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VX2 Carcinoma in Rabbits after Radiofrequency Ablation: Comparison of MR Contrast Agents for Help in Differentiating Benign Periablational Enhancement from Residual Tumor¹

¹ From the Department of Radiology and Clinical Research Institute, Seoul National University Hospital (T.J.K., W.K.M., J.H.C., J.M.G., K.H.L., K.H.K., J.W.L., J.G.H., K.H.C.) and the Institute of Radiation Medicine, Seoul National University Medical Research Center (T.J.K., W.K.M.), 28 Yongon-dong, Chongno-gu, Seoul 110–744, Korea; and Department of Contrast Media Research, Schering, Berlin, Germany (H.J.W.). Supported by grant of the National R & D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0420080–1). W.K.M. supported by a grant from Schering, Berlin, Germany. Received September 11, 2003; revision requested November 24; revision received March 12, 2004; accepted April 22. Address correspondence to W.K.M. (e-mail: moonwk@radcom.snu.ac.kr).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To prospectively compare the accuracy of a blood pool agent, SH L 643A, with that of gadopentetate dimeglumine in differentiating benign periablational enhancement from residual tumor in VX2 carcinomas in rabbits after radiofrequency (RF) ablation.

MATERIALS AND METHODS: Experiment was approved by the animal care committee. Sequential MR images were obtained before and with SH L 643A (17 000 Da, 0.05 mmol/kg) and, after a 24-hour interval, gadopentetate dimeglumine (546 Da, 0.1 mmol/kg) in 12 rabbits with VX2 carcinoma in the back muscle prior to (n = 12) and early (n = 12), 1 week (n = 8), and 4 weeks (n = 4) after RF ablation. RF ablation was performed with output of 90 W but at less than 300 seconds to ensure incomplete tumor ablation. The pathologic specimens were sectioned in the same plane as MR imaging, and the enhancement ratios (ie, the ratios of postcontrast to precontrast signal intensity) and the microvessel densities of residual tumor and benign periablational enhancement were assessed.

RESULTS: With SH L 643A, the peak enhancement ratios of residual tumor (1.64 ± 0.31 [standard deviation]) were significantly higher than those of benign periablational enhancement (0.97 ± 0.16) (P < .001). With gadopentetate dimeglumine, the peak enhancement ratios of residual tumor (1.82 ± 0.33) were not different from those of benign periablational enhancement (1.71 ± 0.36). In benign periablational enhancement, enhancement ratios with injection of SH L 643A were lower than those with injection of gadopentetate dimeglumine for all time points up to 30 minutes (P < .05). The microvessel density was 25.72 ± 5.43 vessels per field of view for residual tumor and 10.37 ± 2.88 vessels per field of view for benign periablational enhancement (P < .001).

CONCLUSION: Blood pool contrast agent SH L 643A permits more accurate differentiation of benign periablational enhancement from residual tumor compared with the extracellular agent gadopentetate dimeglumine.

© RSNA, 2004

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Image-guided percutaneous ablative therapies using thermal energy sources, such as radiofrequency (RF), laser, microwave, and cryoablation, are rapidly evolving as nonsurgical minimally invasive techniques for the treatment of primary and secondary malignant neoplasms (1–4).

Imaging of solid tumors after RF ablation is crucial to judge the completeness of the ablation and later to detect untreated residual tumor (5). This assessment is usually performed with contrast material–enhanced computed tomography (CT) or magnetic resonance (MR) imaging (6,7). However, assessment of the accuracy of completeness of the ablation at immediate or less than 6-month follow-up CT or MR imaging has inevitable limitations, because postablation changes make accurate diagnosis difficult (8–10). The term benign periablational enhancement was recommended by the International Working Group on Image-Guided Tumor Ablation to describe a transient finding at contrast-enhanced imaging that can be seen immediately after ablation and can last as many as 6 months after ablation (10). This finding represents a benign physiologic response to thermal injury (initially, reactive hyperemia; subsequently, fibrosis). Conventional imaging studies with extracellular contrast agents have some limitations in the differentiation between benign periablational enhancement and a small residual or recurrent tumor in follow-up of patients with most types of treated cancer (5,9). The development of more accurate imaging tests or new contrast agents is a challenge to assess RF ablation of solid tumors (3).

Blood pool contrast agents that remain exclusively within the intravascular space are currently under investigation to minimize the problems associated with extracellular contrast agents (11,12). Potential clinical applications for this class of contrast agents include MR angiography and determination of tissue perfusion, angiogenesis, or capillary integrity (13–17). The hyperpermeability of microvessels to macromolecular contrast agents has been shown in malignant tumors and inflammations (16–18), and MR imaging enhanced with a blood pool contrast agent has demonstrated tumor microvascular characteristics that correlate closely with histologic microvessel density, an established surrogate of tumor angiogenesis (16). To our knowledge, a comparison study of blood pool and extracellular contrast agents for distinguishing benign periablational enhancement from residual tumors after RF ablation has not been performed. Thus, the purpose of this study was to prospectively compare the accuracy of a blood pool agent, 24-gadolinium-tetraazacyclododecane tetraacetic acid dendrimer (SH L 643A, Gadomer-17; Schering, Berlin, Germany) with that of gadopentetate dimeglumine in differentiating benign periablational enhancement from residual tumor in VX2 carcinomas in rabbits after RF ablation.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Animal and Experimental Groups
The experiments were performed with 12 New Zealand white rabbits that weighed 2.5–3.0 kg. The animals were sedated with an intramuscular injection of 50 mg of ketamine hydrochloride (Ketalar; Yuhan Yanghang, Seoul, Korea) and 20 mg of xylazine hydrochloride (Rompun; Bayer Korea, Seoul, Korea) at 0.5 mL per kilogram of body weight. This experiment was approved by the animal care committee at Seoul National University Hospital. The animals were allowed food and water ad libitum between the various procedures.

