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(Radiology. 2001;218:570-575.)
© RSNA, 2001

Experimental Studies

Electromagnetic Heating of Breast Tumors in Interventional Radiology: In Vitro and in Vivo Studies in Human Cadavers and Mice1

Ingrid Hilger, PhD, Wilfried Andrä, PhD, Rudolf Hergt, PhD, Robert Hiergeist, PhD, Harald Schubert, PhD and Werner Alois Kaiser, MD, MS

1 From the Institutes of Diagnostic and Interventional Radiology (I.H., W.A.K.) and Animal Research (H.S.), Clinics of Friederich Schiller University Jena, Bachstrasse 18, D-07740 Jena, Germany; and the Institute of Physical High Technology, Jena, Germany (W.A., R. Hergt, R. Hiergeist). From the 1999 RSNA scientific assembly. Received November 28, 1999; revision requested January 11, 2000; final revision received May 30; accepted June 9. Address correspondence to W.A.K. (e-mail: Werner.Kaiser@med.uni-jena.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To assess relevant parameters for the minimally invasive elimination of breast tumors by using a selective application of magnetite and exposure of the breast to an alternating magnetic field.

MATERIALS AND METHODS: The specific absorption rate (SAR) of different magnetite samples was determined calorimetrically. Temperature elevations based on magnetite mass (7–112 mg) and magnetic field amplitude (1.2–6.5 kA/m; frequency, 400 kHz) were investigated by using human breast tissue. Parameter combinations (21 mg ± 9 [SD], 242-second magnetic field exposure, 6.5-kA/m amplitude) were tested in 10 immunodeficient mice bearing human adenocarcinomas (MX-1 cells). Histologic sections of heated tumor tissue were analyzed.

RESULTS: SAR data of different magnetite particle types ranged from 3 to 211 W/g. Temperature elevation ({Delta}T) as a function of the magnetite mass increased linearly up to 28 mg; at higher masses, a saturation of {Delta}T was observed at nearly 88°C. The dependence of {Delta}T on magnetic field amplitude (H) revealed a third-order power law: {Delta}T = 0.26°C/(kA/m)3 · H3, with r2 = 0.95. A mean temperature of 71°C ± 8 was recorded in the tumor region at the end of magnetic field exposure of the mice. Typical macroscopic findings included tumor shrinkage after heating. Histologically nuclear degenerations were observed in heated malignant cells.

CONCLUSION: Magnetic heating of breast tumors is a promising technique for future interventional radiologic treatments.

Index terms: Animals • Breast neoplasms, therapeutic radiology, 00.1299 • Breast neoplasms, therapy, 00.1299 • Neoplasms, experimental studies, 00.1299


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Breast cancer is a common cause of death in women in the Western world (1) and the most common cause of death in women aged 40–55 years. The disease causes 4% of all deaths of women in the United States (2). Among women living in Germany, 18% of deaths recorded in 1995 were attributed to breast cancer (3).

Although breast cancer mortality rates have been declining in recent years in industrialized areas (4), there is still a need for further improvement of the more tolerable therapies. Breast-conserving therapies that involve a combination of wide local surgical tumor excision and chemotherapy or, particularly, radiation therapy are being used increasingly (5). Because such procedures have strong side effects, the development of alternative techniques is worthy of investigation. Therefore, on the basis of previous study results (6,7), we propose local heating induced by selective accumulation of magnetic material within the target tissue followed by exposure of the entire breast to an alternating magnetic field to eliminate tumor.

As observed by several authors (8–12) and by using contrast material for visualization of liver lesions, the application of iron oxides such as magnetite is advantageous from a toxicologic viewpoint. The use of iron oxides in tumor heating was proposed by Gilchrist et al (13). Since then, numerous studies (14–21) involving exposure times longer than 12 minutes and steady temperatures of 43°–55°C have been published. However, about 50% of tumors regress temporarily after hyperthermic treatment with temperatures of up to 44°C (22). Therefore, the authors prefer to use temperatures above 55°C at the tumor border. By doing so, we expect that combinations of this treatment with radiation therapy or chemotherapy would not be necessary. To define this technique, we introduced the term "magnetic thermoablation," a method by which target tissue is magnetically heated at temperatures above 55°C within several minutes. Similar minimally invasive techniques that are being developed for interventional radiology tumor therapy are radio-frequency heating and ultrasonographically guided freezing of liver tumors (23,24).

