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Ultrasonography |
1 From the Department of Medical Imaging, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada (S.R.W., D.M.), and the Department of Medical Biophysics, Sunnybrook and Women's Health Science Centre, Ontario, Canada (P.N.B., J.A.W., X.L.). From the 1998 RSNA scientific assembly. Received June 8, 1999; revision requested July 29; final revision received October 26; accepted November 2. S.R.W. and P.N.B. were supported in part by the Medical Research Council and National Cancer Institute of Canada and Mallinckrodt Medical. Address reprint requests to S.R.W. (e-mail: stephanie.wilson@uhn.on.ca).
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Abstract |
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 TOP Abstract IntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS: Thirty patients with known hepatic masses were examined after injection of a perfluorocarbon microbubble agent. Tumor vascularity was assessed with continuous, harmonic gray-scale imaging with a low mechanical index (MI). Tumor vascular volume was assessed with brief, high-MI insonation called interval-delay imaging, which caused microbubble destruction. As the total contrast agent volume in the liver reflects the total vascular volume, quantitation of lesion enhancement relative to normal hepatic enhancement helped determine the vascular volume of the tumor relative to that of normal parenchyma.
RESULTS: Low-MI continuous harmonic imaging showed lesional vessels in hepatocellular carcinomas, minimal or no vessels in hemangiomas, and variable vascularization in metastases. High-MI interval-delay imaging showed greater enhancement in hepatocellular carcinomas than in normal liver (P < .02) and showed less enhancement in hemangiomas than in normal liver (P < .02). Enhancement in metastases was greater in the margins than in the center; as a result, the lesions appeared smaller (P < .03) and less well defined on the interval-delay images.
CONCLUSION: Contrast-enhanced harmonic imaging appears superior to conventional Doppler US for hepatic mass characterization. Low-MI continuous and high-MI interval-delay imaging can help assess tumor vascular pattern and microvascular volume.
Index terms: Liver, US, 761.12988 • Liver neoplasms, 761.3194, 761.323, 761.3327, 761.3328 • Liver neoplasms, US, 761.12988 • Microbubbles • Ultrasound (US), contrast media, 761.12988 • Ultrasound (US), harmonic study
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Introduction |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Unfortunately, the use of conventional Doppler US to provide vascular information often is limited by hepatic masses that are deep in the abdomen, are small, or are subject to motion artifacts from either respiratory or cardiac activity. To improve the performance of conventional US, two avenues may be pursued: The Doppler ultrasound signal can be enhanced with a contrast agent, or a recent imaging technology such as harmonic imaging can be employed.
Microbubble contrast agents for US currently are under investigation for radiologic applications. They comprise a suspension of gas bubbles whose mean size is smaller than that of a red blood cell but is sufficiently large to remain within the blood pool. They are injected intravenously and result in echo enhancement from systemic arterial vessels of up to 30 dB (1). Contrast agents for US are unique in that they interact with the imaging process. The major determinant of this interaction is the peak negative pressure of the transmitted ultrasound pulse, reflected in the mechanical index (MI), which is indicated on the US machine. By scanning with a low transmit intensity (MI < 0.5), the bubbles of a perfluorocarbon agent can be induced into stable, nonlinear oscillation, which results in harmonic or higher-frequency echoes. It now is well established that by scanning near the maximum output power of a diagnostic US machine (MI = 1.0–1.3), microbubble contrast agents are disrupted by their acoustic oscillation. Results of in vitro trials show that the microbubbles in the circulation emit a strong, very brief echo as they are disrupted at high-MI insonation and show that this echo is rich in harmonics (2,3).
Conventional US machines transmit and receive ultrasound signals at the same frequency. Harmonic imaging preferentially is used to detect higher-frequency echoes, specifically those at the second harmonic. Because moving tissue does not give harmonic echoes, harmonic Doppler US shows bubbles while suppressing artifacts from tissue motion (4). With the use of a low-MI continuous technique, flow in major vessels can be detected with the resolution afforded with gray-scale imaging. Because continuous imaging takes place at a frame rate at which the interval between frames exceeds the time taken for new bubbles to wash into the scanning plane, microscopic vessels are invisible with continuous, harmonic, contrast-enhanced imaging.
