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1
Department of Radiology and Clinical Research Institute, Seoul National
University Hospital and the Institute of Radiation Medicine, SNUMRC 28
Yongon-dong, Chongno-gu, Seoul 110-744, Korea.
2
Contrast Media Research, Schering, Mullerstra. 178, 13353 Berlin,
Germany.
Received August 25, 1999;
accepted after revision October 20, 1999.
Supported by a grant from Schering, Berlin, Germany.
Abstract
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MATERIALS AND METHODS. Fourteen rabbits with experimentally induced bacterial abscesses and VX2 carcinoma in both thighs underwent dynamic contrast-enhanced MR imaging with Gadomer-17 and gadopentetate dimeglumine at a 24-hr interval. The enhancement ratios (postcontrast to precontrast signal intensities) of lesions in the same animal were assessed and correlated with microvessel density.
RESULTS. For Gadomer-17, the enhancement ratio of the abscesses (1.66 ± 0.39) peaked 15 min after the injection, while that of the carcinoma (2.05 ± 0.16) peaked at 10 min. The enhancement ratios of the carcinoma were consistently higher than those of the abscesses up to 30 min. For gadopentetate dimeglumine, peak enhancement ratio of the abscesses (2.30 ± 0.75) was seen 5 min after the injection, while that of the carcinoma (2.32 ± 0.51) was seen at 3 min. The enhancement ratios of the carcinomas were significantly higher at 1 min, but singificantly lower at 20-30 min, compared with those of the abscesses, as a result of rapid decrease of enhancement ratios in the carcinomas. The microvessel density was 9.8 ± 5.2 vessels per field of view for the abscesses and 36.3 ± 9.5 vessels per field of view for the carcinoma (p <0.001).
CONCLUSION. Delayed peak enhancement and slow decay were found in both bacterial abscess and VX2 carcinoma with Gadomer-17, whereas early peak enhancement and rapid decay were found especially in VX2 carcinoma with gadopentetate dimeglumine. Enhancement ratios on MR imaging with a blood-pool contrast agent correlated well with the microvessel density in bacterial abscess and VX2 carcinoma.
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Blood-pool contrast agents that remain exclusively within the intravascular space are currently under investigation to minimize the problems associated with extracellular contrast agents [5]. Potential clinical applications for this class of contrast agents include MR angiography and determination of tissue perfusion, angiogenesis, or capillary integrity [6,7,8,9]. Comparative studies of blood-pool and extracellular contrast agents showed improvement of lesion conspicuity and tumor characterization using blood-pool contrast agents in animal experiments [10, 11]. The hyperpermeability of tumor microvessels to macromolecular contrast agents has been shown in malignant tumors [12].
A 24-gadolinium-tetraazacyclododecane tetraacetic acid (DOTA)-dendrimer (Gadomer-17; Schering, Berlin, Germany), a new macromolecular contrast agent, has an apparent molecular weight of 35,000 d, small enough to guarantee renal excretion and large enough to reduce diffusion through the endothelial cells of intact blood vessels. Because of its high T1 relaxivity (11.9 l · mmol · sec-1 versus 4.9 l · mmol · sec-1 of gadopentetate dimeglumine at 2.0 T), a significantly lower dose is required to achieve an enhancement comparable with that of gadopentetate dimeglumine if both agents distribute in the same volume. The median lethal dose of this new blood-pool contrast agent is three times as high as that of gadopentetate dimeglumine [7, 10].
It is sometimes difficult to distinguish between an abscess and a necrotic tumor on the basis of clinical and radiologic findings, especially in the brain and abdomen [13, 14]. Rim enhancement after administration of CT or MR contrast agents has been known as a characteristic finding for an abscess, but it can also be seen in benign and malignant tumors [15, 16]. Increased vascularity and capillary hyperpermeability are observed both in inflammation and malignant tumors [14, 17, 18]. To our knowledge, a comparison study of blood-pool contrast agents in abscesses and necrotic tumors has not been performed.
We performed this experimental study to compare the enhancement patterns of a new blood-pool contrast agent, Gadomer-17, and a conventional extracellular agent, gadopentetate dimeglumine, in bacterial abscesses and VX2 carcinoma in rabbits and to correlate the enhancement patterns on MR images with microvessel density on the pathologic specimen.
