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    B-Mode Ultrasonography versus Contrast-Enhanced Ultrasonography for Surveillance of Hepatocellular Carcinoma: A Prospective Multicenter Randomized Controlled Trial. Liver cancer BACKGROUND:Current practice guidelines recommend the use of ultrasound (US) as an initial surveillance tool for hepatocellular carcinoma (HCC) in patients with liver cirrhosis. Patients with liver cirrhosis, however, frequently have coarse liver parenchyma, masking the presence of tiny nodules during B-mode US. Contrast-enhanced US (CEUS) with Sonazoid has a long-lasting, stable Kupffer phase, which makes it possible to scan the entire liver to depict small lesions. In addition, defect reperfusion imaging (reinjection imaging) enables to determine whether the detected nodule is HCC or not. This prospective, multicenter, randomized, controlled trial was conducted to demonstrate the usefulness of Kupffer phase surveillance in the detection of small HCC compared to B-mode US. METHODS:A total of 23 institutions joined this study. In total, 656 patients with hepatitis B- or C-related liver cirrhosis were randomized either to the B-mode US surveillance group ( = 313) or the Kupffer phase CEUS with Sonazoid surveillance group ( = 309). The primary endpoint was the maximum size of HCC at the time of the first detection. Secondary endpoints included time to HCC detection, number of tumors, and Barcelona Clinic Liver Cancer stage at the first detection, and sensitivity, specificity, and accuracy of each method in the diagnosis, and the cumulative detection rate of HCC. RESULTS:The mean HCC size at the first detection was significantly smaller in the CEUS (13.0 ± 4.1 mm; = 28) than in the B-mode US group (16.7 ± 4.1 mm; = 26) (p = 0.011). Of the 38 patients with HCV cirrhosis diagnosed with HCC by US alone, mean tumor size at the first detection was significantly smaller in the 20 patients diagnosed by CEUS alone than in the 18 diagnosed by B-mode US alone (12.7 ± 3.1 vs. 17.6 ± 7.0 mm, = 0.012). In contrast, among the 16 patients with HBV cirrhosis diagnosed by US alone, mean tumor size at the first detection was similar in the 8 patients diagnosed by CEUS alone and the 8 diagnosed by B-mode US (13.6 ± 6.0 vs. 14.5 ± 2.7 mm, = 0.715). CONCLUSION:Kupffer phase CEUS surveillance with Sonazoid is extremely useful for the early detection and confirmation of HCC using a reinjection technique. Kupffer phase CEUS with Sonazoid contrast combined with the reinjection technique is, therefore, recommended as first-line screening tool for HCC in patients with liver cirrhosis, especially those with very coarse liver parenchyma. 10.1159/000501082
    The role of contrast enhanced ultrasound (CEUS) in the assessment of liver nodules in patients with cirrhosis. Dănilă Mirela,Sporea Ioan,Sirli Roxana,Popescu Alina,Sendroiu Mădălina,Martie Alina Medical ultrasonography Liver cirrhosis is a major risk factor for the development of hepatocellular carcinoma, hence the need to screen those patients by means of liver ultrasound every 6 months. The differential diagnosis between a regenerative nodule, a dysplastic one and hepatocellular carcinoma is made based on a contrast imaging method (CEUS, MRI or CT) as they all have comparative sensitivities.
