378
Surg Neurol 1990;34:378-82
Magnetic Resonance Imaging of Experimental Rat Brain Tumors: Histopathological Evaluation Takehiko Chihiro
Baba, M.D., Masashi Moriguchi, Katsuki,
M.D., Tooru
Inoue,
M.D., Yoshihiro
M.D., and Masashi Fukui,
Department of Neurosurgery, Neurological Institute, Katsuki Neurosurgical Clinic, Fukuoka, Japan
Faculty of Medicine,
Baba T, Moriguchi M, Natori Y, Katsuki C, Inoue T, Fukui M. Magnetic resonance imaging of experimental rat brain tumors: histopathological evaluation. Surg Neural 1990;34:378-82.
Using RG-C6 glioma-transplanted rats, we studied precontrast and postcontrast magnetic resonance imaging, extravasation of Evans blue, and histology. In all rats, tumor was enhanced with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). The necrotic portion in the tumor, however, was not enhanced. Hemorrhage and hydrocephalus were clearly visualized on both the images. Blood-brain and postcontrast precontrast barrier-disrupted areas stained with Evans blue and areas enhanced with Gd-DTPA on magnetic resonance imaging were nearly consistent. It is suggested that the mechanism of brain tumor enhancement with Gd-DTPA on magnetic resonance imaging is simply related to the degree of alteration of the blood-brain barrier. The Gd-DTPAenhanced magnetic resonance imaging, even with low magnetic field, is useful for the evaluation of size, shape, and location of experimental rat brain tumors. KEY WORDS: Magnetic ylenetriaminepentaacetic
resonance imaging; Gadolinium-diethbaracid; Evans blue; Blood-brain
rier; Rat; RG-C6 glioma
Gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) is an effective contrast agent for magnetic resonance imaging (MRI) and is widely used for detecting brain tumors. This contrast agent is primarily an enhancer of increased blood-brain barrier (BBB) permeability [2,8]. Thus, it is considered that enhancement of brain tumor is also related to the altered BBB, but the mechanism has not been precisely revealed. Therefore, the present study was designed to determine whether it is completely due to BBB disruption or to other factors
Addrea reprint req.vesfsto: Yoshihiro Natori, M.D., Department of Neurosurgery, Neurological Institute, Kyushu University 60, 3-I-1, Maidashi, Higashi-ku, Fukuoka 812, Japan. Received November 24, 1989; accepted May 25,199O. 0 1990 by Elsevier Science Publishmg Co., Inc.
Natori,
Kyushu
M.D.,
M.D. University,
and
that may also be related. We used RG-C6 glioma, for which the BBB is known to be disrupted [1,5]. We compared precontrast and postcontrast MRIs, extravasation of Evans blue (EB), and histology of the tumors. There are a few reports on rat brain tumors examined with a high-field MRI system [6,-i]. However, no one has reported on rat brain tumors using a low-field MRI system, which is clinically more commonly used. Our second aim is to study whether low-field MRI is useful for evaluation of size, shape, and location of rat experimental brain tumors, and, if useful, when is the most suitable time for examination after transplantation.
Materials
and Methods
Tumor Inoculation Twenty-two male Wistar rats, weighing 250-300 g, were used for the experiment. The RG-C6 tumor cells were kept frozen until use, then thawed and grown in Eagle’s minimum essential medium with 1Oyo fetal calf serum for 72 hours. Tumor cells (5 x lo5 in 5 PL solution) were injected into the right cerebral hemisphere of rats with a Hamilton syringe.
Experimental
Design
Magnetic resonance imaging was obtained- 6-34 days after tumor inoculation. One to six examinations were performed for each rat, and each examination included both precontrast and postcontrast scans with Gd-DTPA.
Magnetic Resonance Imaging Study The rats were anesthetized with intraperitoneal pentobarbital (50 mUkg), placed in an animal holder built of nonmagnetic materials, and then placed in the magnet. First, a precontrast MRI was obtained. Next, Gd-DTPA (0.25 mmol/kg) was intraperitoneally injected. Immediately after that, a repeated MRI was obtained. 0090.1019190/$~.50
MRI of Rat Brain Tumors
Surg Neurol 1990;34:378-82
379
D
Figure 1. Tumor with central necrosis. (A) The tumor is isointense on the precontrast MRI (FISP 50122; frip angle 90”). (B)PostcontrastMRI shows ringlike enhancement. (Cj Evans blue dye study shows grade 2 + ringlike staining (m). (D) Histological section (hematoxylin and eosin stain). All of them are from the same rat.
