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Purpose: Liver histology has prognostic relevance and is used in surveillance and therapeutic strategies. This longitudinal study was designed to evaluate the prognostic relevance of ARFI elastography in comparison to liver histology and to the FIB-4 score in a 5-year observation interval., Materials and Methods: Based on the hospital database, patients with an elastography examination of the liver between 2010-2012, a liver biopsy, and a follow-up of 5 years were included in the study. The AUROCs of the events liver-related death, HCC, and liver decompensation/variceal bleeding were calculated for ARFI elastography, liver histology, and FIB-4 and compared using the DeLong test., Results: In the final analysis 113 patients were included with 30 (26.5 %) patients having high-grade fibrosis and 19 (16.8 %) having liver cirrhosis in histology. The AUROC for liver-related death in the 5-year interval (9.7 %, n=11) was 0.80 [0.68-0.92] for ARFI elastography, 0.79 [0.66-0.92] for liver histology, and 0.66 [0.53-0.79] for FIB-4 with a p-value of 0.83 comparing ARFI to histology and a p-value of 0.02 comparing ARFI to FIB-4. The AUROC for liver decompensation/variceal bleeding (13.3 %, n=15) was 0.86 [0.76-0.94] for ARFI, which is significantly higher than the AUROC of liver histology with 0.71 [0.56-0.86] (p=0.02) and FIB-4 with 0.67 [0.54-0.80] (p=0.003). There was no significant difference for the event HCC when comparing ARFI to histology (p=0.33) or FIB-4 (p=0.14)., Conclusion: The prognostic value of ARFI elastography seems to not be inferior to liver histology regarding liver-related survival and might even outperform histology and the FIB-4 score for predicting some liver-related complications., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: Shear wave dispersion imaging is a novel ultrasound-based technique, which analyzes the speed of different shear wave components depending on their frequency. The dispersion of shear wave speed correlates with the viscosity of the liver parenchyma. The aim of this prospective study was to evaluate the use of shear wave dispersion imaging in focal liver lesions in the non-cirrhotic liver., Methods: Patients with unclear focal liver lesions in B-mode ultrasound were prospectively assigned to shear wave dispersion imaging (m/s/kHz). Measurements were conducted within the lesion and in the liver parenchyma of the right liver lobe using an intercostal window. Histology and contrast-enhanced ultrasound served as the reference for the characterization of the lesions., Results: Out of 46 patients included in this study, 24 had liver metastases and 22 had benign liver lesions. Benign lesions consisted mostly of hemangiomas (n=12) and focal nodular hyperplasia (n=8). Malignant lesions showed significantly lower shear wave dispersion (13.0±2.45 m/s/kHz) compared to benign tumors (15.2±2.74 m/s/kHz, p<0.01). In further subgroup analysis, the difference was significant for hemangiomas (15.32±2.42 m/s/kHz, p=0.04) but not for FNHs (14.98±3.36 m/s/kHz, p=0.38). The dispersion of reference liver parenchyma did not differ significantly between the groups (p=0.54)., Conclusion: The quantification of viscosity by shear wave dispersion is a new parameter for the characterization of focal liver lesions with higher dispersion values in hemangiomas and lower dispersion values in metastases. However, it cannot differentiate reliably between benign and malignant lesions., Competing Interests: D. Jesper and B. Schellhaas have received speaker honorarium from Canon Medical Systems., (Thieme. All rights reserved.)

