Contrast Material-enhanced Ultrasonography Research Articles

Contrast-enhanced US Assessment of Focal Liver Lesions in Children.

Ultrasonography (US) is often the first line of imaging for the examination of children suspected of having liver lesions. However, gray-scale US with color Doppler imaging has limitations. The use of US contrast agents has recently been approved by the U.S. Food and Drug Administration (FDA). Compared with other imaging modalities, contrast material-enhanced US (CEUS) enables the assessment of contrast enhancement patterns with a higher temporal resolution and is therefore becoming a valuable alternative imaging technique. CEUS is advantageous owing to its high safety profile; lower cost, compared with the costs of conventional contrast-enhanced computed tomographic and magnetic resonance imaging examinations; reliability; and reproducibility. Furthermore, US examinations obviate the use of sedation, ionizing radiation, and iodinated or gadolinium-based contrast agents. All of these are desirable attributes for an imaging examination for children, the most vulnerable of patients. Focal liver lesions in children are commonly discovered incidentally, and this can pose a dilemma in terms of diagnosis and management. Owing to the FDA's recent approval of the use of a specific US contrast agent for evaluation of focal liver lesions in pediatric patients, CEUS can now be used as a problem-solving tool that complements conventional imaging examinations and aids in the follow-up of lesions. The temporal resolution with CEUS enables US images to readily depict the real-time internal vascularity of a lesion. The characterization of a lesion during different phases of enhancement improves diagnostic confidence and treatment. In this article, the authors review the composition, physiologic properties, and safety profile of CEUS; describe the technique for performing CEUS; and highlight the utility of this examination in the assessment of common focal liver lesions in children. Online supplemental material is available for this article. ©RSNA, 2017.

Contrast-enhanced US-assisted Percutaneous Nephrostomy: A Technique to Increase Success Rate for Patients with Nondilated Renal Collecting System.

Purpose To perform a single-center study of contrast material-enhanced ultrasonography (US)-assisted percutaneous nephrostomy (PCN) for patients with nondilated renal collecting system. Materials and Methods An international review board approved this retrospective study with waiver of informed consent for participation, and the study was approved by the Ethical Committee. From November 2011 to September 2015, 47 patients (mean age, 51.9 years ± 16.2 [standard deviation]; range, 18-80 years) with clinical necessity of urinary drainage, urinary diversion, or provision of access to the collecting system and with nondilated renal collecting system who underwent contrast-enhanced US-assisted PCN for 48 kidneys were included. US contrast agent was injected through the puncture needle and the drainage catheter to confirm successful PCN. The technical success rate and complications were evaluated. Relative frequencies with 95% confidence intervals (CIs) were calculated. Results The technical success rate was 100% (47 of 47, 95% CI: 93.8%, 100%) per patient and 100% (48 of 48, 95% CI: 94.0%, 100%) per kidney. For each kidney, the mean number of needle passes was 1.4 ± 0.5 (range, 1-3). The mean duration of the complete procedure was 18.9 minutes ± 4.8 (range, 8-30 minutes). The mean dose of contrast agent was 12.9 mL ± 3.2 (range, 8-25 mL). No major complications were observed. After a follow-up of 1-30 days (mean, 18.4 days ± 10.3), only four patients (four of 47, 8.5%, 95% CI: 2.37%, 20.4%) had minor complications, including one perirenal hematoma seen at US 9 days after the procedure and three patients with transient macroscopic hematuria that lasted 1-2 days. Conclusion Contrast-enhanced US-assisted PCN in patients with nondilated renal collecting system is valuable with high technical success rate. © RSNA, 2017.

Integration of Contrast-enhanced US into a Multimodality Approach to Imaging of Nodules in a Cirrhotic Liver: How I Do It.

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.

Time-Intensity Curves Obtained after Microbubble Injection Can Be Used to Differentiate Responders from Nonresponders among Patients with Clinically Active Crohn Disease after 6 Weeks of Pharmacologic Treatment