All imaging experiments were performed on a 0.1-T MRI system (Asahi Mark-J, Siemens-Asahi Medical) with a 7-cm-diameter, 8-cm-long, eight-turned spiral coil, which had a nominal spatial resolution of 1 mm in the section imaged. Coronal section at the tumorimplanted region was obtained. Single-sliced section was 5 mm thick. All images were produced using FISP (TR 50 ms, TE 22 ms, frip angle 90”). Images of the series were acquired with two averages using a 256 X 256 matrix, and processed with 10 averages to afford 5 12 x 5 12 pixel images.
Evans Blue Dye and Histological Stzldies In all rats except three, EB 2% (2 mIfkg) was administered intravenously through the right femoral vein after the last postcontrast scan. The rats were decapitated 60 minutes after EB injection. After removal of the brain, the specimens were coronally sectioned. Intensity of tumor staining with EB was evaluated by direct visual observation and graded as follows 151: Grade 0, no staining; grade 2 + , staining; grade 1 + , just noticeable extensive light staining; grade 3 +, extensive deep staining. The specimens were fixed with 10% formalin, sectioned, and stained with hematoxylin and eosin. Size of tumors was measured on both the MRIs and histological specimens, and they were compared with each other. To evaluate tumor size, tumor area was calculated in the section at the level of the bregma.
380
Surg Neural 1990;34:378-82
B
Results Magnetic Resonance lmaging Study In all rats, the tumors were isointense on the preenhanced MRI and enhanced with Gd-DTPA. Necrosis was seen in seven rats, and the necrotic portion in the tumor was not enhanced with GQDTPA (Figure 1). Hemorrhage was seen in three rats, and identified as a hyperintense lesion on preenhanced image (Figure 2). Hydrocephalus due to disseminated tumor was seen in six rats. Dilated lateral ventricles were clearly visualized as hypointense areas on the precontrast image, and the disseminated tumor was enhanced with Gd-DTPA (Figure 3). These images indicated that they were relatively Tl-weighted. The time course of tumor visualization is shown in Table 1.
Baba et al
D
Figure 2. Tumor with intwtumoral hemorrhage. (A) Precontra~t MRI shows hemorrhage in the tumor (FISP 50122; frip angle 90”). (B) Postcontrast MRI shows homogeneous enhancement of the tumor. (C) Evans blue dye study shows grade 2 + staining (m), except hemorrhage @). (D) Histologica[Jection (bematoxylin and eosin stain). All of them are from the Same rat.
Evans Bhe Dye Stzldy In 19 rats, an EB dye study was performed. In three rats, the tumors were partly stained in grade 1+ and partly not stained. In the other rats, the tumors were homogeneously stained, except for the necrotic portion or hemorrhage; grade 1 + in nine and grade 2 + in seven. The ipsilateral hemisphere outside of the tumor and the contralateral hemisphere were not stained in all cases.
MRI of Rat Brain Tumors
Surg Neurol 1990;34:378-82
381
B
Figure 3. Hydrocephalus with disseminated tumor. dilated ventricle (PISP 5012.2; frip angle 90”). shows
(A) Precontrast MRI (B) Postcontrast MRI
shows enhanced small tumor, adjacent to the ventricle. (C) Evans blue dye study shows the partly stained tumor (grade I +) (s). (D) Histological section shows that the tumor has an area that is not stained with Evans blue (bematoxylin and eosin stain). All of them are from the same rat.
Discussion Blood-brain barrier-disrupted areas stained with EB and areas enhanced with Gd-DTPA on MRI were nearly consistent. On the other hand, histologically demon-
Table 1. Time Course of Tumor Visualization
Tumor Size Tumor sizes were compared between the MRIs and histopathological specimens. The size ratio of MRI to specimen was 1.11 + 0.44 (mean 2 SD). In 13 rats, MRI overestimated tumor size. In four rats, MRI and specimen were equal in size. In five rats, MRI underestimated tumor size. The three rats in which brain tumors were only partly stained with EB belonged to the underestimated subgroup. The time course of tumor size on MRI is shown in Figure 4.
