Flash Imaging Used in the Post-vascular Phase of Contrast-Enhanced Ultrasonography is Useful for Assessing the Progression in Patients with Hepatitis C Virus-Related Liver Disease.

Sonazoid is a commonly used contrast agent for characterizing liver tumors in ultrasonography (US). We performed flash imaging in the post-vascular phase of contrast-enhanced US (CEUS) to investigate associations between collapse of Sonazoid microbubbles (MB) and progression of liver disease. This study enrolled 409 patients (205 men, 204 women) with hepatitis C virus-related liver disease (CLD) between 2007 and 2017 (mean age 60 ± 14 y; range 20-90 y). In the post-vascular phase, 10 min after administering Sonazoid, flash imaging was performed to burst MB in the liver parenchyma; the range of bubble destruction was measured from the surface of the liver. The range of bubble destruction, stage of fibrosis, shear wave velocity (Vs), serologic markers and fibrosis-4 (FIB4) index were analyzed in 259 patients who underwent liver biopsy. Fibrosis stage was F0-1 in 108 patients, F2 in 73, F3 in 38 and F4 in 40. In 150 patients with cirrhosis, diagnosis was made based on imaging findings. The range of bubble destruction was 42.0 ± 10.4 mm in F0-1 patients, 42.9 ± 13.2 mm in F2, 51.5 ± 15.9 mm in F3 and 55.4 ± 17.3 mm in F4 and was significantly increased according to progression of fibrosis staging. The range of bubble destruction was positively correlated with Vs (r = 0.34; p < 0.01), total bilirubin (r = 0.25; p < 0.01) and FIB4 index (r = 0.38; p < 0.01). In contrast, the range of bubble destruction was negatively correlated with serum levels of albumin (r = -0.34; p < 0.01), platelet count (r = -0.35; p < 0.01) and prothrombin time (r = -0.36; p < 0.01). The results indicated that flash imaging in the post-vascular phase of CEUS was a non-invasive assessment and could predict disease progression in patients with CLD.

Hepatic arterialization can predict the development of collateral veins in patients with HCV-related liver disease.

PURPOSE: Arrival time parametric imaging (At-PI) using contrast-enhanced ultrasonography (CEUS) is a procedure for evaluating liver disease progression in chronic hepatitis C infection (CHC). We investigated At-PI diagnostic efficacy in predicting development of collateral veins. METHODS: In total, 171 CHC patients underwent CEUS and upper gastrointestinal (UGI) endoscopy before liver biopsy. Conventional US was performed before CEUS to identify paraumbilical veins (PV) or splenorenal shunts (SRS). After intravenous perflubutane, contrast dynamics of liver segments 5-6 and the right kidney were saved as raw data. At-PI image ratio of red (ROR) pixels to the entire liver was analyzed. Receiver operating characteristic (ROC) curves were generated to investigate the utility of At-PI for collateral vein identification. RESULTS: Conventional US revealed PV in two patients and SRS in five patients; UGI endoscopy detected esophageal varices (EV) in eight patients. Diagnostic capability of At-PI for detecting PV, SRS, and EV was satisfactory, and high for PV and SRS [PV; area under the ROC curve (AUROC) 0.929, cutoff value 77.9%, SRS; AUROC 0.970, cutoff value 82.0%, EV; AUROC 0.883, cutoff value 66.9%]. CONCLUSIONS: Evaluation of hepatic arterialization by At-PI was useful for predicting collateral vein development in CHC patients.

Effect of Hepatic Inflammation in Chronic Hepatitis C Infection on Fibrosis Assessment by Arrival Time Parametric Imaging.

Arrival time parametric imaging (At-PI) in contrast-enhanced ultrasonography is useful for assessing liver fibrosis in chronic hepatitis C (CHC) infection. The study aimed to elucidate the effect of hepatic inflammation on At-PI efficiency. Subjects were 159 CHC patients who underwent contrast-enhanced ultrasonography immediately before liver biopsy. Ultrasound contrast agent was injected, and contrast dynamics of the S5 to S6 region of the liver and right kidney were recorded for 40 seconds. The At-PI of liver parenchyma blood flow was generated using saved video clips. Hepatic blood flow during the first 5 seconds after starting contrast injection was displayed in red and that after another 5 seconds was displayed in yellow. The ratio of red (ROR) in At-PI images of the entire liver was measured with ImageJ. Ratio of red values of livers with different activity grades (0-3) were compared for each fibrosis (F) stage as determined by biopsy. Correlations of ROR with alanine aminotransferase (ALT) levels were analyzed using a linear regression line from the distribution map. Comparison of ROR for different activity grades in each F stage revealed no significant differences. Correlation coefficient R (P value) for ALT and ROR was R = -0.0094 (P = 0.43) at F0 to F1, R = -0.186 (P = 0.21) at F2, R = -0.233 (P = 0.27) at F3, and R = 0.041 (P = 0.89) at F4, with no significant correlation between ALT and ROR in any F stage. Hepatic inflammation in CHC infection does not affect At-PI diagnostic accuracy.

Visualization of segmental arterialization with arrival time parametric imaging using Sonazoid-enhanced ultrasonography in portal vein thrombosis: A case report.