In interval-delay imaging, the imaging process is interrupted for several seconds. This allows the entire vascular volume, in which the microvessels are included, to fill with contrast medium. Imaging is then commenced at a high MI. This destroys the accumulated microbubbles, which causes them to release high-intensity, nonlinear ultrasound echoes that are optimally detected by using harmonic imaging (3). It is not necessary for the bubbles to be moving for them to be detected in this way. This harmonic interval-delay method, therefore, allows the detection of blood in the capillary bed, where the flow velocity is too low to be detected with Doppler US flow techniques. In this way, harmonic gray-scale imaging can be used to detect echoes from the contrast agent when it is at very low concentrations and when it is distributed in microscopic vessels.
Our purpose was to characterize blood flow in focal hepatic lesions with non-Doppler US harmonic imaging after the injection of a microbubble contrast agent. Low-MI continuous imaging was used to assess lesional vascularity, and high-MI interval-delay imaging was used to show the total amount of contrast agent in the vascular bed of a lesion compared with that in the surrounding normal liver, a measure of the relative vascular volume.
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MATERIALS AND METHODS |
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The protocol was approved by the Food and Drug Administration, by the Health Protection Branch of Canada, and by our institutional human studies ethics board. Informed consent was obtained from all patients.
Contrast Material Enhancement Monitoring
The efficacy of the contrast agent was monitored quantitatively for each injection by using an independent, specially constructed Doppler US system. A single transducer was clamped and held over the femoral or brachial artery and was connected to a pulsed Doppler US system that operated at a center frequency of 5 MHz and an MI of less than 0.05. Doppler ultrasound signals were recorded digitally and were analyzed to yield a continuous estimate of the relative backscatter intensity of systemic arterial blood. This measurement was used to determine the peak intensity of the enhancement and thereby to time the interval-delay sequences. It also was used to indicate the return to baseline intensity after the washout of the contrast agent.
Patient Selection
Between September 1997 and July 1998, 33 patients who had a confirmed hepatic mass in one of three categories—10 with hemangioma, 12 with hepatocellular carcinoma, and 11 with metastases—were selected randomly from those referred to our US department. A confirmed diagnosis of their hepatic mass was the only inclusion criterion. Patients currently undergoing or who recently (within 30 days) underwent chemotherapy were excluded from recruitment. Informed consent was obtained from all patients.
Baseline US examinations included gray-scale, color, and power Doppler US evaluation of the lesion under study. Blood flow was classified subjectively as absent, sparse, moderate, or profuse on the basis of the number of blood vessels seen within and around the tumor.
After the baseline US examination, all patients underwent imaging after the intravenous administration of human albumin microspheres. Results in three patients were not obtained because of technical or procedural failure. Data in the remaining 30 patients were analyzed both with quantitative analysis and with blinded clinical review.
Hemangioma.—The 10 patients with hemangiomas included five men and five women aged 36–72 years. Diagnosis was confirmed with the results of labeled red blood cell scintigraphy in seven patients, of contrast material-enhanced CT in three patients, of serial US follow-up examinations (an unchanging lesion) for up to 10 years in three patients, and of MR imaging in one patient. Lesions ranged from 1 to 17 cm in maximal diameter. No vascularity was detected with conventional Doppler US in any lesion.
Hepatocellular carcinoma.—Ten patients with hepatocellular carcinoma included seven men and three women aged 34–74 years. Nine patients had histologic confirmation provided with percutaneous biopsy (three patients) or with surgery (six patients). The remaining patient had a clinical diagnosis confirmed with results of MR imaging and CT and with an 
1-fetoprotein level of greater than 2,000 µg/L. The maximal lesion diameter was 2.8–13.5 cm. Baseline Doppler US evaluation showed arterial blood flow in nine of 10 tumors, which was assessed as profuse in five, as moderate in two, and as sparse in two.
Metastases.—Ten patients with metastases comprised eight men and two women aged 45–66 years. Primary tumors included colon cancer (seven patients), carcinoid tumor (one patient), kidney cancer (one patient), and cholangiocarcinoma (one patient). Histologic proof of the diagnosis in nine patients was obtained with percutaneous biopsy (two patients) or with surgery (seven patients). In the one patient without histologic proof of metastasis, there was overwhelming clinical evidence of disseminated malignancy and confirmatory CT scans and MR images.
