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Purpose: Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma., Methods: In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria., Results: Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis., Conclusion: An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma., (© 2021. The Author(s).)

Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy in the assessment of focal liver lesions. Clinical context (presence of liver cirrhosis, history of other malignancy versus incidental finding) is crucial for the correct interpretation of CEUS findings. CEUS has to be preceded by structured anamnesis and clinical examination as well as accurate B-mode sonography. Metastases are the most common malignant liver lesions in a non-cirrhotic liver. According to their contrast enhancement in the arterial phase, metastases are categorized as hyper- and hypo-vascular metastases. A common feature of all metastatic lesions is washout of the contrast agent in the portal venous or late phase. In the context of liver cirrhosis, > 95 % of focal liver lesions are hepatocellular carcinomas (HCCs). HCCs typically show arterial phase hyperenhancement, followed by mild and gradual contrast washout occurring very late in the late phase. For intrahepatic cholangiocellular carcinoma (ICC), the pattern of contrast enhancement in the arterial phase can vary. However, all ICCs typically show early and pronounced washout. Other liver malignancies like lymphoma, angiosarcoma, epithelioid hemangioendothelioma and others are very rare. Except for the contrast washout seen in all liver malignancies, they do not display pathognomonic enhancement patterns upon CEUS. Thus, biopsy is indispensable for definite diagnosis of the tumor entity. Furthermore, CEUS is used for the detection of metastases and therapeutic monitoring after local ablative procedures. The examination procedure differs slightly depending on the specific indication (characterization, detection)., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

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.

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 investigate the spectrum, applicability and diagnostic capacity of intravenous contrast-enhanced ultrasound imaging (CEUS) in a pediatric population. Materials and Methods: From 08/2005 to 11/2015, n = 40 pediatric patients and young adults from 0 - 26 years (Ø 11.4 ± 7.5) and 3.0 - 85.3 kg (Ø 40.8 ± 25.6) with n = 55 investigations received n = 79 IV applications of ultrasound contrast agent (UCA). UCA dose and side effects were documented. Scanned organs were the liver (n = 42), spleen (n = 9), kidney (n = 3), and testis (n = 1). Histology, surgery or reference imaging was compared to CEUS and clinical follow-up. Results: The UCA dose < 20 kg was 0.4 ± 0.3 ml, (0.05 ± 0.02 ml/kg) and > 20 kg was 1.0 ± 0.4 ml (p< 0.0001) (0.02 ± 0.01 ml/kg, p< 0.0001). Adverse effects occurred in 2/79 applications (2.5 %). Agreement CEUS/gold standard resulted in 32/34 investigations. For liver diagnostics (gold standard: MRI, CT, histology, serology), n = 11 malignant and n = 15 benign focal liver lesions were included. The specificity was 100 % (95 % CI: 0.77 - 1.00), the sensitivity was 82 % (95 % CI: 0.48 - 0.98), the positive predictive value was 100 % (95 % CI: 0.69 - 1.00) and the negative predictive value was 88 % (95 % CI: 0.62 - 0.98, p< 0.0001). In n = 2 reference imaging misdiagnosed and CEUS was in accordance with clinical follow-up. All splenic/renal lesions were diagnosed correctly. In n = 1 an insufficient testicular perfusion was ruled out. The observation time was 30.4 ± 30.5 months. Conclusion: CEUS is a well-tolerated and diagnostically equivalent modality in pediatric care, providing fundamental advantages compared to currently approved imaging modalities for these age groups., (© Georg Thieme Verlag KG Stuttgart · New York.)

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.)