The purpose of our study, in which we drew from previous experiences in investigations with organic gels (6,7,25,26), was threefold: to determine (a) the specific absorption rate (SAR)—that is, the energy converted into heat by using magnetic losses per time and mass according to a specific formula (described in the next section)—of commercially available magnetite samples in the magnetic heating of breast tumors; (b) how temperature elevations can be regulated in targeted breast tissue; and (c) what the temperature elevations are during the treatment of human adenocarcinoma in mice and the corresponding histologic findings.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Determining the SAR of Different Magnetite Samples
The SAR of different magnetite samples was determined from time-dependent calorimetric measurements in an alternating magnetic field (frequency, 300 kHz; amplitude, 14 kA/m) according to the formula SAR = {Delta}Q/{Delta}t x mf-1, where {Delta}Q is the energy converted into heat per time ({Delta}t) and mf is the magnetite mass, as described previously (27). The magnetite samples used were from the following manufacturers: sample 1: BASF, Ludwigshafen, Germany; sample 2: A Better Choice of Research Chemicals, Karlsruhe, Germany; sample 3: Ferak, Berlin, Germany; samples 4 and 5: Chemagen Colloids, Berlin, Germany; and sample 6: Ferrofluidics, Nürtingen, Germany. The particle diameters of samples 1–3 were determined by using transmission electron microscopy; the diameters of samples 4–6 were not measured.

In Vitro Experiments
To characterize the baseline conditions and parameters for the proposed treatment method, in vitro experiments were performed by using 28 isolated breast tissue specimens (approximately 60–80 g; diameter, 70 mm) from five human cadavers and magnetite sample 6.

The dependence of temperature elevation on magnetite mass was determined by injecting the tissue specimens with different masses (7–112 mg) of magnetite sample 6. The volume of breast tissue occupied by magnetite was estimated to be between 0.050 and 0.6 mm3. In addition, the variation in temperature dependence on different magnetic field amplitudes (1.2–6.5 kA/m) was studied after the injection of a defined mass (28 mg) of magnetite sample 6.

Temperature measurements were performed mainly as described by Hilger et al (7). In the present study, we used plastic cannulas with an inserted steel needle (Braun, Melsungen, Germany) to easily pierce the tissue. After the injection of magnetite particles, the steel needle was removed and replaced by a thermocouple. The correct positioning of the thermocouple within the area of magnetite deposition was controlled by using radiography (Fig 1). The magnetite samples were placed in the center of a magnetic field applicator that consisted of a 9-cm-diameter circular coil. The exposure to an alternating magnetic field (frequency, 400 kHz; amplitude, 6.1 kA/m) lasted 2 minutes. The temperatures measured, starting at about 15°C, were monitored by using a digital multimeter (Keithley, Germering, Germany). In a control experiment with three breast tissue specimens, the heating effects within the tissue without magnetite were tested under experimental conditions that were identical to those used to test the tissue with magnetite.



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  		Figure 1. Radiograph of breast tissue sample shows the in vitro experimental setup. C = magnetic field applicator coil, B = breast tissue sample containing iron oxides (I) (ie, magnetite), T = thermocouple.

 
In Vivo Experiments
Ten female immunodeficient mice that weighed 23.2 g ± 2.2 (SD) were obtained from the Institute of Animal Research of the Clinics of Friederich Schiller University, Jena. The animals were group housed in a solid-floor cage (Ehret, Berlin, Germany). Sawdust (Altromin Tierlabor Service, Lage, Germany) was used as bedding. Room temperature was controlled at 21°C ± 2. A 10 hours of light, 14 hours of dark cycle was maintained. Animals received a diet of commercially available pellets (Altromin Tierlabor Service, Lage, Germany) and water ad libitum. Experimental tumors grew subcutaneously in the mice after they received an injection of 0.35 mL of Dulbecco Modified Eagle medium (Life Technologies, Karlsruhe, Germany) that contained 2 x 106 human breast adenocarcinoma (MX-1) cells (Deutsches Krebsforschungszentrum, Heidelberg, Germany) in the lateral abdomen. Experiments were started approximately 6 weeks after tumor development. The mean tumor volume (V) was calculated to be 299 mm3 ± 158, as determined by using the formula V = {pi}/6 x (product of three principal diameters), as described by Steel (28). All experiments were approved by the regional animal ethics committee.