Tumor implantation was performed with an aseptic technique by two radiologists (T.J.K., K.H.L.). VX2 carcinoma was inoculated in the muscle on the right side of the back (hereafter, right back muscle) by injecting 0.5 mL of tumor suspension with an 18-gauge needle and fluoroscopic guidance. The needle was inserted vertically into the right back muscle about 2 cm deep and 4 cm above the iliac crest, at which point the muscle bulk was measured as largest. The experimental VX2 rabbit carcinoma was prepared in a manner reported previously (19). Tumor growth was monitored (T.J.K., K.H.L.) at ultrasonography (HDI-3000; Advanced Technology Laboratories, Bothel, Wash) with a 10–5-MHz 38-mm linear transducer. VX2 carcinoma nodules larger than 2.5 cm in diameter were considered appropriate for RF ablation. The period for tumors to reach the size of 2.5 cm ranged from 10 to 12 days.

Twelve rabbits were divided into three groups according to the interval between RF ablation and sacrifice (final MR imaging performed just before sacrifice) as follows: early (n = 4), 1 week (n = 4), and 4 weeks (n = 4). At the aforementioned time points, the four rabbits in each group were sacrificed after MR examination for MR-histopathologic correlation.

RF Ablation
RF ablation was performed by two radiologists (T.J.K., K.H.L.) using the same anesthesia protocol as for carcinoma inoculation. A grounding pad was applied to the animal’s flank before RF ablation. With sonographic guidance, a 15-gauge RF probe (LeVeen Electrode; RadioTherapeutics, Mountain View, Calif) was directly inserted into the tumor. The probe was equipped with four retractable curved prongs. A frequency of 460 kHz and a maximum power output of 100 W were applied by using a monopolar RF generator (RF 2000; RadioTherapeutics). The initial generator output was 50 W for 1 minute; the output was then increased by 10 W for 1 minute, until the power output reached 90 W. The output was maintained at this point for 150–300 seconds (mean, 220 seconds ± 39; median, 210 seconds). In all cases, the RF application time of less than 300 seconds was chosen intentionally to ensure incomplete tumor ablation, because residual tumor was necessary for subsequent measurement of signal intensity for differentiation of benign periablational enhancement from residual tumor. In our preliminary study, in which the same protocols were used as described earlier, 2.5–3.0-cm VX2 carcinomas (n = 3) in the right back muscle of the rabbit were totally ablated at 90 W for 300 seconds (unpublished data, 2001).

Contrast Material
The gadolinium-based macromolecular contrast agent SH L 643A and the conventional small-molecular-weight (546 Da) contrast agent gadopentetate dimeglumine (Magnevist; Schering) were used in this study. SH L 643A contains 24 gadolinium complexes at the surface of a dendritic backbone, and the molecular weight is 17 000 Da. Because of the globular shape of the molecule, the apparent molecular weight is approximately 35 000 Da (12). This results in a reduced diffusion into the extravascular compartment. In addition to its blood pool characteristics, SH L 643A offers a high T1 relaxivity (11.9 L · mmol^–1 · sec^–1), which is twice or more than that of gadopentetate dimeglumine (4.9 L · mmol^–1 · sec^–1). SH L 643A has low toxicity and is eliminated by glomerular filtration.

MR Imaging
The same anesthetic regimen used for RF ablation was used for MR imaging. All examinations were performed with a 1.5-T MR imaging system (Magnetom Vision Plus; Siemens, Erlangen, Germany) and a knee coil for better resolution. All images were acquired in the transverse plane. Animals were imaged in the prone position. After routine localization images and transverse T2-weighted spin-echo images (repetition time msec/echo time msec, 4000/96; 4-mm section thickness) were acquired, two sets of sequential T1-weighted images were acquired. For the first set of images, 0.05 mmol/kg SH L 643A was administrated to each animal via the ear vein by means of manual fast bolus injection; for the second set of images, acquired after a 24-hour interval, 0.1 mmol/kg gadopentetate dimeglumine was administered in the same fashion. For a randomized order of the two contrast agents, half of the animals were imaged in a crossover fashion with one agent and then 24 hours later, with the other agent. Sequential MR imaging was performed with a fast spin-echo sequence (450/16) before and 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 minutes after bolus injection of the contrast agent. The echo train length was 10, the bandwidth was 16 kHz, and the acquisition time was 1 minute. The section thickness was 4 mm, and the field of view was 15 cm with an acquisition matrix of 256 x 128.

MR images were obtained to follow-up tumor growth and monitor the changes the day before (n = 12) and early (n = 12), 1 week (n = 8), and 4 weeks (n = 4) after RF ablation. In the early group, half of the animals were imaged within 1 hour after RF ablation and the other half were imaged 24 hours later.