    Integration of Contrast-enhanced US into a Multimodality Approach to Imaging of Nodules in a Cirrhotic Liver: How I Do It. Jo Patricia C,Jang Hyun-Jung,Burns Peter N,Burak Kelly W,Kim Tae Kyoung,Wilson Stephanie R Radiology Accurate characterization of cirrhotic nodules and early diagnosis of hepatocellular carcinoma (HCC) are of vital importance. Currently, computed tomography (CT) and magnetic resonance (MR) imaging are standard modalities for the investigation of new nodules found at surveillance ultrasonography (US). This article describes the successful integration of contrast material-enhanced US into a multimodality approach for diagnosis of HCC and its benefits in this population. The application of contrast-enhanced US immediately following surveillance US allows for prompt dynamic contrast-enhanced evaluation, removing the need for further imaging of benign lesions. Contrast-enhanced US also provides dynamic real-time assessment of tumor vascularity so that contrast enhancement can be identified regardless of its timing or duration, allowing for detection of arterial hypervascularity and portal venous washout. The purely intravascular nature of US contrast agents is valuable as the rapid washout of nonhepatocyte malignancies is highly contributory to their differentiation from HCC. The authors believe contrast-enhanced US provides complementary information to CT and MR imaging in the characterization of nodules in high-risk patients. RSNA, 2017 Online supplemental material is available for this article. 10.1148/radiol.2016151732
    Evaluation of contrast-enhanced ultrasound for diagnosis of dysplastic nodules with a focus of hepatocellular carcinoma in liver cirrhosis patients. Wu Wei,Chen Minhua,Yan Kun,Dai Yin,Yin Shanshan,Yang Wei,Fan Zhihui Chinese journal of cancer research = Chung-kuo yen cheng yen chiu OBJECTIVE:To compare the enhancement features of dysplastic nodules with a focus of hepatocellular carcinoma (DN-HCC) versus HCC and regenerative nodules (RN) in cirrhotic patients. METHODS:One hundred and ninety-three cirrhotic patients were enrolled in this study; they had 215 focal liver lesions, 1.0-3.5 cm in size, which were examined using contrast-enhanced ultrasound (CEUS) with SonoVue(®) and diagnosed as HCC, RN or DN-HCC by biopsy. Samples were obtained using 18-gauge needles in the different enhanced areas. The enhancement features of DN-HCC, HCC and RN were evaluated. RESULTS:There were 86 HCC lesions, 102 RN lesions, and 27 DN-HCC lesions diagnosed by biopsy. Of 86 HCC lesions, 87.2% (75/86) showed complete enhancement during the arterial phase, and 12.8% (11/86) had inhomogeneous enhancement, with no enhancement in the central area during the arterial phase; 100% (86/86) exhibited washout during the late phase. Of 102 RN lesions, 95.1% (97/102) had delayed or simultaneous enhancement during the arterial phase, and 4.9% (5/102) displayed slight enhancement during the arterial phase; 26.5% (27/102) exhibited washout and 73.5% (75/102) exhibited no washout during the late phase. In 27 DN-HCC lesions, only part of the lesions enhanced during the arterial phase and washed out during the late phase; the other areas had delayed or simultaneous enhancement during the arterial phase, and 29.6% (8/27) exhibited slight washout in the late phase. In 86 HCCs, the pathological feature was HCC in the enhanced area of 75 lesions, hepatocellular fatty degeneration in the slightly enhanced area of 7 lesions, and hepatocellular necrosis in the unenhanced area and HCC in the enhanced area of 4 lesions. In 102 RNs, the pathological diagnosis was hepatocyte proliferation with or without fatty degeneration. In 27 DN-HCCs, the pathological feature was HCC in the enhanced area and hepatocyte regeneration in the unenhanced area. CONCLUSIONS:CEUS is useful for the diagnosis of focal liver lesions in cirrhotic patients. CEUS can help determine the progression from RN to DN-HCC to HCC by analyzing the hemodynamics. CEUS can promote the diagnostic accuracy of a biopsy by providing more accurate information on the site of the biopsy. 10.3978/j.issn.1000-9604.2015.02.06
    Characterization of dysplastic nodules, early hepatocellular carcinoma and progressed hepatocellular carcinoma in cirrhosis with contrast-enhanced ultrasound. Giorgio Antonio,Calisti Giorgio,di Sarno Antonella,Farella Nunzia,de Stefano Giorgio,Scognamiglio Umberto,Giorgio Valentina Anticancer research BACKGROUND:During the progression from low-grade dysplastic nodule (DN) to progressed hepatocellular carcinoma (HCC), intranodular portal tracts gradually disappear, while unpaired arteries develop increasingly. Contrast-enhanced ultrasound (CEUS) is highly accurate in depicting intranodular vascularity. This study evaluates the usefulness of CEUS in the characterization of DN, early HCC and progressed HCC in cirrhotic livers. MATERIALS AND METHODS:Forty consecutive patients with cirrhosis and a single hepatic nodule ≤2 cm underwent CEUS and subsequent ultrasound-guided biopsy of the nodule. Imaging and pathological findings of DN and HCC were compared. RESULTS:The homogeneous pattern of hypervascularization during the arterial phase identified progressed HCC with a sensitivity of 90.9% and a specificity of 100%, whereas the inhomogeneous and reticular pattern identified early HCC with a sensitivity of 85.7% and a specificity of 96.1%. CONCLUSION:DN, early HCC and progressed HCC can be accurately differentiated with CEUS on the basis of the vascularization pattern during the arterial phase.
