The AFSUMB Consensus Statements and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound using Sonazoid.

The first edition of the guidelines for the use of ultrasound contrast agents was published in 2004, dealing with liver applications. The second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some nonliver applications. The third edition of the contrast-enhanced ultrasound (CEUS) guidelines was the joint World Federation for Ultrasound in Medicine and Biology-European Federation of Societies for Ultrasound in Medicine and Biology (WFUMB-EFSUMB) venture in conjunction with other regional US societies such as Asian Federation of Societies for Ultrasound in Medicine and Biology, resulting in a simultaneous duplicate on liver CEUS in the official journals of both WFUMB and EFSUMB in 2013. However, no guidelines were described mainly for Sonazoid due to limited clinical experience only in Japan and Korea. The new proposed consensus statements and recommendations provide general advice on the use of Sonazoid and are intended to create standard protocols for the use and administration of Sonazoid in hepatic and pancreatobiliary applications in Asian patients and to improve patient management.

Comparison of contrast-enhanced ultrasonograpy with Gd-EOB-DTPA-enhanced MRI in the diagnosis of liver metastasis from colorectal cancer.

PURPOSE: To compare contrast-enhanced ultrasonography (CEUS) using Sonazoid with Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in the diagnosis of liver metastases in patients with colorectal cancer. METHODS: A total of 69 patients diagnosed with or suspected of having liver metastasis were enrolled. These hepatic lesions were diagnosed by histopathological examination after surgical resection or based on follow-up using various imaging modalities. The diagnostic accuracies of CEUS and EOB-MRI were compared. RESULTS: One hundred thirty-three lesions were detected. Of these lesions, 109 were diagnosed as liver metastases. Of the 133 lesions, 90.2% were detected on CEUS, and 98.5% on EOB-MRI. One hundred nine lesions were diagnosed as liver metastasis. The areas under the receiver operating characteristic curve for diagnosis were 0.906 and 0.851 on CEUS and EOB-MRI, respectively (p = 0.41). Sensitivity, specificity, positive predictive value (PPV), negative predictive value, and overall accuracy were 90.8%, 84.5%, 97.1%, 67.1%, and 90.2%, respectively, for CEUS, and 95.4%, 70.8%, 93.7%, 77.3%, and 91%, respectively, for EOB-MRI. CONCLUSIONS: CEUS has a higher specificity and PPV for the diagnosis of liver metastasis than EOB-MRI. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:138-144, 2017.

[Plasma Biomarkers as Predictive Factors for Advanced Hepatocellular Carcinoma with Sorafenib].

We examined plasma biomarkers as predictive factors for advanced hepatocellular carcinoma(ad-HCC)patients treated with sorafenib. We analyzed a-fetoprotein(AFP), AFP-L3, des-g-carboxy prothrombin(DCP), neutrophil-to-lymphocyte ratio(NLR), platelet-to-lymphocyte ratio(PLR), and vascular endothelial growth factor(VEGF)before sorafenib therapy, and changes in AFP-L3, NLR, PLR, and VEGF 1 month after sorafenib therapy in 16 patients. High AFP-L3(hazard ratio: 1.058, 95%CI: 1.019-1.098, p=0.003)and high NLR(hazard ratio: 1.475, 95%CI: 1.045-2.082, p=0.027)were significantly associated with poor prognosis in ad-HCC patients treated with sorafenib. There were no significant differences in changes in AFP-L3, NLR, PLR, and VEGF 1 month after sorafenib therapy. We suggest that AFP-L3 and NLR levels before sorafenib therapy in patients with ad-HCC are an important predictive factor for the therapeutic effect of sorafenib and patient survival.

[Evaluation of Sorafenib for Hepatocellular Carcinoma with Low α-Fetoprotein by Arrival Time Parametric Imaging Using Contrast-Enhanced Ultrasonography with Sonazoid].

