Radionecrosis and cellular changes in small volume stereotactic brain radiosurgery in a porcine model

Hamed Zaer,Jens Chr Hedemann Sørensen,Esben Schjødt Worm,Morten Bjørn Jensen,Lone Hoffmann,John R Adler,Dariusz Orlowski,Kim Vang Hansen,Slávka Lukacova,Bret M Schneider,Rune Hansen,Morten Høyer,Andreas Nørgaard Glud

doi:10.1038/s41598-020-72876-w

Hamed Zaer, Jens Chr Hedemann Sørensen + Show 11 more

Open Access

https://doi.org/10.1038/s41598-020-72876-w

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Abstract

Stereotactic radiosurgery (SRS) has proven an effective tool for the treatment of brain tumors, arteriovenous malformation, and functional conditions. However, radiation-induced therapeutic effect in viable cells in functional SRS is also suggested. Evaluation of the proposed modulatory effect of irradiation on neuronal activity without causing cellular death requires the knowledge of radiation dose tolerance at very small tissue volume. Therefore, we aimed to establish a porcine model to study the effects of ultra-high radiosurgical doses in small volumes of the brain. Five minipigs received focal stereotactic radiosurgery with single large doses of 40–100 Gy to 5–7.5 mm fields in the left primary motor cortex and the right subcortical white matter, and one animal remained as unirradiated control. The animals were followed-up with serial MRI,PET scans, and histology 6 months post-radiation. We observed a dose-dependent relation of the histological and MRI changes at 6 months post-radiation. The necrotic lesions were seen in the grey matter at 100 Gy and in white matter at 60 Gy. Furthermore, small volume radiosurgery at different dose levels induced vascular, as well as neuronal cell changes and glial cell remodeling.

Highlights

Stereotactic radiosurgery (SRS) has proven an effective tool for the treatment of brain tumors, arteriovenous malformation, and functional conditions
Thereafter the Gamma knife (GK) was used in functional brain surgery for targeting deep fiber tracts or nuclei, and this opened the door to a new world in the field of functional neurosurgery for non-invasive treatment of Parkinson disease, psychiatric disorders, and intractable pain
A notable exception was the treatment of trigeminal neuralgia, during which Leksell observed that the mechanism of action involved changes that barely could be explained in his view by cell death concerning the decrease in pain intensity and frequency right after r adiosurgery[4,5]

Summary

Introduction

Stereotactic radiosurgery (SRS) has proven an effective tool for the treatment of brain tumors, arteriovenous malformation, and functional conditions. A notable exception was the treatment of trigeminal neuralgia, during which Leksell observed that the mechanism of action involved changes that barely could be explained in his view by cell death concerning the decrease in pain intensity and frequency right after r adiosurgery[4,5] This trend led to other studies of the dose–effect association suggesting a different mechanism of cell death in radiosurgery, namely death by nuclear damage and reproductive disruption, in contrast to the interphase cell degeneration by cytoplasmic membrane lesions[6,7,8,9]. The present study aimed to establish a porcine model for investigating the dose-dependent tissue reaction of ultra-high single radiation doses to very small volumes of the cerebral white and grey matter in a large animal. The Göttingen minipig has been established as a large animal model, which is an ethically acceptable alternative to primate models, and it allows more specific radiosurgical targeting due to the larger pig brain compared to r odents[22,23]

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