A 55-year-old male was admitted in mid-April 2011 with a fever of >39°C and pain in the lower right abdomen. A medical examination revealed sepsis originating from colonic diverticulitis. Abdominal B-mode ultrasonography (US) performed on admission detected thrombi in the superior mesenteric vein and in the right branch of the hepatic portal vein. Arrival time parametric imaging (At-PI) using Sonazoid-enhanced US showed arterialization of the entire right lobe of the liver. The treatment for the sepsis and portal thrombi that had been started upon admission dissolved the thrombi by day 22, with the exception of one thrombus in the P8 branch of the portal vein. At-PI performed on the same day confirmed arterialization in segment 8, but portal vein dominance was restored elsewhere. When the blood inflow from the hepatic portal vein was reduced, the hepatic arterial blood flow was increased to compensate for the reduction in the total blood supply. The At-PI functions used in the Sonazoid-enhanced US were simple yet effective in visualizing the changes in the hepatic hemodynamics caused by the portal thrombus.

Budesonide/formoterol maintenance and reliever therapy via Turbuhaler versus fixed-dose budesonide/formoterol plus terbutaline in patients with asthma: phase III study results.

BACKGROUND AND OBJECTIVE: To evaluate the efficacy and tolerability of budesonide/formoterol as maintenance and reliever therapy versus budesonide/formoterol maintenance plus terbutaline in adults with persistent asthma not adequately controlled with inhaled corticosteroid (ICS) therapy alone. METHODS: In this 12-month, randomized, double-blind, parallel-group, phase III study (NCT00839800), patients (age ≥ 16 years; receiving maintenance ICS; ≥ 1 severe exacerbation in the 12 months prior to study entry) were randomized to either budesonide/formoterol 160/4.5 µg 1 inhalation twice daily plus budesonide/formoterol 160/4.5 µg as-needed or budesonide/formoterol 160/4.5 µg 1 inhalation twice daily plus terbutaline 0.4 mg as-needed for 12 months. PRIMARY OUTCOME: time to first severe asthma exacerbation; secondary outcomes included: lung function, asthma symptom variables and tolerability. RESULTS: Two thousand and ninety-one patients were randomized: 170 (16%) receiving budesonide/formoterol maintenance and reliever therapy experienced 259 severe exacerbations versus 229 patients (22%) receiving budesonide/formoterol plus terbutaline who experienced 363 severe exacerbations. Budesonide/formoterol maintenance and reliever therapy prolonged the time to first severe exacerbation versus budesonide/formoterol plus terbutaline (P = 0.0007) and reduced the instantaneous risk of an exacerbation by 30% (hazard ratio 0.70, 95% confidence interval 0.57-0.85, P = 0.0003). Times to first oral steroid use, first hospitalization and first emergency room treatment were all significantly prolonged in the budesonide/formoterol maintenance and reliever group versus budesonide/formoterol plus terbutaline. Both treatment groups were well tolerated. CONCLUSIONS: Budesonide/formoterol maintenance and reliever therapy provided more effective asthma control, including a prolonged time to first severe asthma exacerbation, than budesonide/formoterol plus terbutaline and was well tolerated. Budesonide/formoterol maintenance and reliever therapy also improved lung function and asthma symptoms.

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.

Evaluation of sorafenib for hepatocellular carcinoma by contrast-enhanced ultrasonography: a pilot study.

AIM: To determine the usefulness of arrival time parametric imaging (AtPI) using contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating early response to sorafenib for hepatocellular carcinoma (HCC). METHODS: Fourteen advanced HCC patients who received sorafenib 400/800 mg/d for at least 4 wk and were followed up by CEUS were enrolled in this study. CEUS was performed before treatment and 2 and 4 wk after treatment, and images of the target lesion in the arterial phase were recorded for each patient. The images were analyzed by AtPI. Color mapping (CM) images obtained by AtPI were compared before and after the treatment. In these CM images, the mean arrival time of the contrast agent in the region of interest from the starting point [mean time (MT)] was calculated. In each patient, differences between MT before and MT 2 and 4 wk after the treatment were compared with responses evaluated 4-8 wk after the treatment by dynamic computed tomography (CT), and statistical analysis was performed. Modified response evaluation criteria in solid tumors was used for the response evaluation. RESULTS: In CM images both 2 and 4 wk after the treatment, delays in the arrival time of the contrast agent were noted in 8 of the 14 patients. In the other 6 patients, no color changes were observed in the tumor, or red and/or yellow increase, suggesting a decrease in blood flow velocity between images 2 and 4 wk after the treatment and those before the treatment. Dynamic CT could be performed 4-8 wk after the treatment in 13 of the 14 patients. Median differences in the MT were 1.13 s and 1.015 s, 2 and 4 wk after the treatment, respectively, in the 8 patients who showed stable disease (SD)/partial response (PR) on dynamic CT. Median differences in the MT were -0.39 s and -0.95 s, 2 and 4 wk after the treatment, respectively, in the 5 patients who showed progressive disease (PD). Differences in the median MT between SD/PR and PD groups were significant 2 and 4 wk after the treatment with P = 0.019 and P = 0.028, respectively. CONCLUSION: AtPI by CEUS using Sonazoid is suggested to be useful for evaluating early responses to sorafenib.