BACKGROUNDEnhancement patterns on contrast-enhanced ultrasound (CEUS) help to distinguish different liver tumors., Objective: Assessing the diagnostic value of dynamic contrast-enhanced ultrasound (DCEUS) for the discrimination of different malignant liver lesions., Methods: 148 malignant focal liver lesions were assessed prospectively with DCEUS (hepatocellular carcinoma = HCC; cholangiocellular carcinoma = CCC; pancreatic adenocarcinoma = PCA; breast cancer = BC; colorectal cancer = CRC; melanoma = MM). Focal-nodular-hyperplasias (FNH) served as a reference for benign lesions. DCEUS-clips were recorded continuously over three minutes. DCEUS-values were compared between the tumor entities. For better inter-individual comparability, perfusion kinetics were analyzed considering the perfusion characteristics of the surrounding liver parenchyma (Relative Signal Intensity = RSI: lesion-liver tissue/liver tissue) at different points in time., Results: Absolute signal intensity in FNH showed a tendency towards higher values compared with malignant liver lesions [Peak Enhancement(a.u.): FNH 7111.4; HCC 549.9; CCC -6654.3; PCA -7307.9; BC -4562.4; CRC -10672.9; MM -3034.1]. Washout was significantly less in FNH versus PCA and CRC, and more pronounced and earlier in PCA and CRC versus HCC [RSI 30 seconds after PE-lesion(%): FNH +52; PCA -65; CRC -76; HCC -26]. Rise Time, Fall Time and mean-Transit-Time did not differ significantly., Conclusions: DCEUS-values reflect significant differences between malignant liver lesions, especially at peak enhancement and during the washout phases.

Objectives:  This pilot study aimed at assessing interobserver agreement with two contrast-enhanced ultrasound (CEUS) algorithms for the diagnosis of hepatocellular carcinoma (HCC) in high-risk patients., Methods:  Focal liver lesions in 55 high-risk patients were assessed independently by three blinded observers with two standardized CEUS algorithms: ESCULAP (Erlanger Synopsis of Contrast-Enhanced Ultrasound for Liver Lesion Assessment in Patients at risk) and ACR-CEUS-LI-RADSv.2016 (American College of Radiology CEUS-Liver Imaging Reporting and Data System). Lesions were categorized according to size and ultrasound contrast enhancement in the arterial, portal-venous and late phase. Interobserver agreement for assessment of enhancement pattern and categorization was compared between both CEUS algorithms. Additionally, diagnostic accuracy for the definitive diagnosis of HCC was compared. Histology and/or CE-MRI and follow-up served as reference standards., Results:  55 patients were included in the study (male/female, 44/ 11; mean age: 65.9 years). 90.9 % had cirrhosis. Histological findings were available in 39/55 lesions (70.9 %). Reference standard of the 55 lesions revealed 48 HCCs, 2 intrahepatic cholangiocellular carcinomas (ICCs), and 5 non-HCC-non-ICC lesions. Interobserver agreement was moderate to substantial for arterial phase hyperenhancement (ĸ = 0.53 - 0.67), and fair to moderate for contrast washout in the portal-venous or late phase (ĸ = 0.33 - 0.53). Concerning the CEUS-based algorithms, the interreader agreement was substantial for the ESCULAP category (ĸ = 0.64 - 0.68) and fair for the CEUS-LI-RADS ® category (ĸ = 0.3 - 0.39). Disagreement between observers was mostly due to different perception of washout., Conclusion:  Interobserver agreement is better for ESCULAP than for CEUS-LI-RADS ® . This is mostly due to the fact that perception of contrast washout varies between different observers. However, interobserver agreement is good for arterial phase hyperenhancement, which is the key diagnostic feature for the diagnosis of HCC with CEUS in the cirrhotic liver., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Therapeutic approaches in the treatment of hepatocellular carcinoma (HCC) depend on tumour stage, liver function and patient comorbidities. The aim of this study was to investigate the influence of tumour stage and therapeutic approach on overall survival in HCC., Materials and Methods: Two hundred and fourteen patients with HCC diagnosed between December 2012 and May 2017 