Purpose To assess whether contrast material-enhanced ultrasonography (US) can be used to differentiate responders from nonresponders among patients with clinically active Crohn disease after 6 weeks of pharmacologic treatment. Materials and Methods This prospective study was approved by our ethics committee, and written informed consent was obtained from all patients. Fifty consecutive patients (26 men and 24 women; mean age, 34.76 years ± 9) with a proved diagnosis of active Crohn disease who were scheduled to begin therapy with biologics (infliximab or adalimumab) were included, with enrollment from June 1, 2013, to June 1, 2015. In each patient, the terminal ileal loop was imaged with contrast-enhanced US before the beginning and at the end of week 6 of pharmacologic treatment. Time-intensity curves obtained in responders (those with a decrease in the Crohn disease endoscopic index of severity score of 25-44 before treatment to 10-15 after treatment, an inflammatory score <7, and/or a decrease ≥70 in the Crohn disease activity index score compared with baseline) and nonresponders were compared with Mann-Whitney test. Results Responders (n = 31) and nonresponders (n = 19) differed (P < .05) in the percent change of peak enhancement (-40.78 ± 62.85 vs 53.21 ± 72.5; P = .0001), wash-in (-34.8 ± 67.72 vs 89.44 ± 145.32; P = .001) and washout (-5.64 ± 130.71 vs 166.83 ± 204.44; P = .002) rate, wash-in perfusion index (-42.29 ± 59.21 vs 50.96 ± 71.13; P = .001), area under the time-intensity curve (AUC; -46.17 ± 48.42 vs 41.78 ± 87.64; P = .001), AUC during wash-in (-43.93 ± 54.29 vs 39.79 ± 70.85; P = .001), and AUC during washout (-49.36 ± 47.42 vs 42.65 ± 97.09; P = .001). Responders and nonresponders did not differ in the percent change of rise time (5.09 ± 49.13 vs 6.24 ± 48.06; P = .93) and time to peak enhancement (8.82 ± 54.5 vs 10.21 ± 43.25; P = .3). Conclusion Analysis of time-intensity curves obtained after injection of microbubble contrast material 6 weeks after beginning pharmacologic treatment can be used to differentiate responders from nonresponders among patients with clinically active Crohn disease. © RSNA, 2016.

Extrauterine Pelvic Serous Carcinomas: Current Update on Pathology and Cross-sectional Imaging Findings.

The spectrum of extrauterine pelvic serous carcinomas includes ovarian serous carcinoma, primary peritoneal serous carcinoma, and primary fallopian tube carcinoma. Ovarian serous carcinoma, the most common ovarian malignant epithelial neoplasm, consists of two distinct entities: high-grade and low-grade serous carcinomas. Primary peritoneal serous carcinoma and primary fallopian tube carcinoma are rare malignancies that share many characteristics of high-grade serous carcinomas. Recent advances in the genetics and molecular biology of gynecologic cancers have suggested a common origin of many extrauterine pelvic serous carcinomas from fallopian tube epithelium. With the exception of low-grade serous carcinomas, which arise from cortical inclusion cysts lined by tubal epithelium, most extrauterine pelvic serous carcinomas are believed to originate from serous tubal intraepithelial carcinomas and show similar clinical-biologic behaviors and natural histories. Indeed, the International Federation of Gynecology and Obstetrics Committee on Gynecologic Oncology recently recognized that these cancers should be considered collectively, with a common system of staging and management strategies for ovarian, primary peritoneal, and fallopian tube cancers. A paradigm shift has occurred in our understanding of the pathogenesis of extrauterine pelvic serous carcinomas that has the potential to change current strategies for screening, prevention, diagnosis, and management. Ultrasonography (US), computed tomography (CT), magnetic resonance imaging, and combined positron emission tomography and CT are pivotal in screening, initial diagnosis, and treatment follow-up; however, because of this paradigm shift, new radiologic techniques, such as contrast material-enhanced US and molecular US imaging, and various optical imaging techniques are being investigated as important screening and diagnostic tools. Because of evolving knowledge of genetic and molecular changes underlying the pathogenesis of extrauterine pelvic serous carcinomas, new targeted therapies are being developed to improve patient prognosis. (©)RSNA, 2016.

Accuracy of Contrast-enhanced US for Differentiating Benign from Malignant Solid Small Renal Masses.