Metastatic lesions ranged in maximal diameter from 1 to 12 cm. Baseline Doppler US showed moderate lesional arterial vascularity in the two lesions from vascular primary tumors (carcinoid and kidney cancer). Doppler ultrasound signals were absent on baseline studies in the remaining eight lesions.
US Technique
All scans were obtained with HDI 3000 and 5000 scanners (ATL Ultrasound, Bothell, Wash) by using a C4-2 or C5-2 curvilinear transducer and by using prototype research software (ATL Ultrasound) for harmonic imaging. Low MIs in the range of 0.1–0.6 were selected for the blood vessel assessment, and a maximum MI of 1.3 was selected for the bubble disruption that was required for the interval-delay vascular volume assessments.
Four contrast medium injections were made with the following machine selections: injection 1, conventional color or power Doppler US; injection 2, harmonic color or power Doppler US, consistent with injection 1; injection 3, fundamental (conventional) gray-scale imaging; and injection 4, harmonic gray-scale imaging. Volumes of 2 mL were administered over approximately 1
minutes for the Doppler US studies. Injections 3 and 4, during the gray-scale imaging sequences, were administered as 4-mL boluses.
All imaging was performed by maintaining a constant position of the transducer over the region of interest to show the lesion and to include some normal liver. For each of the four injections, imaging was divided into two components: low-MI continuous imaging and high-MI interval-delay imaging. During the delivery of the contrast agent, low-MI continuous imaging was performed to show the enhanced blood signals in both the normal hepatic blood vessels—first the hepatic artery and then the portal vein—and the lesional blood vessels, which were assessed for their number, location, and morphology.
Vascular volume, including the arterial, venous, and capillary blood volumes in the field of view, was assessed with high-MI interval-delay imaging as follows: At the point determined with the femoral or brachial arterial Doppler ultrasound signal to be the peak of contrast medium enhancement in the systemic circulation, scanning was ceased for 5–8 seconds during a breath hold while the transducer was maintained over the lesion. Brief reinsonation caused the contrast agent bubbles that had accumulated in the microvasculature of the liver and the lesion to disrupt. In the color and power Doppler US modes, this was seen as a strong color flash throughout the region of accumulated contrast agent.
In the gray-scale fundamental and harmonic modes, on the other hand, the disruption of the bubbles occurred first in the near field, then in the midfield, and finally in the far field. The progression of the contrast agent disruption through the liver appeared as if a bright veil had been dropped through the liver (Fig 1). Freezing the imaging after the appearance of the gray-scale veil allowed for the reevaluation of the progress of the veil with a cine loop. The liver, which always contains contrast agent after an interval delay, showed increased echogenicity in the veil.
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All studies were recorded on S-VHS video, with selected digital images and cine loops stored on a magneto-optical disk.
Analysis: Blinded Reading
Two reviewers (including D.M.) blinded to the patient's name, medical record number, diagnosis, and US findings independently scored the degree of visualized vascularity and the change in diagnostic quality of the postcontrast scan as compared with the baseline scan by using the videotaped recordings of each study. Differences in grading were then resolved with consensus. Vascularity was evaluated on images obtained with low-MI continuous imaging and was compared with that on baseline color or power Doppler US images. A score of 0 was assigned if there was no change in vessel assessment from baseline imaging; 1, for sparse vascularity not seen at baseline imaging; 2, for moderate vascularity not seen at baseline imaging; and 3, for profuse vascularity not seen at baseline imaging. Because vascularity assessment is inversely affected by artifacts, we assigned a score of –1 for mild artifacts, -2 for moderate artifacts, and –3 for severe artifacts with reduced image quality.
Qualitative vascular volume assessment was performed on images of the gray-scale veil obtained with the high-MI interval-delay technique. A score of 0 was assigned if there was little or no participation of the lesion in the veil; a score of 1, if there was participation of the lesion margin in the veil; a score of 2, if there was participation of the lesion equal to that of the normal liver; and a score of 3, if there was participation of the lesion in excess of that of the normal liver.
Analysis: Quantitative
The apparent size of the lesion on a baseline image was compared with the apparent size of the lesion on a harmonic gray-scale image obtained during injection 4 that showed the peak of the gray-scale veil at the same depth from the transducer as the lesion. These images were selected by consensus by S.R.W. and P.N.B. The maximal lesion diameters on these two images were measured and compared by a single observer (J.A.W.).