Magnetic
on
Resonance Imaging
Days after tumor inoculation
Examined number
Tumor
visualization on MRI
0 (0%)
51 8-14
t
15-17
11
1(17%)
6 (55%)
18-21
19
13 (68%)
22-24 25-28
18
17 (94%)
11
10 (91%)
229
5
Abbreviation: MRI, magnetic resonance imaging.
5 (100%)
382
Baba et al
Surg Neurol 1990;34:378-82
turn01 size (mm2
n=ll
h n=5
n=18
were still asymptomatic. Fourth, hemorrhage and hydrocephalus are also clearly visualized. When rats in this condition are not suitable for experimentation, we can exclude them before we begin. Gadolinium-diethylenetriaminepentaacetic acid is reported to be a safe contrast agent, and is expected to have minimal side effects. Intraperitoneal injection for experimental animals is technically easy to apply. For these reasons, Gd-DTPA-enhanced MRI with a low magnetic field is also useful for examination of animal brain tumors in vivo.
n=6 n=l
Conclusion
I
days
after
tumor
inoculation
Figure 4. Time course of tumor size on MRI. Tumor Jize is represented by area calculated in the section at the level of the bregma.
tumor tissue, in which the BBB was preserved, that is, not stained with EB, was not visualized on GdDTPA-enhanced MRIs. Therefore, it is suggested that the mechanism of brain tumor enhancement with GdDTPA on MRI is simply related to the degree of alteration of the BBB. It is reported that Gd-DTPA can clarify the border between the tumor tissue and perifocal edema [3,4}. In our series, however, tumor size on MRI tended to be larger than it really was. We suppose this result is not because the perifocal edema was enhanced by GdDTPA, but simply because a nominal spatial resolution of the MRI system used in this experiment was relatively large, considering the tumor size. Results from this study also provide some advantages of using Gd-DTPA-enhanced MRI in animal brain tumor experiments. First, the time course of tumor progression can be easily demonstrated. Second, accurate location and extent of tumor can be determined without killing the animals. Third, we can use asymptomatic animals after tumor transplantation, whose physiological condition is stable and suitable for experiments. In our series, almost 100% of the intracerebrally transplanted tumors were visualized by MRI in the fourth week (Figure 4 and Table 1). In this stage, however, most rats strated
The results from our study suggest that the mechanism of brain tumor enhancement with Gd-DTPA on MRI is simply related to the degree of alteration of the BBB. The Gd-DTPA-enhanced MRI using a low magnetic field is also useful for animal brain tumor experiments. In our series, the fourth week after transplantation is the most suitable time for examination. The authors thank Miss Chieko Kubo for technical
assistance.
References and 1. Benda P, Someda K, Messer J, Sweet WH. Morphological immunochemical studies of rat glial tumors and clonal strains propagated in culture. J Neurosurg 197 1;34:3 10-23. 2. Brasch RC, Weinmann HJ, Wesby GE. Contrast-enhanced NMR imaging: animal studies using gadolinium-DTPA complex. AJR 1984;142:625-30. HP, Young IR. 3. Bydder GM, Kingsley DPE, Brown J, Niendorf MR imaging of meningiomas including studies with and without gadolinium-DTPA. J Comput Assist Tomogr 1985;9:690-7. 4. Felix R, Schorner W, Laniado M, Niendorf HP, Claussen C, Fiegler W, Speck U. Brain tumors: MR imaging with gadolinium-DTPA. Radiology 1985;156:681-8. 5. Inoue T, Fukui M, Nishio S, Kitamura K, Nagara H. Hyperosmotic blood-brain barrier disruption in brains of rats with an intracerebrally transplanted RG-C6 tumor. J Neurosurg 1987;66:256-63. 6. Ross BD, Higgins RJ, Boggan JE, Knittel B, Garwood M. 3’P NMR spectroscopy of the in vivo metabolism of an intracerebral glioma in the rat. Magn Reson Med 1988;6:403-17. 7. Runge VM, Jacobson S, Wood ML, Kaufman S, Adelman imaging of rat brain glioma: Gd-DTPA versus Gd-DOTA. ogy 1988;166:835-8.
LS. MR Radiol-
8. Runge VM, Price AC, Wehr CJ, Atkinson JB, Tweedle MF. Contrast enhanced MRI: evaluation of a canine model of osmotic blood-brain barrier disruption. Invest Radio1 1985;20:830-44.
