the combinations of LI-RADS major features for definitive diagnosis of HCC was calculated. A reverse, stepwise logistical regression sub-analysis was also performed., Results: This study included 114 observations indeterminate on both CT/MRI and CEUS. These observations were categorized as LR-3 (n = 37), LR-4 (n = 41), and LR-M (n = 36) on CT/MRI and LR-3 (n = 48), LR-4 (n = 36), LR-M (n = 29), and LR-TIV (n = 1) on CEUS. Of them, 43.0% (49/114) were confirmed as HCC, 37.3% (43/114) non-malignant, and 19.3% (22/114) non-hepatocellular malignancies. The highest diagnostic accuracy among the combinations of imaging features was achieved in CT/MRI LR-3 observations, where the combination of CEUS arterial phase hyper-enhancement (APHE) + CT/MRI APHE had 96.7% specificity, 75.0% positive predictive value (PPV), and 86.5% accuracy for HCC., Conclusion: The combination of LI-RADS major features on CT/MRI and CEUS showed higher specificity, PPV, and accuracy compared to individual modalities' assessments, particularly for CT/MRI LR-3 observations., (© 2024. The Author(s).)

Background and Aims: The objective of this study is to determine the diagnostic accuracy of the American College of Radiology Contrast-Enhanced Ultrasound (CEUS) Liver Imaging Reporting and Data System LR-5 characterization for HCC diagnosis in North American or European patients., Approach and Results: A prospective multinational cohort study was performed from January 2018 through November 2022 at 11 academic and nonacademic centers in North America and Europe. Patients at risk for HCC with at least 1 liver observation not previously treated, identified on ultrasound (US), or multiphase CT or MRI performed as a part of standard clinical care were eligible for the study. All participants were examined with CEUS of the liver within 4 weeks of CT/MRI or tissue diagnosis to characterize up to 2 liver nodules per participant using ACR CEUS Liver Imaging Reporting and Data System. Definite HCC diagnosis on the initial CT/MRI, imaging follow-up, or histology for CT/MRI-indeterminate nodules were used as reference standards. A total of 545 nodules had confirmed reference standards in 480 patients, 73.8% were HCC, 5.5% were other malignancies, and 20.7% were nonmalignant. The specificity of CEUS LR-5 for HCC was 95.1% (95% CI 90.1%-97.7%), sensitivity 62.9% (95% CI 57.9%-67.7%), positive predictive value 97.3% (95% CI 94.5%-98.7%), and negative predictive value 47.7% (95% CI 41.7%-53.8%). In addition, benign CEUS characterization (LR-1 or LR-2) had 100% specificity and 100% positive predictive value for nonmalignant liver nodules., Conclusions: CEUS Liver Imaging Reporting and Data System provides an accurate categorization of liver nodules in participants at risk for HCC., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background Contrast-enhanced (CE) US has been studied for use in the detection of residual viable hepatocellular carcinoma (HCC) after locoregional therapy, but multicenter data are lacking. Purpose To compare two-dimensional (2D) and three-dimensional (3D) CE US diagnostic performance with that of CE MRI or CT, the current clinical standard, in the detection of residual viable HCC after transarterial chemoembolization (TACE) in a prospective multicenter trial. Materials and Methods Participants aged at least 21 years with US-visible HCC scheduled for TACE were consecutively enrolled at one of three participating academic medical centers from May 2016 to March 2022. Each underwent baseline 2D and 3D CE US before TACE, 2D and 3D CE US 1-2 weeks and/or 4-6 weeks after TACE, and CE MRI or CT 4-6 weeks after TACE. CE US and CE MRI or CT were evaluated by three fellowship-trained radiologists for the presence or absence of viable tumors and were compared with reference standards of pathology (18%), angiography on re-treatment after identification of residual disease at 1-2-month follow-up imaging (31%), 4-8-month CE MRI or CT (42%), or short-term (approximately 1-2 months) CE MRI or CT if clinically decompensated and estimated viability was greater than 50% at imaging (9%). Diagnostic performance criteria, including sensitivity and specificity, were obtained for each modality and time point with generalized estimating equation analysis. Results A total of 132 participants were included (mean age, 64 years ± 7 [SD], 87 male). Sensitivity of 2D CE US 4-6 weeks after TACE was 91% (95% CI: 84, 95), which was higher than that of CE MRI or CT (68%; 95% CI: 58, 76; P < .001). Sensitivity of 3D CE US 4-6 weeks after TACE was 89% (95% CI: 81, 94), which was higher than that of CE MRI or CT ( P < .001), with no evidence of a difference from 2D CE US ( P = .22). CE MRI or CT had 85% (95% CI: 76, 91) specificity, higher than that of 4-6-week 2D and 3D CE US (70% [95% CI: 56, 80] and 67% [95% CI: 53, 78], respectively; P = .046 and P = .023, respectively). No evidence of differences in any diagnostic criteria were observed between 1-2-week and 4-6-week 2D CE US ( P > .21). Conclusion The 2D and 3D CE US examinations 4-6 weeks after TACE revealed higher sensitivity in the detection of residual HCC than CE MRI or CT, albeit with lower specificity. Importantly, CE US performance was independent of follow-up time. Clinical trial registration no. NCT02764801 © RSNA, 2023 Supplemental material is available for this article.

Background US contrast agents are gas-filled microbubbles (MBs) that can be locally destroyed by using external US. Among other bioeffects, US-triggered MB destruction, also known as UTMD, has been shown to sensitize solid tumors to radiation in preclinical models through localized insult to the vascular endothelial cells. Purpose To evaluate the safety and preliminary efficacy of combining US-triggered MB destruction and transarterial radioembolization (TARE) in participants with hepatocellular carcinoma (HCC). Materials and Methods In this pilot clinical trial, participants with HCC scheduled for sublobar TARE were randomized to undergo either TARE or TARE with US-triggered MB destruction 1-4 hours and approximately 1 and 2 weeks after TARE. Enrollment took place between July 2017 and February 2020. Safety of US-triggered MB destruction was evaluated by physiologic monitoring, changes in liver function tests, adverse events, and radiopharmaceutical distribution. Treatment efficacy was evaluated by using modified Response Evaluation Criteria in Solid Tumors (mRECIST) on cross-sectional images, time to required next treatment, transplant rates, and overall survival. Differences across mRECIST reads were compared by using a Mann-Whitney U test, and the difference in prevalence of tumor response was evaluated by Fisher exact test, whereas differences in time to required next treatment and overall survival curves were compared by using a log-rank (Mantel-Cox) test. Results Safety results from 28 participants (mean age, 70 years ± 10 [standard deviation]; 17 men) demonstrated no significant changes in temperature ( P = .31), heart rate ( P = .92), diastolic pressure ( P = .31), or systolic pressure ( P = .06) before and after US-triggered MB destruction. No changes in liver function tests between treatment arms were observed 1 month after TARE ( P > .15). Preliminary efficacy results showed a greater prevalence of tumor response (14 of 15 [93%; 95% CI: 68, 100] vs five of 10 [50%; 95% CI: 19, 81]; P = .02) in participants who underwent both US-triggered MB destruction and TARE ( P = .02). Conclusion The combination of US-triggered microbubble destruction and transarterial radioembolization is feasible with an excellent safety profile in this patient population and appears to result in improved hepatocellular carcinoma treatment response. © RSNA, 2020.