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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

Histologic scores correlate with MR-derived necrotic volumes and post-irradiation time.A. Correlation between MR-derived necrotic volumes and histological scores. MR-derived volumes, mean ± SD (n = 30, 37, 27, and 53 for Grade 0, 1, 2, and 3, respectively), of radiation necrosis vs. histological score for irradiated mice, independent of specific radiation dose (45–60 Gy) and treatment schedules. B. Correlation between histological scores and time post irradiation. Box-and-whisker plots of the histological scores for mice receiving 50/60-Gy of radiation, at 4, 8, and 13 weeks post irradiation. The 25th-75th percentiles are blocked by the box, the band inside the box is the mean, and the whiskers mark the maximum and minimum values.
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pone.0139596.g006: Histologic scores correlate with MR-derived necrotic volumes and post-irradiation time.A. Correlation between MR-derived necrotic volumes and histological scores. MR-derived volumes, mean ± SD (n = 30, 37, 27, and 53 for Grade 0, 1, 2, and 3, respectively), of radiation necrosis vs. histological score for irradiated mice, independent of specific radiation dose (45–60 Gy) and treatment schedules. B. Correlation between histological scores and time post irradiation. Box-and-whisker plots of the histological scores for mice receiving 50/60-Gy of radiation, at 4, 8, and 13 weeks post irradiation. The 25th-75th percentiles are blocked by the box, the band inside the box is the mean, and the whiskers mark the maximum and minimum values.

Mentions: Consistent with the earliest appearance of hyperintensity in MR images, tissue damage was first noted at three to four weeks post radiation in animals that received a single fraction of 50- or 60-Gy of radiation. By histologic examination, no specific changes suggestive of radiation injury were observed at earlier post-irradiation time points. For each graded histology slide, the MR-derived necrotic volume was calculated from the T2-weighted image for a single slice, covering the same anatomic features as the histological slide. The average MR-derived necrotic volumes vs. histological scores are plotted in Fig 6A. The two measures are highly correlated (correlation coefficient = 0.948, with p<0.0001) and the differences among the four cohorts (n = 30, 37, 27, and 53 for Grade 0, 1, 2, and 3, respectively) are all statistically significant (p<0.0001). Further, the correlation between histological score and time post irradiation (correlation coefficient = 0.508, with p<0.0001) is displayed in Fig 6B. The differences among the three cohorts (n = 17, 15, and 20 for 4, 8, and 13 weeks following 50/60-Gy of radiation) are all statistically significant (p<0.0001). These strong correlations help to validate the MR results and demonstrate that the histologic grading system is a useful tool for the classification of the severity of radiation necrosis.


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)

Histologic scores correlate with MR-derived necrotic volumes and post-irradiation time.A. Correlation between MR-derived necrotic volumes and histological scores. MR-derived volumes, mean ± SD (n = 30, 37, 27, and 53 for Grade 0, 1, 2, and 3, respectively), of radiation necrosis vs. histological score for irradiated mice, independent of specific radiation dose (45–60 Gy) and treatment schedules. B. Correlation between histological scores and time post irradiation. Box-and-whisker plots of the histological scores for mice receiving 50/60-Gy of radiation, at 4, 8, and 13 weeks post irradiation. The 25th-75th percentiles are blocked by the box, the band inside the box is the mean, and the whiskers mark the maximum and minimum values.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139596.g006: Histologic scores correlate with MR-derived necrotic volumes and post-irradiation time.A. Correlation between MR-derived necrotic volumes and histological scores. MR-derived volumes, mean ± SD (n = 30, 37, 27, and 53 for Grade 0, 1, 2, and 3, respectively), of radiation necrosis vs. histological score for irradiated mice, independent of specific radiation dose (45–60 Gy) and treatment schedules. B. Correlation between histological scores and time post irradiation. Box-and-whisker plots of the histological scores for mice receiving 50/60-Gy of radiation, at 4, 8, and 13 weeks post irradiation. The 25th-75th percentiles are blocked by the box, the band inside the box is the mean, and the whiskers mark the maximum and minimum values.
Mentions: Consistent with the earliest appearance of hyperintensity in MR images, tissue damage was first noted at three to four weeks post radiation in animals that received a single fraction of 50- or 60-Gy of radiation. By histologic examination, no specific changes suggestive of radiation injury were observed at earlier post-irradiation time points. For each graded histology slide, the MR-derived necrotic volume was calculated from the T2-weighted image for a single slice, covering the same anatomic features as the histological slide. The average MR-derived necrotic volumes vs. histological scores are plotted in Fig 6A. The two measures are highly correlated (correlation coefficient = 0.948, with p<0.0001) and the differences among the four cohorts (n = 30, 37, 27, and 53 for Grade 0, 1, 2, and 3, respectively) are all statistically significant (p<0.0001). Further, the correlation between histological score and time post irradiation (correlation coefficient = 0.508, with p<0.0001) is displayed in Fig 6B. The differences among the three cohorts (n = 17, 15, and 20 for 4, 8, and 13 weeks following 50/60-Gy of radiation) are all statistically significant (p<0.0001). These strong correlations help to validate the MR results and demonstrate that the histologic grading system is a useful tool for the classification of the severity of radiation necrosis.

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