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British Journal of Radiology (2005) 78, 512-518
© 2005 British Institute of Radiology
doi: 10.1259/bjr/59648297
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Real-time blood-pool images of contrast enhanced ultrasound with Definity in the detection of tumour nodules in the liver

H Maruyama, MD 1 S Matsutani, MD 1 H Saisho, MD 1 Y Mine, PhD 2 N Kamiyama, PhD 2 T Hirata, PhD 3 and M Sasamata, PhD 3

1 Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, 2 Toshiba Corporation, Medical Systems Company, 1385, Shimoishigami, Otawara-shi, Tochigi, 324-8550 and 3 Pharmaceutical Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21, Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Lower mechanical index (MI) technique with newer microbubble agents has been introduced into clinical practice as a newer ultrasound (US) imaging. However, the efficacy in detecting tumour nodules has not been proven scientifically. The aim of this study was to elucidate the efficacy of a blood-pool image of real-time contrast-enhanced US under low MI in detecting liver tumours. 15 rabbits with VX-2 tumour were used; the number of implantations was none in two rabbits, one in four, two in five and three in four. US equipment was APLIO (Toshiba) with linear probe (3.5/7.0 MHz). The number, location and size of tumour nodules were examined by non-contrast tissue harmonic imaging (NC-US) or contrast-enhanced pulse subtraction harmonic imaging (C-US) under extra-low MI (MI 0.065) with the injection of Definity (30 µl kg–1). The number of tumour nodules detected by both NC-US and C-US were consistent with the histopathological results in five rabbits – two with none, two with one nodule and one with two nodules. In the other 10 rabbits, C-US showed all the implanted tumours and small daughter nodules around them that were confirmed by histopathology. However, NC-US failed to demonstrate two implanted nodules and all the daughter nodules. On the basis of the histopathological results, detectability of implanted tumour was not significantly different between NC-US (24/26, 92.3%) and C-US (26/26, 100%). However C-US was superior to NC-US in delineating the nodules and in detecting small daughter nodules. The sizes of the implanted tumour nodules measured by histopathology correlated closely with those measured by C-US. Real-time blood-pool images by pulse subtraction harmonic imaging under extra-low MI with Definity will contribute to the improvement of the ultrasound delineation and detection of liver tumours.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Contrast-enhanced ultrasound (US) can demonstrate the vascularity and haemodynamics of liver tumours precisely [1–3]. With this background, contrast enhancement technology can be expected to improve the US diagnosis of liver tumours in terms of detection, differentiation and therapeutic effect [4–15].

Some kinds of microbubbles such as Levovist and Sonazoid show accumulation in the liver, and the enhanced US images with those agents have been reported to be useful for detecting liver tumours [16–24]. However, some other microbubbles such as Definity and Sonovue exhibit this behaviour, though the mechanism has not been clarified [25–27]. The possible efficacy for the detection of liver tumours with these US contrast agents has not yet been widely investigated.

Definity, a recently developed US contrast agent with perfluoropropane gas-filled lipid stabilized microbubbles, provides a continuous and remarkable enhancement of the liver and tumours under extra-low mechanical index (MI) harmonic imaging [28, 29]. This agent is reported to be a blood-pool contrast agent that does not have a late liver-specific parenchymal phase with accumulated microbubbles [25, 26]. For this reason, it has not been clear whether contrast-enhanced blood-pool images with Definity could improve the US detection of small tumour nodules in the liver.

The purpose of the present study was to evaluate the efficacy of real-time blood-pool images with contrast-enhanced US in detecting tumour nodules in the liver. In this study, we examined the detectability of tumour nodules with non-contrast tissue harmonic imaging and contrast pulse subtraction harmonic imaging under extra-low MI with Definity in the rabbit liver.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Animals
15 New Zealand White male rabbits weighing 2.0–2.4 kg (2.1±0.1 kg, mean ± standard deviation (SD)) were used in this study. 13 rabbits were implanted VX-2 tumour tissue cubes of approximately 2 mm3 from carrier rabbits; the number of implanted VX-2 tumour tissue cubes was one in four rabbits, two in five rabbits and three in four rabbits. The other two rabbits did not receive an implantation, but incisions were made on the abdomen similar to the rabbits with implanted VX-2 tumours. The US examination was conducted 4–5 weeks after the implantation.