To test the hypothesis that qualitative and quantitative features of contrast material-enhanced ultrasonography (US) can be used to differentiate benign from malignant small renal masses. This is an institutional review board approved, HIPAA-compliant prospective study with written informed consent. Patients with histologically characterized solid small renal masses, excluding lipid-rich angiomyolipomas, underwent qualitative contrast-enhanced US with a combination of three different US machines. A subgroup of patients underwent quantitative contrast-enhanced US. Patients received a bolus injection of 0.2 mL of contrast material for qualitative and quantitative evaluations and were followed for 3 minutes. Two radiologists independently reviewed videotaped qualitative contrast-enhanced US examinations and were blinded to the final diagnoses. Features that were evaluated included lesion vascularity relative to the adjacent cortex in the arterial phase, the presence of a capsule, homogeneity, the pattern of vascularity, and washout. One radiologist separately reviewed a subset of contrast-enhanced US examinations that were performed with all three machines. Parameters of a first-pass time intensity curve were calculated for quantitative analysis. The Mann-Whitney test was used for quantitative parameters, the χ(2) or Fisher exact test was used for qualitative parameters, and κ statistics and Fleiss methodology were used to determine interobserver and intermachine agreement. The study population consisted of 91 patients (35 women and 56 men) with 94 lesions. The mean age was 62 years ± 14 (range, 21-91). Three patients had two lesions each, which were evaluated at two different sessions. There were 26 benign small renal masses (including 18 oncocytomas, seven lipid-poor angiomyolipomas, and one hemangioblastoma) and 68 malignant masses (including 41 clear cell, 20 papillary, and seven chromophobe renal cell carcinomas [RCCs[) that were 1.1-4.0 cm in diameter (mean, 2.7 cm ± 0.9). All patients underwent contrast-enhanced US on the same one machine, and 68 patients were imaged on all three machines. Vascularity was present in all lesions (n = 94) at contrast-enhanced US. Lesion hypovascularity relative to the adjacent cortex in the arterial phase was seen in only malignant lesions by both reviewers; reviewer 1 saw hypovascularity in 24 of 94 lesions (P = .0001), and reviewer 2 saw hypovascularity in 21 of 94 lesions (P = .0006), for a specificity of 100% (95% confidence interval [CI]: 84, 100). This feature had κ values of 0.91 (95%CI: 0.82, 1.00) between the two reviewers and 0.85 (95% CI: 0.72, 0.99) between the three machines. Eighteen of 20 papillary RCCs were hypovascular. Quantitative parameters of area under the receiver operating characteristics curve, peak intensity, wash-in slope of 10%-90% and 5%-45%, and washout slope of 100%-10% and 50%-10% were significantly higher in malignant renal masses (P = .018, P = .002, P = .036, P = .016, P = .001, and P = .005, respectively) than in benign lesions. Excluding lipid-rich angiomyolipoma, hypovascularity-which has high interobserver and intermachine agreement-of solid small renal masses relative to the cortex in the arterial phase has 100% specificity (95% CI: 84, 100) for detecting malignancy, most often papillary RCC.

Evaluation of Indeterminate Renal Masses with Contrast-enhanced US: A Diagnostic Performance Study

To determine the utility of contrast material-enhanced ultrasonography (US) in the characterization of indeterminate renal masses. This retrospective performance study was approved by the institutional review board and was HIPAA compliant, with waiver of informed consent. Patients included 721 individuals referred for contrast-enhanced US with 1018 indeterminate renal masses from 1999 to 2010, identified initially with an imaging study. Three hundred twenty patients (44.4%) were female, and 401 (55.6%) were male. Patient ages ranged from 17 to 95 years (mean ± standard deviation, 70 years ± 15). Lesion size varied from 2 to 161 mm (mean, 26.6 mm ± 19.5). Contrast-enhanced US enhancement patterns were used to characterize masses as benign or malignant. For lesions with a definitive diagnosis, 306 of 1018 (30.0%) were correlated with contrast-enhanced US findings: 167 (54.6%) were benign, and 139 (45.4%) were malignant. For lesions without a pathologic diagnosis, 712 (70.0%) were followed for as long as 10 years. Diagnostic accuracy measures were calculated by using pathologic diagnosis as the reference standard, as well as lesion stability at 3 and 5 years. Contrast-enhanced US had a sensitivity of 100% (126 of 126; 95% confidence interval [CI]: 97.1%, 100%), specificity of 95.0% (132 of 139; 95% CI: 89.9%, 98.0%), positive predictive value (PPV) of 94.7% (126 of 133), and negative predictive value (NPV) of 100% (132 of 132). The five false-positive masses included three oncocytomas and two Bosniak category 3 cystic lesions. Of the 290 lesions that had follow-up of at least 36 months, none of the lesions demonstrated changes that necessitated lesion reclassification. If these lesions were included, assuming lesions classified as malignant were malignant, then of the 596 lesions, sensitivity was 100% (161 of 161), specificity was 96.6% (420 of 435), PPV was 91.5% (161 of 176), and NPV was 100% (420 of 420). Contrast-enhanced US evaluation is a highly sensitive and specific method for characterization of indeterminate renal masses. Online supplemental material is available for this article.

Real-time Contrast-enhanced Transrectal US-guided Prostate Biopsy: Diagnostic Accuracy in Men with Previously Negative Biopsy Results and Positive MR Imaging Findings