On the same pre- and postinjection images, regions of interest were placed in the tumor mass and in the normal hepatic parenchyma at the same depth. By using knowledge of the display dynamic range and the gray-scale map, these regions were transformed on a pixel-by-pixel basis to their corresponding echo levels. Research software (HDI LAB; ATL Ultrasound) was used to derive a mean echo amplitude and SD for each region of interest. From these data, a mean echo amplitude of the lesion relative to the normal liver was calculated. This value corresponded to the relative amplitude of the detected echo and was independent of instrument display parameters such as the gray-scale map.
Where the lesion appearance was heterogeneous within the veil, as was the case for the metastases, the region of interest included the entire lesion. The mean echo level of the lesion was compared with that of the surrounding parenchyma in each of the three lesion types before and after the administration of the contrast agent. The difference between the two measurements was assessed by using the Student t test and the Wilcoxon signed rank test.
From the data recorded by using the pulsed Doppler US arterial monitor, time-response curves of the contrast medium injections were produced by using a linear analysis method that provided a measure of the backscatter enhancement in the systemic arterial circulation without destroying the bubbles. The method and its validation are described elsewhere (5). The following measures of enhancement were calculated from these curves: the peak enhancement intensity (in decibels), the duration of enhancement (in minutes), and the time to peak enhancement (in seconds).
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RESULTS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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In all but four of the 30 patients, the veil was imaged adequately for quantitative analysis. The four patients with incomplete imaging underwent technically demanding examinations that required suspended respiration for the lesion to be maintained in the field of view.
The contrast agent proved easy to handle and was stable and tolerated well by all patients. No (major or minor) adverse events associated with the administration of contrast agent were observed.
Blinded Review
The results of the blinded review are shown in Figure 2a. Injection 1, in which the contrast agent was used as a simple echo enhancer in conventional color or power Doppler US, resulted in the deterioration of the diagnostic quality of the images in 29 of the 30 (97%) patients, with 18 (60%) patients having images judged to show severe artifacts. The color and power Doppler US modes had a severe blooming artifact and saturation of the color box, with no interpretable information.
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After injection 3, for which conventional gray-scale imaging was used, we detected some vascularity in 29 of 30 (97%) patients but detected profuse vessels in none (0%) and failed to detect the agent's presence at all in one (3%) patient.
The same dose was given in injection 4, for which harmonic gray-scale imaging was performed, and 29 of 30 (97%) patients showed improved visualization of vascularity over that with conventional imaging, with 23 of 30 (77%) showing profuse patterns not seen on the baseline images. Harmonic gray-scale imaging also improved structural contrast in the image, although it frequently was associated with deterioration in image resolution.
Lesion-Specific Findings
The findings for the three classes of tumor are summarized descriptively in Table 1; the quantitative measurements are shown in Table 2 and in Figure 3.
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Metastases.—The metastases from the colon showed variable echogenicity at baseline imaging (Fig 7,A). On low-MI continuous, harmonic gray-scale postcontrast images, small circumferential vessels were seen around the lesion, with irregular, penetrating branches that coursed toward the lesion center (Fig 7,B).
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Quantitative Measurements
The quantitative results of the measurement of the echogenicity of each hepatic lesion relative to the parenchyma both before and during the veil are shown in Table 2 and are shown graphically in Figure 2.
The measurements show that, on average, the hemangiomas were 2.23 dB more echogenic than normal liver at baseline imaging. In the harmonic gray-scale veil, however, the same lesions were on average 3.09 dB less echogenic than the surrounding liver, as the liver enhanced in excess of the hemangiomas.
The hepatocellular carcinomas, in comparison, were seen as hypoechoic masses at baseline imaging (mean echogenicity, -2.36 dB with respect to the liver) but were brighter than the liver during the veil (mean echogenicity, 2.80 dB). Both these differences from baseline imaging were significant (P < .02).
On average, the gray-scale veil reduced the echogenicity of the metastases with respect to the liver, which reflected the greater enhancement of the normal parenchyma with the contrast medium. These differences were not statistically significant, however, and reflected the highly variable appearance of metastasis at baseline scanning. However, the metastases were measured consistently to have a smaller apparent diameter during the veil than at baseline imaging (P < .03), which reflected the participation of the periphery or of the margin of the tumor in the veil.