The animals were anaesthetized with pentobarbital at a dose of 30 mg kg–1 by bolus injection followed by continuous infusion at 3.0 mg kg–1h–1 into the auricular vein. The skin of the abdomen was shaved after the animal was stabilized, and US examination was performed at the body surface in a supine position. A 3 Fr 1.35 mm catheter was inserted into the right femoral vein and a three-way stopcock was applied at the end of the catheter, with one branch being used for administration of a contrast agent and another for the saline flush after its administration. A 4 Fr 1.0 mm plastic tube was inserted into the femoral artery to monitor and record arterial pressure and pulse rate during the examination. All studies were conducted in compliance with the regulations of the Animal Ethics Committee of Yamanouchi Pharmaceutical Co. Ltd.

Equipment
US images were obtained with SSA-770A (APLIO; Toshiba, Tokyo, Japan) with a linear probe that transmits and receives centre frequencies of 3.5/7.0 MHz. Imaging methods in this study were tissue harmonic imaging (THI) for non-contrast enhanced ultrasound (NC-US) and pulse subtraction harmonic imaging (PHI) for contrast enhanced ultrasound (C-US). All the images were taken by continuous scan at a frame rate of 48–49 Hz for THI and 15 Hz for PHI with the dynamic range at 50–60 dB throughout the examination. Gain and sensitivity time control (STC) were set at optimal levels and the focus point was set at the bottom level of the liver.

The mechanical index (MI) level used in this study was as follows; 1.0 for NC-US, a maximum level, 0.065 for C-US, a suitable level for obtaining a real-time enhancement image in liver parenchyma [29].

Contrast agent
The contrast agent used in this study was DefinityTM (a perfluoropropane gas-filled lipid-stabilized microbubble, Bristol-Myers Squibb, North Billerica, MA). The contrast effect in this study was evaluated at a dose of 30 µl kg–1, which is three times the recommended dose for cardiac imaging [28–30]. After shaking with an agitation machine for 45 s, the agent was injected into the rabbits via a cannula inserted into the femoral vein by manual injection at a rate of about 0.1 ml s–1, followed by a 2.0 ml of saline solution flush. The images were recorded on digital videotape before and after enhancement.

Experimental procedure
Eight rabbits were examined by HM and seven rabbits by SM, both experienced in the use of US, and they were blinded to the information of the implanted VX-2 tumours. After NC-US examination, the operator investigated tumour nodules by continuous scan during a blood-pool image in the liver, which was obtained several seconds after the beginning of contrast enhancement effect. The location, number and size of the tumour nodules were examined and noted in each rabbit before and after enhancement. After US examination, all rabbits were killed with an overdose of pentobarbital (5.0 g). Histopathological examination of the liver was conducted by TH, who was blinded to the US findings. KM, who was neither the operator of US examination nor the conductor of histopathological examination, compared the histopathological results with the US results concerning the location, number and size of the tumour nodules.

Statistical analysis
The results were compared by Student's t-test and Pearson's correlation coefficient. Probability values less than 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Non-contrast tissue harmonic images (NC-US) of VX-2 tumour nodules
Tumour nodules were detected in 13 of 15 rabbits by NC-US (Table 1Go); the number of tumour nodules was none in two rabbits, one in five rabbits, two in five rabbits and three in three rabbits. All the nodules were visualized with an isoechoic pattern with heterogeneous appearance, ranging in size from 9.2 mm to 26.9 mm (14.7±5.1 mm).


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  		Table 1. Number of tumour nodules; implanted nodules, detected by ultrasound and histopathological examination

 
Contrast-enhanced blood-pool images (C-US) of VX-2 tumour nodules with Definity
After the injection of Definity, the liver image became distinct, with homogeneous enhancement of the liver parenchyma in all rabbits, and tumours were visualized as unenhanced nodules with or without peripheral enhancement. The size of the tumour nodules measured by C-US included the peripheral enhancement area in those cases with the enhancement. The deepest depth of the examined liver was 42 mm from the body surface.

The blood-pool phase of contrast enhancement with Definity lasted more than 4 min, long enough to examine real-time images of a whole liver. In seven of the 15 rabbits, however, shadowing phenomenon disturbed the observation of the deep area in the early phase of contrast enhancement. This phenomenon disappeared gradually after 30 s from the beginning of contrast enhancement.