To retrospectively evaluate diagnostic accuracy of real-time contrast material-enhanced (CE) ultrasonography (US) transrectal US-guided biopsies in patients with persistently elevated prostate-specific antigen (PSA) levels, previous negative systematic transrectal US-guided biopsy results, and positive prostate multiparametric magnetic resonance (MR) findings. Institutional review board approval was obtained for this retrospective study. Informed consent was waived. From 2007 to 2011, 178 patients with increased PSA levels (mean, 10.7 ng/mL [10.7 μg/L]), previous negative findings of random biopsies, and targets depicted at multiparametric MR imaging underwent transrectal US-guided prostate biopsies after injection of sulfur hexafluoride microbubbles. CE US-targeted biopsies were performed systematically in cancer-suggestive regions, followed by random acquisition of 12 nontargeted cores in all other regions. Diagnostic accuracy of CE US-targeted biopsies was measured with sensitivity, specificity, and positive and negative predictive values. Fisher exact and Mann-Whitney U tests were used to compare subgroups of patients. Potential predictive variables were examined with a logistic regression model. CE US findings were positive in a first group of 158 patients and negative in a second group of 20 patients. Prostate carcinoma (PCa) was detected in 75 patients in the first group (47.5%) and in eight of the second group (40.0%). Overall cancer detection rate was 46.6% (83 of 178). In the first group, PCa was detected with targeted biopsies alone in 18 patients (24%), with nontargeted biopsies alone in 23 (30.7%), and with both in 34 (45.3%). Mean number of CE US-targeted cores per cancer-suggestive region was 2.2. CE US-targeted biopsies had a positive overall detection rate of 30.9%, while it was 6.9% for 12-core nontargeted biopsies (P < .001). PSA level and Gleason score were associated with positivity of CE US-targeted biopsies (P = .031 and P = .015, respectively). Real-time CE US-targeted transrectal US biopsy offers excellent sensitivity for PCa detection in men with previous negative biopsy results and positive findings at multiparametric MR imaging. It may be combined with conventional random biopsies to increase specificity.

Obstruction at Middle Hepatic Venous Tributaries in Modified Right Lobe Grafts after Living-Donor Liver Transplantation: Diagnosis with Contrast-enhanced US

To investigate the ability of contrast material-enhanced ultrasonography (US) to help diagnose obstruction of middle hepatic venous (MHV) tributaries soon after living-donor liver transplantation with modified right lobe grafts. The institutional review board approved the study and waived requirement for informed consent. Sixty-five consecutive patients (48 men, 17 women; mean age, 52.8 years; range, 33-69 years) who underwent living-donor liver transplantation with modified right lobe grafts between February and May 2009 were included. All patients underwent contrast-enhanced US and Doppler US on postoperative day 1 and underwent computed tomography (CT) within 7 days after US. At contrast-enhanced US, parenchymal enhancement patterns in the territory of each MHV tributary during arterial and portal venous phases were evaluated. With use of most frequent enhancement patterns in patients with obstruction at MHV tributaries as a criterion, diagnostic performance of contrast-enhanced US was compared with that of Doppler US for diagnosis of obstruction at MHV tributaries; CT was the reference standard. Generalized estimating equations were used to adjust for data clustering. Of 148 MHV tributaries in 65 patients, 36 (24.3%) in 31 patients were diagnosed as obstructed at CT. With arterial high echogenicity or portal low echogenicity used as a criterion for hepatic venous obstruction, contrast-enhanced US had sensitivity, specificity, and accuracy of 91% (33 of 36), 97% (109 of 112), and 95% (142 of 148), respectively, whereas Doppler US had values of 83% (30 of 36), 86% (97 of 112), and 85% (127 of 148), respectively. Contrast-enhanced US was significantly more specific and accurate than Doppler US for diagnosis of obstruction at MHV tributaries (P=.024 and .01, respectively). Arterial high echogenicity was noted only in the hepatic venous obstruction group. Contrast-enhanced US can help accurately assess hepatic venous obstruction at MHV tributaries after living-donor liver transplantation with a modified right lobe graft. Contrast-enhanced US was significantly more specific than Doppler US, with arterial hyperenhancement in the affected area being specific to hepatic venous obstruction.

Time-resolved CT Angiography for the Detection and Classification of Endoleaks

To assess the feasibility and diagnostic performance of time-resolved computed tomographic (CT) angiography in the detection and classification of endoleaks after endovascular aortic aneurysm repair (EVAR) in high-risk patients. The study was approved by our ethics committee. Written informed consent was obtained from all participating patients. Fifty-four patients (42 male and 12 female patients; mean age, 70.9 years ± 9.3 [standard deviation]) with either thoracic (n = 8) or abdominal (n = 46) aortic aneurysms treated with a stent-graft were prospectively included. The patients were examined with a time-resolved CT angiographic protocol consisting of 12 low-dose phases (80 kVp; 120 mAs [effective]; scan range, 27 cm), with 60 mL of iomeprol. Patients with abdominal aneurysm repair also underwent contrast material-enhanced (CE) ultrasonography (US). The time delay between contrast enhancement within the stent lumen and the endoleak was measured. Effective radiation dose was calculated from the scanner protocols. Measures of diagnostic performance for the detection of endoleaks were calculated for time-resolved CT angiography, with CE US serving as the reference standard. All time-resolved CT angiographic data sets were diagnostic. Mean effective radiation dose was 14.6 mSv. Four thoracic and 19 abdominal endoleaks were identified by using time-resolved CT angiography. Seventeen of 19 abdominal endoleaks were confirmed with CE US. This rate resulted in a sensitivity of 94%, a specificity of 93%, a positive predictive value of 89%, and a negative predictive value of 96% for time-resolved CT angiography after abdominal EVAR. Type I endoleaks showed significantly earlier mean peak contrast enhancement (0.28 second ± 0.83) compared with that for type II endoleaks (9.17 seconds ± 3.59, P < .0001). Time-resolved CT angiography with 12 low-dose phases is feasible for patients after thoracic and abdominal EVAR. The protocol approximates the radiation dose of standard triphasic protocols. Its dynamic information differentiates types of endoleaks and shows high diagnostic performance.