Surg Neurol 1990;34:378-82
Magnetic Resonance Imaging of Experimental Rat Brain Tumors: Histopathological Evaluation Takehiko Chihiro
Baba, M.D., Masashi Moriguchi, Katsuki,
M.D., Tooru
Inoue,
M.D., Yoshihiro
M.D., and Masashi Fukui,
Department of Neurosurgery, Neurological Institute, Katsuki Neurosurgical Clinic, Fukuoka, Japan
Faculty of Medicine,
Baba T, Moriguchi M, Natori Y, Katsuki C, Inoue T, Fukui M. Magnetic resonance imaging of experimental rat brain tumors: histopathological evaluation. Surg Neural 1990;34:378-82.
Using RG-C6 glioma-transplanted rats, we studied precontrast and postcontrast magnetic resonance imaging, extravasation of Evans blue, and histology. In all rats, tumor was enhanced with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). The necrotic portion in the tumor, however, was not enhanced. Hemorrhage and hydrocephalus were clearly visualized on both the images. Blood-brain and postcontrast precontrast barrier-disrupted areas stained with Evans blue and areas enhanced with Gd-DTPA on magnetic resonance imaging were nearly consistent. It is suggested that the mechanism of brain tumor enhancement with Gd-DTPA on magnetic resonance imaging is simply related to the degree of alteration of the blood-brain barrier. The Gd-DTPAenhanced magnetic resonance imaging, even with low magnetic field, is useful for the evaluation of size, shape, and location of experimental rat brain tumors. KEY WORDS: Magnetic ylenetriaminepentaacetic
resonance imaging; Gadolinium-diethbaracid; Evans blue; Blood-brain
rier; Rat; RG-C6 glioma
Gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) is an effective contrast agent for magnetic resonance imaging (MRI) and is widely used for detecting brain tumors. This contrast agent is primarily an enhancer of increased blood-brain barrier (BBB) permeability [2,8]. Thus, it is considered that enhancement of brain tumor is also related to the altered BBB, but the mechanism has not been precisely revealed. Therefore, the present study was designed to determine whether it is completely due to BBB disruption or to other factors
Addrea reprint req.vesfsto: Yoshihiro Natori, M.D., Department of Neurosurgery, Neurological Institute, Kyushu University 60, 3-I-1, Maidashi, Higashi-ku, Fukuoka 812, Japan. Received November 24, 1989; accepted May 25,199O. 0 1990 by Elsevier Science Publishmg Co., Inc.
Natori,
Kyushu
M.D.,
M.D. University,
and
that may also be related. We used RG-C6 glioma, for which the BBB is known to be disrupted [1,5]. We compared precontrast and postcontrast MRIs, extravasation of Evans blue (EB), and histology of the tumors. There are a few reports on rat brain tumors examined with a high-field MRI system [6,-i]. However, no one has reported on rat brain tumors using a low-field MRI system, which is clinically more commonly used. Our second aim is to study whether low-field MRI is useful for evaluation of size, shape, and location of rat experimental brain tumors, and, if useful, when is the most suitable time for examination after transplantation.
Materials
and Methods
Tumor Inoculation Twenty-two male Wistar rats, weighing 250-300 g, were used for the experiment. The RG-C6 tumor cells were kept frozen until use, then thawed and grown in Eagle’s minimum essential medium with 1Oyo fetal calf serum for 72 hours. Tumor cells (5 x lo5 in 5 PL solution) were injected into the right cerebral hemisphere of rats with a Hamilton syringe.
Experimental
Design
Magnetic resonance imaging was obtained- 6-34 days after tumor inoculation. One to six examinations were performed for each rat, and each examination included both precontrast and postcontrast scans with Gd-DTPA.
Magnetic Resonance Imaging Study The rats were anesthetized with intraperitoneal pentobarbital (50 mUkg), placed in an animal holder built of nonmagnetic materials, and then placed in the magnet. First, a precontrast MRI was obtained. Next, Gd-DTPA (0.25 mmol/kg) was intraperitoneally injected. Immediately after that, a repeated MRI was obtained. 0090.1019190/$~.50
MRI of Rat Brain Tumors
Surg Neurol 1990;34:378-82
379
D
Figure 1. Tumor with central necrosis. (A) The tumor is isointense on the precontrast MRI (FISP 50122; frip angle 90”). (B)PostcontrastMRI shows ringlike enhancement. (Cj Evans blue dye study shows grade 2 + ringlike staining (m). (D) Histological section (hematoxylin and eosin stain). All of them are from the same rat.