Before the experiments, the animals received anesthetic agents (0.5 mg of medetomidine hydrochloride [Domitor; Pfizer, Karlsruhe, Germany], 5.0 mg of midazolam hydrochloride [Dormicum; Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany], and 0.05 mg of fentanyldihydrogen citrate [Fentanyl; Janssen-Cilag GmbH, Neuss, Germany], all per kilogram of body weight). On the basis of tumor volume, 50–100 µL of magnetic fluid sample 6 was injected intratumorally (50 µL/min) by using 27-gauge cannulas. The mean mass of magnetite per 299 mm3 of tumor tissue was 21 mg ± 9. The distribution of magnetite in the tumor was determined at radiography.

For magnetic thermoablation of tumors, the mice were exposed to an alternating magnetic field (frequency, 400 kHz; amplitude, 6.5 kA/m) for 242 seconds. Rectal and intratumoral temperatures (Fig 2) were monitored during magnetic thermoablation.



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  		Figure 2. Radiograph of a recumbent mouse shows the in vivo experimental setup. C = magnetic field applicator coil, T = thermocouple.

 
After tumor treatment, the mice were sacrificed by using decapitation, as approved by the regional animal ethics committee. Tumor dissection was followed by tissue fixation in 4% formalin. The samples were processed for methacrylate embedding (Technovit 7100; Heraeus-Kulzer, Wehrheim, Germany). Specimens were cut into 4-µm-thick sections by using a microtome (Microm, Walldorf, Germany) and stained with azure II for light microscopy to study the coagulation necrosis effects of magnetic thermoablation on tumor cells.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Determining the SAR of Different Magnetite Samples
The data listed in the Table show that the SARs of the different magnetite samples varied between 3 and 211 W/g with the given field parameters. Concomitantly, the total particle diameters of the investigated samples ranged from 10 to 280 nm. One sample consisted of needle-shaped particles with dimensions of 50 x 1,500 nm.


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  		SARs of Magnetite Samples and Corresponding Particle Features
 
In Vitro Experiments
The results of experiments with isolated breast tissue showed that the temperature elevation with an exposure time of 2 minutes as a function of magnetite mass increased linearly (r2 = 0.97) with masses of up to about 28 mg (Fig 3); at higher masses, the temperature elevation saturated at nearly 88°C. In particular, for a mass of 21 mg, a temperature elevation of 48°C was observed.



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  		Figure 3. Graph of calculated (line) and experimental ({bullet}) values of temperature elevation as a function of magnetite mass in breast tissue after an exposure time of 2 minutes. The functional dependency for sample 6 magnetite masses of up to 28 mg is calculated as follows: {Delta}T = 2.31 · M, with r2 = 0.97, where M is the mass of magnetite and {Delta}T is the temperature elevation. The data, which are based on an alternating current magnetic field with a 400-kHz frequency and 6.5-kA/m amplitude, show that the temperature elevation as a function of magnetite mass increases linearly (r2 = 0.97) with a mass of up to about 28 mg; at higher masses, the temperature elevation saturates. The vertical error bars represent the SD from the mean temperature elevations. Experiments were performed in triplicate.

 
Figure 4 shows the temperature elevations obtained after an exposure time of 2 minutes with different magnetic field amplitudes and a defined mass of magnetite (28 mg). A third-order power law of dependency between the temperature elevations and the magnetic field amplitude after a 2-minute heating period was observed. This relationship is described by the equation {Delta}T = 0.26°C/(kA/m)3 · H3, with r2 = 0.95, where {Delta}T is the temperature elevation and H is the magnetic field amplitude.