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To perform an intraindividual comparison study, 14 bacterial abscesses and 14 VX2 carcinomas were experimentally induced in both thighs of each rabbit. Bacterial abscesses were made in the left thigh of each rabbit by injection of 0.3 ml of suspension containing 107 organisms per milliliter of Escherichia coli with an 18-gauge needle. VX2 carcinoma was inoculated in the right thigh by injection of 0.5 ml of tumor suspension with an 18-gauge needle. VX2 carcinoma of rabbits was prepared in a manner reported previously [10, 19]. VX2 carcinoma is an experimental tumor, developed from a rabbit squamous epithelium testicular cancer. It is characterized by fast tumor growth and occurrence of central necrosis when the tumor exceeds 2 cm in diameter [10]. To make the size of the bacterial abscess and VX2 carcinoma similar, the induction of the abscess was performed five days after the inoculation of the VX2 carcinoma [19, 20]. A pilot study showed more rapid growth of bacterial abscess compared with VX2 carcinoma 2-3 weeks after the inoculation.
Abscess formation and tumor growth were monitored with sonography. The animals were included in the study if a mass larger than 2 cm in diameter and a definable abscess wall were noted on sonography. The above criteria were selected to include the capsular stage of the bacterial abscess and VX2 carcinoma with central necrosis.
MR Imaging
All examinations were performed on a Signa 1.5-T scanner (General Electric
Medical Systems, Milwaukee, WI) using a head coil. MR imaging was performed 2
weeks (n = 10) or 3 weeks (n = 4) after the inoculation of
VX2 carcinoma. Animals were imaged in the prone position. After routine
localization images and axial T2-weighted spin-echo images (TR/TE, 4000/96;
7-mm slice thickness), dynamic T1-weighted images were acquired, for which two
types of contrast agents were administrated via the ear vein by manual fast
bolus injection in each animal with a 24-hr interval; one with IV injection of
0.05 mmol/kg Gadomer-17 and another with 0.1 mmol/kg gadopentetate
dimeglumine. Gadomer-17 was supplied as an aqueous formulation with a
concentration of 500 mmol/l. In all animals, the study was performed first
with injection of gadopentetate dimeglumine and 24 hr later with injection of
Gadomer-17. At the time of the Gadomer-17 injection, the gadopentetate
dimeglumine was almost completely cleared from the lesions; the ratios of
signal intensities measured in the bacterial abscesses and VX2 carcinoma
before gadopentetate dimeglumine injection and signal intensities before
Gadomer-17 injection ranged from 1.0 to 1.1. Dynamic T1-weighted MR imaging
was performed with a fast spin-echo sequence (TR/TE, 450/16) before and 1, 2,
3, 4, 5, 10, 15, 20, 25, and 30 min after bolus injection of contrast agent.
Echo train length was 10 and bandwidth was 16 kHz. The slice thickness was 7
mm and the field of view was 15 cm with an acquisition matrix of 256 x
128.
Histologic Analysis
After MR images were obtained, all animals were sacrificed by a lethal dose
(90 mg/kg) of IV sodium pentobarbital (Pentothal; Choong Wae Pharmacy, Seoul,
Korea). The pathologic specimens were sectioned in the same axial plane as MR
imaging with 7-mm intervals and stained with H and E for histologic
evaluation. For determination of the number of vessels, immunohistochemical
staining of the specimens was performed by using factor VIII antibody,
according to methods described by Weidner et al.
[21]. The microvessel density
was determined by averaging the numbers of capillary vessels in five fields of
view in the areas corresponding to enhancement on MR images. All slides were
reviewed by two observers using a double-headed light microscope
simultaneously. Discrepant interpretations were resolved by means of
discussion between the two observers.
Image Analysis
All dynamic contrast-enhanced MR images were assessed by two radiologists
by consensus for size and enhancement patterns of lesions.
The MR imaging signal intensities were measured with the region-of-interest method in the most enhancing areas of the abscess wall and the solid portion of VX2 carcinoma. The enhancement ratio determined by comparison of the unenhanced with enhanced signal intensity was calculated for each time point. Enhancement ratios (enhanced / unenhanced signal intensities) were plotted against the time as mean values ± standard deviations for both bacterial abscess and VX2 carcinoma. In all cases, the slope of the curve (the percentage increase in enhancement ratio per minute over the baseline value) was derived by using the following equation [2, 22]: slope = (ERmax - ERpre) x 100 / (ERpre x Tmax), where ERpre represents the enhancement ratio of a given region of interest before injection of contrast agents. The maximum enhancement ratio (ERmax) was determined to be the value at a time point (Tmax) beyond which the sum of slopes measured for the two intervals between three consecutive time points on each curve was 10%/min or less. The slope values of bacterial abscess and VX2 carcinoma were compared for the two contrast agents.