We aimed to determine the usefulness of arrival time parametric imaging (AtPI) using contrast-enhanced ultrasonography (CEUS)with Sonazoid in the evaluation of early response to sorafenib for hepatocellular carcinoma (HCC). Thirteen ad- vanced HCC patients with low a / -fetoprotein (AFP) level (≤35 ng/mL) who received sorafenib for at least 4 weeks were enrolled in this study. CEUS was performed before and after treatment (2 weeks), and the images of the target lesion in the arterial phase were analyzed by AtPI. In the color mapping images obtained by AtPI, the mean arrival time of the contrast agent in the target lesion from the starting point (mean time: MT) was calculated. In each patient, differences between MT before and MT 2 weeks after treatment were compared. MT (+) and MT(-) groups were designated as such if the difference was 0 or greater(blood flow velocity of the lesion was reduced)and less than 0 sec(blood flow velocity of the lesion was increased), respectively. The overall survival was evaluated between the 2 groups. In the MT (+) group (7 patients) and MT (-) group (6 patients), the median survival times were 307 and 208 days, respectively, which was statistically significant. We suggest AtPI is useful for evaluating early response to sorafenib in advanced HCC patients with low AFP level.

The correlation between plasma aprepitant concentration and antiemetic effect in Japanese gastric or esophageal cancer patients.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are significant problems in cancer patients, but a correlation between plasma aprepitant concentration and antiemetic effect has not been reported. This study aimed to characterize the correlation between plasma aprepitant concentration and clinical antiemetic effect in a limited group of Japanese gastric or esophageal cancer patients. METHODS: Thirty-three Japanese cancer patients receiving cisplatin-based chemotherapy for the first time following oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3) were enrolled. The plasma aprepitant concentrations 48 h after the first administration were determined using liquid chromatography-mass spectrometry. Patients were allocated to the high-concentration group (plasma aprepitant concentration was >331.1 ng/ml) or the low-concentration group (plasma aprepitant concentration was ≤ 331.1 ng/ml) to investigate the relationship between plasma aprepitant concentration and antiemetic effects. RESULTS: No significant differences were found between the two groups in terms of percentage of CINV prevention. Of 13 patients who experienced CINV [MASCC Antiemesis Tool (MAT) score >3], those in the high-concentration group showed a significant improvement in CINV following aprepitant administration (days 1-3). CONCLUSION: The present study suggests that the antiemetic effect of aprepitant is associated with plasma aprepitant concentration. A plasma aprepitant concentration of 331.1 ng/ml may be a valid threshold for identifying its optimal antiemetic effects in Japanese gastric or esophageal cancer patients.

[Efficacy of Sorafenib versus Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma Refractory to Transcatheter Arterial Chemoembolization].

We compared the benefits of sorafenib with that of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (ad-HCC) refractory to transcatheter arterial chemoembolization (TACE). We evaluated the patient characteristics, the median survival time (MST), and the prognostic factors in 17 patients in the sorafenib group and in 26 patients in the HAIC group. No significant difference was observed in the patient characteristics between the groups. The MST in the sorafenib group and HAIC group was 483 days and 284 days, respectively. A significantly longer survival time was noted in the sorafenib group (p=0.033). The prognostic factors were sorafenib therapy in all 43 patients(hazard ratio: 3.32 [95% CI: 1.36-8.10], p=0.008) and the longer treatment period of sorafenib in the sorafenib group(hazard ratio: 0.99 [95% CI: 0.984- 0.999], p=0.009). When compared with HAIC, sorafenib showed favorable treatment results in patients with ad-HCC refractory to TACE.

Comparison of Sorafenib and Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Study.