The approval of microbubbles with the inert gas sulfur hexafluoride (SF6) and a palmitic acid shell (SonoVue(®), Bracco Geneva, CH) for the diagnostic imaging of liver tumors in adults and children by the FDA in the United States represents a milestone for contrast-enhanced ultrasound (CEUS).This warrants a look back at the history of the development of CEUS. The first publications based on echocardiographic observations of right ventricular contrast phenomena caused by tiny air bubbles following i. v. injection of indocyanine green appeared around 1970 1 2 3. A longer period of sporadic publications but no real progress then followed since, in contrast to X-ray methods, ultrasound works quite well without a contrast agent.It is noteworthy that the foundations for further development were primarily laid in Europe. The development and approval (1991) of the contrast agent Echovist(®) by a German contrast manufacturer for echocardiography unsuitable for passing through lungcapillaries 4 5 resulted in the first extracardiac indications, e. g. for detecting retrovesical reflux and tubal patency, in the mid-1980 s 6 7 8. The sensitivity of color Doppler was not able to compensate for the lack of an ultrasound contrast agent compared to CT with its obligatory contrast administration.Studies of SHU 508 - microbubbles of air moderately stabilized with galactose and palmitic acid - began in 1990 9 10 11 12 13 14 15 and the contrast agent was then introduced in 1995 in Germany as Levovist(®). The most important publications by Blomley, Cosgrove, Leen, and Albrecht are named here on a representative basis 16 17 18 19 20.SHU 508 along with other US contrast agents provided impressive proof of the superiority of CEUS for the diagnosis of liver metastases. However, practical application remained complicated and required skill and technical know-how because of a lack of suitable software on US units 21 22 23 24 25. The monograph regarding the use of contrast agent in the liver by Wermke and Gaßmann is impressive but unfortunately only available in German 26. In addition to being applied in the heart and the liver, CEUS was first used in transcranial applications 27 and in vessels 28, the kidneys 29, and the breast 30. Measurements at transit times were also of particular interest 31. It was difficult to convince ultrasound device manufacturers of the need to adapt US units to US contrast agents and not vice versa.The breakthrough came with low MI phase contrast inversion and the introduction of SonoVue(®) in many European countries in 2001. This more stable US contrast agent is easy to use and is becoming indispensable in diagnostic imaging of the liver 32 33 34 35 36 37 38 39 40. Studies have shown its excellent tolerability 41 and diagnostic reliability comparable to that of MDCT and MRI in the liver 42 43. Today it would be unimaginable to diagnose liver tumors without CEUS 44. This also applies to very small lesions 45 46.EFSUMB published the first CEUS guidelines in 2004 47 which have since been reissued and divided into hepatic 48 and extrahepatic applications 49. The first recommendations regarding quantitative assessment have also been published 50.The increasing scientific interest in CEUS is evident based on the greater number of PubMed hits for Echovist(®) (ca. 130), Levovist(®) (ca. 500) and SonoVue(®) (ca. 1500) as well as on the fact that publications regarding CEUS comprise almost 20 % of UiM/EJU articles in the last 10 years. The number of CEUS articles in UiM/EJU continues to be high 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75.In the clinical reality, CEUS has been able to become established alongside CT and MRI according to the saying "better is the enemy of good" 76 as the method of choice after B-mode ultrasound in the evaluation of liver tumor malignancy in Germany, where the technically challenging method is promoted. In the case of unclear CT and MRI findings, CEUS performed by an experienced examiner/clinician often provides the solution, particularly in the case of small lesions, and is the last resort before US-guided biopsy 45 46. However, there is a lack of competent CEUS examiners and Germany continues to be the world champion of X-ray examinations with no noticeable reverse trend. In almost every doctor's office and hospital, ultrasound costs are by far not fully covered, resulting in an extremely high frequency of CT use with CT being available to everyone regardless of insurance status.The USA is now in the starting position for CEUS. It will be exciting to see how the method will develop there. The FDA's decision to approve sulfur hexafluoride (Lumason(®) = SonoVue(®)) should be considered against the background of the radiation exposure caused by CT examinations and the fact that MRI using gadolinium-containing contrast agents is no longer considered noninvasive because of nephrogenic systemic fibrosis (NSF) and the accumulation of the agent in the cerebrum. An essential point of the campaign regarding the avoidance of diagnostic radiation exposure triggered in the USA by the publications of Brenner et al. 77 78 was that the agent was approved for use in the liver even for children 79 80 - still off label in Europe - without additional comprehensive studies due to the available scientific results and the very low side effects profile of Lumason(®) (= SonoVue(®)). It is admittedly unclear why other indications (except the heart which has been approved since 2014) are excluded even though the microbubbles as a pure blood pool contrast agent can be diagnostically used in the entire vascular system and bed of all organs. To our knowledge, there is no such restriction on the approval of X-ray contrast agents.Like echocardiography and emergency ultrasound, CEUS began in Europe but will probably only establish its final diagnostic value as a "reimport".This is a major opportunity to permanently define the role of Ultrasound as a highly valuable, patient-centered imaging method in the German health care system.This may prompt some of our international readers to reflect upon the role of CEUS in their own countries., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: According to the German guidelines on colorectal cancer, unenhanced ultrasound is recommended for follow-up. On the other hand, ultrasound and radiology societies specify the use of contrast-enhanced ultrasound for ruling out liver metastases. Studies focusing on the follow-up of cancer patients are lacking. The goal of this multicenter study initiated by the German Ultrasound Society (DEGUM) was to determine the potential benefit of contrast-enhanced ultrasound in the follow-up of patients with colon cancer., Materials and Methods: Follow-up patients with colon cancer (UICC > IIa) were investigated. As scheduled according to the German guidelines, unenhanced ultrasound was performed followed by contrast-enhanced ultrasound. All liver lesions were recorded. In case of additional metastases detected on contrast-enhanced ultrasound, contrast-enhanced CT, MRI or biopsy was performed to confirm additional liver metastases., Results: A total of 45 liver metastases were detected in 26/290 patients (= 9 %) using unenhanced ultrasound. A further 28 metastases were detected on contrast-enhanced ultrasound in these 26 patients. In 18 patients showing no liver metastases, 40 additional metastases were detected on unenhanced ultrasound. This means that 44 patients with a total of 113 liver metastases were detected on contrast-enhanced ultrasound (p = 0.0006)., Conclusion: Contrast-enhanced ultrasound should be recommended in the follow-up of patients with colon cancer in addition to unenhanced ultrasound - the up-to-date standard., (© Georg Thieme Verlag KG Stuttgart · New York.)