US-guided Percutaneous Microwave Ablation of Renal Cell Carcinoma: Intermediate-term Results

To retrospectively review intermediate-term (median, 20.1 months) clinical outcomes after microwave ablation (MWA) of renal cell carcinoma (RCC). This retrospective study was approved by the institutional review board. The results from 46 patients with 49 RCC nodules (diameter, 0.6-7.7 cm; mean, 3.0 cm ± 1.5 [standard deviation]) treated with ultrasonography (US)-guided percutaneous MWA with cooled-shaft needle antenna from April 2006 to December 2010 were reviewed. One antenna was used for tumors smaller than 2 cm; two, for tumors 2 cm or larger. The patients were followed up with contrast material-enhanced US and computed tomography or magnetic resonance imaging at 1, 3, and 6 months and every 6 months thereafter. The effect of changes in key parameters (including overall survival, disease-free survival, and local tumor progression rate) was statistically analyzed by using the log-rank test. Technical effectiveness (complete ablation at follow-up enhanced imaging 1 month after MWA) was achieved in 48 of 49 (98.0%) tumors, and the metastasis-free rate was 100% (46 of 46). The 1-, 2-, and 3-year local tumor progression rates were 4.6%, 7.7%, and 7.7%, respectively. The cancer-specific survival rate was 100% (46 of 46), and 1-, 2-, and 3-year overall survival rates were 100%, 100%, and 97.8%, respectively. The 1-, 2-, and 3-year disease-free survival rates were 95.4%, 92.3%, and 92.3%, respectively. No major complications occurred. Multivariate analysis showed that tumor number (P = .046), tumor growth patterns (P = .003), and ablation time (P = .04) were independent unfavorable prognostic factors. In the intermediate term, US-guided percutaneous MWA appears to be a safe and effective technique for the management of RCC, especially small RCC, in selected patients.

Multiple Sclerosis: Cerebral Circulation Time

To assess cerebral circulation times (CCTs) in patients with multiple sclerosis (MS) and control subjects by using contrast material-enhanced ultrasonography (US) to determine whether vascular abnormalities can be detected in this disease. This study was approved by the local ethics committee, and informed consent was obtained from all subjects. One hundred three patients with MS and 42 control subjects underwent extracranial and transcranial venous echo-color Doppler ultrasonography (US) and contrast-enhanced US. CCT was defined as the difference in arrival time of the US contrast agent bolus between the carotid artery and the internal jugular vein. The presence of chronic cerebrospinal venous insufficiency (CCSVI) was defined according to previously reported criteria for the extracranial and transcranial US techniques. Nonparametric statistics, including the Mann-Whitney U test and the Kruskal-Wallis analysis of variance, were used to compare contrast-enhanced US parameters between groups. The longest and average CCTs were substantially prolonged in patients with MS compared with those in control subjects (median longest CCT in patients with MS, 6.47 seconds [range, 3.29-29.24 seconds]; that in control subjects, 5.54 seconds [range, 2.57-7.63 seconds]; P < .001; median average CCT in patients with MS, 5.76 seconds [range, 2.64-17.51 seconds]; that in control subjects, 5.01 seconds [range, 2.57-7.06 seconds]; P < .002). No correlation was found between CCTs and clinical parameters. The prevalence of CCSVI was higher in patients with MS than in control subjects (77% vs 28%, P < .0001). CCT was not significantly different between patients with MS who had CCSVI and patients with MS who did not (P = .182). These results suggest that contrast-enhanced US with CCT assessment may have a role in the evaluation of cerebral blood flow in patients with MS and that a vascular impairment could be associated with MS. The finding of a prolonged CCT at contrast-enhanced US does not result from outflow impairment. Further studies are required to verify these observations and to clarify if CCT and CCSVI have any physiologic and clinical relevance in MS.

Enhancement Patterns and Parameters of Breast Cancers at Contrast-enhanced US: Correlation with Prognostic Factors