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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To our knowledge, most studies of contrast agents in the liver reported on to date have been limited by the use of conventional gray-scale and Doppler US technology. Our experience shows that simply adding contrast agents in conventional color and power Doppler US imaging actually reduces the diagnostic utility of the examination. Images from such examinations show extensive color blooming and saturation of the color box, artifacts that obscure appreciation of the enhancement of Doppler ultrasound signals from the tumor vessels.
It is the application of harmonic imaging that greatly improves the options for hepatic mass evaluation with contrast agents. To image the contrast agent in blood vessels without destroying the bubbles, a low MI must be used, which reduces the sensitivity of the image. In spite of this, low-MI continuous harmonic imaging reveals vessels not seen by using conventional Doppler US modes, with or without contrast material enhancement. One reason for this is the absence of motion artifacts with the contrast-enhanced harmonic approach. At blinded review, the harmonic gray-scale images consistently showed the fewest artifacts and showed the most evidence of lesional vascularity. Furthermore, the resolution afforded on the harmonic gray-scale images was superior to that on color and power Doppler US images, in which blooming made the vessels appear much larger than they actually were.
The gray-scale veil, descending throughout the liver with high-MI interval-delay imaging, is a consequence of bubble destruction, which occurs when the peak intensity of the ultrasound beam exceeds a critical peak pressure value (which corresponds to an MI of approximately 1.0) that disrupts the bubble. Because the disrupting bubbles attenuate the ultrasound intensity, those carried in superficial tissue "shield" the bubbles more distally during the first imaging frame. That frame shows a bright band as the superficial bubbles are disrupted. The second frame then disrupts the band beneath, and so on, until the bubbles in the entire field of view are destroyed and the veil has descended to the distal portion of the perfused organ.
The intensity of the echo that produces the ultrasound veil is proportional to the intensity of the backscattered echo from the bubbles, which has been shown to be proportional to the number of microbubbles present within the ultrasound beam (12). As the bubbles carried in the vascular system are too large to diffuse outside the vascular space, this signal level is then related directly to the total vascular volume within the scanning plane. This measurement requires the use of microbubble contrast agents and harmonic imaging and offers information not previously available with US.
To assess the vascular volume of a hepatic lesion relative to that of the surrounding parenchyma, this echo level was measured simply in two regions of interest, one in the lesion and one in the liver, at equal depths from the transducer. These measurements were made from the echo signal itself and were independent of the postprocessing map used to create the video image.
A high-vascular-volume lesion appears as white or as whiter than the adjacent parenchyma, whereas an avascular lesion appears less white or even black relative to the adjacent enhancing normal hepatic parenchyma. The quantitative measurements in Table 2 confirm this. Thus, a hepatocelluar carcinoma that is echo poor relative to the surrounding liver on baseline images becomes echogenic during the veil (Fig 6c); a hemangioma that is echogenic relative to the surrounding liver on baseline images becomes echo poor during the veil (Fig 4b–4d). This reversal in echogenicity was statistically significant for both lesions, as shown in Table 2.
These lesion-specific observations suggest that the hepatocelluar carcinomas have a vascular volume in excess of that of the normal liver, whereas the hemangiomas have a vascular volume less than that of the normal liver. These observations may appear inconsistent with those from contrast-enhanced CT and MR imaging, in which, for example, a hemangioma is seen to opacify slowly from the margin to the center with time.
However, unlike the CT and MR imaging contrast agents, which diffuse through the permeable vascular endothelium, US contrast agent microbubbles stay within the vascular space, and their number reflects its volume. After many minutes, these agents remain within the blood pool, even in cancers, in which changes in vascular permeability are commonly associated with tumor angiogenesis (13,14). For this reason, we do not believe that the results of this study should be compared directly with the findings of CT and MR imaging studies of focal hepatic lesions.
The limitations of this preliminary study must be appreciated. We restricted inclusion of patients to those with the three most commonly encountered hepatic masses—metastatic disease, hemangioma, and hepatocellular carcinoma. In this study, the diagnosis of the lesions was made before the inclusion of patients. The overall number of patients in each category was small, and the emphasis on colorectal primary carcinoma for the metastatic tumor group reflects the demographics at our institution.