This is the first part of the Guidelines on Interventional Ultrasound of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and covers all general aspects of ultrasound-guided procedures (short version; the long version is published online)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: The aim of the study was the comparison of tumor vascularization and contrast enhancement in contrast-enhanced ultrasound (CEUS) for the characterization of hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC). We present data of the subpopulations HCC and ICC examined in the DEGUM multicenter trial for the characterization of focal liver lesions in clinical practice., Materials and Methods: Based on the data of the DEGUM multicenter trial (1349 patients), all patients with histologically proven HCC (n = 278) and ICC (n = 42) were analyzed. The vascularity pattern and contrast enhancement pattern during the arterial, portal-venous and late phase were compared., Results: An underlying liver cirrhosis was found in 214/278 patients with HCC (76.9 %) and 7/42 patients with ICC (16.7 %). In CEUS, HCC showed a global arterial hyperenhancement compared to ICC (HCC: tumor center: 60.3 %; tumor periphery: 75 %; ICC: tumor center: 16.7 %; tumor periphery: 40.5 %). ICC showed an initial contrast enhancement primarily at the tumor periphery (ICC: 85.7 % vs. HCC: 61 %) followed by an early portal-venous contrast washout in the tumor center (ICC: 85.8 % vs. HCC: 49.8 %) and tumor periphery (ICC: 66.7 % vs. HCC: 32.6 %). HCC showed a delayed contrast washout (late phase hypoenhancement: HCC: 75 % vs. ICC: 92.9 %)., Conclusion: ICCs are rare in cirrhotic livers. CEUS can demonstrate differences in the vascularization patterns between HCC and ICC. HCC showed an arterial global hyperenhancement and delayed contrast washout in the late phase. ICCs are characterized by an arterial contrast enhancement at the tumor periphery with early contrast washout of the vascularized parts of the lesions in the portal-venous and late phase., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: In order to detect an early response to anti-angiogenic therapy, this study aims at analyzing specific effects of a sorafenib-based regime on intra-tumoral D-CEUS flow parameters of patients with HCC., Materials and Methods: Videos of the arterial phase were captured before initiation of a therapy with sorafenib and 1 and 3 months after (n = 9). Patients receiving a non-anti-angiogenic therapy (TACE, n = 10) served as a comparison group. Cross-sectional imaging was performed at the same time points and patients were followed up for 1 year., Results: In the responder group (RE), the absolute (percentage) TTP was 11.28 s ± 2.03 s (1.00) before treatment, 13.60 s ± 1.52 s (1.53 ± 0.08) after one month (p = 0.0405), and 16.17 s ± 2.35 s (1.46 ± 0.07) after three months of treatment (p = 0.0071). The TTP increased significantly in the RE group as early as 1 month after initiation of sorafenib compared to the non-responder group. There were no significant differences in the non-responder group or between the NR and the TACE group at any time point. D-CEUS values from all sorafenib-treated patients showed good accordance with RECICL (response evaluation criteria in cancer of the liver) criteria (R2 = 0.7154, p = 0.0001)., Conclusions: Quantitative CEUS reveals variations of dynamic parameters of blood flow during anti-tumoral therapy in liver cancer patients. Further investigations and clinical trails have to confirm that the TTP is a promising parameter in the prediction of early response to sorafenib-based therapy., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To check the feasibility of the easy quantification of tumor vascularization derived from dynamic contrast-enhanced ultrasound (DCE-US) in comparison to dynamic contrast-enhanced computed tomography (DCE-CT) in patients with hepatocellular carcinoma (HCC)., Materials and Methods: 19 patients with cirrhosis and histologically proven HCC prospectively underwent CEUS (SonoVue) and CT (Imeron400). Following CEUS, the software ImageJ was used for the easy quantification of the echogenicity in HCC lesions and tumor-free liver parenchyma. For DCE-CT we used the software Hepacare and created arterial enhancement fraction color maps of the whole liver and HCC lesions., Results: Unifocal/multifocal HCCs were detected in 12/7 (US) and 10/9 patients (CT) and biopsied nodules were defined as a reference lesion with a median of 40 mm (US) and 42 mm (CT). CEUS showed HCC-typical hyper-/hypoenhancement in the arterial/late phase in 16/19 reference lesions, while all reference lesions showed an HCC-typical vascular pattern in CT. With DCE-US, quantitative assessment could not be performed in 3/19 patients due to respiratory motion or insufficient image quality. 13/16 reference lesions showed an HCC-typical vascular pattern. Quantitative assessment was possible with DCE-CT in all patients and all reference nodules showed HCC-typical values of the arterial enhancement fraction. There was no statistical difference between CEUS, DCE-US and DCE-CT in the quantitative assessment of contrast enhancement., Conclusion: The quantitative evaluation of DCE-US was feasible in HCC without a statistical difference with respect to DCE-CT. Further studies with a larger study population including small nodules ≤ 2 cm are needed to assess whether this technique is helpful in routine ultrasound., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Evaluation of mesenteric transit time (MTT) - measured by contrast-enhanced ultrasound - as a marker for inflammatory activity in Crohn's disease., Materials and Methods: The time of maximum enhancement of the contrast agent in the superior mesenteric artery and vein was determined visually and by software analysis. The MTT was calculated as the difference between these two time points. Findings were correlated with the Harvey-Bradshaw Index (HBI) using the Pearson correlation coefficient (r). In addition, a healthy control group was evaluated both in the fasting state and 1, 2, 3 and 4 hours postprandially., Results: In 20 healthy controls the mean visual MTT during fasting was 9.76 ± 2.83 sec and decreased to a minimum 1 hour after the meal (6.6 ± 2.27 sec). 45 patients with Crohn's disease (9 males, 36 females, mean age 35 years) had a mean HBI of 5.9 ± 4.7 points. The mean software-based MTT of 9.76 ± 3.7 sec was significantly higher (p = 0.034) than the mean visual MTT of 8.22 ± 3.05 sec. The two figures correlated well (r = 0.72, p < 0.001). The HBI correlated neither with the visual (r = 0.14, p = 0.371) nor with the software-based (r = 0.16, p = 0.293) MTT., Conclusion: The MTT decreases in the first two hours after eating. The visually assessed and the software-based MTT correlate well, however MTT does not correlate with disease activity in patients with Crohn's disease., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To evaluate the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) in the differential diagnosis of small and subcentimetric liver tumors in clinical practice., Materials and Methods: 1349 patients with a hepatic tumor lacking a definite diagnosis based on B-mode ultrasound and power Doppler ultrasound were examined at 14 hospitals by CEUS using a standardized protocol (pulse/phase inversion imaging, mechanical index < 0.4). Differential diagnosis was based on the vascularity pattern and contrast enhancement pattern during the arterial, portal, and late phase according to the EFSUMB guidelines. 335 patients with focal liver lesions (FLL) ≤ 20  mm were analyzed. The tumor status established after CEUS was compared to histology (73.2 %) or in some cases to CT or MRI., Results: A definitive diagnosis based on the gold standard was possible in 329 FLLs, while 6 FLLs remained unclear even in the combined gold standard (histology and/or CT and/or MRI). The final diagnoses of ≤ 20  mm FLL with histological confirmation (n = 241) included 87 benign and 154 malignant entities. The overall diagnostic accuracy of CEUS in FLL ≤ 20  mm with histological confirmation was 83.8 %. CEUS correctly identified 144 /154 malignant FLLs (sensitivity 93.5 %) and 58 /87 benign FLLs (specificity 66.7 %). 24 /241 FLLs remained unclear after CEUS (9.9 %). CEUS misclassified 15 /241 FLLs (6.2 %; 12 benign and 3 malignant FLLs). The positive predictive value of CEUS for a malignant FLL was 92.3 % and the negative predictive value was 95.1 %. Out of 241 small FLLs with histological confirmation, 62  FLLs were ≤ 10  mm (diagnostic accuracy of CEUS 80.6 %) and 179 FLLs were > 10  mm and ≤ 20  mm (diagnostic accuracy of CEUS 84.9 %)., Conclusion: CEUS has a high diagnostic accuracy for the differential diagnosis of small and subcentimetric FLLs in clinical practice., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: The goal of this study was to assess the informative value of contrast-enhanced ultrasound after radiofrequency ablation (RFA). Patients who had undergone RFA of malignant liver tumors were followed up with contrast-enhanced sonography (CEUS), computed tomography (CT) and/or magnetic resonance tomography (MRI), and the outcomes were compared., Materials and Methods: 76 patients undergoing 194 RFAs for 118 hepatic neoplasms (n = 55 HCC, n = 63 metastases) in the course of a 7-year period were examined post-interventionally using CEUS and CT or MRI. During follow-up (gold standard of evaluation), contrast agent rim accumulations with a diameter greater than 5 mm and a growth rate of at least 25 % were counted as a recurrence., Results: CEUS-CT comparison group: A total of 65 scan pairs were compared. In 54 cases (83.1 %) the findings were the same with either method. In 7 cases (10.8 %) CEUS confirmed the correct diagnosis, and in 2 cases (3.1 %) only CT was correct. In 2 cases (3.1 %) both methods yielded incorrect results. Diagnostic accuracy (DA): CEUS 93.8 %, CT 86.2 %. CEUS-MRI comparison group: In 23 cases (88.5 %) of a total of 26 scan pairs, the findings were the same for both CEUS and MRI. In 3 discordant cases only CEUS confirmed the correct diagnosis (3 cases, 11.5 %). Diagnostic accuracy DA (n = 26): CEUS 100 %, MRI 88.4 %., Conclusion: CEUS performs equally to CT and MRI in the follow-up of patients treated for liver tumors by RFA., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Postsurgical evaluation of bone microcirculation in osseous and osseocutaneus free flaps by contrast enhanced ultrasound (CEUS) with time intensity curve (TIC) analysis and [18F]-positron emission tomography/computed tomography (Fluoride-PET/CT)., Patients and Methods: 10 patients with osseous or osseocutaneus microvascular flaps were evaluated with CEUS. Ultrasound was carried out by an experienced examiner with a high resolution linear probe (6-9 MHz, LOGIQ E9, GE) after intravenous bolus injection of 2.4 ml SonoVue® (BRACCO, Germany). Time intensity curves (TIC) in selected regions of interest (ROI) were analyzed and compared with the evaluation of [18F]-positron emission tomography/computed tomography and the clinical course for at least 2 month., Results: 9/10 patients showed evidence for soft tissue and osseous microcirculation of the transplants in CEUS correlating with the clinical course. The soft tissue parts of the transplant showed a mean value of 84% (range 51-98%) and the bone parts a mean value of 39% (range 11-75%) for the Area under the curve (AuC) compared with the AuC for the anastomotic vessel region. Mean values for time to peak (TTP) were 27,1 sec (range 8.7-52.0 sec) for the anastomotic vessels, 29.3 sec (range 7.9-62.0 sec) for the soft tissue of and 32.0 sec (range 7.4-69.0 sec) for the transplant bone. In 1/10 patients flap failure occurred, after denudation the bone was left as an avascular transplant. AuC showed a mean value of 0.5 % for the bone region compared with the vessel region. Fluoride-PET/CT assessed bone vitality in 7 patients as "good" in 1 patient as "uncertain" and in 1 patient as "poor". CEUS assessment was corresponding with Fluoride-PET/CT in 4 patients, clinical assessment in 6 patients., Conclusion: Fluoride-PET/CT is a valuable tool to make an indirect statement about the perfusion of the transplanted bone and was used as control in this study. CEUS is a new and promising method for the evaluation of microcirculation of buried free microvascular bone grafts and the osseous part of osseocutaneous flaps and may be used for a steady monitoring in the first postoperative days.