Histopathologic Analysis
Animals were sacrificed with a lethal dose (90 mg/kg) of intravenously administered sodium pentobarbital (Pentothal; Choong Wae Pharmacy, Seoul, Korea). The pathologic specimens were sectioned in the same transverse plane used at MR imaging with 5-mm intervals. In each tumor, two radiologists (T.J.K., K.H.L.) selected two representative sections that were matched with the corresponding MR images with the largest enhanced areas. They were fixed with 10% formalin and stained with hematoxylin-eosin on large (5 x 7.5 cm) microscopic slides.

Histopathologic findings of the tumor after RF ablation were correlated with MR imaging findings by the consensus opinion of two radiologists (T.J.K., K.H.L.) and a pathologist, with particular emphasis on the enhanced area of the images. The presence of viable tumors, coagulation necrosis, and a benign physiologic response to thermal injury, such as reactive hyperemia and fibrosis, were documented. The maximal diameter of viable tumors and coagulation necrosis was measured with calipers. The microvessel density of residual tumor and benign periablational enhancement were also determined by averaging the counted numbers of capillary vessels in five fields of view at a magnification factor of 200 in the areas corresponding to areas of enhancement on MR images.

Image Analysis
First, two radiologists (T.J.K., K.H.L.) with 5–7 years of experience in MR imaging assessed all MR images by consensus, with full knowledge of histologic findings. The maximal diameters of VX2 carcinomas before and after RF ablation at MR imaging were measured. On unenhanced T1- and T2-weighted MR images, the signal intensity of lesion was compared with that of the right psoas muscle. Dynamic contrast-enhanced MR images obtained just before sacrifice were used for signal intensity analysis of residual tumor and benign periablational enhancement after RF ablation.

Circular regions of interest (area, 0.03 cm²) were positioned by one author (K.H.L.) to measure the signal intensities in the enhancing areas corresponding to the largest residual tumor and benign periablational enhancement on the histologic slide. The signal intensities were measured in three portions of the residual tumor, and benign periablational enhancement and the average values were obtained. For each time point, the enhancement ratio (ER) determined by comparison of the precontrast signal intensity (SI_pre) with postcontrast signal intensity (SI_post) relative to precontrast signal intensity of the psoas muscle (SI_prepsoas), as a reference, was calculated by using the following equation: ER = (SI_post – SI_pre)/SI_prepsoas. The enhancement ratio curve was obtained by plotting the enhancement ratios against time as mean values ± standard deviations for both residual tumor and benign periablational enhancement. In each case, the peak enhancement ratio (ER_peak) was determined as the value at a time point (peak time, T_max) beyond which the sum of slopes measured for the two intervals between three consecutive time points on each curve was 10% per minute or less (20). The slope of the curve defined as the percentage increase in enhancement ratio per minute over the baseline value was derived from the following equation: slope = (ER_peakx 100)/T_max.

The difference between the mean enhancement ratios of residual tumor and benign periablational enhancement at each time point was calculated for each contrast agent. The parameters representing the characteristics of enhancement such as peak enhancement ratios, peak time, and slope were compared according to the contrast agents used and residual tumor and benign periablational enhancement.

Second, three radiologists (J.H.C., K.H.K., J.W.L.) who were blinded to the contrast agent used and the histologic findings independently reviewed MR images obtained at T_max after injection of SH L 643A and gadopentetate dimeglumine. The areas of residual tumor and benign periablational enhancement selected for this analysis were the same as those chosen for obtaining quantitative region-of-interest measurements. Signal intensity of a possible residual tumor or a possible benign periablational enhancement was visually assessed as very high, high, same, low, and very low. Very high and high were regarded as a positive reading for residual tumor, and sensitivity of contrast-enhanced MR images was calculated. To compare the zone of ablation measured on MR images with the standard zone of ablation as determined at histopathologic analysis, the maximal diameter of a nonenhanced area on post–RF ablation images was also independently measured by the three radiologists using electronic calipers and a workstation monitor (model DR 110; Dataray, Denver, Colo), and the average values were obtained. The maximum diameter of the ablated lesion as determined at MR imaging with the two contrast agents was compared with the measurements taken at histopathologic examination in terms of the mean difference, minimum and maximum differences, and standard deviation.

Statistical Analysis
The SPSS software package (version 9.0; SPSS, Chicago, Ill) was used for statistical data analysis. The Mann-Whitney U test was applied to assess the statistical significance of the differences in peak enhancement ratio, enhancement ratios at each time point, and slope values between residual tumor and benign periablational enhancement for the two contrast agents. Two-way analyses of variance were used to assess the differences in peak enhancement ratio and slope values between the two contrast agents for residual tumor and benign periablational enhancement. The Wilcoxon signed rank test was used to evaluate the statistical significance of the difference between the mean enhancement ratio of residual tumor and that of benign periablational enhancement for the two contrast agents. The Mann-Whitney U test was also used to assess the difference in microvessel density between residual tumor and benign periablational enhancement. Binomial test (ie, exact analogue of the McNemar test) was used to assess the statistical significance of the differences in radiologists’ sensitivity at MR imaging between the two contrast agents. Simple regression analysis was used to assess the correlation of the maximum diameter of the ablated lesions obtained with MR findings and pathologic measurements.