Hepatic mass evaluation with US contrast agents is in its infancy. Harmonic US imaging with microbubble contrast material can be used to assess both the tumor vessel morphology with low-MI continuous imaging and the relative microvascular volume of the tumor with high-MI interval-delay imaging. We believe this success is related to the superior resolution and artifact reduction of harmonic gray-scale imaging compared with that of conventional color and power Doppler US, contrast material enhanced or not. The results of this small study are promising and suggest the potential to differentiate hepatic tumors on the basis of their appearance and response to US contrast agents; however, the specific vascular features of each tumor group need to be validated in a much larger prospective trial.
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Footnotes |
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Author contributions: Guarantors of integrity of entire study, S.R.W., P.N.B.; study concepts and design, S.R.W., P.N.B.; definition of intellectual content, S.R.W., P.N.B.; literature research, S.R.W., P.N.B.; clinical studies, S.R.W., D.M.; data acquisition, X.L., J.A.W.; data analysis, J.A.W., P.N.B.; statistical analysis, P.N.B.; manuscript preparation, editing, and review, S.R.W., P.N.B.
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E. Quaia, F. Calliada, M. Bertolotto, S. Rossi, L. Garioni, L. Rosa, and R. Pozzi-Mucelli Characterization of Focal Liver Lesions with Contrast-specific US Modes and a Sulfur Hexafluoride-filled Microbubble Contrast Agent: Diagnostic Performance and Confidence Radiology, August 1, 2004; 232(2): 420 - 430. [Abstract] [Full Text] [PDF]
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 M. Brannigan, P. N. Burns, and S. R. Wilson Blood Flow Patterns in Focal Liver Lesions at Microbubble-enhanced US RadioGraphics, July 1, 2004; 24(4): 921 - 935. [Abstract] [Full Text] [PDF]
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V. Migaleddu, G. Virgilio, D. Turilli, M. Conti, G. Campisi, N. Canu, D. Sirigu, and I. Vincentelli Characterization of Focal Liver Lesions in Real Time Using Harmonic Imaging with High Mechanical Index and Contrast Agent Levovist Am. J. Roentgenol., June 1, 2004; 182(6): 1505 - 1512. [Abstract] [Full Text] [PDF]
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Y. L. Wen, M. Kudo, R. Q. Zheng, H. Ding, P. Zhou, Y. Minami, H. Chung, M. Kitano, T. Kawasaki, and K. Maekawa Characterization of Hepatic Tumors: Value of Contrast-Enhanced Coded Phase-Inversion Harmonic Angio Am. J. Roentgenol., April 1, 2004; 182(4): 1019 - 1026. [Abstract] [Full Text] [PDF]
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F. Forsberg, B. B. Goldberg, C. R. B. Merritt, L. Parker, A. J. Maitino, J. J. Palazzo, D. A. Merton, S. M. Schultz, and L. Needleman Diagnosing Breast Lesions With Contrast-Enhanced 3-Dimensional Power Doppler Imaging J. Ultrasound Med., February 1, 2004; 23(2): 173 - 182. [Abstract] [Full Text] [PDF]
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M. J. Kim, H. K. Lim, S. H. Kim, D. Choi, W. J. Lee, S. J. Lee, and J. H. Lim Evaluation of Hepatic Focal Nodular Hyperplasia With Contrast-Enhanced Gray Scale Harmonic Sonography: Initial Experience J. Ultrasound Med., February 1, 2004; 23(2): 297 - 305. [Abstract] [Full Text] [PDF]
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S. Sartori, I. Nielsen, L. Trevisani, P. Tombesi, P. Ceccotti, and V. Abbasciano Contrast-Enhanced Sonography as Guidance for Transthoracic Biopsy of a Peripheral Lung Lesion With Large Necrotic Areas J. Ultrasound Med., January 1, 2004; 23(1): 133 - 136. [Full Text] [PDF]
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T. Isozaki, K. Numata, T. Kiba, K. Hara, M. Morimoto, T. Sakaguchi, H. Sekihara, T. Kubota, H. Shimada, T. Morizane, et al. Differential Diagnosis of Hepatic Tumors by Using Contrast Enhancement Patterns at US Radiology, December 1, 2003; 229(3): 798 - 805. [Abstract] [Full Text] [PDF]