Purpose: Liver metastases lead to a shortening of the HTT of an echo enhancer. Studies using SonoVue™ also showed a shortening of the HTT in healthy controls. Hence the HTT depends on the applied contrast agent. We examined whether the HTT of SonoVue™, Luminity™ und Levovist™ is useful to discriminate between patients with and without liver metastases., Materials and Methods: We compared the arteriovenous HTT of Levovist™, Sonovue™ und Luminity™ in 20 patients with liver metastases and in 15 controls. An Acuson Sequoia™ ultrasound system was used. The HTT results from the difference of the arrival time of the microbubbles in the hepatic artery and a hepatic vein., Results: Using Levovist™ six patients and three controls had to be excluded from further analysis. The arrival time was undetectable. The mean HTT values in healthy controls were: Levovsit™ 14.75 sec (SD ± 2.53 sec), SonoVue™ 9.27 sec (SD ± 2.41 sec) and Luminity™ 9.2 sec (SD ± 2.34 sec). In patients the mean HTT values were: Levovist™ 9.89 sec (SD ± 1.04 sec), SonoVue™ 6.28 sec (SD ± 2.41 sec) and Luminity™ 6.33 sec (SD ± 1.37 sec). Using a cut off of 8 sec for SonoVue™ and Luminity™, the sensitivity to exclude liver metastases was 75% and 80%., Conclusion: The mean HTT values of all contrast agents were shorter in patients. Levovist™ showed a longer HTT in patients and controls than Luminity™ and SonoVue™. Levovist™ showed the best separation between patients and controls but some patients and controls had to be excluded. The HTT could still be a useful tool to exclude liver metastases but the HTT depends on the contrast agent and the applied contrast technique., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To compare software-based quantification of contrast-enhanced ultrasound (CEUS) examinations of focal liver lesions in the arterial and late phases with the enhancement patterns established by the sonologist., Materials and Methods: The study cohort comprised 12 malignant and 21 benign hepatic lesions in 33 patients (18 female and 15 male; aged 57 +/- 13 years). All underwent dynamic real-time low mechanical index (<0.3) CEUS, which was stored as video sequences of the various enhancement phases. A software was used for analysis by using different regions of interest (ROI) in a double-blinded manner. The software generated and the visual enhancement patterns were compared, and the t-test was performed., Results: The videos containing the arterial phase had a mean length of 37.5 +/- 36.7 s and the late phase sequences a mean length of 15.2 +/- 9.2 s. In the arterial phase complete agreement between software and sonologist was 100%, 93.9% and 87.9% with regard to the entire lesion, its centre and its periphery, respectively. The late phase analysis revealed corresponding figures of 90.9%, 87.9% and 90.9%. In the late phase, benign lesions revealed a mean relative enhancement of +65.1 +/- 103.6% and malignant lesions -56.9 +/- 26.3% (p=0.0005) vis-à-vis liver parenchyma. All the malignant and 14% of the benign tumors showed hypo-enhancement of less than -10%., Conclusion: The complete agreement between the quantitative analysis and the sonologist within the arterial and late phase showed excellent results. Software analysis of the late phase could dichotomise benign and malignant lesions. Objective establishment of iso-enhancement in the late phase excludes malignancy., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Aim: To evaluate the incidence and diagnostic accuracy of tumor-specific vascularization pattern in contrast-enhanced ultrasound (CEUS) in the differential diagnosis of liver tumors in clinical practice., Materials and Methods: From May 2004 to December 2006 1349 patients (male 677, female 672) with a hepatic tumor lacking a definite diagnosis based on B-mode ultrasound and power Doppler ultrasound were examined at 14 hospitals by CEUS using a standardized protocol (pulse/phase inversion imaging, mechanical index < 0.4). Vascularity pattern and contrast enhancement pattern were analyzed in focal lesions during the arterial, portal, and late phase. The tumor-specific diagnosis established after CEUS was compared to histology (> 75 % cases) or in some cases to CT or MRI., Results: The final diagnosis of 573 benign hepatic tumors included hemangiomas (n = 242) and focal nodular hyperplasia (n = 170), other benign lesions (n = 161). Tumor-specific vascularization pattern such as a wheel-spoke pattern and arterial hyperenhancement followed by isoenhancement in the late phase in FNH or a nodular peripheral enhancement and partial or complete fill-in pattern in hemangiomas could be assessed in the majority, but not all lesions. The diagnostic accuracy of CEUS was 83.1 % for all benign lesions and 82.2 % for hemangioma and 87.1 % for FNH. The final diagnosis of 755 malignant hepatic tumors included metastases n = 383, hepatocellular carcinoma n = 279 and other malignant lesions n = 93. Late phase hypoenhancement was seen in almost all liver metastases (94.7 %) The diagnostic accuracy of CEUS was 95.8 % for all malignant lesions and 91.4 % for liver metastases and 84.9 % for hepatocellular carcinomas., Conclusion: Tumor-specific vascularization pattern in CEUS have a high diagnostic impact on the overall high diagnostic accuracy of CEUS for the differential diagnosis of hepatic tumors in clinical practice., ((c) Georg Thieme Verlag KG Stuttgart, New York.)

