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A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis.

Jiang X, Yuan L, Engelbach JA, Cates J, Perez-Torres CJ, Gao F, Thotala D, Drzymala RE, Schmidt RE, Rich KM, Hallahan DE, Ackerman JJ, Garbow JR - PLoS ONE (2015)

Bottom Line: MRI measurements demonstrate that TRD is a more important determinant of both time-to-onset and progression of RN than fractionation.A semi-quantitative (0 to 3) histologic grading system, capturing both the extent and severity of injury, is described and illustrated.MR imaging provides reliable quantification of the necrotic volume that correlates well with histologic score.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Washington University, St. Louis, Missouri, United States of America.

ABSTRACT

Purpose: To develop a Gamma Knife-based mouse model of late time-to-onset, cerebral radiation necrosis (RN) with serial evaluation by magnetic resonance imaging (MRI) and histology.

Methods and materials: Mice were irradiated with the Leksell Gamma Knife® (GK) PerfexionTM (Elekta AB; Stockholm, Sweden) with total single-hemispheric radiation doses (TRD) of 45- to 60-Gy, delivered in one to three fractions. RN was measured using T2-weighted MR images, while confirmation of tissue damage was assessed histologically by hematoxylin & eosin, trichrome, and PTAH staining.

Results: MRI measurements demonstrate that TRD is a more important determinant of both time-to-onset and progression of RN than fractionation. The development of RN is significantly slower in mice irradiated with 45-Gy than 50- or 60-Gy, where RN development is similar. Irradiated mouse brains demonstrate all of the pathologic features observed clinically in patients with confirmed RN. A semi-quantitative (0 to 3) histologic grading system, capturing both the extent and severity of injury, is described and illustrated. Tissue damage, as assessed by a histologic score, correlates well with total necrotic volume measured by MRI (correlation coefficient = 0.948, with p<0.0001), and with post-irradiation time (correlation coefficient = 0.508, with p<0.0001).

Conclusions: Following GK irradiation, mice develop late time-to-onset cerebral RN histology mirroring clinical observations. MR imaging provides reliable quantification of the necrotic volume that correlates well with histologic score. This mouse model of RN will provide a platform for mechanism of action studies, the identification of imaging biomarkers of RN, and the development of clinical studies for improved mitigation and neuroprotection.

No MeSH data available.


Related in: MedlinePlus

Gamma-Knife dose radiation contours superimposed on a CT image of a mouse.Panels A, B, and C show sagittal, coronal, and transaxial views, respectively. The three contours shown are at 75% (yellow), 50% (green), and 25% (orange) isodose. The red cross-hairs in each panel identify the location of the imaging planes shown in the other two panels.
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pone.0139596.g001: Gamma-Knife dose radiation contours superimposed on a CT image of a mouse.Panels A, B, and C show sagittal, coronal, and transaxial views, respectively. The three contours shown are at 75% (yellow), 50% (green), and 25% (orange) isodose. The red cross-hairs in each panel identify the location of the imaging planes shown in the other two panels.

Mentions: Six-to-eight week old, female Balb/c mice (Harlan; Indianapolis, IN) were used for the study and observed daily and weighed weekly to ensure that interventions were well tolerated. Mice were irradiated with the Leksell Gamma Knife® (GK) Perfexion™ (Elekta AB; Stockholm, Sweden; http://www.elekta.com/). They were supported on a specially designed platform mounted to the stereotactic frame that attaches to the treatment couch of the GK. Mice were anesthetized with a mixture of ketamine (25 mg/kg), acepromazine (5 mg/kg) and xylazine (5 mg/kg), injected intraperitoneally 5 min before the start of irradiation. Fig 1 shows Gamma Knife radiation isodose contours modeled using the GammaPlan® treatment planning system and superimposed on the CT image of a mouse on the platform. The isodoses result from an irradiation using the 4 mm collimator aperture of the GK with all 192 sources focused on a single stereotactic position, whose location depends on the position of the mouse on the platform. This dose distribution illustrates that radiation is effectively concentrated to a single hemisphere of the mouse brain, and is greatly reduced in other radiation-sensitive anatomy, including the eyes or esophagus.