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  		Figure 4. Graph of calculated (line) and experimental ({bullet}) values of temperature elevation as a function of magnetic field amplitude in breast tissue after an exposure time of 2 minutes. The functional dependency is calculated as follows: {Delta}T = 0.26°C/(kA/m)3 · H3, with r2 = 0.95, where {Delta}T is the temperature elevation and H is the magnetic field amplitude. The data, which are based on an alternating current magnetic field with a 400-kHz frequency and a magnetite mass (sample 6) of 28 mg, show that the relationship between temperature elevation and magnetic field amplitude is described by a third-order power law of dependency. The vertical error bars represent the SD from the mean temperature elevations. Experiments were performed in triplicate.

 
Control measurements in which breast tissue without magnetite was exposed to an alternating current magnetic field with an amplitude of 6.5 kA/m revealed a temperature elevation of only 3°C for an exposure time of 2 minutes (data not shown).

In Vivo Experiments
The temperature curves measured for 10 mice were averaged to give the curves in Figure 5; the SD from the mean temperatures is represented by the vertical error bars. The data reveal that, starting with an intratumoral temperature of 26°C ± 1, the temperature increased in the expected manner (26). In particular, after 2 minutes of exposure, a mean temperature of 63°C was measured; this is equivalent to a 37°C temperature elevation from the 26°C baseline tumor temperature.



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  		Figure 5. Graph of intratumoral and rectal temperature courses during exposure of 10 tumor-bearing mice to an alternating magnetic field (frequency, 400 kHz; amplitude, 6.5 kA/m) for 242 seconds after intratumoral injection of 21 mg ± 9 of magnetite (sample 6) per 299 mm3 of tissue. The intratumoral temperature, which began at 26°C ± 1, increased to 71°C ± 8 at the end of treatment (242 seconds). No substantial increase in rectal temperature was observed. {bullet} = mean intratumoral temperature data, {blacktriangleup} = mean rectal temperature data. The vertical error bars represent the SD from the mean temperature.

 
At the end of treatment, a mean temperature of 71°C ± 8 was observed, the maximum temperature registered was 79°C, and the minimum temperature was 58°C. The rectal temperatures increased from 26.7°C ± 1.9 at the beginning to 29.3°C ± 2.5 at the end of treatment.

The ventral-dorsal radiographs of a mouse in Figure 6 show the typical findings before and after magnetic thermoablation of the tumors. The radiograph of a recumbent mouse bearing a tumor loaded with magnetite is shown in Figure 6a; the opacities indicate that the magnetite particles were mainly at the tumor periphery. This distribution was found in seven of 10 mice. The tumor tissue typically shrank after magnetic field exposure, as seen on the image in Figure 6b. However, deterioration (indicated by changes in coloration) of the liver areas directly underneath were observed macroscopically in three cases. Histologic analysis revealed early stages of coagulation necrosis, with predominant nuclear degenerations, such as chromatin margination along the inner nuclear envelope and nuclear pyknosis (Fig 7), seen in all treated tumor tissue samples.



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  		Figure 6a. Radiographs of a recumbent mouse show the macroscopic tumor (arrow) (a) before and (b) after magnetic thermoablation.

 


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  		Figure 6b. Radiographs of a recumbent mouse show the macroscopic tumor (arrow) (a) before and (b) after magnetic thermoablation.

 


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  		Figure 7a. Histologic sections (4 µm; with Azure II stain) show human breast adenocarcinoma cells (a) before and (b) after magnetic thermoablation. In contrast to findings in the nonheated tumor cells with normal nuclear morphology (a), substantial nuclear degeneration effects, such as chromatin margination along the nuclear envelope (arrows) and nuclear pyknosis (arrowheads), can be observed in the heated cells (b). In a and b, the horizontal line in the bottom right corner represents a length of 50 µm.

