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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

MRI-derived necrotic volumes.Mean volumes ± SD (n = 15), vs. time post-irradiation for mice irradiated hemispherically with different dose schedules: 60-Gy in 1 fraction (red), 60-Gy in 3 fractions (green), 50-Gy in 1 fraction (black) and 45-Gy in 1 fraction (blue).
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pone.0139596.g003: MRI-derived necrotic volumes.Mean volumes ± SD (n = 15), vs. time post-irradiation for mice irradiated hemispherically with different dose schedules: 60-Gy in 1 fraction (red), 60-Gy in 3 fractions (green), 50-Gy in 1 fraction (black) and 45-Gy in 1 fraction (blue).

Mentions: Fig 3 shows the progressions of the volumes of MRI-derived necrotic regions for irradiated mice, in which mice received four different radiation dose schedules, including 60-Gy in a single fraction (red), 60-Gy in three fractions (green), 50-Gy in a single fraction (black), 45-Gy in a single fraction (blue). Mice that received either 60-Gy or 50-Gy of radiation developed RN 4 weeks post irradiation and had significant, expansive RN (>30% of the volume of the irradiated hemisphere), as determined by anatomic MRI, at approximately 13 weeks post irradiation. While time-to-onset of necrosis following 45-Gy irradiation delivered in a single fraction occurs much later than with 60-/50-Gy irradiation, the pattern of injury progression following onset is similar.


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)

MRI-derived necrotic volumes.Mean volumes ± SD (n = 15), vs. time post-irradiation for mice irradiated hemispherically with different dose schedules: 60-Gy in 1 fraction (red), 60-Gy in 3 fractions (green), 50-Gy in 1 fraction (black) and 45-Gy in 1 fraction (blue).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139596.g003: MRI-derived necrotic volumes.Mean volumes ± SD (n = 15), vs. time post-irradiation for mice irradiated hemispherically with different dose schedules: 60-Gy in 1 fraction (red), 60-Gy in 3 fractions (green), 50-Gy in 1 fraction (black) and 45-Gy in 1 fraction (blue).
Mentions: Fig 3 shows the progressions of the volumes of MRI-derived necrotic regions for irradiated mice, in which mice received four different radiation dose schedules, including 60-Gy in a single fraction (red), 60-Gy in three fractions (green), 50-Gy in a single fraction (black), 45-Gy in a single fraction (blue). Mice that received either 60-Gy or 50-Gy of radiation developed RN 4 weeks post irradiation and had significant, expansive RN (>30% of the volume of the irradiated hemisphere), as determined by anatomic MRI, at approximately 13 weeks post irradiation. While time-to-onset of necrosis following 45-Gy irradiation delivered in a single fraction occurs much later than with 60-/50-Gy irradiation, the pattern of injury progression following onset is similar.

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