    Contrast-enhanced ultrasound of hepatocarcinogenesis in liver cirrhosis. Wu Wei,Chen Min-Hua,Sun Maryellen,Yan Kun,Yang Wei,Li Ji-You Chinese medical journal BACKGROUND:Hepatocellular carcinoma (HCC) often occurs in association with liver cirrhosis. A stepwise carcinogenesis for HCC has been proposed. The purpose of this study was to observe the enhancement pattern of hepatocellular nodules in cirrhotic patients using contrast-enhanced ultrasound (CEUS) and to correlate patterns of enhancement at CEUS with the diagnosis of hepatocellular nodules using pathologic correlation as the gold standard. METHODS:Ninety-three cirrhotic patients with indeterminate hepatocellular nodules at ultrasound, underwent biopsy of each indeterminate nodule. Patients with nodules found to have pathologic diagnoses of regenerative nodules (RNs), dysplastic nodules (DNs), or DNs with focus of HCC (DN-HCC), were enrolled in this study. Enhancement patterns of all nodules were examined throughout the various vascular phases of CEUS and classified into five enhancement patterns: type I, isoenhancement to hepatic parenchyma at all phases; type II, hypoenhancement in the arterial phase, and isoenhancement in the portal venous phase and late phase; type III, iso-to-hypoenhancement in arterial and portal venous phase, and hypoenhancement in the late phase (washout); type IV, slight hyperenhancement in the arterial and portal venous phase and hypoenhancement in the late phase (washout); and type V, partial hyperenhancement in the arterial phase and hypoenhancement in the late phase; and another partial iso-to-hypoenhancement in the arterial and portal venous phase and hypoenhancement in the late phase (washout). The correlation between the contrast enhancement patterns and the pathological diagnoses was analyzed by the chi-squared test. RESULTS:Totally 132 lesions were examined with CEUS in 93 patients. Pathologic diagnoses included 45 DN, 68 RN, and 19 DN-HCC. The enhancement patterns observed were as follows: type I, 49 (37.1%); type II, 27 (20.5%); type III, 28 (21.2%); type IV, 9 (6.8%); type V, 19 (14.4%). Nodules with type I enhancement showed dysplasia in 5 (10.2%) cases; nodules with type II were dysplastic in 11 (40.7%) of cases; nodules with type III enhancement pattern were dysplastic in 22 (78.6%), and those with type IV enhancement contained dysplasia in 7 (77.8%) of cases. Type V enhancement corresponded to DN-HCC in 19 (100%) of cases. CEUS enhancement pattern was correlated with likelihood of dysplasia at pathologic analysis (Trend chi-square test, P < 0.001). Pathological diagnosis was HCC in the enhanced area and hepatocyte dysplasia in the un-enhanced area in the 19 DN-HCC. CONCLUSION:Pattern of enhancement at CEUS correlates with the pathologic diagnosis of hepatocellular nodules in liver cirrhosis, and may be helpful in predicting the progress from RN to HCC nodules.
    The diagnostic value of contrast-enhanced ultrasound LI-RADS for hepatocellular carcinoma in patients with cirrhosis and chronic hepatitis B. Yang Dan,Hu Hong,Li Rui,Tang Chun-Lin,Ma Kuan-Sheng,Guo De-Yu Abdominal radiology (New York) PURPOSE:To explore the diagnostic value of American College of Radiology Contrast-Enhanced Ultrasound-Liver Imaging Reporting and Data System (ACR-CEUS-LI-RADS) for hepatocellular carcinoma (HCC) in patients with cirrhosis and chronic hepatitis B. METHODS:A total of 205 patients at high risk of HCC with solitary hepatic nodule were enrolled and retrospectively analyzed. All patients were over 18 years old and had a single lesion with a diameter < 50 mm. Lesions were categorized according to size and contrast enhancement patterns in the arterial, portal venous and late phases. Diagnostic efficacy of CEUS LI-RADS for HCC, and the rate of non-HCC malignancies in the LR-M class were compared between patients with cirrhosis and chronic hepatitis B. RESULTS:Of all 205 nodules (median nodule size was 34 mm), 142 (69.3%) were HCC. Of the 127 (61.9%) LR-5 category nodules, 95.8% (92/96) nodules were corresponded to HCC in cirrhosis, while 61.3% (19/31) nodules were corresponded to HCC in chronic hepatitis B (P = 0.000). Positive predictive value (PPV) of LR-5 category for HCC was 95.8% in cirrhosis and 61.3% in chronic hepatitis B (P = 0.000). More category of LR-4 nodules were proved to be HCC in patients with cirrhosis than chronic hepatitis B (80.0% vs 8.3%, P = 0.000). Of 41 LR-M category nodules, more non-HCC malignancies were found in chronic hepatitis B (76.0%) than that in cirrhosis (25.0%, P = 0.001). CONCLUSIONS:The LR-5 category is highly specific for the diagnosis of HCC in patients with cirrhosis. However, LR-5 category nodules require further CT or MRI examination or histological confirmation in patients with chronic hepatitis B for its unsatisfactory PPV for HCC. 10.1007/s00261-021-03345-9