 


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  		Figure 7b. Histologic sections (4 µm; with Azure II stain) show human breast adenocarcinoma cells (a) before and (b) after magnetic thermoablation. In contrast to findings in the nonheated tumor cells with normal nuclear morphology (a), substantial nuclear degeneration effects, such as chromatin margination along the nuclear envelope (arrows) and nuclear pyknosis (arrowheads), can be observed in the heated cells (b). In a and b, the horizontal line in the bottom right corner represents a length of 50 µm.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
The different SARs of the investigated magnetite samples are based on the fact that heating effects are strongly dependent on the magnetic properties of magnetite particles. The magnetic properties of different samples may vary appreciably on the basis of particle size and microstructure. As described by Hergt et al (27), different loss mechanisms are responsible for the corresponding SARs. By these loss processes, the magnetic energy provided by the external magnetic field is transformed into heat. It must be considered that the SARs listed in the Table are based on the defined combination of frequency and amplitude of the alternating current magnetic field used in the present study.

In vitro experiments with breast tissue were performed to elucidate the baseline parameters that are applicable to the proposed method. From the viewpoint that the SAR of a sample is a constant parameter, one can expect a steady linear increase in temperature and magnetite mass. The findings in Figure 3 can be interpreted to indicate that for magnetite masses higher than 36 mg, the temperature elevations are sufficient to boil the tissue and, consequently, the temperature elevation saturates. Nevertheless, the aforementioned dependencies are valid only for the selected magnetic field parameters and the magnetite sample (no. 6) used in the present study. The scattering of measurements in Figures 3 and 4 is attributed to dispersion irregularities of magnetite particles in breast tissue that were caused by texture variations in the tissue samples.

In regard to the dependency between temperature elevation and magnetic field amplitude (Fig 4), our findings were in agreement with those in studies in which organic gel was used as the magnetite suspension medium (25). These relationships are of interest in connection with the adjustment of the magnetic field parameters—for example, in relation to the limitation of excessive heating due to eddy currents. According to Atkinson et al (29) and Stauffer et al (30), the product of the amplitude and frequency for a whole-body coil should be below 4.85 x 108A/m · sec if the diameter of the exposed tissue is 30 cm. According to Brezovich (31), the deposited power is proportional to this diameter squared. This influence has to be considered when comparing experiments with different tissue parameters. Consequently, with a frequency of 400 kHz and a diameter of the field-exposed tissue of 15 cm (ie, estimated diameter of the breast), the corresponding amplitude must be adjusted to a value of less than 4.85 kA/m to fulfill the previously mentioned requirement. In this case, the loss of temperature elevation (Fig 4) must be balanced—for example, by using greater magnetite masses or magnetite samples with higher SARs—to achieve complete tumor cell inactivation.

On the basis of results of experiments with muscle tissue, Hilger et al (7) deduced that a frequency of 400 kHz and an amplitude of 6.5 kA/m may be tolerable for the exposure of parts of the body with diameters of up to 15 cm if short exposure times are used. Results of the present in vivo experiments, in which there was only a slight elevation in rectal temperature (Fig 5), are in agreement with these expectations.

For the frequency range applied in the present study, there were no frequency-based variations in tissue penetration. The inhomogeneity of the field amplitude across the animal body region of interest was negligible.

Although several authors (14–20) have described the use of magnetic heating under in vivo conditions, the data presented herein are, to the best of our knowledge, the first evidence that short-duration exposures to an alternating current magnetic field can lead to temperatures of up to approximately 80°C in implanted adenocarcinomas within 4 minutes. In other studies (13,19), tumors have been treated by using lower temperatures (48°C–50°C) and longer exposure times (30 minutes).

Taking into account that the mean intratumorally injected magnetite mass was 21 mg, different temperature elevations between the human breast tissue and mouse tumor tissue (temperature elevation, 48°C vs 37°C, respectively [Figs 3 and 5, respectively]) were observed during a 2-minute treatment period with nearly the same mean injected magnetite mass of 21 mg. The explanation could be related to the fact that the breast tissue samples, which were composed mainly of fat, had a lower thermal conductivity than did the tumors induced in the mice. Moreover, the comparatively low temperature elevation in tumor tissue in the mice could have been attributed to heat dissipation caused by blood flow. Nevertheless, because of the superficial tumor location, the surrounding air may have, to a certain extent, counteracted the heat dispersion. Such interrelations must be cleared up in future studies.