All imaging experiments were performed on a 0.1-T MRI system (Asahi Mark-J, Siemens-Asahi Medical) with a 7-cm-diameter, 8-cm-long, eight-turned spiral coil, which had a nominal spatial resolution of 1 mm in the section imaged. Coronal section at the tumorimplanted region was obtained. Single-sliced section was 5 mm thick. All images were produced using FISP (TR 50 ms, TE 22 ms, frip angle 90”). Images of the series were acquired with two averages using a 256 X 256 matrix, and processed with 10 averages to afford 5 12 x 5 12 pixel images.
Evans Blue Dye and Histological Stzldies In all rats except three, EB 2% (2 mIfkg) was administered intravenously through the right femoral vein after the last postcontrast scan. The rats were decapitated 60 minutes after EB injection. After removal of the brain, the specimens were coronally sectioned. Intensity of tumor staining with EB was evaluated by direct visual observation and graded as follows 151: Grade 0, no staining; grade 2 + , staining; grade 1 + , just noticeable extensive light staining; grade 3 +, extensive deep staining. The specimens were fixed with 10% formalin, sectioned, and stained with hematoxylin and eosin. Size of tumors was measured on both the MRIs and histological specimens, and they were compared with each other. To evaluate tumor size, tumor area was calculated in the section at the level of the bregma.
380
Surg Neural 1990;34:378-82
B
Results Magnetic Resonance lmaging Study In all rats, the tumors were isointense on the preenhanced MRI and enhanced with Gd-DTPA. Necrosis was seen in seven rats, and the necrotic portion in the tumor was not enhanced with GQDTPA (Figure 1). Hemorrhage was seen in three rats, and identified as a hyperintense lesion on preenhanced image (Figure 2). Hydrocephalus due to disseminated tumor was seen in six rats. Dilated lateral ventricles were clearly visualized as hypointense areas on the precontrast image, and the disseminated tumor was enhanced with Gd-DTPA (Figure 3). These images indicated that they were relatively Tl-weighted. The time course of tumor visualization is shown in Table 1.
Baba et al
D
Figure 2. Tumor with intwtumoral hemorrhage. (A) Precontra~t MRI shows hemorrhage in the tumor (FISP 50122; frip angle 90”). (B) Postcontrast MRI shows homogeneous enhancement of the tumor. (C) Evans blue dye study shows grade 2 + staining (m), except hemorrhage @). (D) Histologica[Jection (bematoxylin and eosin stain). All of them are from the Same rat.
Evans Bhe Dye Stzldy In 19 rats, an EB dye study was performed. In three rats, the tumors were partly stained in grade 1+ and partly not stained. In the other rats, the tumors were homogeneously stained, except for the necrotic portion or hemorrhage; grade 1 + in nine and grade 2 + in seven. The ipsilateral hemisphere outside of the tumor and the contralateral hemisphere were not stained in all cases.
MRI of Rat Brain Tumors
Surg Neurol 1990;34:378-82
381
B
Figure 3. Hydrocephalus with disseminated tumor. dilated ventricle (PISP 5012.2; frip angle 90”). shows
(A) Precontrast MRI (B) Postcontrast MRI
shows enhanced small tumor, adjacent to the ventricle. (C) Evans blue dye study shows the partly stained tumor (grade I +) (s). (D) Histological section shows that the tumor has an area that is not stained with Evans blue (bematoxylin and eosin stain). All of them are from the same rat.
Discussion Blood-brain barrier-disrupted areas stained with EB and areas enhanced with Gd-DTPA on MRI were nearly consistent. On the other hand, histologically demon-
Table 1. Time Course of Tumor Visualization
Tumor Size Tumor sizes were compared between the MRIs and histopathological specimens. The size ratio of MRI to specimen was 1.11 + 0.44 (mean 2 SD). In 13 rats, MRI overestimated tumor size. In four rats, MRI and specimen were equal in size. In five rats, MRI underestimated tumor size. The three rats in which brain tumors were only partly stained with EB belonged to the underestimated subgroup. The time course of tumor size on MRI is shown in Figure 4.