BACKGROUND/AIMS: This prospective non-randomized controlled trial aimed to compare the efficacy of sorafenib vs hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma. METHODOLOGY: Forty-seven patients treated with sorafenib (sorafenib group) and 77 patients treated with HAIC (HAIC group) were investigated retrospectively using propensity score matching (PSM) to minimize selection bias. The cumulative survival rate was investigated before and after PSM in each of the sorafenib and HAIC groups. The cumulative survival rate was compared between the sorafenib and HAIC groups, and among the TNM stage by the Liver Cancer Study Group of Japan (LCSGJ TNM stage). RESULTS: No significant difference was noted in overall survival (OS) between the sorafenib and HAIC groups regardless of before or after PSM. On comparison of the cumulative survival rate between the groups by the same LCSGJ TNM stage, significant prolongation of OS was noted in stage IVB only in the sorafenib group (p = 0.032) after PSM. CONCLUSIONS: It may be better to actively introduce sorafenib for stage IVB, i.e., patients with extrahepatic metastasis.

Host Immunity Influences the Efficacy of Combined Intra-Arterial Chemotherapy for Advanced Hepatocellular Carcinoma in Liver Cirrhosis Patients.

BACKGROUND/AIMS: It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of Th1 cells promotes such immunity. The aim of this study was to assess changes of host immunity in relation to efficacy in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy (CIAC). METHODOLOGY: Forty-three adult Japanese LC patients who had aHCC received CIAC. Blood samples were collected before and after CIAC. RESULTS: Eleven of the 43 patients showed a partial response (group PR) and 21 patients had stable disease (group SD), but 11 patients showed no response (group PD). There were no significant differences of Th1 or Th2 cells between before and after CIAC in each group. However, groups SD and PD had higher levels of Th2 cells than in group PR before and after CIAC. The percentage of regulatory T (Treg) cells in group PD was significantly increased after CIAC compared with before CIAC, whereas groups PR and SD showed significant decrease after CIAC. CONCLUSIONS: The percentage of Th2 cells is useful for predicting the response to CIAC and the percentage of Treg cells is useful for assessment of efficacy in LC patients with aHCC receiving CIAC.

A case of sclerosing angiomatoid nodular transformation of the spleen: correlations between contrast-enhanced ultrasonography and histopathologic findings.

Sclerosing angiomatoid nodular transformation (SANT) is a recently recognized benign vascular lesion of the spleen. Detection of SANT as an incidentaloma has increased due to improvements in imaging techniques. However, a definitive diagnosis of SANT on CT or MRI remains difficult. We report the use of contrast-enhanced ultrasonography with Sonazoid in a case of SANT in a 50-year-old woman, with gross and microscopic pathologic correlations.

A case of solitary bile duct hamartoma with advanced gastric carcinoma: findings in contrast-enhanced ultrasonography.

Bile duct hamartomas (BDH), which are also known as von Meyenburg complexes, are benign neoplasms that involve cystic dilatation of the bile duct surrounded by fibrous stroma. However, multiple lesions develop in most cases of BDH, whereas a solitary lesion, as seen in our case, is relatively rare. We report here the co-existence of gastric carcinoma and BDH mimicking metastasis in a 30-year-old woman. A lesion measuring 13 × 9 mm with the appearance of a hyperechoic nodule with no pulsatile blood flow signals was observed on US and Doppler US in S4 of the liver. On contrast-enhanced ultrasonography (CEUS), the septum-like structure in the tumor was weakly enhanced at 17 s after administration of Sonazoid. There has been no description of solitary BDH findings on CEUS in the literature. We present the US findings of BDH, including those yielded by CEUS using Sonazoid, along with the microscopic pathological correlation.

Influence of etiology on host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma receiving intra-arterial chemotherapy.