Comparison of the detection of tumour nodules between US and pathology (Table 1Go) (Figures 1 and 2GoGo)
Pathological examination showed large tumour nodules of a size greater than 10 mm in 13 of 15 rabbits, and the number of tumour nodules agreed with the implanted number in each rabbit. The number of these nodules detected by C-US was also consistent with the number on pathology. However, NC-US failed to detect two of the nodules (14.4 mm, 17 mm). There was no false-positive detection of nodules either by NC-US or C-US.



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  		Figure 1. VX-2 tumour in the rabbit liver, Case 11, right lobe. (a) Non-contrast tissue harmonic image. One tumour nodule with heterogeneous ultrasound pattern was observed (arrow). The margin of the tumour nodule was not clear. Other tumour nodules were not detected. (b) Contrast-enhanced pulse subtraction harmonic image with Definity. One tumour nodule was observed as an unenhanced nodule with peripheral enhancement (arrow, white), and small tumour nodules were demonstrated as unenhanced nodules around this nodule (arrows, grey). All the tumour nodules were delineated clearly with homogeneous enhancement of the surrounding liver parenchyma. (c) Histopathological findings. One implanted tumour nodule 18 mm in size (arrow, white) and daughter tumour nodules (arrows, black) were observed. The implanted tumour was hypervascular in the peripheral area, corresponding to the peripheral enhancement in (b) and it was necrotic in the central area.

 


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  		Figure 2. VX-2 tumour in the rabbit liver, Case 4. (a) Non-contrast tissue harmonic image. The one detected tumour nodule had an isoechoic appearance with a central hypoechoic area (arrow, white). The ultrasound pattern of the liver parenchyma was heterogeneous, but other tumour nodules were not clear. (b) Contrast-enhanced pulse subtraction harmonic image with Definity. Homogeneous enhancement was seen in the liver parenchyma. Two tumours were observed as unenhanced nodules with clear delineation, with one of them (right side) showing peripheral enhancement (arrows, white). Small tumours were demonstrated as unenhanced nodules around the two tumour nodules (arrows, grey). (c) Histopathological findings. There were two implanted tumour nodules, 14.4 mm and 19 mm, in the liver (arrows, white and black). Small tumour nodules were observed around the implanted tumours, and were believed to be metastatic tumour nodules (arrows, grey). The tumour tissues were necrotic, but one of them (arrow, black) had tumour vessels in the peripheral area corresponding to the peripheral enhancement in (b).

 
Pathology showed multiple satellite nodules smaller than 10 mm around the implanted tumours in 10 rabbits. These satellite nodules were thought to be daughter nodules because of the distribution of these nodules around the main implanted tumour nodules. Although NC-US did not show any of these daughter nodules, C-US demonstrated them as unenhanced areas in all 10 rabbits.

Comparison of the size of tumour nodules between US and pathology
The maximum sizes of the implanted tumour nodules were 14.7±5.1 mm (9.3–26.9 mm) on NC-US, 15.9±4.6 mm (11.1–25.5 mm) on C-US, and 16.1±4.6 mm (11–26 mm) on histopathological examination. The correlation coefficients for the comparison with the histopathological measurements were 0.751 (p=0.002) for NC-US and 0.996 (p<0.0001) for C-US. Thus, the measurement by C-US showed a close correlation with the size of tumour nodules by histopathological examination. Furthermore, the distribution of daughter nodules on C-US was similar to the pathological findings, and the smallest size of daughter nodule detected by C-US measured 2.0 mm on histopathological examination in case 11 (Figure 3Go).



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  		Figure 3. VX-2 tumour in the rabbit liver, Case 11, left lobe. (a) Non-contrast tissue harmonic image. No tumour nodules were recognized with non-contrast ultrasound in this case. (b) Contrast-enhanced pulse subtraction harmonic images with Definity. One tumour nodule (arrow, white) and small nodule (arrow, grey) were observed as unenhanced focal lesions. (c) Near the same tumour as in (b), two other small tumours were demonstrated as unenhanced nodules in the surface area of the liver. (d) Histopathological findings. One implanted tumour nodule 17 mm in size was found in the liver (arrow, white). Small tumour nodule was observed around the implanted tumour (arrow, black), and was thought to be metastatic tumour nodules. Two tumour nodules 2 mm in size were seen in the surface area of the liver (arrows, grey).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Detection of tumour nodules in the liver is of major importance for formulating therapeutic strategy and predicting a prognosis in malignant disease. Diagnosis of small liver tumours has always been the greatest concern in imaging diagnosis [10–19, 31].