    Contrast-Enhanced Ultrasound: a Simple and Effective Tool in Defining a Rapid Diagnostic Work-up for Small Nodules Detected in Cirrhotic Patients during Surveillance. Giorgio Antonio,Montesarchio Luca,Gatti Piero,Amendola Ferdinando,Matteucci Paolo,Santoro Bruno,Merola Maria Gabriella,Merola Francesca,Coppola Carmine,Giorgio Valentina Journal of gastrointestinal and liver diseases : JGLD BACKGROUND AND AIMS:Disappearance of portal blood flow and arterial vascularization is the hallmark of hepatocarcinogenesis. The capability of a dynamic imaging modality detecting arterial hypervascularization of small nodules is crucial to promote a rapid diagnostic and therapeutic work-up improving survival. We aimed to evaluate the capability of CEUS to detect arterial vascularization of ≤ 2 cm HCC nodules arising during surveillance so as to shorten the diagnostic and therapeutic work-up. METHODS:From October 2009 to September 2014, among 1757 consecutive cirrhotic patients under surveillance with ultrasound (US), 243 patients had new single nodules 7-20 mm; 229/243 had a conclusive histologic diagnosis and comprised the study group. All patients underwent CEUS followed by enhanced MRI and US guided percutaneous 18G needle core biopsy of the nodules. Of the 229 nodules, 27 were hyperechoic, 171 hypoechoic and 31 isoechoic lesions. RESULTS:The histology results revealed that 199/229 nodules were HCC and 30 were benign. Of 199 HCC, CEUS evidenced arterial hypervascularity in 190 nodules (95.5%) (sensitivity 94.48 %, specificity 100%, PPV 100%, NPV 76.92 %). Of the 39 CEUS arterial-unenhanced nodules, 30 were benign and 9 (23%) were well-differentiated HCC. eMRI showed arterial hypervascularity in 199 nodules (86,9%). Of these, only 193 (97%) were histologically HCCs while 6 were benign (sensitivity: 97%, specificity: 80%, PPV: 97%, NPV: 80%). CONCLUSIONS:CEUS has a great capability to detect arterial hypervascularity of small HCC. Because only 4.5% of new nodules escape the demonstration of arterial hyervascularity, CEUS must be performed immediately after conventional US to contrast the malignant fate of small lesions arising in a cirrhotic liver. 10.15403/jgld.2014.1121.252.chu
    Contrast-enhanced ultrasound for the differentiation of small atypical hepatocellular carcinomas from dysplastic nodules in cirrhosis. Shin Seung Kak,Kim Yun Soo,Choi Seung Joon,Shim Young Sup,Jung Dong Hae,Kwon Oh Sang,Choi Duck Joo,Kim Ju Hyun Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver BACKGROUND:Contrast-enhanced ultrasound is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to evaluate the usefulness of contrast-enhanced ultrasound for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules showing atypical or not coincidental typical vascular pattern on two dynamic imaging techniques (computed tomography and magnetic resonance imaging). METHODS:A total of 46 patients with cirrhosis and a liver nodule smaller than 3cm showing an atypical or non-coincident typical vascular pattern on two dynamic imaging techniques, who underwent liver contrast-enhanced ultrasound and ultrasound-guided liver biopsy, were retrospectively reviewed. Contrast-enhanced ultrasound findings were compared with histopathological and clinical data, and with the two dynamic imaging findings. RESULTS:Significantly different contrast-enhanced ultrasound enhancement patterns were observed among dysplastic nodules, Edmondson grade I and grade II-III hepatocellular carcinomas. Ten out of 11 (90.9%) non-hypervascular hepatocellular carcinomas on two dynamic imaging techniques showed a hypervascular pattern on contrast-enhanced ultrasound, and these made it possible to distinguish hepatocellular carcinomas from dysplastic nodules. CONCLUSION:Contrast-enhanced ultrasound is useful for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules. 10.1016/j.dld.2015.05.001