were assessed retrospectively for tumour stage [Barcelona Clinic Liver Cancer (BCLC)], liver function (Child-Pugh score), therapeutic approach and outcome (mean survival time). The results were compared to two historical cohorts from our centre diagnosed between 1999 and 2013 and 1988 and 1999, respectively., Results: Nowadays, HCC is diagnosed in earlier tumour stages and with better liver function compared with the historical cohorts (P<0.001). Survival times depend on both BCLC stages and liver function for all therapeutic approaches. The 1-year survival rate in the present cohort was 79.4% compared with 58.6% in the historical cohort.In terms of BCLC stages, therapeutic approaches followed HCC guidelines in 43.9% of cases.Whereas the percentage of patients receiving resection or ablation did not change between the historical and the present cohort, there was a tendency towards a decrease in transarterial chemoembolization, with a shift towards selective internal radiotherapy, accompanied by an increase in systemic therapy with sorafenib.Also, the percentage of patients receiving single instead of multiple therapies was significantly higher in the present cohort compared with the historical cohort (P=0.016). In 62/83 patients receiving single therapy (64.7%), tumour remission was maintained during the period of follow-up., Conclusion: HCC is increasingly being diagnosed in earlier stages, so that single therapy is often sufficient. Besides BCLC stages, therapy in HCC must consider liver function, tumour location, local expertise and patients' comorbidities and preferences. Further research is needed to evaluate the benefit of early multimodal concepts. Therapeutic approaches in HCC remain individual decisions.

Objectives: We compared the interobserver agreement for the recently introduced contrast-enhanced ultrasound (CEUS)-based algorithm CEUS-LI-RADS (Liver Imaging Reporting and Data System) versus the well-established magnetic resonance imaging (MRI)-LI-RADS for non-invasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients., Methods: Focal liver lesions in 50 high-risk patients (mean age 66.2 ± 11.8 years; 39 male) were assessed retrospectively with CEUS and MRI. Two independent observers reviewed CEUS and MRI examinations, separately, classifying observations according to CEUS-LI-RADSv.2016 and MRI-LI-RADSv.2014. Interobserver agreement was assessed with Cohen's kappa., Results: Forty-three lesions were HCCs; two were intrahepatic cholangiocarcinomas; five were benign lesions. Arterial phase hyperenhancement was perceived less frequently with CEUS than with MRI (37/50 / 38/50 lesions = 74%/78% [CEUS; observer 1/observer 2] versus 46/50 / 44/50 lesions = 92%/88% [MRI; observer 1/observer 2]). Washout appearance was observed in 34/50 / 20/50 lesions = 68%/40% with CEUS and 31/50 / 31/50 lesions = 62%/62%) with MRI. Interobserver agreement was moderate for arterial hyperenhancement (ĸ = 0.511/0.565 [CEUS/MRI]) and "washout" (ĸ = 0.490/0.582 [CEUS/MRI]), fair for CEUS-LI-RADS category (ĸ = 0.309) and substantial for MRI-LI-RADS category (ĸ = 0.609). Intermodality agreement was fair for arterial hyperenhancement (ĸ = 0.329), slight to fair for "washout" (ĸ = 0.202) and LI-RADS category (ĸ = 0.218) CONCLUSION: Interobserver agreement is substantial for MRI-LI-RADS and only fair for CEUS-LI-RADS. This is mostly because interobserver agreement in the perception of washout appearance is better in MRI than in CEUS. Further refinement of the LI-RADS algorithms and increasing education and practice may be necessary to improve the concordance between CEUS and MRI for the final LI-RADS categorization., Key Points: • CEUS-LI-RADS and MRI-LIRADS enable standardized non-invasive diagnosis of HCC in high-risk patients. • With CEUS, interobserver agreement is better for arterial hyperenhancement than for "washout". • Interobserver agreement for major features is moderate for both CEUS and MRI. • Interobserver agreement for LI-RADS category is substantial for MRI, and fair for CEUS. • Interobserver-agreement for CEUS-LI-RADS will presumably improve with ongoing use of the algorithm.