To investigate the correlation between enhancement patterns and parameters of contrast material-enhanced ultrasonography (US) with prognostic factors in breast cancers. The study was approved by the institutional ethics committee, and written informed consent was obtained. Surgical resection specimens of 74 malignant breast lesions in 74 women (mean age, 55 years; age range, 32-78 years) who had undergone contrast-enhanced US were included. Different contrast enhancement patterns (enhancement degree, order, and margin; internal homogeneity; perfusion defect; and radial or penetrating vessels) and parameters (wash-in time, peak intensity, time to peak, area under the time-intensity curve, ascending slope, and descending slope) were evaluated. Pathologic prognostic factors, including histologic grade, lymph node status, tumor diameter, microvessel density (MVD), estrogen and progesterone receptor status, and c-erb-B2, p53, and Ki-67 expression were determined. Correlation of enhancement patterns and parameters with prognostic factors was analyzed with the Pearson χ2 test, Spearman rank correlation test, and logistic regression analysis. Some enhancement features were associated, albeit not significantly, with prognostic factors. Perfusion defect was the most accurate enhancement criterion for higher histologic grade (grade III) (P=.016), negative estrogen receptor expression (P=.006), positive c-erb-B2 expression (P=.013), larger tumor diameter (≥2 cm) (P=.016), and increased MVD (P=.019). Radial or penetrating vessels were associated with lymph node status (P=.010). Hyperenhancement may be useful in reflecting increased MVD (P=.008) and positive p53 expression (P=.037). For contrast enhancement parameters, ascending slope was the best discrimination criterion for proliferative activity (P=.003). Enhancement patterns and parameters of contrast-enhanced US may be useful in the noninvasive prediction of prognostic factors of breast cancers.

Quantification and Monitoring of Inflammation in Murine Inflammatory Bowel Disease with Targeted Contrast-enhanced US

To evaluate ultrasonography (US) by using contrast agent microbubbles (MBs) targeted to P-selectin (MB(P-selectin)) to quantify P-selectin expression levels in inflamed tissue and to monitor response to therapy in a murine model of chemically induced inflammatory bowel disease (IBD). All procedures in which laboratory animals were used were approved by the institutional administrative panel on laboratory animal care. Binding affinity and specificity of MB(P-selectin) were tested in cell culture experiments under flow shear stress conditions and compared with control MBs (MB(Control)). In vivo binding specificity of MB(P-selectin) to P-selectin was tested in mice with trinitrobenzenesulfonic acid-induced colitis (n = 22) and control mice (n = 10). Monitoring of anti-tumor necrosis factor α antibody therapy was performed over 5 days in an additional 30 mice with colitis by using P-selectin-targeted US imaging, by measuring bowel wall thickness and perfusion, and by using a clinical disease activity index score. In vivo targeted contrast material-enhanced US signal was quantitatively correlated with ex vivo expression levels of P-selectin as assessed by quantitative immunofluorescence. Attachment of MB(P-selectin) to endothelial cells was significantly (P = .0001) higher than attachment of MB(Control) and significantly (ρ = 0.83, P = .04) correlated with expression levels of P-selectin on endothelial cells. In vivo US signal in mice with colitis was significantly higher (P = .0001) with MB(P-selectin) than with MB(Control). In treated mice, in vivo US signal decreased significantly (P = .0001) compared with that in nontreated mice and correlated well with ex vivo P-selectin expression levels (ρ = 0.69; P = .04). Colonic wall thickness (P ≥ .06), bowel wall perfusion (P ≥ .85), and clinical disease activity scoring (P ≥ .06) were not significantly different between treated and nontreated mice at any time. Targeted contrast-enhanced US imaging enables noninvasive in vivo quantification and monitoring of P-selectin expression in inflammation in murine IBD.

Differentiation of Focal Liver Lesions: Usefulness of Parametric Imaging with Contrast-enhanced US

To evaluate whether parametric imaging with contrast material-enhanced ultrasonography (US) is superior to visual assessment for the differential diagnosis of focal liver lesions (FLLs). This study had institutional review board approval, and verbal patient informed consent was obtained. Between August 2005 and October 2008, 146 FLLs in 145 patients (63 women, 82 men; mean age, 62.5 years; age range, 22-89 years) were imaged with real-time low-mechanical-index contrast-enhanced US after a bolus injection of 2.4 mL of a second-generation contrast agent. Clips showing contrast agent uptake kinetics (including arterial, portal, and late phases) were recorded and subsequently analyzed off-line with dedicated image processing software. Analysis of the dynamic vascular patterns (DVPs) of lesions with respect to adjacent parenchyma allowed mapping DVP signatures on a single parametric image. Cine loops of contrast-enhanced US and results from parametric imaging of DVP were assessed separately by three independent off-site readers who classified each lesion as benign, malignant, or indeterminate. Sensitivity, specificity, accuracy, and positive and negative predictive values were calculated for both techniques. Interobserver agreement (κ statistics) was determined. Sensitivities for visual interpretation of cine loops for the three readers were 85.0%, 77.9%, and 87.6%, which improved significantly to 96.5%, 97.3%, and 96.5% for parametric imaging, respectively (P < .05, McNemar test), while retaining high specificity (90.9% for all three readers). Accuracy scores of parametric imaging were higher than those of conventional contrast-enhanced US for all three readers (P < .001, McNemar test). Interobserver agreement increased with DVP parametric imaging compared with conventional contrast-enhanced US (change of κ from 0.54 to 0.99). Parametric imaging of DVP improves diagnostic performance of contrast-enhanced US in the differentiation between malignant and benign FLLs; it also provides excellent interobserver agreement.

