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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

Pathological features in post-irradiation mouse brain.A. Micro-hemorrhage and dilated vessels (arrow, 20X); B. Hemorrhage (arrowheads) and fibrinoid vascular necrosis (arrows) (H&E staining, 20X); C. PTAH staining shows fibrinoid vascular necrosis in dark blue (arrows, 20X); D. Trichrome staining demonstrates fibrinoid vascular necrosis (red, arrows) and collagen deposition (light blue, arrow heads)(60X); E. Macrophages surrounding damaged tissues (arrow, 20x); F. Cellular atypia (arrows, 60X); G. Edema (arrows, 20X); H. Neuronal necrosis (arrows, 60X).
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pone.0139596.g005: Pathological features in post-irradiation mouse brain.A. Micro-hemorrhage and dilated vessels (arrow, 20X); B. Hemorrhage (arrowheads) and fibrinoid vascular necrosis (arrows) (H&E staining, 20X); C. PTAH staining shows fibrinoid vascular necrosis in dark blue (arrows, 20X); D. Trichrome staining demonstrates fibrinoid vascular necrosis (red, arrows) and collagen deposition (light blue, arrow heads)(60X); E. Macrophages surrounding damaged tissues (arrow, 20x); F. Cellular atypia (arrows, 60X); G. Edema (arrows, 20X); H. Neuronal necrosis (arrows, 60X).

Mentions: Histologic changes are shown in control and irradiated mice (Figs 4 and 5). Changes include microhemorrhages, edema, vascular changes ranging from increased numbers of delicate telangiectatic vessels to fibrinoid vascular necrosis and hyalinization, development of foamy macrophages, infiltration of polymorphonuclear leukocytes, astrocytosis, and loss of tissue elements, ranging from neuronal loss to frank involvement of all tissue elements with microcavitation. The severity of histologic changes for a total of 96 mice was independently scored by three individuals, including a clinical neuropathologist (RES), in blinded fashion, using a semi-quantitative, 0 to 3 grading system. Fig 4 shows typical changes characteristic of radiation necrosis in the weeks following irradiation of the murine brains at both low and high magnifications. Grade 0 was assigned to no histologic changes (Fig 4A and 4B). Grade 1 described mild histological changes associated with radiation injury, including early events such as micro-hemorrhages accompanied by increased numbers of telangiectatic vessels (Fig 4C and 4D). Grade 2 injuries (Fig 4E and 4F), were characterized by moderate histologic changes, including changes seen in Grade 1 with the addition of vascular hyalinization, astrocytosis, and tissue loss. Grade 3 injuries (Fig 4G and 4H) resembled those of Grade 2 but were more severe, often including extensive tissue loss. Grade 3 injuries also more frequently featured fibrinoid vascular necrosis. The agreement in histologic grading amongst the three independent scorers was measured via Kendall’s concordance coefficient. The calculated value of Kendall’s coefficient was 0.86 (p<0.0001), indicating substantial concordance in grading amongst the scorers.


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)

Pathological features in post-irradiation mouse brain.A. Micro-hemorrhage and dilated vessels (arrow, 20X); B. Hemorrhage (arrowheads) and fibrinoid vascular necrosis (arrows) (H&E staining, 20X); C. PTAH staining shows fibrinoid vascular necrosis in dark blue (arrows, 20X); D. Trichrome staining demonstrates fibrinoid vascular necrosis (red, arrows) and collagen deposition (light blue, arrow heads)(60X); E. Macrophages surrounding damaged tissues (arrow, 20x); F. Cellular atypia (arrows, 60X); G. Edema (arrows, 20X); H. Neuronal necrosis (arrows, 60X).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139596.g005: Pathological features in post-irradiation mouse brain.A. Micro-hemorrhage and dilated vessels (arrow, 20X); B. Hemorrhage (arrowheads) and fibrinoid vascular necrosis (arrows) (H&E staining, 20X); C. PTAH staining shows fibrinoid vascular necrosis in dark blue (arrows, 20X); D. Trichrome staining demonstrates fibrinoid vascular necrosis (red, arrows) and collagen deposition (light blue, arrow heads)(60X); E. Macrophages surrounding damaged tissues (arrow, 20x); F. Cellular atypia (arrows, 60X); G. Edema (arrows, 20X); H. Neuronal necrosis (arrows, 60X).
Mentions: Histologic changes are shown in control and irradiated mice (Figs 4 and 5). Changes include microhemorrhages, edema, vascular changes ranging from increased numbers of delicate telangiectatic vessels to fibrinoid vascular necrosis and hyalinization, development of foamy macrophages, infiltration of polymorphonuclear leukocytes, astrocytosis, and loss of tissue elements, ranging from neuronal loss to frank involvement of all tissue elements with microcavitation. The severity of histologic changes for a total of 96 mice was independently scored by three individuals, including a clinical neuropathologist (RES), in blinded fashion, using a semi-quantitative, 0 to 3 grading system. Fig 4 shows typical changes characteristic of radiation necrosis in the weeks following irradiation of the murine brains at both low and high magnifications. Grade 0 was assigned to no histologic changes (Fig 4A and 4B). Grade 1 described mild histological changes associated with radiation injury, including early events such as micro-hemorrhages accompanied by increased numbers of telangiectatic vessels (Fig 4C and 4D). Grade 2 injuries (Fig 4E and 4F), were characterized by moderate histologic changes, including changes seen in Grade 1 with the addition of vascular hyalinization, astrocytosis, and tissue loss. Grade 3 injuries (Fig 4G and 4H) resembled those of Grade 2 but were more severe, often including extensive tissue loss. Grade 3 injuries also more frequently featured fibrinoid vascular necrosis. The agreement in histologic grading amongst the three independent scorers was measured via Kendall’s concordance coefficient. The calculated value of Kendall’s coefficient was 0.86 (p<0.0001), indicating substantial concordance in grading amongst the scorers.

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