Aim: The aim of our study was to evaluate the diagnostic value of Contrast-Enhanced Ultrasound (CEUS) for the characterization of focal liver lesions in a prospective multi-center study in clinical practice. For this purpose CEUS was compared with the spiral-CT (SCT), the standard radiological method., Material and Methods: 1349 patients with unclear liver lesions after fundamental ultrasound diagnostics including color doppler analysis were examined with standardized CEUS (pulse inversion method, mechanical index < 0.4) from May 2004 to December 2006 in 14 hospitals in a prospective study. The enhancement of contrast medium in the liver tumors was analyzed according to known tumor-specific vascular patterns, using standardized documentation and analysis methods for the differentiation of tumor differentiation (malign or benign) and tumor specification (entity). A subcollective of 267 patients was additionally examined by standardized SCT method. Final diagnosis was based on histology, SCT or MRI in typical findings of liver hemangioma and FNH and on proved clinical data and additional follow up., Results: The subcollective of 267 patients was divided in two subgroups. In 109 of these patients (subgroup A) there was no histological verification, diagnoses based on clear SCT-findings in 79 cases of hemangioma or FNH, as well as in 20 cases with a clear clinical diagnosis. 6 cases (5.5 %) remained unclear. In this subgroup the assessment of tumor differentiation was concordant with CEUS in 90 cases, discordant in 19 cases and the assessment of tumor specification was concordant in 82 and and discordant in 27 cases. In 158 patients (subgroup B) a histological finding was also present, only in 4 cases no definitive tumor diagnosis was achieved. In this subgroup assessment of tumor differentiation with CEUS and SCT was concordant in 124 cases and discordant in 30 cases (CEUS/SCT: sensitivity 94.0 / 90.7 %, specificity 83.0 / 81.5 %, PPV 91.6 / 91.5 %, NPV 87.5 / 80.0 %, accuracy 90.3 / 87.8 %). Tumor specification matched in 103cases and were different in 51 cases (CEUS/SCT: sensitivity 95.3 / 90.6 %, specificity 83.7 / 81.6 %, PPV 92.7 / 91.4 %, NPV 89.1 / 80.0 %, accuracy 91.6 / 87.7 %). A statistically significant difference could not be established. The analysis of particular tumor specification showed a statistically non significant slight advantage in tumor differentiation for CEUS in the case of hemangioma, FNH, HCC and metastases., Conclusion: In a multi-center approach under routine clinical conditions, this prospective study demonstrates CEUS to be of equal rank to the CT-scan in regard to the assessment of tumor differentiation and specification. No statistically significant differences could be established. CEUS should be employed before computed tomography is performed for the differentiation of liver tumors, because radiation exposure and invasive biopsies can be avoided in veritable numbers of cases, when precise clinical evaluation of the findings is implemented., ((c) Georg Thieme Verlag KG Stuttgart, New York.)