BACKGROUND/AIMS: We have shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced HCC (aHCC) in patients with HCV-related (C-LC) or alcoholic (A-LC) liver cirrhosis (LC) patients than in patients with HBV-related LC (B-LC). This study retrospectively assesses the difference of etiology on host immunity in LC patients with aHCC treated by IACC. METHODOLOGY: Forty-seven adult LC patients with aHCC were treated by IACC between 2005 and 2008, with inoperable tumors according to CT findings. IACC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was delivered via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. The control group comprised 13 healthy volunteers. RESULTS: Twelve of the 47 patients with aHCC had B-LC, 27 had C-LC, and 8 had A-LC. In the B-LC group, 1 out of 12 patients had a Japan Integrated Staging (JIS) score of 2, 4 had a JIS score of 3, 7 had a JIS score of 4, and no patients had a JIS score of 5, while the respective numbers were 6, 9, 10 and 2 in the C-LC group, and 1, 1, 5 and 1 in the A-LC group. The response rates were 37.0%, 37.5% and 8.3% in the C-LC, A-LC and B-LC group, respectively. In the C-LC group, the percentage of Th1 cells before and after chemotherapy was significantly higher than in the control group. In the B-LC group, the percentage of Th2 cells after chemotherapy was significantly higher than that in the control group. However, there were no significant differences of Th1 and Th2 cells between the A-LC group and the control group. CONCLUSIONS: These results indicate that IACC was more effective for aHCC in A-LC patients with normal Th1/Th2 balance and in C-LC patients without Th2 dominance than in B-LC patients who showed Th2 dominance after chemotherapy.

Duct of Luschka diagnosed by sonography in a patient with bile duct carcinoma and intrahepatic bile duct dilatation.

The bile duct of Luschka (BDL) is an anatomic anomaly that is an important cause of bile leakage after bile duct surgery. We report a case of bile duct carcinoma with dilated BDL that was diagnosed by ultrasonography (US). An 83-year-old man presented with an obstructive jaundice. US on admission revealed the presence of a solid hypoechoic mass in the bile duct at the hepatic duct confluence and a branch of the bile duct, about 2-4 mm in diameter, distinct from the dilated right anterior hepatic duct slightly upstream of the tumor. This branch had a spiral structure, extended along the gallbladder bed on the surface of segment 5 (S5) of the liver, and emanated small branches that entered the hepatic parenchyma. There has been no previous report of delineation of BDL by preoperative US.

Right hepatic artery pseudoaneurysm complicating acute pancreatitis: a case report.

OBJECTIVE: To report a rare case of right hepatic artery pseudoaneurysm complicating acute pancreatitis based upon imaging findings obtained before and after the development of pseudoaneurysm. CLINICAL PRESENTATION AND INTERVENTION: A 32-year-old male with a history of acute pancreatitis 1 year prior was readmitted for acute pancreatitis. Computed tomography (CT) and angiography after admission revealed pseudoaneurysm of the right hepatic artery. Transcatheter arterial embolization with coils was used to successfully treat the pseudoaneurysm. A CT and angiography 1 year earlier did not reveal any pseudoaneurysm. CONCLUSION: This patient with a rare right hepatic artery pseudoaneurysm complicating acute pancreatitis was successfully treated with coil embolization.

Hepatic parenchymal hemodynamics of cholangitis with portal trunk thrombus using contrast-enhanced ultrasonography with Sonazoid: delineation of so-called central and peripheral zonal differentiation by arrival-time parametric imaging.

We carried out contrast-enhanced ultrasonography using Sonazoid for a patient who had portal thrombosis due to choledocholith and cholangitis, and the video images were analyzed by an offline procedure using arrival-time parametric imaging. Colors were changed with the time course from red to orange, yellow, green, light blue, and blue, with the time the contrast agent reached the right hepatic artery as the starting point. The central part of the liver was primarily colored blue, and the peripheral part primarily yellowish-green. In other words, we confirmed the central and peripheral zonal differentiation observed in the arterial phase of dynamic computed tomography by color mapping image of arrival-time parametric imaging. Particularly, real-time changes in the hemodynamics of the hepatic parenchyma could be captured by color mapping image using arrival-time parametric imaging.

Ultrasonography of intrahepatic bile duct adenoma with renal cell carcinoma: correlation with pathology.

