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Technical Developments |
1 From the Department of Imaging, Hammersmith Hospital, Du Cane Road, London W12 0HS, United Kingdom (R.A.H., D.O.C., M.J.K.B., R.J.E., C.J.H.), and Toshiba Medical Systems, Tokyo, Japan (Y.M.). Received June 24, 1999; revision requested August 30; revision received October 28; accepted November 1. M.J.K.B. and C.J.H. supported by grants from the Medical Research Council, London, England. R.J.E. supported by a grant from Schering, Berlin, Germany. Address correspondence to R.A.H. (e-mail: soundray@web.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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Index terms: Liver neoplasms, metastases, 761.33 • Liver neoplasms, US, 761.12988, 761.32 • Ultrasound (US), contrast media, 761.12988 • Ultrasound (US), harmonic study, 761.12988, 761.12989 • Ultrasound (US), technology, 761.12988
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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SH U 508A (Schering, Berlin, Germany) consists of galactose microaggregates that, when suspended in water, release air bubbles of a median 3-µm diameter. Palmitic acid (1 mg per gram of SH U 508A granules) is added as a stabilizer. Blood-pool enhancement starts within seconds after intravenous injection of a bolus of the contrast material and lasts for as long as 5 minutes.
Findings in previous research showed that during the late phase after bolus injection of SH U 508A (after clearance from the blood pool and as long as 30 minutes after injection), microbubbles accumulate in the liver and spleen. Stimulated acoustic emission, a transient phenomenon that can be demonstrated in color Doppler velocity mode, increases the conspicuity of malignant lesions because they appear as signal voids. The spatial resolution of color Doppler currently limits this method to use with lesions greater than 8 mm in diameter (2). By offering higher spatial resolution, ISHGS US promises to extend the applicability of the principle of stimulated acoustic emission to smaller lesions. In animal experiments, ISHGS US highlighted normal liver tissue after intravenous injection of SH U 508A, rendering liver tumors more conspicuous (3). We hypothesized that (a) ISHGS US would demonstrate this effect in humans with use of standard doses of SH U 508A and (b) the conspicuity of focal liver lesions would be increased.
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Materials and Methods |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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In Vitro Study
A series of in vitro studies was performed to gain knowledge about ISHGS US microbubble enhancement and how it was affected by system parameters. The main objective was to quantify the deactivation of microbubbles. First, we sought to determine how many frames of a rapid sequence were required to inactivate all the microbubbles within an imaging plane. A frame acquired after microbubble inactivation provided a reference image to compare with the contrast material–enhanced ISHGS US images from the same imaging plane. Second, to allow valid comparisons of gray-scale reduction across rapid sequences that differed in the total number of frames, evidence was required that the power deposition per frame was independent of the total number of acquisitions in the rapid sequence. Third, the influence of the focal zone depth on the power deposition pattern was explored.
A dose of 0.03 mg of SH U 508A was injected into a 1,000-mL infusion bag containing 0.9 g/dL sodium chloride solution (Viaflex; Baxter Healthcare, Thetford, England). The curved-array scanning head was fixed horizontally in a jig that held the transducer surface against the base of the infusion bag, which lay horizontally. Clinical coupling gel was applied to achieve optimum sound transmission into the bag. This setup ensured that attenuation from objects other than microbubbles was kept to a minimum within the area of interest. The dose of the microbubble agent was chosen because it produced marked enhancement at ISHGS US, but the low-power monitor mode remained unchanged before and after microbubble injection into the model. This replicated the in vivo scanning situation, in which the monitor mode also appeared unchanged before and after administration of SH U 508A.
In all experiments, the image depth was kept constant at 11.9 cm; the focal zone depth was set to 7.8 cm; and the number of acquisitions in a rapid sequence was varied between four, six, and eight. Acquisition was repeated at least four times with each number of acquisitions (six times with six acquisitions). The sequence order was varied to reduce the confounding effect of spontaneous bubble decay. Effects due to the focal zone depth were assessed by means of two additional series of three four-acquisition rapid sequences at focal zone depths of 5 and 11 cm.
After the parameters were set up, a rapid sequence was triggered manually. The infusion bag was then squeezed gently to ensure homogeneity of the microbubble distribution and left to rest for 10–20 seconds to minimize movement at the time of the next triggering. These images were analyzed by means of the integrated quantitation software of the scanners. Oval regions of interest about 200 mm2 were set at depths of 4 and 7 cm. The setup, experimentation, and analysis were conducted by a radiologist (R.A.H.) and a physicist (R.J.E.).