Aim: We aimed to characterise the vascularisation patterns of hepatocellular carcinomas in contrast-enhanced sonography in correlation to the histological differentiation of hepatocellular carcinomas (HCC), and we also compared the diagnostic value of contrast-enhanced sonography in addition to B-scan sonography and power Doppler sonography., Methods: 51 hepatocellular carcinomas (21 well differentiated, 27 moderately differentiated, 3 poorly differentiated) were examined: by B-scan sonography, power Doppler sonography and contrast-enhanced sonography using phase or pulse inversion harmonic imaging with a low mechanical index (< 0.3) and second generation microbubble contrast medium (Optison, Sonovue) as echo-enhancing agent. Lesion vascularity and the kinetics of contrast enhancement within the lesions in the early arterial phase, arterial phase, portal phase and late phase were analysed. The final diagnosis of a HCC was assessed after B-scan sonography, power Doppler sonography and contrast-enhanced sonography., Results: Hypervascularisation and/or irregular tumour vascularisation could be detected in 18/48 HCCs (37.5%) by power Doppler sonography. After contrast application, 46/51 HCCs (90.2%) were identified as hyperechoic lesions during the early arterial or arterial phase with no correlation to histological differentiation. In the portal phase and late phase, the echogenicity of HCCs after contrast application was variable. A hypoechoic appearance was noted in 17/51 HCCs (33.3%) in the portal phase and in 21/51 HCCs (41.2%) in the late phase. Moderately differentiated HCCs were more often hypoechoic than well differentiated HCCs (p = 0.04)., Conclusion: Contrast-enhanced sonography is highly efficient for the detection of tumour vascularity in HCCs. The majority of HCCs--regardless of histological differentiation--can be characterised as hypervascular lesions in the early arterial and arterial phase with irregular tumour vessels using contrast-enhanced sonography. In addition to B-scan sonomorphology, contrast-enhanced sonography may offer helpful information in patients with liver cirrhosis and focal liver lesions.