    Contrast-enhanced ultrasound in the diagnosis of nodules in liver cirrhosis. Kim Tae Kyoung,Jang Hyun-Jung World journal of gastroenterology Contrast-enhanced ultrasound (CEUS) using microbubble contrast agents are useful for the diagnosis of the nodules in liver cirrhosis. CEUS can be used as a problem-solving method for indeterminate nodules on computed tomography (CT) or magnetic resonance imaging (MRI) or as an initial diagnostic test for small newly detected liver nodules. CEUS has unique advantages over CT and MRI including no renal excretion of contrast, real-time imaging capability, and purely intravascular contrast. Hepatocellular carcinoma (HCC) is characterized by arterial-phase hypervascularity and later washout (negative enhancement). Benign nodules such as regenerative nodules or dysplastic nodules are usually isoechoic or slightly hypoechoic in the arterial phase and isoechoic in the late phase. However, there are occasional HCC lesions with atypical enhancement including hypovascular HCC and hypervascular HCC without washout. Cholangiocarcinomas are infrequently detected during HCC surveillance and mostly show rim-like or diffuse hypervascularity followed by rapid washout. Hemangiomas are often found at HCC surveillance and are easily diagnosed by CEUS. CEUS can be effectively used in the diagnostic work-up of small nodules detected at HCC surveillance. CEUS is also useful to differentiate malignant and benign venous thrombosis and to guide and monitor the local ablation therapy for HCC. 10.3748/wjg.v20.i13.3590
    Real-life assessment of standardized contrast-enhanced ultrasound (CEUS) and CEUS algorithms (CEUS LI-RADS®/ESCULAP) in hepatic nodules in cirrhotic patients-a prospective multicenter study. Strobel D,Jung E-M,Ziesch M,Praktiknjo M,Link A,Dietrich C F,Klinger C,Schultheiß M,Jesper D,Schellhaas B European radiology OBJECTIVES:Hepatocellular carcinoma (HCC) can be diagnosed non-invasively with contrast-enhanced ultrasound (CEUS) in cirrhosis if the characteristic pattern of arterial phase hyperenhancement followed by hypoenhancement is present. Recent studies suggest that diagnosis based on this "hyper-hypo" pattern needs further refinement. This study compares the diagnostic accuracies of standardized CEUS for HCC according to the current guideline definition and following the newly developed CEUS algorithms (CEUS LI-RADS®, ESCULAP) in a prospective multicenter real-life setting. METHODS:Cirrhotic patients with liver lesions on B-mode ultrasound were recruited prospectively from 04/2018 to 04/2019, and clinical and imaging data were collected. The CEUS standard included an additional examination point after 4-6 min in case of no washout after 3 min. The diagnostic accuracies of CEUS following the guidelines ("hyper-hypo" pattern), based on the examiner's subjective interpretation ("CEUS subjective"), and based on the CEUS algorithms ESCULAP and CEUS LI-RADS® were compared. RESULTS:In total, 470 cirrhotic patients were recruited in 43 centers. The final diagnosis was HCC in 378 cases (80.4%) according to the reference standard (histology 77.4%, MRI 16.4%, CT 6.2%). The "hyper-hypo" pattern yielded 74.3% sensitivity and 63% specificity. "CEUS subjective" showed a higher diagnostic accuracy (sensitivity, 91.5%; specificity, 67.4%; positive predictive value, 92%; negative predictive value, 66%). Sensitivity was higher for ESCULAP (95%) and "CEUS subjective" (91.5%) versus CEUS LI-RADS® (65.2%; p < 0.001). Specificity was highest for CEUS LI-RADS® (78.6%; p < 0.001). CONCLUSIONS:CEUS has an excellent diagnostic accuracy for the non-invasive diagnosis of HCC in cirrhosis. CEUS algorithms may be a helpful refinement of the "hyper-hypo" pattern defined by current HCC guidelines. KEY POINTS:• Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy for the non-invasive diagnosis of hepatocellular carcinoma (HCC) in cirrhosis. • The CEUS algorithm ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) showed the highest sensitivity, whereas the CEUS LI-RADS® (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System) algorithm yielded the highest specificity. • A standardized CEUS examination procedure with an additional examination point in the late phase, after 4-6 min in lesions with no washout after 3 min, is vital. 10.1007/s00330-021-07872-3