In general, estimations of the degree to which blood flow influences the local heating of breast tumors are still insufficient. This fact is attributed to the heterogeneity of vascularization density inside tumors, which determines tumor aggressiveness (32), as well as that in regions surrounding tumors. Breast tumors seem to be favorable for magnetic heating, because the breast is poorly vascularized (ie, as compared with the liver and kidney). Therefore, mainly the blood flow within the tumor region may be important for the temperature curves during magnetic heating.

The low baseline tumor temperatures before treatment (Fig 5) can be attributed to anesthetic effects. Because unpredictable and traumatic side effects could have occurred during our in vivo experiments and thus led to severe pain and stress, we performed these experiments with anesthetized animals. Such problems will have minor consequences while treating breast tumors, because of the longer distance of the breast to the vital organs (eg, liver, spleen, and heart).

The extent of SDs in Figure 5 is attributed to interindividual or intertumoral variations in magnetite particle distribution in the target tissue. To obtain a reproducible intratumoral tissue load for refined heat-focusing requirements, the techniques of magnetite particles at the target have to be improved. In comparison to our approach, for example, the technique of Jordan et al (19) involved the insertion of multiple needles into intramuscularly implanted mammary carcinomas (C3H) in mice. That technique may be suitable for treatment of breast tumors that are in close proximity to the skin but inappropriate for lesions in the breast core.

Figures 6 and 7 illustrate the effectiveness of using magnetic heating of tumor tissue with the described parameters. Tumor shrinkage was attributed to intercellular fluid losses that were caused by cell membrane ruptures. The deterioration of areas of underlying liver tissue could have been the result of extratumoral localization of magnetite particles, which may have led to a shift in the heating focus toward the torso, with a pronounced heating extension in underlying organs such as the liver. The proposed method has a high cell-killing potential: The findings of chromatin margination along the nuclear envelope and nuclear pyknosis (Figure 7) are known to be early symptoms of the onset of cell death (33).

On the basis of our study data, tumors with volumes of approximately 300 mm3 can be heated. No potential problems with heating larger tissue volumes (eg, >=1,000 mm3) are expected if there is proper regulation of the magnetite mass and the intratumoral particle distribution.

A possible limitation of the described technique is in the accurate localization of tumor margins at imaging. This problem could be circumvented by heating an additional small fringe of normal tissue around the tumor. Moreover, there is a need to find out which of the currently available imaging methods is most appropriate for refined temperature monitoring during magnetic heating of tumors.

On the basis of experiences with other thermoablation techniques (34), no serious systemic side effects from oncologic treatments (eg, nausea or radiation pneumonitis) are expected, and treatment could be focused directly in the tumorous area. Possible disadvantages are the induction of skin damages in superficially located tumors and difficulties in heating hypervascular tumors to therapeutic temperatures and in the intratumoral treatment of highly multifocal tumors with iron oxides.

Practical application: Although some issues still need to be elucidated, our study results show that by using specific parameters—for example, magnetic material, magnetic field characteristics, and exposure times—it may be possible in future interventional radiologic treatments to destroy breast tumors by using magnetic heating.


   ACKNOWLEDGMENTS
 
The authors thank Marlies Fleck, MD, of the Institute of Diagnostic and Interventional Radiology, Clinics of Friederich Schiller University, Jena, for helpful discussions and Doreen Schröder for valuable technical assistance.


   FOOTNOTES
 
Abbreviation: SAR = specific absorption rate

Author contributions: Guarantors of integrity of entire study, R. Hergt, W.A., I.H., W.A.K.; study concepts, H.S., I.H.; study design, I.H.; definition of intellectual content, I.H.; literature research, R. Hergt, I.H., R. Hiergeist, W.A.; experimental studies, R. Hiergeist, I.H.; data acquisition, I.H.; data analysis, H.S., R. Hergt, R. Hiergeist, I.H., W.A.; manuscript preparation and editing, I.H.; manuscript revision/review, R. Hergt, W.A.; manuscript final approval, W.A.K.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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I. Hilger, A. Rapp, K.-O. Greulich, and W. A. Kaiser
Assessment of DNA Damage in Target Tumor Cells after Thermoablation in Mice
Radiology, November 1, 2005; 237(2): 500 - 506.
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