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K. W. Kim, B. I. Choi, S. H. Park, H.-C. Kim, M. W. Lee, S. H. Kim, K. H. Lee, C. H. Park, J. S. Kim, H.-J. Won, et al. Hepatocellular Carcinoma: Assessment of Vascularity With Single-Level Dynamic Ultrasonography During the Arterial Phase J. Ultrasound Med., September 1, 2003; 22(9): 887 - 896. [Abstract] [Full Text] [PDF]
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J. H. Youk, C. S. Kim, and J. M. Lee Contrast-Enhanced Agent Detection Imaging: Value in the Characterization of Focal Hepatic Lesions J. Ultrasound Med., September 1, 2003; 22(9): 897 - 910. [Abstract] [Full Text] [PDF]
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H. Maruyama, S. Matsutani, H. Saisho, Y. Mine, H. Yuki, and K. Miyata Extra-Low Acoustic Power Harmonic Images of the Liver With Perflutren: Novel Imaging for Real-Time Observation of Liver Perfusion J. Ultrasound Med., September 1, 2003; 22(9): 931 - 938. [Abstract] [Full Text] [PDF]
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M. Morimoto, K. Shirato, K. Sugimori, A. Kokawa, N. Tomita, T. Saito, T. Imada, N. Tanaka, A. Nozawa, K. Numata, et al. Contrast-Enhanced Harmonic Gray-Scale Sonographic-Histologic Correlation of the Therapeutic Effects of Transcatheter Arterial Chemoembolization in Patients with Hepatocellular Carcinoma Am. J. Roentgenol., July 1, 2003; 181(1): 65 - 69. [Abstract] [Full Text] [PDF]
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 J U Harrer, L Mayfrank, M Mull, and C Klotzsch Second harmonic imaging: a new ultrasound technique to assess human brain tumour perfusion J. Neurol. Neurosurg. Psychiatry, March 1, 2003; 74(3): 333 - 342. [Abstract] [Full Text] [PDF]
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S. A. Teefey, C. C. Hildeboldt, F. Dehdashti, B. A. Siegel, M. G. Peters, J. P. Heiken, J. J. Brown, E. G. McFarland, W. D. Middleton, D. M. Balfe, et al. Detection of Primary Hepatic Malignancy in Liver Transplant Candidates: Prospective Comparison of CT, MR Imaging, US, and PET Radiology, February 1, 2003; 226(2): 533 - 542. [Abstract] [Full Text] [PDF]
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K. Numata, T. Isozaki, Y. Ozawa, T. Sakaguchi, T. Kiba, T. Kubota, A. Ito, K. Sugimori, K. Shirato, M. Morimoto, et al. Percutaneous Ablation Therapy Guided by Contrast-Enhanced Sonography for Patients with Hepatocellular Carcinoma Am. J. Roentgenol., January 1, 2003; 180(1): 143 - 149. [Abstract] [Full Text] [PDF]
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A. von Herbay, C. Vogt, and D. Haussinger Pulse Inversion Sonography in the Early Phase of the Sonographic Contrast Agent Levovist: Differentiation Between Benign and Malignant Focal Liver Lesions J. Ultrasound Med., November 1, 2002; 21(11): 1191 - 1200. [Abstract] [Full Text] [PDF]
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T.-M. Chen, S.-N. Lu, J.-H. Wang, C.-H. Hung, and H.-D. Tung Relationship Between Flash Echo Gray Scale Imaging Features and Pathologic Findings in Hepatic Adenoma J. Ultrasound Med., July 1, 2002; 21(7): 821 - 824. [Full Text] [PDF]
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G. L. Bennett, G. A. Krinsky, R. J. Abitbol, S. Y. Kim, N. D. Theise, and L. W. Teperman Sonographic Detection of Hepatocellular Carcinoma and Dysplastic Nodules in Cirrhosis: Correlation of Pretransplantation Sonography and Liver Explant Pathology in 200 Patients Am. J. Roentgenol., July 1, 2002; 179(1): 75 - 80. [Abstract] [Full Text] [PDF]
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 J. U. Harrer and C. Klotzsch Second Harmonic Imaging of the Human Brain: The Practicability of Coronal Insonation Planes and Alternative Perfusion Parameters Stroke, June 1, 2002; 33(6): 1530 - 1535. [Abstract] [Full Text] [PDF]
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 D. A. Merton Contrast-Enhanced Hepatic Sonography Journal of Diagnostic Medical Sonography, January 1, 2002; 18(1): 5 - 15. [Abstract] [PDF]