The aim of this study was to evaluate changes of hepatic transit time (HTT) in patients treated by radiofrequency ablation (RFA). Five consecutive patients (2 females, 3 males; mean age 66 years) referred for treatment of liver neoplasm with percutaneous application of RFA were included in this study. The HTT of contrast agent (Sonovue(R); Bracco International B.V., Amsterdam, The Netherlands) was measured in patients with liver metastases on the basis of time intensity curve (TIC(R)) before and after RFA, respectively. Changes of HTT before vs after RFA were compared with therapeutic response based on three-phase dynamic CT or MRI. Before RFA HTT in all 5 patients was less than 10 s (mean 6.2+/-1.5 s). After RFA HTT in patients with complete therapeutic response was 11.3+/-1.2 s, whereas two patients with incomplete treatment showed unchanged HTT below 10 s (mean 6.3+/-1.8 s). Successful RFA leads to a normalization in HTT. HTT using ultrasound contrast agent appears to provide a new and alternative approach in assessing the therapeutic effect of RFA in liver metastases.

Objective: Can sonographic measurements of the transit time of an echo enhancer from the hepatic artery to the hepatic vein discriminate between patients with and without liver metastases?, Method: The hepatic transit time (hepatic artery to hepatic vein delay) of an echo enhancer (Optison) was measured in pulse inversion mode on the basis of time intensity curves (TIC) in patients with gastrointestinal tumours with proven liver metastases and in patients without liver metastases., Results: Sixty-four patients (46 males, 18 females, mean age 61 +/- 13 years) were admitted to the study. Fourteen patients had metastatic growth in the liver with a primary tumour in situ (group A). Fourteen patients had liver metastases following primary tumour resection (group B). Twenty-eight patients had a known primary tumour but no liver metastases (group C), and eight patients had neither liver symptoms nor a primary tumour (group D). The mean hepatic transit time in patients with liver metastases was 6.6 +/- 1.8 s in group A and 6.7 +/- 1.7 s in group B, whereas in patients without liver metastases it was significantly longer; namely, 15.7 +/- 4.4 s in group C and 15.0 +/- 2.0 s in group D (P < 0.001). The transit times in all patients with liver metastases were < or = 10 s, while in all patients without metastases except for four the times were > or = 12 s and one of the four had already developed liver metastases on early follow-up., Conclusions: Measurement of the hepatic transit time permits discrimination of patients with and without liver metastases.

Aim: To compare detection rates for liver metastases for conventional ultrasound, US using tissue harmonic imaging (THI), echo-enhanced pulse inversion harmonic imaging using Optison and Levovist., Method: In 73 patients with histologically proven gastrointestinal tumors spiral CT (S-CT), conventional US, US in the THI-mode, echo-enhanced ultrasound in the portal venous phase (ECI Optison ) and in the liver specific late phase (ECI Levovist) were performed and reviewed by blinded readers., Results: 73 patients (25 female, 48 male, age 63 +/- 11) were included. S-CT detected 158 liver metastases. Conventional US detected 117, THI 119, ECI Optison 169 and ECI Levovist 166 liver metastases. Especially for small (< 2 cm) liver metastases and metastases near the diaphragm echo-enhanced ultrasound exceeded conventional US (p < 0.001). Between both echo enhancers there was no significant difference., Conclusion: Using echo enhancers increases the ultrasound detection rate significantly. Examination in the portalvenous phase using a second generation enhancer (Optison) is equal to a late-phase examination using Levovist.