For all tests, a P value of less than .05 was considered to indicate a statistically significant difference. In blinded analysis, the statistics were computed for interobserver variability with accompanying 95% confidence intervals. The following values represented qualitative degree of agreement: less than 0.2, poor; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, good; and 0.81–1.0, very good.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
MR Findings with Histopathologic Correlation
Before RF ablation, the maximal diameter of the VX2 carcinoma in 12 rabbits ranged from 2.7 to 3.5 cm (mean, 2.9 cm ± 0.3). All tumors appeared slightly hyperintense on T1-weighted MR images and strongly hyperintense on T2-weighted MR images, compared to the signal intensity of psoas muscle, and showed heterogeneous enhancement after the injection of contrast agents.

Early after RF ablation, the ablated tumor remained slightly hyperintense on T1- and T2-weighted MR images and was surrounded by a 1–2-mm-thick rim of high signal intensity on T2-weighted images in all cases. On contrast-enhanced MR images, ablated tumors were unenhanced but were surrounded by an enhancing rim corresponding to the previous hyperintense rim on T2-weighted images. In 10 cases, 3–8-mm nodular enhancing abnormalities were noted at the periphery of the ablated tumor. Compared with the MR images obtained within 1 hour after RF ablation, greater conspicuity and sharper margins between RF-treated and untreated regions of the tumor were seen on T2-weighted and contrast-enhanced images obtained 24 hours after RF ablation. Peritumoral rim of high signal intensity on T2-weighted images and rim enhancement on contrast-enhanced images were more prominent and clearly defined on images obtained 24 hours after RF ablation. However, there was no difference in the size of an enhancing rim or in nodular enhancing abnormalities. One week after RF ablation, the rim enhancement along the ablated tumor became more prominent compared with that immediately after RF ablation on contrast-enhanced MR images, and 3–14-mm nodular enhancing abnormalities were noted at the periphery of the ablated tumor (Fig 1) in all cases but one. Four weeks after RF ablation, 9–47-mm nodular enhancing abnormalities and a 2–4-mm rim enhancement were noted on contrast-enhanced MR images in 11 cases, and only ablated tumor with 2-mm rim enhancement was seen in one case.

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Transverse spin-echo MR images (a-f) and a photomicrograph (g) of a back muscle 1 week after RF ablation of VX2 tumor with the rabbit in prone position. (a) T2-weighted image (4000/96) obtained before injection of SH L 643A shows heterogeneous-signal-intensity mass with hyperintense center and surrounding hyperintense rim (arrowheads). A hyperintense nodule (arrow) abutting the treated area is suspicious for residual tumor. (b) T1-weighted image (450/16) obtained before injection of SH L 643A shows slightly hyperintense mass with irregular margin compared to signal intensity of psoas muscle. (c) T1-weighted image (450/16) obtained 2 minutes after injection of SH L 643A shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note mild enhancement of the surrounding rim compared to that of nodular lesion. (d) T1-weighted image (450/16) obtained 10 minutes after injection of SH L 643A shows that enhancement of residual tumor is greater than that seen in c. The peripheral nodular enhancing tumor (arrow) and rim enhancement (arrowheads) demonstrate more discrete margins compared to those seen in e. (e) T1-weighted image (450/16) obtained 2 minutes after injection of gadopentetate dimeglumine also shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note strong enhancement of the surrounding rim compared to that of residual tumor. (f) T1-weighted image (450/16) obtained 10 minutes after injection of gadopentetate dimeglumine also shows both nodular enhancing residual tumor (arrow) and rim enhancement (arrowheads) but allows only poor differentiation between these two areas compared to e. (g) Photomicrograph shows viable tumor (arrows) and mixture of inflammatory granulation tissue and early fibrosis (arrowheads), which correspond to enhancing nodule and the peripheral rim at contrast-enhanced MR imaging, respectively. Necrotic areas filled with degenerated tumor cells and tissue loss surrounding the inserted needle correspond to the two inner zones on T2-weighted MR images and unenhanced ablated tumor on contrast-enhanced MR images. (Hematoxylin-eosin stain; original magnification, x2.)

View larger version (110K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Transverse spin-echo MR images (a-f) and a photomicrograph (g) of a back muscle 1 week after RF ablation of VX2 tumor with the rabbit in prone position. (a) T2-weighted image (4000/96) obtained before injection of SH L 643A shows heterogeneous-signal-intensity mass with hyperintense center and surrounding hyperintense rim (arrowheads). A hyperintense nodule (arrow) abutting the treated area is suspicious for residual tumor. (b) T1-weighted image (450/16) obtained before injection of SH L 643A shows slightly hyperintense mass with irregular margin compared to signal intensity of psoas muscle. (c) T1-weighted image (450/16) obtained 2 minutes after injection of SH L 643A shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note mild enhancement of the surrounding rim compared to that of nodular lesion. (d) T1-weighted image (450/16) obtained 10 minutes after injection of SH L 643A shows that enhancement of residual tumor is greater than that seen in c. The peripheral nodular enhancing tumor (arrow) and rim enhancement (arrowheads) demonstrate more discrete margins compared to those seen in e. (e) T1-weighted image (450/16) obtained 2 minutes after injection of gadopentetate dimeglumine also shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note strong enhancement of the surrounding rim compared to that of residual tumor. (f) T1-weighted image (450/16) obtained 10 minutes after injection of gadopentetate dimeglumine also shows both nodular enhancing residual tumor (arrow) and rim enhancement (arrowheads) but allows only poor differentiation between these two areas compared to e. (g) Photomicrograph shows viable tumor (arrows) and mixture of inflammatory granulation tissue and early fibrosis (arrowheads), which correspond to enhancing nodule and the peripheral rim at contrast-enhanced MR imaging, respectively. Necrotic areas filled with degenerated tumor cells and tissue loss surrounding the inserted needle correspond to the two inner zones on T2-weighted MR images and unenhanced ablated tumor on contrast-enhanced MR images. (Hematoxylin-eosin stain; original magnification, x2.)