Magnetic
on
Resonance Imaging
Days after tumor inoculation
Examined number
Tumor
visualization on MRI
0 (0%)
51 8-14
t
15-17
11
1(17%)
6 (55%)
18-21
19
13 (68%)
22-24 25-28
18
17 (94%)
11
10 (91%)
229
5
Abbreviation: MRI, magnetic resonance imaging.
5 (100%)
382
Baba et al
Surg Neurol 1990;34:378-82
turn01 size (mm2
n=ll
h n=5
n=18
were still asymptomatic. Fourth, hemorrhage and hydrocephalus are also clearly visualized. When rats in this condition are not suitable for experimentation, we can exclude them before we begin. Gadolinium-diethylenetriaminepentaacetic acid is reported to be a safe contrast agent, and is expected to have minimal side effects. Intraperitoneal injection for experimental animals is technically easy to apply. For these reasons, Gd-DTPA-enhanced MRI with a low magnetic field is also useful for examination of animal brain tumors in vivo.
n=6 n=l
Conclusion
I
days
after
tumor
inoculation
Figure 4. Time course of tumor size on MRI. Tumor Jize is represented by area calculated in the section at the level of the bregma.
tumor tissue, in which the BBB was preserved, that is, not stained with EB, was not visualized on GdDTPA-enhanced MRIs. Therefore, it is suggested that the mechanism of brain tumor enhancement with GdDTPA on MRI is simply related to the degree of alteration of the BBB. It is reported that Gd-DTPA can clarify the border between the tumor tissue and perifocal edema [3,4}. In our series, however, tumor size on MRI tended to be larger than it really was. We suppose this result is not because the perifocal edema was enhanced by GdDTPA, but simply because a nominal spatial resolution of the MRI system used in this experiment was relatively large, considering the tumor size. Results from this study also provide some advantages of using Gd-DTPA-enhanced MRI in animal brain tumor experiments. First, the time course of tumor progression can be easily demonstrated. Second, accurate location and extent of tumor can be determined without killing the animals. Third, we can use asymptomatic animals after tumor transplantation, whose physiological condition is stable and suitable for experiments. In our series, almost 100% of the intracerebrally transplanted tumors were visualized by MRI in the fourth week (Figure 4 and Table 1). In this stage, however, most rats strated
The results from our study suggest that the mechanism of brain tumor enhancement with Gd-DTPA on MRI is simply related to the degree of alteration of the BBB. The Gd-DTPA-enhanced MRI using a low magnetic field is also useful for animal brain tumor experiments. In our series, the fourth week after transplantation is the most suitable time for examination. The authors thank Miss Chieko Kubo for technical
assistance.
References and 1. Benda P, Someda K, Messer J, Sweet WH. Morphological immunochemical studies of rat glial tumors and clonal strains propagated in culture. J Neurosurg 197 1;34:3 10-23. 2. Brasch RC, Weinmann HJ, Wesby GE. Contrast-enhanced NMR imaging: animal studies using gadolinium-DTPA complex. AJR 1984;142:625-30. HP, Young IR. 3. Bydder GM, Kingsley DPE, Brown J, Niendorf MR imaging of meningiomas including studies with and without gadolinium-DTPA. J Comput Assist Tomogr 1985;9:690-7. 4. Felix R, Schorner W, Laniado M, Niendorf HP, Claussen C, Fiegler W, Speck U. Brain tumors: MR imaging with gadolinium-DTPA. Radiology 1985;156:681-8. 5. Inoue T, Fukui M, Nishio S, Kitamura K, Nagara H. Hyperosmotic blood-brain barrier disruption in brains of rats with an intracerebrally transplanted RG-C6 tumor. J Neurosurg 1987;66:256-63. 6. Ross BD, Higgins RJ, Boggan JE, Knittel B, Garwood M. 3’P NMR spectroscopy of the in vivo metabolism of an intracerebral glioma in the rat. Magn Reson Med 1988;6:403-17. 7. Runge VM, Jacobson S, Wood ML, Kaufman S, Adelman imaging of rat brain glioma: Gd-DTPA versus Gd-DOTA. ogy 1988;166:835-8.
LS. MR Radiol-
8. Runge VM, Price AC, Wehr CJ, Atkinson JB, Tweedle MF. Contrast enhanced MRI: evaluation of a canine model of osmotic blood-brain barrier disruption. Invest Radio1 1985;20:830-44.
