Abstract
BackgroundRadiation-induced brain injury is a common concern for survivors of adult and pediatric brain cancer. Pre-clinically, rodent models are the standard approach to evaluate mechanisms of injury and test new therapeutics for this condition. However, these rodent models fail to recapitulate the radiological and histological characteristics of the clinical disease.MethodsHere we describe a hemispheric mini-pig model of radiation-induced brain injury generated with a clinical 6 MV photon irradiator and evaluated with a clinical 3T MRI. Two pairs of Yucatan mini-pigs each received either 15 Gy or 25 Gy to the left brain hemisphere. Quality of intensity modulated radiation therapy treatment plans was evaluated retrospectively with parameters reported according to ICRU guidelines. The pigs were observed weekly to check for any outright signs of neurological impairment. The pigs underwent anatomical MRI examination before irradiation and up to 6 months post-irradiation. Immediately after the last imaging time point, the pigs were euthanized and their brains were collected for histopathological assessment.ResultsAnalysis of the dose volume histograms showed that 93% of the prescribed dose was delivered to at least 93% of the target volume in the left hemisphere. Organs at risk excluded from the target volume received doses below clinical safety thresholds. For the pigs that received a 25 Gy dose, progressive neurological impairment was observed starting at 2 months post-irradiation leading to the need for euthanasia by 3–4 months. On MRI, these two animals presented with diffuse white matter pathology consistent with the human disease that progressed to outright radiation necrosis and severe brain swelling. Histology was consistent with the final MRI evaluation. The pigs that received a 15 Gy dose appeared normal all the way to 6 months post-irradiation with no obvious neurological impairment or lesions on MRI or histopathology.ConclusionBased on our results, a mini-pig model of radiation-induced brain injury is feasible though some optimization is still needed. The mini-pig model produced lesions on MRI that are consistent with the human disease and which are not seen in rodent models. Our data shows that the ideal radiation dose for this model likely lies between 15 and 25 Gy.
Highlights
Radiation-induced brain injury is a common concern for survivors of adult and pediatric brain cancer
Radiation necrosis is usually a focal injury that presents as a mass lesion with focal neurologic abnormalities and evidence of elevated intracranial pressure, whereas cognitive impairment is characterized by diffuse white matter injury [4, 5]
Regarding the brainstem the high maximum (D2%) doses especially for P1 and P2 were seen as expected at the side adjacent to the planning target volume (PTV)
Summary
Radiation-induced brain injury is a common concern for survivors of adult and pediatric brain cancer. Pre-clinically, rodent models are the standard approach to evaluate mechanisms of injury and test new therapeutics for this condition. These rodent models fail to recapitulate the radiological and histological characteristics of the clinical disease. Late-onset radiation effects, which occur months to years after therapy and do not self-resolve, are the primary concern in terms of radiation-induced brain toxicity. Late-onset radiationinduced brain injury can be categorized into two broad types based on their radiological characteristics: focal and diffuse lesions [4]. Radiation necrosis is usually a focal injury that presents as a mass lesion with focal neurologic abnormalities and evidence of elevated intracranial pressure, whereas cognitive impairment is characterized by diffuse white matter injury [4, 5]. Radiation necrosis and diffuse white matter injury have specific and distinct histological and MRI characteristics [6]
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