View larger version (117K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. Transverse spin-echo MR images (a-f) and a photomicrograph (g) of a back muscle 1 week after RF ablation of VX2 tumor with the rabbit in prone position. (a) T2-weighted image (4000/96) obtained before injection of SH L 643A shows heterogeneous-signal-intensity mass with hyperintense center and surrounding hyperintense rim (arrowheads). A hyperintense nodule (arrow) abutting the treated area is suspicious for residual tumor. (b) T1-weighted image (450/16) obtained before injection of SH L 643A shows slightly hyperintense mass with irregular margin compared to signal intensity of psoas muscle. (c) T1-weighted image (450/16) obtained 2 minutes after injection of SH L 643A shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note mild enhancement of the surrounding rim compared to that of nodular lesion. (d) T1-weighted image (450/16) obtained 10 minutes after injection of SH L 643A shows that enhancement of residual tumor is greater than that seen in c. The peripheral nodular enhancing tumor (arrow) and rim enhancement (arrowheads) demonstrate more discrete margins compared to those seen in e. (e) T1-weighted image (450/16) obtained 2 minutes after injection of gadopentetate dimeglumine also shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note strong enhancement of the surrounding rim compared to that of residual tumor. (f) T1-weighted image (450/16) obtained 10 minutes after injection of gadopentetate dimeglumine also shows both nodular enhancing residual tumor (arrow) and rim enhancement (arrowheads) but allows only poor differentiation between these two areas compared to e. (g) Photomicrograph shows viable tumor (arrows) and mixture of inflammatory granulation tissue and early fibrosis (arrowheads), which correspond to enhancing nodule and the peripheral rim at contrast-enhanced MR imaging, respectively. Necrotic areas filled with degenerated tumor cells and tissue loss surrounding the inserted needle correspond to the two inner zones on T2-weighted MR images and unenhanced ablated tumor on contrast-enhanced MR images. (Hematoxylin-eosin stain; original magnification, x2.)

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 1d. Transverse spin-echo MR images (a-f) and a photomicrograph (g) of a back muscle 1 week after RF ablation of VX2 tumor with the rabbit in prone position. (a) T2-weighted image (4000/96) obtained before injection of SH L 643A shows heterogeneous-signal-intensity mass with hyperintense center and surrounding hyperintense rim (arrowheads). A hyperintense nodule (arrow) abutting the treated area is suspicious for residual tumor. (b) T1-weighted image (450/16) obtained before injection of SH L 643A shows slightly hyperintense mass with irregular margin compared to signal intensity of psoas muscle. (c) T1-weighted image (450/16) obtained 2 minutes after injection of SH L 643A shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note mild enhancement of the surrounding rim compared to that of nodular lesion. (d) T1-weighted image (450/16) obtained 10 minutes after injection of SH L 643A shows that enhancement of residual tumor is greater than that seen in c. The peripheral nodular enhancing tumor (arrow) and rim enhancement (arrowheads) demonstrate more discrete margins compared to those seen in e. (e) T1-weighted image (450/16) obtained 2 minutes after injection of gadopentetate dimeglumine also shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note strong enhancement of the surrounding rim compared to that of residual tumor. (f) T1-weighted image (450/16) obtained 10 minutes after injection of gadopentetate dimeglumine also shows both nodular enhancing residual tumor (arrow) and rim enhancement (arrowheads) but allows only poor differentiation between these two areas compared to e. (g) Photomicrograph shows viable tumor (arrows) and mixture of inflammatory granulation tissue and early fibrosis (arrowheads), which correspond to enhancing nodule and the peripheral rim at contrast-enhanced MR imaging, respectively. Necrotic areas filled with degenerated tumor cells and tissue loss surrounding the inserted needle correspond to the two inner zones on T2-weighted MR images and unenhanced ablated tumor on contrast-enhanced MR images. (Hematoxylin-eosin stain; original magnification, x2.)