Objective: A comparison is made of two contrast-enhanced ultrasound (CEUS) algorithms for the diagnosis of hepatocellular carcinoma (HCC) in high-risk patients: Erlanger Synopsis of Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at Risk (ESCULAP) and American College of Radiology Contrast-Enhanced Ultrasound-Liver Imaging Reporting and Data System (ACR-CEUS-LI-RADSv.2016)., Patients and Methods: Focal liver lesions in 100 high-risk patients were assessed using both CEUS algorithms (ESCULAP and CEUS-LI-RADSv.2016) for a direct comparison. Lesions were categorized according to size and contrast enhancement in the arterial, portal venous and late phases.For the definite diagnosis of HCC, categories ESCULAP-4, ESCULAP-Tr and ESCULAP-V and CEUS-LI-RADS-LR-5, LR-Tr and LR-5-V were compared. In addition, CEUS-LI-RADS-category LR-M (definitely/probably malignant, but not specific for HCC) and ESCULAP-category C [intrahepatic cholangiocellular carcinoma (ICC)] were compared.Histology, CE-computed tomography and CE-MRI served as reference standards., Results: The reference standard among 100 lesions included 87 HCCs, six ICCs and seven non-HCC-non-ICC-lesions. For the diagnosis of HCC, the diagnostic accuracy of CEUS was significantly higher with ESCULAP versus CEUS-LI-RADS (94.3%/72.4%; p<0.01). Sensitivity, specificity and positive predictive value (PPV) and negative predictive value for ESCULAP/CEUS-LI-RADS were 94.3%/72.4%; 61.5%/69.2%; 94.3%/94%; and 61.5%/27.3%, respectively.The diagnostic accuracy for ICC (LR-M/ESCULAP-C) was identical with both algorithms (50%), with higher PPV for ESCULAP-C versus LR-M (75 vs. 50%)., Conclusion: CEUS-based algorithms contribute toward standardized assessment and reporting of HCC-suspect lesions in high-risk patients. ESCULAP shows significantly higher diagnostic accuracy, sensitivity and negative predictive value with no loss of specificity compared with CEUS-LI-RADS. Both algorithms have an excellent PPV. Arterial hyperenhancement is the key feature for the diagnosis of HCC with CEUS. Washout should not be a necessary prerequisite for the diagnosis of definite HCC. CEUS-LI-RADS in its current version is inferior to ESCULAP for the noninvasive diagnosis of HCC. There are two ways to improve CEUS-LI-RADS: firstly, combination of the categories LR-4 and LR-5 for the diagnosis of definite HCC, and secondly, use of subtotal infiltration of a liver lobe as an additional feature.

Background: Contrast-enhanced ultrasound (CEUS) is a valuable tool in the diagnostic approach of focal liver lesions, but occasionally subjective and observer-dependent. Semiquantitative evaluation of dynamic CEUS (DCEUS) with standardised software programmes such as Dynamic Vascular Pattern (DVP) could help to improve diagnostic accuracy and objectivity in liver tumour assessment., Objectives: The present study aimed at evaluation of diagnostic accuracy of DVP in a clinical setting., Materials and Methods: DVP images of 52 focal liver lesions [30 hepatocellular carcinomas (HCCs), 15 intrahepatic cholangiocellular carcinomas (ICCs), 7 focal nodular hyperplasias (FNHs)] were analysed by four blinded observers with different levels of CEUS-experience. Diagnostic accuracies for the assessment of dignity and entity were evaluated., Results: Mean sensitivity, specificity, positive and negative predictive value for detection of malignancy with DVP were 48.4% /67.8% /92.7% and 29.3%, respectively. Total diagnostic accuracies for dignity/entity were 63.9% /38.5% (HCC: 58.3% /25.8%; ICC: 73.3% /50%; FNH: 67.9% /67.9%). Interreader-agreement was moderate (κ= 0.42-0.58). Differential diagnosis between ICC and HCC was most challenging., Conclusion: Although developed to improve diagnostic accuracy and objectivity in the assessment of focal liver lesions, DVP alone seems insufficient for differential diagnosis of HCC, ICC and FNH and cannot replace the skills of an experienced observer.