Tumor Angiogenic Marker Expression Levels during Tumor Growth: Longitudinal Assessment with Molecularly Targeted Microbubbles and US Imaging

To evaluate the use of molecularly targeted microbubbles (MBs) and ultrasonography (US) in the noninvasive assessment of the level of expression of three angiogenic markers, α(v)β(3) integrin, endoglin, and vascular endothelial growth factor receptor (VEGFR) 2, on tumor vascular endothelial cells in vivo during tumor growth. All procedures using laboratory animals were approved by the Institutional Administrative Panel on Laboratory Animal Care. Binding specificity of three types of targeted MBs (MB(Integrin), MB(Endoglin), MB(VEGFR2)) was tested in cell culture under flow shear stress conditions. In vivo targeted contrast material-enhanced US imaging signal using the three MB types was measured at three tumor stages (small, medium, large) in three subcutaneous cancer xenografts (breast, ovarian, pancreatic cancer) in mice (n = 54). In vivo US imaging signal was correlated with ex vivo angiogenic marker expression. Significant differences were evaluated by using the Student t, analysis of variance, Wilcoxon, and Tukey Honest Significant Difference tests. Cell attachment of all three MB types was significantly (P = .016) higher compared with control MBs, and this attachment could be significantly (P = .026) decreased by blocking antibodies. Angiogenic marker-expressing cells bound significantly (P = .003) more targeted MBs than negative control cells, and MB attachment significantly (P < .001) correlated with marker expression levels on cells (ρ = 0.87). In early stage breast and ovarian cancers, in vivo targeted contrast-enhanced US demonstrated significantly (P ≤ .04) higher endoglin expression than both α(v)β(3) integrin and VEGFR2 expression, whereas in early stage pancreatic cancer, marker expressions were not significantly different (P ≥ .07). There was good correlation (ρ ≥ 0.63; P ≤ .05) between in vivo targeted contrast-enhanced US imaging signals using the three MB types and ex vivo immunoblotting results regarding expression levels of the three angiogenic markers. Immunofluorescence confirmed expression of α(v)β(3) integrin, endoglin, and VEGFR2 on tumor vascular endothelial cells. Targeted contrast-enhanced US imaging allows noninvasive in vivo assessment of the expression levels of α(v)β(3) integrin, endoglin, and VEGFR2, which vary during tumor growth in subcutaneous cancer xenografts.

Correlation of Carotid Artery Atherosclerotic Lesion Echogenicity and Severity at Standard US with Intraplaque Neovascularization Detected at Contrast-enhanced US

To correlate echogenicity and severity of atherosclerotic carotid artery lesions at standard ultrasonography (US) with the degree of intraplaque neovascularization at contrast material-enhanced (CE) US. This HIPAA-compliant study was approved by the local ethics committee, and all patients provided informed consent. A total of 175 patients (113 [65%] men, 62 [35%] women; mean age, 67 years ± 10 [standard deviation]) underwent standard and CE US of the carotid artery. Lesion echogenicity (class I to IV), degree of stenosis, and maximal lesion thickness were evaluated for each documented atherosclerotic lesion. The degree of intraplaque neovascularization at CE US was categorized as absent (grade 1), moderate (grade 2), or extensive (grade 3). Correlation of neovascularization with echogenicity, degree of stenosis, and maximal lesion thickness was made by using Spearman ρ and χ(2) test for trend. In a total of 293 atherosclerotic lesions, echogenicity was inversely correlated with grade of intraplaque neovascularization (ρ = -0.199, P < .001). More echolucent lesions had a higher degree of neovascularization compared with more echogenic ones (P < .001). The degree of stenosis was significantly correlated with grade of intraplaque neovascularization (ρ = 0.157, P = .003). Lesions with higher degree of stenosis had higher grade of neovascularization (P = .008), and maximal lesion thickness increased with the grade of neovascularization (P < .001) and was significantly correlated with grade of neovascularization (ρ = 0.233, P < .001). Neovascularization visualized with CE US correlates with lesion severity and with morphologic features of plaque instability, contributing to the concept that more vulnerable plaques are more likely to have a greater degree of neovascularization. Therefore, CE US may be a valuable tool for further risk stratification of echolucent atherosclerotic lesions and carotid artery stenosis of different degrees. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10101008/-/DC1.