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 1e. Transverse spin-echo MR images (a-f) and a photomicrograph (g) of a back muscle 1 week after RF ablation of VX2 tumor with the rabbit in prone position. (a) T2-weighted image (4000/96) obtained before injection of SH L 643A shows heterogeneous-signal-intensity mass with hyperintense center and surrounding hyperintense rim (arrowheads). A hyperintense nodule (arrow) abutting the treated area is suspicious for residual tumor. (b) T1-weighted image (450/16) obtained before injection of SH L 643A shows slightly hyperintense mass with irregular margin compared to signal intensity of psoas muscle. (c) T1-weighted image (450/16) obtained 2 minutes after injection of SH L 643A shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note mild enhancement of the surrounding rim compared to that of nodular lesion. (d) T1-weighted image (450/16) obtained 10 minutes after injection of SH L 643A shows that enhancement of residual tumor is greater than that seen in c. The peripheral nodular enhancing tumor (arrow) and rim enhancement (arrowheads) demonstrate more discrete margins compared to those seen in e. (e) T1-weighted image (450/16) obtained 2 minutes after injection of gadopentetate dimeglumine also shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note strong enhancement of the surrounding rim compared to that of residual tumor. (f) T1-weighted image (450/16) obtained 10 minutes after injection of gadopentetate dimeglumine also shows both nodular enhancing residual tumor (arrow) and rim enhancement (arrowheads) but allows only poor differentiation between these two areas compared to e. (g) Photomicrograph shows viable tumor (arrows) and mixture of inflammatory granulation tissue and early fibrosis (arrowheads), which correspond to enhancing nodule and the peripheral rim at contrast-enhanced MR imaging, respectively. Necrotic areas filled with degenerated tumor cells and tissue loss surrounding the inserted needle correspond to the two inner zones on T2-weighted MR images and unenhanced ablated tumor on contrast-enhanced MR images. (Hematoxylin-eosin stain; original magnification, x2.)

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 1f. Transverse spin-echo MR images (a-f) and a photomicrograph (g) of a back muscle 1 week after RF ablation of VX2 tumor with the rabbit in prone position. (a) T2-weighted image (4000/96) obtained before injection of SH L 643A shows heterogeneous-signal-intensity mass with hyperintense center and surrounding hyperintense rim (arrowheads). A hyperintense nodule (arrow) abutting the treated area is suspicious for residual tumor. (b) T1-weighted image (450/16) obtained before injection of SH L 643A shows slightly hyperintense mass with irregular margin compared to signal intensity of psoas muscle. (c) T1-weighted image (450/16) obtained 2 minutes after injection of SH L 643A shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note mild enhancement of the surrounding rim compared to that of nodular lesion. (d) T1-weighted image (450/16) obtained 10 minutes after injection of SH L 643A shows that enhancement of residual tumor is greater than that seen in c. The peripheral nodular enhancing tumor (arrow) and rim enhancement (arrowheads) demonstrate more discrete margins compared to those seen in e. (e) T1-weighted image (450/16) obtained 2 minutes after injection of gadopentetate dimeglumine also shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note strong enhancement of the surrounding rim compared to that of residual tumor. (f) T1-weighted image (450/16) obtained 10 minutes after injection of gadopentetate dimeglumine also shows both nodular enhancing residual tumor (arrow) and rim enhancement (arrowheads) but allows only poor differentiation between these two areas compared to e. (g) Photomicrograph shows viable tumor (arrows) and mixture of inflammatory granulation tissue and early fibrosis (arrowheads), which correspond to enhancing nodule and the peripheral rim at contrast-enhanced MR imaging, respectively. Necrotic areas filled with degenerated tumor cells and tissue loss surrounding the inserted needle correspond to the two inner zones on T2-weighted MR images and unenhanced ablated tumor on contrast-enhanced MR images. (Hematoxylin-eosin stain; original magnification, x2.)

View larger version (152K): [in this window] [in a new window] [Download PPT slide]   Figure 1g. Transverse spin-echo MR images (a-f) and a photomicrograph (g) of a back muscle 1 week after RF ablation of VX2 tumor with the rabbit in prone position. (a) T2-weighted image (4000/96) obtained before injection of SH L 643A shows heterogeneous-signal-intensity mass with hyperintense center and surrounding hyperintense rim (arrowheads). A hyperintense nodule (arrow) abutting the treated area is suspicious for residual tumor. (b) T1-weighted image (450/16) obtained before injection of SH L 643A shows slightly hyperintense mass with irregular margin compared to signal intensity of psoas muscle. (c) T1-weighted image (450/16) obtained 2 minutes after injection of SH L 643A shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note mild enhancement of the surrounding rim compared to that of nodular lesion. (d) T1-weighted image (450/16) obtained 10 minutes after injection of SH L 643A shows that enhancement of residual tumor is greater than that seen in c. The peripheral nodular enhancing tumor (arrow) and rim enhancement (arrowheads) demonstrate more discrete margins compared to those seen in e. (e) T1-weighted image (450/16) obtained 2 minutes after injection of gadopentetate dimeglumine also shows nodular enhancing residual tumor (arrow) with rim enhancement (arrowheads) along the ablated margin. Note strong enhancement of the surrounding rim compared to that of residual tumor. (f) T1-weighted image (450/16) obtained 10 minutes after injection of gadopentetate dimeglumine also shows both nodular enhancing residual tumor (arrow) and rim enhancement (arrowheads) but allows only poor differentiation between these two areas compared to e. (g) Photomicrograph shows viable tumor (arrows) and mixture of inflammatory granulation tissue and early fibrosis (arrowheads), which correspond to enhancing nodule and the peripheral rim at contrast-enhanced MR imaging, respectively. Necrotic areas filled with degenerated tumor cells and tissue loss surrounding the inserted needle correspond to the two inner zones on T2-weighted MR images and unenhanced ablated tumor on contrast-enhanced MR images. (Hematoxylin-eosin stain; original magnification, x2.)