Purpose: To develop a contrast-enhanced ultrasound algorithm (LI-RADS-CEUS = liver imaging reporting and data system with contrast-enhanced ultrasound) for the diagnosis of hepatocellular carcinoma (HCC) in patients at risk. Materials and Methods: A CEUS algorithm (LI-RADS-CEUS) was designed analogously to CT- and MRI-based LI-RADS. LI-RADS-CEUS was evaluated retrospectively in 50 patients at risk with confirmed HCC or non-HCC lesions (test group) with subsequent validation in a prospective cohort of 50 patients (validation group). Results were compared to histology, CE-CT and CE-MRI as reference standards. Results: Tumor diagnosis in the test group/validation group (n = 50/50) were 46/41 HCCs, 3/3 intrahepatic cholangiocellular carcinomas (ICCs) and 1/6 benign lesions. The diagnostic accuracy of LI-RADS-CEUS for HCC, ICC and non-HCC-non-ICC-lesions was 89 %. For the diagnosis of HCC, the diagnostic accuracy was 93.5 % (43/46 cases) in the test group and 95.1 % (39/41 cases) in the validation group. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 94.3 %, 66.6 %, 94.3 % and 66.6 %, respectively (mean values from both cohorts). Histological findings of HCC were available in 40 versus 23 cases (in total: G1 / G2/G3: 15/35/13). Arterial hyperenhancement was seen in 68/87 (78.2 %) of HCCs. Arterial hyperenhancement with subsequent portal venous or late phase hypoenhancement was seen in 66 % of HCCs. Conclusion: LI-RADS-CEUS offers a CEUS algorithm for standardized assessment and reporting of focal liver lesions in patients at risk for HCC. Arterial hyperenhancement in CEUS is the key feature for the diagnosis of HCC in patients at risk, whereas washout is not a necessary prerequisite., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: In a prospective study, we compared the different perfusion kinetics of HCC and ICC using dynamic contrast-enhanced ultrasound (DCE-US)., Materials and Methods: Patients with proven HCC and ICC were included. Three-minute video clips of CEUS examinations (CPS - low MI mode) after a bolus injection of 1.2 ml SonoVue were recorded and analyzed with quantification software (VueBox). Parameters for the arterial contrast enhancement [rise time (RT), time-to-peak (TTP)] towards portal venous contrast enhancement [mean transit time (local) (mTTl) and fall time (FT)] were quantified. Furthermore, contrast wash-out after peak enhancement (PE) (40 s, 80 s, 100 s and 120 s after PE) was compared between HCC and ICC., Results: 43 patients with proven HCC (n = 23 HCC; cirrhosis n = 16) and ICC (n = 20 ICC; Cirrhosis n = 6) were examined. No statistical difference of the arterial DCEUS parameters was found between HCC and ICC. Contrast enhancement of the portal venous and late phases showed significantly lower values in the ICC group indicating early wash-out of the contrast agent: mTTl (p = 0.0209): HCC 118.4 s (SD± 88.4); ICC 64.8 s (SD± 49.7). FT (p = 0.0433): HCC 42.5 s (SD± 27.7); ICC 27.7 s (SD± 16.2). The percental loss of intensity at a definite time point after PE was significantly higher in ICC than in HCC lesions., Conclusion: DCE-US is able to detect and quantify differences in perfusion kinetics between HCC and ICC. Whereas arterial contrast enhancement patterns may overlap between HCC and ICC, a timed characterization of wash-out kinetics may offer an additional tool to characterize HCC and ICC. The presence of a rapid loss of signal intensity in the early portal venous phase is significantly higher in ICC than in HCC lesions., (© Georg Thieme Verlag KG Stuttgart · New York.)