Background and Aims: We compared contrast-enhanced power Doppler sonography (CEPD) and phase-inversion harmonic imaging (PIHI) in the assessment of liver lesion vascularity and characterization of focal liver lesions., Materials and Methods: We examined 101 focal liver lesions by CEPD and PIHI using Optison as echo-enhancing agent. Amount and architecture of lesion vascularity and the kinetics of contrast enhancement in the lesions were analyzed. A tumor diagnosis was assessed after each examination., Results: Analysis of tumor vascularity was not possible in 30 liver lesions (30%) due to motion or blooming artifacts by CEPD. Vascularity was detected in 61% of liver lesions by CEPD and in 95% by PIHI. PIHI identified significantly more tumor vascularity pattern (93%) than CEPD (57%). Specific lesion diagnosis based on PIHI led to correct results in 92% compared to 59% by CEPD., Conclusion: PIHI is highly efficient in detecting tumor vascularity and is superior to CEPD in characterizing focal liver lesions.

The aim of this paper was to investigate the diagnostic value of dynamic contrast-enhanced power Doppler sonography in the differential diagnosis of liver lesions. We prospectively examined 85 focal liver lesions in 71 patients by real-time gray-scale sonography, power Doppler sonography, and contrast-enhanced power Doppler using two ultrasound contrast agents (Levovist, Optison). Amount and architecture of lesion vascularity and the kinetics of contrast enhancement within the lesions were analyzed. Vascularity was detected in 61% of liver lesions (52/85) by conventional power Doppler, compared to 86% (73/85) by contrast-enhanced power Doppler sonography. Dynamic contrast-enhanced power Doppler identified arterial radial hypervascularity <16 s after contrast injection in 19/22 focal nodular hyperplasias (86%). Irregular hypervascularity was seen with contrast enhancement in the arterial phase in 14/15 hepatocellular carcinomas (93%). In 14/25 hemangiomas (56%), a circular vascularization pattern was noted. Specific lesion diagnosis based on B-scan and conventional and dynamic contrast-enhanced power Doppler sonography led to correct diagnosis in 86% (73/85, 95% confidence interval 78%-94%) compared to 57% (48/85, 95% confidence interval 47%-94%) by B-scan criteria and conventional power Doppler sonography. Contrast-enhanced power Doppler sonography improves diagnostic accuracy in the differential diagnosis of focal liver lesions.

Objective: To compare the detection rate of conventional ultrasonography and contrast-enhanced wide-band harmonic ultrasonographic imaging in the detection of small liver metastases., Methods: Consecutive patients with histologically proved gastrointestinal carcinoma liver metastases were studied. Biphasic helical computed tomography, conventional ultrasonography, and contrast-enhanced wide-band harmonic imaging were performed on all patients within a 5-day period. The biphasic helical computed tomographic scans were reviewed and interpreted by a skilled radiologist. The number of lesions and their descriptive characteristics were recorded for analysis. In addition, videotape recordings of the conventional ultrasonography and contrast-enhanced wide-band harmonic imaging were blindly reviewed, after which the number of detected lesions and their characteristics were then compared with those detected on biphasic helical computed tomography, considered the standard of reference., Results: Twenty-eight patients (10 female and 18 male; age range, 45-72 years) were studied. Conventional ultrasonography detected 37 (59%) of all lesions visualized by biphasic helical computed tomography. The detection rate for contrast-enhanced wide-band harmonic imaging was significantly higher (61 [97%] of 63). In our series, two 10-mm lesions near the diaphragm were not visualized by wide-band harmonic imaging., Conclusions: The use of contrast-enhanced imaging techniques significantly improves the ultrasonographic detection of liver metastases. Our results achieved the sensitivity of biphasic helical computed tomography.

Purpose: We investigated the value of contrast-enhanced color Doppler sonography in the differential diagnosis of liver tumors., Methods: We prospectively examined 105 focal liver lesions in 100 patients by real-time gray-scale sonography, color Doppler sonography, and contrast-enhanced color Doppler sonography with galactose-based microbubbles (SH U 508A; Levovist). The final diagnoses of the liver lesions as confirmed by pathology or additional imaging techniques were 31 metastases, 25 hemangiomas, 19 hepatocellular carcinomas, 19 focal nodular hyperplasias, 2 cholangiocellular carcinomas, and 9 other lesions., Results: Vascularity could be detected in 43 (41%) of the 105 lesions by conventional color Doppler sonography compared to 67 (64%) by contrast-enhanced color Doppler sonography. Contrast-enhanced color Doppler sonography identified moderate or extensive vascularity in all 19 focal nodular hyperplasias, moderate or extensive vascularity in 16 hepatocellular carcinomas and both cholangiocellular carcinomas, and no or minor vascularity in all but 3 hemangioma. The combination of gray-scale, conventional color Doppler, and contrast-enhanced color Doppler sonography led to the correct diagnosis in 81% of cases (85 of 105), compared to 57% (60/105) for gray-scale and conventional color Doppler sonography and 31% (33/105) for gray-scale sonography alone., Conclusions: Contrast-enhanced color Doppler sonography improves the detection of tumor vascularity and is useful in the differential diagnosis of liver lesions., (Copyright 2000 John Wiley & Sons, Inc.)