The mean microvessel density, in terms of vessels per field of view, was 25.72 ± 5.43 (range, 14–36; magnification, x200) for residual tumor and 10.37 ± 2.88 (range, 6–17; magnification, x200) for benign periablational enhancement. The difference was statistically significant (P < .001). When the vessel count was compared among the three groups, there was also significant difference between residual tumor and benign periablational enhancement: 24.53 ± 5.87 and 9.15 ± 2.52 in early group (P < .001), 25.44 ± 5.22 and 10.65 ± 2.81 in 1-week group (P < .001), and 27.20 ± 5.09 and 11.30 ± 2.99 in 4-week group (P < .001), respectively.

Enhancement Ratio Curve Analysis
With injection of SH L 643A, enhancement ratios of residual tumor were significantly higher than those of benign periablational enhancement up to 30 minutes in all three groups (P < .05) (Fig 2), whereas with injection of gadopentetate dimeglumine, enhancement ratios of residual tumor were not significantly higher than those of benign periablational enhancement up to 30 minutes in all three groups (P > .05), except for 1 and 2 minutes in the 4-week group (Fig 3). At all time points, the difference between the mean enhancement ratios of residual tumor and benign periablational enhancement with injection of SH L 643A was greater than the difference with injection of gadopentetate dimeglumine. With injection of SH L 643A, the differences were 0.34–0.75 (mean, 0.54 ± 0.10); with injection of gadopentetate dimeglumine, they ranged from 0 to 0.48 (mean, 0.11 ± 0.11) (P < .001).

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. Graphs show mean enhancement ratio of residual tumor and benign periablational enhancement after injection of 0.05 mmol/kg SH L 643A in (a) early, (b) 1-week, and (c) 4-week groups. Delayed peak enhancement and slow decay are seen in both residual tumor and benign periablational enhancement after injection. Enhancement ratios of residual tumor are significantly higher than those of benign periablational enhancement up to 30 minutes in all three groups (P < .01). Error bars represent standard deviations.

View larger version (32K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. Graphs show mean enhancement ratio of residual tumor and benign periablational enhancement after injection of 0.05 mmol/kg SH L 643A in (a) early, (b) 1-week, and (c) 4-week groups. Delayed peak enhancement and slow decay are seen in both residual tumor and benign periablational enhancement after injection. Enhancement ratios of residual tumor are significantly higher than those of benign periablational enhancement up to 30 minutes in all three groups (P < .01). Error bars represent standard deviations.

View larger version (31K): [in this window] [in a new window] [Download PPT slide]   Figure 2c. Graphs show mean enhancement ratio of residual tumor and benign periablational enhancement after injection of 0.05 mmol/kg SH L 643A in (a) early, (b) 1-week, and (c) 4-week groups. Delayed peak enhancement and slow decay are seen in both residual tumor and benign periablational enhancement after injection. Enhancement ratios of residual tumor are significantly higher than those of benign periablational enhancement up to 30 minutes in all three groups (P < .01). Error bars represent standard deviations.

View larger version (31K): [in this window] [in a new window] [Download PPT slide]   Figure 3a. Graphs show mean enhancement ratio of residual tumor and benign periablational enhancement after injection of 0.1 mmol/kg gadopentetate dimeglumine in (a) early, (b) 1-week, and (c) 4-week groups. Early peak enhancement and rapid decay in both residual tumor and benign periablational enhancement are seen after injection. Enhancement ratios of residual tumor are not significantly higher than those of benign periablational enhancement up to 30 minutes in all three groups (P > .05), except for 1 and 2 minutes in the 4-week group (P < .05). Error bars represent standard deviations.

View larger version (31K): [in this window] [in a new window] [Download PPT slide]   Figure 3b. Graphs show mean enhancement ratio of residual tumor and benign periablational enhancement after injection of 0.1 mmol/kg gadopentetate dimeglumine in (a) early, (b) 1-week, and (c) 4-week groups. Early peak enhancement and rapid decay in both residual tumor and benign periablational enhancement are seen after injection. Enhancement ratios of residual tumor are not significantly higher than those of benign periablational enhancement up to 30 minutes in all three groups (P > .05), except for 1 and 2 minutes in the 4-week group (P < .05). Error bars represent standard deviations.

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Figure 3c. Graphs show mean enhancement ratio of residual tumor and benign periablational enhancement after injection of 0.1 mmol/kg gadopentetate dimeglumine in (a) early, (b) 1-week, and (c) 4-week groups. Early peak enhancement and rapid decay in both residual tumor and benign periablational enhancement are seen after injection. Enhancement ratios of residual tumor are not significantly higher than those of benign periablational enhancement up to 30 minutes in all three groups (P > .05), except for 1 and 2 minutes in the 4-week group (P < .05). Error bars represent standard deviations.