Levovist, a popular US contrast agent, is a galactose-based microbubble for use by intravenous injection [5–10, 16–18, 20, 23]. As Levovist accumulates in the liver, a metastatic liver tumour appears as an unenhanced nodule in a late liver-specific parenchymal phase of contrast enhanced ultrasound [16, 17], and this phase is reported to be useful for detection of metastatic liver tumours. (However, some contrast agents with a different structure and chemical nature from Levovist apparently do not possess this phase with the accumulation of microbubbles in the liver.)

A newly developed US contrast agent, Definity, allows real-time observation with homogeneous and stable enhancement of the liver parenchyma under an extra-low MI level [28, 29]. This microbubble agent is reported to be a blood-pool contrast agent [25, 26]. So far, there has been little discussion of whether a real-time blood-pool image with circulating microbubbles is suitable for detecting tumour nodules in the liver. In this study, we evaluated the ability of real-time contrast-enhanced blood-pool images with Definity to detect a VX-2 tumour in rabbit liver as a metastatic liver tumour model.

As shown in the present study, pulse subtraction harmonic imaging under extra-low MI with Definity was superior to non-contrast tissue harmonic imaging in detecting small tumour nodules. Furthermore, C-US was superior to NC-US in delineating the nodules in all rabbits because a correlation with the tumour size by histopathological examination was closer in C-US result than in NC-US. The enhanced liver image originating from microbubble signals provided a continuous and stable enhancement of the liver parenchyma, giving the tumour nodules a more distinct appearance than on non-contrast US.

There have been some studies regarding the improvement of the detection of occult hepatic metastases with enhanced ultrasound using Levovist. However, those studies have not fully compared the results with the histopathological findings [16, 17]. According to Harvey et al the evidence of these lesions detected on a late liver-specific parenchymal image with Levovist was difficult to confirm with biopsy, because the images appeared on only a few ultrasound frames [18]. Meanwhile, the blood-pool imaging in this study has advantages for real-time and repeated observation of a whole liver with sufficient duration, which improves the reproducibility of detecting small tumour nodules in the liver. Further studies will be necessary to conclude whether the real-time blood-pool imaging under extra-low MI with newer US contrast agents is comparable with late liver specific parenchymal imaging with Levovist in detecting liver tumours.

Tissue harmonic imaging is more sensitive than fundamental grey-scale imaging in detecting focal liver lesions [32, 33], as it provides better delineation of tumours due to improved lateral resolution and signal-to-clutter ratio, and also reduces near-field artefacts [31, 34–36]. In the present study, however, tissue harmonic imaging failed to demonstrate a few of the implanted main tumour nodules and all the small metastatic tumour nodules, and pulse subtraction contrast harmonic imaging under extra-low MI with Definity was superior to tissue harmonic imaging in the detection of tumour nodules in the liver. One of the reasons for the poor detectability of tumours with NC-US may be that the US field in this study was too near the body surface to generate harmonic signals by non-linear propagation of a sound wave. Furthermore, the tumour nodules in rabbit liver showed an isoechoic appearance and were very small. However, the US pattern and tumour size did not disturb the detection with contrast harmonic imaging.

The present results have several shortcomings in terms of their application to the human clinical setting. As the enhanced findings were evaluated in rabbit liver with implanted VX-2 tumours, the MI level employed for this study may not be optimal for humans [28, 29]. In addition, whether the detection of tumour nodules deeply located in human liver is possible with observation under extra-low acoustic power levels remains to be elucidated.

Shadowing phenomenon caused by excessive enhancement around the surface level of the liver was observed at the beginning of echo-enhancement in seven of 15 rabbits, disturbing deep-area observation in the liver. Although the long duration time of the blood-pool phase with contrast enhancement allowed sufficient assessment of the whole liver, missing the early arterial phase of enhanced liver images is unfortunate. Continuous injection of contrast agent by drip infusion may reduce this artefact [37]. Furthermore, improvement of US equipment to reduce these phenomena may be necessary, perhaps by a modulation of the focus point and/or auto-regulation of the transmit/receive echo signals.

In conclusion, the real-time blood-pool phase of contrast-enhanced ultrasound with Definity improves the delineation and detection of liver tumours in rabbit livers. However, the translation of these results to human liver still remains to be determined.

Received for publication August 3, 2004. Revision received December 6, 2004. Accepted for publication January 19, 2005.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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