Clinical Data Acquisition
The study was approved by the institutional research ethics committee. Study days were scheduled according to availability of personnel, and all patients referred for abdominal computed tomography (CT) who met the inclusion criteria on these days were invited to participate. Inclusion criteria were (a) CT findings suggestive of malignant focal liver lesions, (b) known malignant disease in the liver, or (c) known malignant disease elsewhere if a clinical query of liver involvement had been raised. Twenty-three patients (14 men and nine women; age range, 34–76 years; mean age, 59 years) agreed to participate after the nature and purpose of the procedure were explained, and they gave written informed consent. All patients underwent portal phase or dual-phase contrast-enhanced helical CT of the liver on the date of ISHGS US (±1 day). The CT scans were interpreted by an experienced radiologist.
At each imaging examination, a 1.2-mm intravenous cannula was placed in an antecubital fossa. SH U 508A was reconstituted to a 400 mg/mL suspension according to the manufacturer’s instructions. Doses of 8 g were injected via an anesthesia syringe pump (model P4000; IVAC Medical Systems, San Diego, Calif) at a rate of 2 mL/min, giving an infusion time of about 6 minutes. On the basis of findings by Kamiyama et al (4), 1-second intervals were used between rapid sequences of two to six acquisitions. Two-second intervals or manual triggering were preferred in patients with body habitus that made imaging difficult or when careful aiming at a region of interest was required. Five minutes after the infusion was started, the liver was scanned systematically (D.O.C., M.J.K.B.) in an attempt to collect images from all regions. The curved-array transducer was used first, and then the sector transducer was used if image quality was unsatisfactory.
Observer-centered Data Analysis
The patient studies were recorded on video tape for subsequent subjective review by two observers (R.A.H., M.J.K.B.) experienced in contrast-enhanced US. The quality of enhancement was judged by looking at areas apparently unaffected by focal lesions. Enhancement quality was rated on a visual analog scale from 0 to 10: score of 0, no visible effect; score of 3, weak enhancement across a depth band of 1–2 cm; score of 5, fair enhancement across a band of 3–4 cm; score of 7, distinct enhancement across a band of 5–6 cm; score of 10, the best enhancement that was regularly achieved in the in vitro setup (across a band of 8 cm) (Fig 1). The rating was determined by consensus.
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Results |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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The frame-by-frame decrease in gray-scale intensity at the level of the focal zone within a rapid sequence was independent of the total number of acquisitions (Table 1).
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Clinical Study
The primary malignancies (n = 22) were colonic or colorectal carcinoma (n = 7), carcinoid tumor (n = 5), metastatic gastrinoma (n = 3), pancreatic carcinoma (n = 2), ovarian carcinoma (n = 1), prostate carcinoma (n = 1), other neuroendocrine tumor (n = 1), renal cell carcinoma (n = 1), and a metastasis of unknown primary origin (n = 1). Liver involvement was evident at CT in 15 patients. Of the remaining seven patients, one died, three were not followed up at our hospital, and three had negative follow-up CT scans at 1 year. One patient had a suspect lesion that was sampled at biopsy, and the diagnosis was focal nodular hyperplasia (n = 1).
Five minutes after beginning the SH U 508A infusion at ISHGS US, both observers noted contrast enhancement in the liver parenchyma. The median subjective rating for quality of contrast enhancement was 6. Technical failures in two patients resulted in images that were inadequate for assessment of lesion conspicuity or new defects. One of these patients (diagnosis, gastrinoma without liver involvement) had a strongly attenuating fatty liver that compromised the quality of the conventional US image, and the contrast enhancement effect could barely be identified (quality rating, 1) on the ISHGS US image. In another patient (diagnosis, prostate carcinoma without liver involvement), repeated obstruction of the intravenous access site prevented administration of the full dose of SH U 508A at the intended flow rate, which resulted in poor contrast enhancement (quality rating, 3).
In 12 of the 15 patients with known malignant liver disease, echo-poor lesions previously identified at conventional gray-scale US appeared as signal voids within the zone of contrast enhancement at ISHGS US. Sequences in five patients were suitable for evaluation of objective conspicuity. The average objective conspicuity was 20 dB in frame 1 compared with 6 dB after bubble deactivation (frame 4) (P < .002, Student t test).
New gray-scale defects that fit all our criteria (true-positive findings) were seen by both observers in 12 of 15 patients with malignant liver involvement (Fig 3). Neither observer noted such defects in any patient who had benign disease or a malignancy without liver involvement (no false-positive findings) (Table 2).