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S. Tanaka, T. Ioka, O. Oshikawa, Y. Hamada, and F. Yoshioka Dynamic Sonography of Hepatic Tumors Am. J. Roentgenol., October 1, 2001; 177(4): 799 - 805. [Abstract] [Full Text] [PDF]
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H. Rhim, S. N. Goldberg, G. D. Dodd III, L. Solbiati, H. K. Lim, M. Tonolini, and O. K. Cho Essential Techniques for Successful Radio-frequency Thermal Ablation of Malignant Hepatic Tumors RadioGraphics, October 1, 2001; 21(90001): S17 - 35. [Abstract] [Full Text] [PDF]
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M. F. Meloni, S. N. Goldberg, T. Livraghi, F. Calliada, P. Ricci, M. Rossi, D. Pallavicini, and R. Campani Hepatocellular Carcinoma Treated with Radiofrequency Ablation: Comparison of Pulse Inversion Contrast-Enhanced Harmonic Sonography, Contrast-Enhanced Power Doppler Sonography, and Helical CT Am. J. Roentgenol., August 1, 2001; 177(2): 375 - 380. [Abstract] [Full Text] [PDF]
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H. Ding, M. Kudo, H. Onda, Y. Suetomi, Y. Minami, and K. Maekawa Hepatocellular Carcinoma: Depiction of Tumor Parenchymal Flow with Intermittent Harmonic Power Doppler US during the Early Arterial Phase in Dual-Display Mode Radiology, August 1, 2001; 220(2): 349 - 356. [Abstract] [Full Text] [PDF]
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T. Albrecht, M. J. K. Blomley, S. R. Wilson, and P. N. Burns Characteristics of Hepatic Hemangiomas at Contrast-enhanced Harmonic US Drs Wilson and Burns respond: Radiology, July 1, 2001; 220(1): 269 - 270. [Full Text] [PDF]
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K. Numata, K. Tanaka, T. Kiba, S. Saito, T. Isozaki, K. Hara, M. Morimoto, H. Sekihara, H. Yonezawa, and T. Kubota Using Contrast-Enhanced Sonography to Assess the Effectiveness of Transcatheter Arterial Embolization for Hepatocellular Carcinoma Am. J. Roentgenol., May 1, 2001; 176(5): 1199 - 1205. [Abstract] [Full Text] [PDF]
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H. Ding, M. Kudo, H. Onda, Y. Suetomi, Y. Minami, and K. Maekawa Contrast-Enhanced Subtraction Harmonic Sonography for Evaluating Treatment Response in Patients with Hepatocellular Carcinoma Am. J. Roentgenol., March 1, 2001; 176(3): 661 - 666. [Abstract] [Full Text] [PDF]
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H. Ding, M. Kudo, H. Onda, Y. Suetomi, Y. Minami, H. Chung, T. Kawasaki, and K. Maekawa Evaluation of Posttreatment Response of Hepatocellular Carcinoma with Contrast-enhanced Coded Phase-Inversion Harmonic US: Comparison with Dynamic CT Radiology, December 1, 2001; 221(3): 721 - 730. [Abstract] [Full Text] [PDF]
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M. J. Dill-Macky, P. N. Burns, K. Khalili, and S. R. Wilson Focal Hepatic Masses: Enhancement Patterns with SH U 508A and Pulse-Inversion US Radiology, January 1, 2002; 222(1): 95 - 102. [Abstract] [Full Text] [PDF]
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F. Forsberg, C. W. Piccoli, J.-B. Liu, N. M. Rawool, D. A. Merton, D. G. Mitchell, and B. B. Goldberg Hepatic Tumor Detection: MR Imaging and Conventional US versus Pulse-Inversion Harmonic US of NC100100 during Its Reticuloendothelial System-Specific Phase Radiology, March 1, 2002; 222(3): 824 - 829. [Abstract] [Full Text] [PDF]
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), and 5th-95th-percentile ranges (short horizontal line). (a) Box plot for low-MI US imaging shows observer scores of the response to contrast agent in the four imaging modes: Negative scores indicate artifact, and positive scores indicate improved visualization of vessels. Inj = injection. (b) Box plot for high-MI harmonic, interval-delay US imaging shows observer scores of the participation of the three lesions that were studied in the gray-scale veil. In a and b, 
= individual data points outside the 5%-95% range, vertical line = 5%-95% range.