Statistical Analysis
Wilcoxon's rank sum test was used to assess the statistical significance of
the differences in enhancement ratios, slope values between bacterial abscess
and VX2 carcinoma, and between both contrast agents. The Student's t
test was used to assess the difference in the microvessel density between
bacterial abscess and VX2 carcinoma. Statistical correlation between maximum
enhancement ratio and microvessel density in bacterial abscess and VX2
carcinoma was performed with the Spearman's rank correlation coefficient test.
A p value of less than 0.05 was considered significant.
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Peak enhancement ratios in both bacterial abscess and VX2 carcinoma were higher with injection of gadopentetate dimeglumine than those with injection of Gadomer-17 (Figs. 3 and 4). Standard deviations of enhancement ratios of bacterial abscess and VX2 carcinoma were much wider with injection of gadopentetate dimeglumine than those with injection of Gadomer-17 (p <0.001). For Gadomer-17, the enhancement ratio of bacterial abscess (1.66 ± 0.39) peaked at 15 min, while that of VX2 carcinoma (2.05 ± 0.16) peaked at 10 min. Enhancement ratios of VX2 carcinoma were consistently higher than those of bacterial abscess up to 30 min (Fig. 3) and the difference was statistically significant within 2-30 min. For gadopentetate dimeglumine, the peak enhancement ratio of bacterial abscess (2.30 ± 0.75) was seen at 5 min, whereas that of VX2 carcinoma (2.32 ± 0.51) was seen at 3 min. The enhancement ratios of VX2 carcinoma were higher than those of bacterial abscess only within 4 min after the injection of gadopentetate dimeglumine because of the rapid decrease of enhancement ratios in VX2 carcinoma (Fig. 4). Enhancement ratios of VX2 carcinoma were significantly higher at 1 min, but significantly lower at 20-30 min compared with those of bacterial abscess.
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The enhancement ratios of bacterial abscess and VX2 carcinoma were notably different after injection of both contrast agents. In bacterial abscess, the enhancement ratios with injection of gadopentetate dimeglumine were significantly higher than those with injection of Gadomer-17 up to 30 min (p < 0.05). In VX2 carcinoma, the enhancement ratios with injection of gadopentetate dimeglumine were significantly higher at 1-5 min compared with those with injection of Gadomer-17 (p <0.05).
The slope values for bacterial abscess and VX2 carcinoma were 9.4-45.0%/min (mean, 31.4%/min ± 19.9) and 33.3-76.0%/min (mean, 46.6%/min ± 15.1) after Gadomer-17 injection and 25.0-132.0%/min (mean, 81.2%/min ± 58.6) and 43.0-230.6%/min (mean, 123.8%/min ± 62.9) after gadopentetate dime-glumine injection. The difference was not statistically significant for the two contrast agents.
Histologically, all bacterial abscesses had necrotic and cellular debris in the center and well-defined walls composed of granulation tissue and a fibrous layer. Inflammatory cells were mainly polymorphonuclear leukocytes and lymphocytes. Some macrophages were seen at the inner portion of the abscess walls. These findings were consistent with the abscess in the capsular stage. All VX2 carcinomas had necrotic areas in the center and viable tumor cells in the periphery. Peripheral margins adjacent to normal skeletal muscle were well delineated with reactive fibrosis. In bacterial abscesses, vessels were found in the granulation tissue and fibrous layer. In VX2 carcinomas, the periphery of the tumors and the border between skeletal muscle and neoplastic tissue were rich with new vessel formation.
The microvessel density was 9.8 ± 5.2 vessels per field of view (magnification, x200) for bacterial abscess and 36.3 ± 9.5 vessels per field of view (magnification, x200) for VX2 carcinoma. No bacterial abscess had more microvessels than VX2 carcinoma in any cases. The difference was statistically significant (p <0.001). The correlation between maximum enhancement ratio and microvessel density was statistically significant both in bacterial abscess (p <0.05) and VX2 carcinoma (p <0.01).