The maximum diameter of the ablated lesions visible on MR images enhanced with SH L 643A was within 2 mm (mean, 1.0 mm ± 0.7; range, 0–2 mm) of the actual measurement at the histopathologic examination in all cases. The radiologic-pathologic correlation coefficient was 0.98. For gadopentetate dimeglumine, the mean difference was 1.7 mm ± 0.4 (range, 1–2 mm), and the radiologic-pathologic correlation coefficient was 0.97.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The results of our experimental study indicate that the blood pool contrast agent SH L 643A, which is confined to the vascular space, can reflect the blood volume of the residual tumor and benign periablational enhancement more accurately than can gadopentetate dimeglumine. With SH L 643A, the peak enhancement ratios of benign periablational enhancement were consistently and significantly lower than those of residual tumors, whereas the peak enhancement ratios of benign periablational enhancement, particularly in the early and 1-week groups, were almost the same as those of residual tumor with gadopentetate dimeglumine. Peak enhancement ratios, which are related to the blood volume and correlated with microvessel density, were probably better determined with SH L 643A, because with gadopentetate dimeglumine, the peak enhancement ratio was related to the blood volume obscured by the capillary permeability (20–22). The difference between the mean enhancement ratios of the residual tumor and benign periablative enhancement was significantly greater with SH L 643A than with gadopentetate dimeglumine, which supports the idea that SH L 643A reflects blood volume more accurately than does gadopentetate dimeglumine.

The goal of diagnostic follow-up in a patient after RF ablation is to detect the presence of residual tumor when it is as small as possible while minimizing the false-positive diagnosis that leads to unnecessary biopsy or treatment. With gadopentetate dimeglumine, the presence or the extent of residual tumor after RF ablation tends to be overestimated at MR imaging, because nonmalignant reactive tissue can also be enhanced, particularly within 1 month after the therapy (5,9). Small-molecular-weight (546 Da) gadopentetate dimeglumine not only enhances the vascular space but also diffuses rapidly into the interstitial space (23). Furthermore, residual tumors can be missed without adequate MR techniques because of the rapid washout of the extracellular contrast agent (5,6). In this study, all three radiologists could better differentiate residual tumor and benign periablational enhancement with SH L 643A than with gadopentetate dimeglumine in the blinded review, and the difference was statistically significant for two of the radiologists. We also compared the diameter of nonenhanced area on MR images (zone of nonperfusion) with the standard zone of ablation as determined at histopathologic analysis, and a tighter correlation was found with SH L 643A than with gadopentetate dimeglumine. The agreement was on the order of a millimeter. Findings of comparative studies of blood pool and extracellular MR contrast agents in other animal experiments also showed improvement in tumor characterization and lesion conspicuity by using blood pool contrast agents (24–27).

We focused on enhancement ratio curve analysis of dynamic contrast-enhanced MR images because MR-histopathologic correlation after RF ablation of solid tumor was described in detail in the literature (8,28,29). In this study, we calculated the parameters representing the characteristics of enhancement such as peak enhancement ratio, peak time, and slope from the enhancement ratio curves and found that enhancement ratio was the most useful to differentiate benign periablational enhancement from residual tumor. The use of a more complicated pharmacokinetic model would have allowed the calculation of more precise quantitative parameters like blood volume and capillary permeability (16,19,21,22,28).

Our study had several limitations. Immunohistochemical staining for exact microvessel density was not performed because the antibodies for rabbit tumor were not commercially available at the time of the study. Special vital stainings to detect lactate dehydrogenase, maleate dehydrogenase, and nicotinamide adenine dinucleotide phosphate diaphorase, or NADPH, activity were used by other investigators to confirm true necrosis of tumors in human and pig studies (30,31), whereas only conventional hematoxylin-eosin staining was used in our study. In the present study, residual tumor and benign periablational enhancement were created and coexisted within the same lesion with use of RF ablation; hence, the animal model provided very similar conditions to the clinical situation. However, the results obtained in this study are from a single type of tumor in rabbits and may not represent the general enhancement pattern of all other human tumors. In this study, the dose of injected SH L 643A was 0.05 mmol/kg, that is, half the dose of gadopentetate dimeglumine (0.1 mmol/kg). However, the T1 relaxivity of SH L 643A was 11.9 L · mmol^–1 · sec^–1—more than twice that of gadopentetate dimeglumine (4.9 L · mmol^–1 · sec^–1) (12). Thus, we concluded there was no bias in this study in terms of the injected dose.

In conclusion, findings of the present experimental study in rabbits suggest that the blood pool contrast agent, SH L 643A, might permit more accurate differentiation of benign periablational enhancement from residual tumor after RF ablation compared with the extracellular agent, gadopentetate dimeglumine.

Practical application: The results of our experimental study indicate that the blood pool contrast agent, which is confined to the vascular space, can reflect the blood volume of the residual tumor, as opposed to benign periablational enhancement, more accurately than can gadopentetate dimeglumine. In oncology imaging, the differentiation between posttherapeutic changes from residual or recurrent tumor is a major interest in the determination of therapeutic adequacy. Blood pool contrast agents could be applicable for this differentiation, and they should be tested in future experimental and clinical investigations.

	FOOTNOTES

 
Abbreviation: RF = radiofrequency

Author contributions: Guarantor of integrity of entire study, W.K.M.; study concepts and design, all authors; literature research, T.J.K., W.K.M.; experimental studies, T.J.K., K.H.L., K.H.K., J.W.L.; data acquisition, T.J.K., W.K.M., K.H.L.; data analysis/interpretation, all authors; statistical analysis, T.J.K., J.W.L.; manuscript editing, T.J.K., W.K.M., J.W.L.; manuscript preparation, definition of intellectual content, revision/review, and final version approval, all authors

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