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Discussion |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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In a series of in vitro tests to insonate SH U 508A microbubbles with multiple image pulses, we established that the contrast enhancement was maximal in the first frame. By the fourth frame, the gray-scale intensity had decreased to a low level, which could not be further reduced by subsequent pulses. We concluded that the fourth frame in a rapid sequence can be used as the equivalent of a nonenhanced baseline harmonic image. To verify the correctness of our approach, we had to ensure that the power deposition with each imaging pulse was independent of the total number of acquisitions that the scanner was configured to generate in rapid sequence. We found that the frame-by-frame gray-scale reduction was constant with different numbers of acquisitions, demonstrating that our approach was correct. The experimental setup was also used to investigate the way different settings of the focal zone depth would affect distribution of the power deposition as measured on the basis of reduction in gray-scale intensity. We found that the most rapid microbubble deactivation took place in the region of the focal zone.
The ISHGS US technique preferentially images microbubbles, independent of whether they are stationary or mobile. SH U 508A shows an initial blood-pool phase that lasts for 3–5 minutes after intravenous injection, and then it accumulates in the liver. Between 5 and 30 minutes after the injection, stationary microbubbles can be traced within the liver on the basis of an effect termed "stimulated acoustic emission" (2). Findings in our study showed that ISHGS US can also be used to generate enhanced gray-scale images of normal liver tissue in the late phase after SH U 508A injection. Malignant tumors affecting the liver appeared not to share the accumulating behavior of SH U 508A in normal liver tissue and thus stood out as areas of relatively reduced signal intensity on ISHGS US scans. In all five patients with studies evaluated quantitatively, this behavior resulted in increased objective conspicuity of known malignant liver lesions from 6 to 20 dB (P < .002). In addition, 12 of these 15 patients had defects in areas that were not previously suspect at CT or US (12 true-positive and zero false-positive findings). Such new defects were not seen in any of the 11 patients without liver malignancy. We speculate that these defects are, in fact, metastases that could not be identified with any other method. We could not conclusively exclude the possibility that they were artifacts, so this suggestion needs to be verified, ideally by means of targeted sampling at biopsy with ISHGS US guidance.
Further development of the method is required to address the following problems: (a) The effect is transient, (b) the depth range of the effect depends on individual factors such as attenuation, (c) the depth range of the effect is also closely related to the focal zone setting, and (d) the intermittent imaging mode lacks the immediacy and controllability of real-time imaging. The generation of microbubble agents that are now in clinical trials are more stable and may resist inactivation over a larger number of acquisitions, providing a harmonic signal over a longer time.
It was interesting that signal enhancement was noticeable from within the mass in the patient with focal nodular hyperplasia (Fig 5). This finding is reminiscent of the behavior of radioactive sulphur colloid at scintigraphy of focal nodular hyperplasia, possibly indicating the presence of functionally normal liver tissue in the lesion.
There are several limitations to this study. The dose of SH U 508A chosen for the study protocol was probably higher than necessary. Injection of a 4-g bolus instead of an infusion might have been sufficient to achieve good contrast enhancement at ISHGS US. Only five of our 15 patients with liver metastases had studies suitable for objective analysis of conspicuity. This problem could have been avoided if we had followed a more strict acquisition protocol from the beginning of the study. Sequences for analysis were selected subjectively for suitability and were therefore not representative.
At present, the sensitivity of conventional transabdominal US for the detection of liver lesions is low, only 20% for liver metastases of gastrointestinal carcinomas less than 1 cm in diameter (5). US diagnosis can be particularly difficult because of tissue attenuation in patients with cirrhosis (6). Findings in this study suggest that ISHGS US may be a useful method to increase the sensitivity of US while maintaining its advantages in terms of availability and noninvasiveness.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, R.A.H.; study concepts, R.A.H., M.J.K.B., D.O.C., Y.M.; study design, R.A.H., M.J.K.B., D.O.C.; definition of intellectual content, R.A.H., M.J.K.B., D.O.C., Y.M.; literature research, R.A.H., M.J.K.B., C.J.H.;clinical studies, M.J.K.B., D.O.C., C.J.H., R.A.H.; experimental studies, R.A.H., R.J.E.; data acquisition and analysis, R.A.H., R.J.E.; statistical analysis, R.A.H.; manuscript preparation, R.A.H.; manuscript editing and review, all authors.
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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