Crohn Disease: Correlation of Findings at Contrast-enhanced US with Severity at Endoscopy

To evaluate the effectiveness of visualization of vascularization at contrast material-enhanced ultrasonography (US) for assessment of the activity of Crohn disease, with severity grade determined at endoscopy as the reference standard. Ethics committee approval and written informed consent were obtained. Sixty-one patients (age range, 21-67 years; median age, 36 years) who had Crohn disease underwent both colonoscopy and US, including color Doppler and contrast-enhanced US, prospectively. To assess the vascularization of the involved bowel loop in a region expected to be seen at colonoscopy, the contrast agent uptake was measured by using quantitative analysis of the enhancement in regions of interest. Measurement of contrast enhancement was assessed as the increase in wall brightness with respect to the baseline brightness. Results were compared with the severity grade determined at endoscopy by using the area under the receiver operating characteristic curve and logistic regression analysis. Colonoscopy showed inflammatory lesions in 53 patients (mild disease, seven; moderate disease, 12; and severe disease, 34). Bowel wall thickness and grade at color Doppler US (P = .019 and .002, respectively) correlated with severity grade at endoscopy. Mural contrast enhancement in patients with active disease at endoscopy was markedly increased in comparison with enhancement in patients with inactive disease (P < .001). Multivariate logistic regression analysis revealed that an increase in wall brightness was a significant and independent variable predictive of severity grade at endoscopy. A threshold brightness value of percentage of increase of 46% had a sensitivity and specificity of 96% and 73%, respectively, in the prediction of moderate or severe grade for inflammation at endoscopy. Quantitative measurements of bowel enhancement obtained by using contrast-enhanced US correlate with severity grade determined at endoscopy. Contrast-enhanced US could be a useful technique to monitor the activity of Crohn disease. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2531082269/-/DC1.

Effect of Signal Intensity from the Accumulated Microbubbles in the Liver for Differentiation of Idiopathic Portal Hypertension from Liver Cirrhosis

To examine the possibility of using contrast material-enhanced ultrasonography (US) to differentiate idiopathic portal hypertension (IPH) from cirrhosis. This was an institutional review board-approved prospective study with written informed consent. The study consisted of 23 patients (mean age, 60 years +/- 11; range, 37-85 years) with biopsy-proved cirrhosis, 10 patients (mean age, 65 years +/- 8; range, 51-78 years) with IPH, and 27 control subjects (mean age, 46 years +/- 17; range, 26-82 years) without any focal hepatic lesions or portal vein thrombosis. The patients underwent contrast-enhanced US for the observation of the right liver lobe. The time of the onset of contrast enhancement in the right hepatic artery and right portal vein was examined at vascular phase under continuous low-power emission, and signal intensity differences (in decibels) by using instantaneous high-power emission in the liver parenchyma were analyzed at late phase (15 minutes). Interobserver variability was quantified as coefficients of variation. Onset time of contrast enhancement in the right portal vein was significantly longer for both IPH (22 sec +/- 3.9, P = .0035) and cirrhosis (19.3 sec +/- 4.7, P = .04) patients than for control subjects (17 sec +/- 3.3), with no significant difference in the onset time in the right hepatic artery. Images obtained in both IPH patients (21.2 dB +/- 1.4) and control subjects (22.1 dB +/- 2.2) had significantly higher signal intensity differences than those obtained in cirrhosis patients (13.8 dB +/- 2.8, P < .0001), with no significant difference between images of IPH patients and control subjects. Signal intensity differences of more than 18 dB had 100% sensitivity and specificity for the diagnosis in IPH patients and control subjects. Interobserver variability for signal intensity differences was 8.7%. Contrast-enhanced US may offer the possibility for a simple, easy, and noninvasive diagnosis of IPH.

Correlation of Carotid Plaque Neovascularization Detected by Using Contrast-enhanced US with Clinical Symptoms

To determine the correlation between the degree of plaque enhancement with contrast agent microbubbles and clinical symptoms in patients with carotid atherosclerotic plaque. The study was approved by the hospital ethical committee, and informed consent was obtained from all patients. One hundred four patients (83 men: mean age, 64 years +/- 9 [standard deviation]; 21 women: mean age, 61 years +/- 10) with carotid plaques were studied with standard and contrast material-enhanced ultrasonography (US). Contrast enhancement in the plaque was evaluated with visual interpretation and quantitative analysis. Among the 104 patients, 35 (34%) had transient ischemic attack and/or cerebrovascular ischemic stroke. Plaque enhancement was found in 28 (80%) of 35 symptomatic patients and in 21 (30%) of 69 asymptomatic patients (P < .001). Enhanced intensity in the plaque (13.9 dB +/- 6.4) and the ratio of enhanced intensity in the plaque to that in the lumen of the carotid artery (0.54 +/- 0.23) in symptomatic patients were significantly greater than those in asymptomatic patients (8.8 dB +/- 5.2 [P < .001] and 0.33 +/- 0.19 [P < .001], respectively). Sensitivity and specificity were 74% and 62%, respectively, for enhanced intensity in the plaque (cutoff value, 10.0 dB) and 74% and 75%, respectively, for ratio of enhanced intensity in the plaque to that in the lumen of the carotid artery (cutoff value, 0.46). Symptomatic patients had more intense contrast agent enhancement in the plaque than asymptomatic patients, suggesting that contrast-enhanced carotid US may be used for plaque risk stratification.