Intrahepatic bile duct adenoma (BDA) is a relatively rare benign tumor. Most cases are incidentally discovered during surgery or autopsy. We report here the co-existence of renal cell carcinoma and BDA mimicking metastasis in a 30-year-old female. An isoechoic nodule with a hypoechoic rim sized 10 × 9 mm was observed by ultrasonography in S2 of the liver. On contrast-enhanced ultrasonography (CEUS), the mass was enhanced in the early vascular phase and a defect with a clear border appeared in the post-vascular phase. We present the ultrasonography findings of BDA, including those yielded by CEUS using Sonazoid, along with the gross and microscopic pathological correlation.

JSUM ultrasound elastography practice guidelines: liver.

In diffuse liver disease, it is extremely important to make an accurate diagnosis of liver fibrosis prior to determining indications for therapy or predicting treatment outcome and malignant potential. Although liver biopsy has long been the gold standard in the diagnosis of liver fibrosis, it is still an invasive method. In addition, the sampling error is an intrinsic problem of liver biopsy. Non-invasive serological methods for the diagnosis of liver fibrosis can be affected by factors unrelated to the liver. Recently, after the introduction of FibroScan, it became possible to measure liver fibrosis directly and non-invasively by elastography, which has attracted attention as a non-invasive imaging diagnostic tool for liver fibrosis. In addition, real-time tissue elastography is currently being used to conduct clinical trials at many institutions. Moreover, virtual touch quantification enables the observation of liver stiffness at any location by simply observing B-mode images. Furthermore, the recently developed ShearWave elastography visualizes liver stiffness on a color map. Elastography is thought to be useful for all types of diffuse liver diseases. Because of its association with portal hypertension and liver carcinogenesis, elastography is expected to function as a novel prognostic tool for liver disease. Although various elastographic devices have been developed by multiple companies, each device has its own measurement principle, method, and outcome, creating confusion in clinical settings. Therefore, it is extremely important to understand the characteristics of each device in advance. The objective of this guideline, which describes the characteristics of each device based on the latest knowledge, is for all users to be able to make the correct diagnosis of hepatic fibrosis by ultrasound elastography.

Sorafenib prevents escape from host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma.

PURPOSE: It has been reported that Th2 cytokines downregulate antitumor immunity, while activation of type T cells promotes antitumor immunity. The aim of this paper was to evaluate host immunity in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) receiving sorafenib therapy. METHODS: Forty-five adult Japanese LC patients received sorafenib for aHCC between 2009 and 2011 at our hospital. Sorafenib was administered at a dose of 200-800 mg/day for 4 weeks. Blood samples were collected before and after treatment. RESULTS: Eleven patients were treated with sorafenib at 200 mg/day (200 group), 27 patients received sorafenib at 400 mg/day (400 group), and 7 patients were given sorafenib at 800 mg/day (800 group). There was no significant change in the percentage of Th1 cells after treatment in any group. However, the percentages of Th2 cells and regulatory T cells were significantly decreased after treatment in the 400 group and 800 group compared with before treatment, although there was no significant change after treatment in the 200 group. CONCLUSIONS: These results indicate that treatment with sorafenib might induce Th1 dominance and prevent the escape of tumor cells from the host immune system in LC patients with aHCC.

Usefulness of arrival time parametric imaging in evaluating the degree of liver disease progression in chronic hepatitis C infection.