A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis.

Jiang X, Yuan L, Engelbach JA, Cates J, Perez-Torres CJ, Gao F, Thotala D, Drzymala RE, Schmidt RE, Rich KM, Hallahan DE, Ackerman JJ, Garbow JR - PLoS ONE (2015)

Gamma-Knife dose radiation contours superimposed on a CT image of a mouse.Panels A, B, and C show sagittal, coronal, and transaxial views, respectively. The three contours shown are at 75% (yellow), 50% (green), and 25% (orange) isodose. The red cross-hairs in each panel identify the location of the imaging planes shown in the other two panels.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595209&req=5

pone.0139596.g001: Gamma-Knife dose radiation contours superimposed on a CT image of a mouse.Panels A, B, and C show sagittal, coronal, and transaxial views, respectively. The three contours shown are at 75% (yellow), 50% (green), and 25% (orange) isodose. The red cross-hairs in each panel identify the location of the imaging planes shown in the other two panels.
Mentions: Six-to-eight week old, female Balb/c mice (Harlan; Indianapolis, IN) were used for the study and observed daily and weighed weekly to ensure that interventions were well tolerated. Mice were irradiated with the Leksell Gamma Knife® (GK) Perfexion™ (Elekta AB; Stockholm, Sweden; http://www.elekta.com/). They were supported on a specially designed platform mounted to the stereotactic frame that attaches to the treatment couch of the GK. Mice were anesthetized with a mixture of ketamine (25 mg/kg), acepromazine (5 mg/kg) and xylazine (5 mg/kg), injected intraperitoneally 5 min before the start of irradiation. Fig 1 shows Gamma Knife radiation isodose contours modeled using the GammaPlan® treatment planning system and superimposed on the CT image of a mouse on the platform. The isodoses result from an irradiation using the 4 mm collimator aperture of the GK with all 192 sources focused on a single stereotactic position, whose location depends on the position of the mouse on the platform. This dose distribution illustrates that radiation is effectively concentrated to a single hemisphere of the mouse brain, and is greatly reduced in other radiation-sensitive anatomy, including the eyes or esophagus.

Bottom Line: MRI measurements demonstrate that TRD is a more important determinant of both time-to-onset and progression of RN than fractionation.A semi-quantitative (0 to 3) histologic grading system, capturing both the extent and severity of injury, is described and illustrated.MR imaging provides reliable quantification of the necrotic volume that correlates well with histologic score.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Washington University, St. Louis, Missouri, United States of America.

ABSTRACT

Purpose: To develop a Gamma Knife-based mouse model of late time-to-onset, cerebral radiation necrosis (RN) with serial evaluation by magnetic resonance imaging (MRI) and histology.

Methods and materials: Mice were irradiated with the Leksell Gamma Knife® (GK) PerfexionTM (Elekta AB; Stockholm, Sweden) with total single-hemispheric radiation doses (TRD) of 45- to 60-Gy, delivered in one to three fractions. RN was measured using T2-weighted MR images, while confirmation of tissue damage was assessed histologically by hematoxylin & eosin, trichrome, and PTAH staining.

Results: MRI measurements demonstrate that TRD is a more important determinant of both time-to-onset and progression of RN than fractionation. The development of RN is significantly slower in mice irradiated with 45-Gy than 50- or 60-Gy, where RN development is similar. Irradiated mouse brains demonstrate all of the pathologic features observed clinically in patients with confirmed RN. A semi-quantitative (0 to 3) histologic grading system, capturing both the extent and severity of injury, is described and illustrated. Tissue damage, as assessed by a histologic score, correlates well with total necrotic volume measured by MRI (correlation coefficient = 0.948, with p<0.0001), and with post-irradiation time (correlation coefficient = 0.508, with p<0.0001).

Conclusions: Following GK irradiation, mice develop late time-to-onset cerebral RN histology mirroring clinical observations. MR imaging provides reliable quantification of the necrotic volume that correlates well with histologic score. This mouse model of RN will provide a platform for mechanism of action studies, the identification of imaging biomarkers of RN, and the development of clinical studies for improved mitigation and neuroprotection.

No MeSH data available.


Related in: MedlinePlus