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Dynamic contrast-enhanced MR imaging is a method of physiologic imaging, providing information on the early sequential enhancement kinetics of a water-soluble contrast agent after IV bolus injection [1,2,3]. After IV injection of gadopentetate dimeglumine, a conventional extracellular agent, the contrast agent diffuses rapidly from the intravascular into the interstitial space and the enhancement pattern results from various properties of the lesion including blood volume, blood supply, vascular and extracellular spaces, and endothelial permeability [4]. On the contrary, the blood-pool contrast agent that is confined to the vascular space reflects the size of the vascular space and only in certain abnormal conditions, such as malignancy and inflammation, will also reflect the size of the interstitial space [8, 11, 23].
The earlier and stronger enhancement of bacterial abscess and VX2 carcinoma after injection of the extracellular compound compared with the blood-pool contrast agent was noted in this study and others [10, 11]. In bacterial abscess, slow washout of contrast agent in the wall was found after injection of both Gadomer-17 and gadopentetate dimeglumine, whereas in VX2 carcinoma rapid washout of contrast agent in the periphery was found after injection of gadopentetate dimeglumine. Rapid washout of contrast agent in the periphery of the tumor has been reported as a specific indicator of malignancy on dynamic contrast-enhanced MR imaging using an extracellular contrast agent and is attributed to higher turnover of contrast agent in the periphery than in the center [24, 25]. On dynamic contrast-enhanced MR imaging using blood-pool contrast agents, gradual accumulation of the macromolecular agent within the mass and slow washout have been regarded as a useful marker of malignancy [18]; however, this enhancement pattern was also observed in this study in the capsular stage of bacterial abscesses because of their leaky capillaries.
MR imaging enhanced with a macromolecular contrast agent has shown tumor microvascular characteristics that correlate closely with histologic microvascular density, an established surrogate of tumor angiogenesis [9, 18]. This correlation is consistent with the results of our study. With injection of Gadomer-17, enhancement ratios of VX2 carcinoma were higher than those of bacterial abscess up to 30 min, whereas, with injection of gadopentetate dimeglumine, enhancement ratios of VX2 carcinoma were higher only within 4 min. Persistently higher enhancement ratios of VX2 carcinoma on MR imaging with a blood-pool contrast agent correlated well with higher microvessel density in the VX2 carcinoma. Lower enhancement ratios of bacterial abscess on MR imaging with a blood-pool contrast agent correlated well with lower microvessel density in the abscess. MR imaging showed the difference of microvascularity between a bacterial abscess and a necrotic tumor, such as VX2 carcinoma, more consistently with a blood-pool contrast agent than with gadopentetate dimeglumine.
The kinetics of contrast agents and degree of contrast enhancement reflecting the vascularity and the permeability of bacterial abscess and VX2 carcinoma would be dependent on the stage of the disease process and physiologic factors of the animal [19, 20, 26]. To minimize these effects, we made the size of the tumor and the abscess similar in the same animal and studied the animal twice using two contrast agents within a 24-hr interval. To the best of our knowledge, this is the first study in which a blood-pool contrast agent has been administered to distinguish bacterial abscess from necrotic tumor like VX2 carcinoma and where the enhancement properties of such an agent have been compared intraindividually with an extracellular agent like gadopentetate dimeglumine. The results obtained in this study, however, are from a comparison of a single type of abscess and a single type of tumor in rabbits and may not represent the general enhancement patterns of abscesses and tumors. Our results are preliminary and should be confirmed in future clinical trials.
We tried to perform this dynamic contrast-enhanced MR imaging study in a situation identical to real clinical circumstances. We did not perform parameter calculations or parameter imaging. The analysis was focused on the uptake phase of the contrast agent because this is clinically more useful than analysis of the elimination phase. For practical reasons, the quantification of capillary permeability was not performed in the present study. In this study, MR examinations were separated by a 24-hr interval and rapid tumor growth of VX2 carcinoma might have affected the results.
In summary, the enhancement patterns of Gadomer-17 and gadopentetate dimeglumine were quite different in both bacterial abscess and VX2 carcinoma. With Gadomer-17, delayed peak enhancement and slow decay were found in both bacterial abscess and VX2 carcinoma, whereas early peak enhancement and rapid decay were found especially in VX2 carcinoma with gadopentetate dimeglumine. MR imaging with a blood-pool contrast agent, Gadomer-17, correlated well with the microvessel density in bacterial abscess and VX2 carcinoma.
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