OBJECTIVE: To determine whether the degree of liver disease progression in chronic hepatitis C infection can be evaluated by arrival time parametric imaging using contrast-enhanced sonography with Sonazoid (perfluorobutane; GE Healthcare, Oslo, Norway). METHODS: In this study, 60 patients with liver disease in chronic hepatitis C infection were examined and compared with 10 healthy volunteers who served as controls. A recommended dose of the sonographic contrast agent Sonazoid was intravenously infused, and the S5 or S6 region of the liver and right kidney were observed concurrently while movies of the procedure were saved. Arrival time parametric images of liver parenchymal blood flow were created, with red pixels to indicate an arrival time of 0 to 5 seconds and yellow pixels to indicate an arrival time of 5 to 10 seconds. From the obtained images, the ratio of the red area to the entire enhanced area of the liver was calculated using image-processing software. Each participant was subsequently subjected to liver biopsy for liver fibrosis staging according to Metavir scores, and the determined fibrosis stage was compared with the ratio of red. The serum albumin level, platelet count, and prothrombin time were also compared with the ratio of red for each participant. RESULTS: The ratio of red increased significantly as liver fibrosis stage advanced (P < .01 for F1 versus F2; P < .01 for F1 versus F3; P < .01 for F1 versus F4; and P < .01 for F2 versus F4). As the ratio of red increased, significant decreases were observed in the serum albumin level (r = -0.29; P = .027), platelet count (r = -0.46; P = .0003), and prothrombin time (r = -0.46; P = .0002). CONCLUSIONS: Arrival time parametric imaging using Sonazoid-enhanced sonography enables noninvasive evaluation of the degree of progression of liver disease in chronic hepatitis C infection and is thus considered clinically useful.

[The chemotherapy of peritoneal malignant mesothelioma].

Peritoneal malignant mesothelioma is a rare disorder with a poor prognosis, and a standard treatment for it has not yet been established. Therefore, treatment of this disorder tends to be selected according to pleura malignant mesothelioma. We analyzed case reports in Japan. The median survival time(MST)with this disease was 12 months and the 1-year survival rate was 47. 3% in the chemotherapy group. It was found through a case-series study that platinum pharmaceutical plus antimetabolite are effective against peritoneal malignant mesothelioma. A gemcitabine(GEM)plus cisplatin(CDDP)regimen had been selected as a conventional treatment, but subsequently, pemetrexed(MTA)was covered by health insurance for pleural malignant mesothelioma in 2007, and the MTA plus CDDP regimen became the standard treatment. However, a phase III trial of GEM plus CDDP regimen and MTA plus CDDP regimen was not performed. There is a need to perform these phase III trials in the future. In our institution, the MTA plus CDDP regimen was the first-line treatment, and the GEM plus CDDP regimen was the second-line treatment against peritoneal malignant mesothelioma. Palonosetron hydrochloride and aprepitant should be used actively in treatment. Also, carboplatin(CBDCA)is effective as an alternative therapy of the CDDP against renal disorder case, but hematotoxicity requires attention.

Comparison of the hemodynamics between patients with alcoholic or HCV-related cirrhosis.

BACKGROUND/AIMS: Hyperdynamic circulation, which is characterized by increased cardiac output (CO), normal or low arterial blood pressure (BP), and decreased systemic vascular resistance (SVR), occurs in patients with liver cirrhosis (LC). However, differences of hemodynamics between patients with alcoholic LC (ALC) and viral LC are not well understood. The aim of the present study was to compare hemodynamics between patients with alcoholic LC and patients with HCV-related LC (CLC). METHODOLOGY: Eighteen healthy Japanese volunteers (HV), 10 patients with chronic hepatitis (CH), 46 patients with CLC, and 22 ALC patients with ALC were included in the study. The CLC group was divided into two subgroups (34 non-ascites and 12 ascites patients), as was the ALC group (11 non-ascites and 11 ascites patients). The CO, portal blood flow (PBF), and hepatic congestion index (HCI) were measured by ultrasound. RESULTS: The CO of the CLC and the ALC groups was higher than that of the HV group, while the SVR of the CLC and ALC groups was lower than that of the HV group. These changes were more marked in the ALC group. The HCI of the ascitic ALC subgroup was higher than that of the HV group. PBF did not differ among the CLC, ALC and HV groups. CONCLUSIONS: Progression of liver diseases such as ALC or CLC leads to a hyperdynamic circulation. The decrease of SVR was more marked in ALC patients than that CLC patients and an increase of the HCI was only found in ALC patients with ascites.