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Novel technique for high-precision stereotactic irradiation of mouse brains

Neuartige Bestrahlungsmethode für stereotaktische Hochpräzisionsbestrahlung von Maushirnen

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Abstract

Background and purpose

Small animal irradiation systems were developed for preclinical evaluation of tumor therapy closely resembling the clinical situation. Mostly only clinical LINACs are available, so protocols for small animal partial body irradiation using a conventional clinical system are essential. This study defines a protocol for conformal brain tumor irradiations in mice.

Materials and methods

CT and MRI images were used to demarcate the target volume and organs at risk. Three 6 MV photon beams were planned for a total dose of 10 fractions of 1.8 Gy. The mouse position in a dedicated applicator was verified by an X‑ray patient positioning system before each irradiation. Dosimetric verifications (using ionization chambers and films) were performed. Irradiation-induced DNA damage was analyzed to verify the treatment effects on the cellular level.

Results

The defined treatment protocol and the applied fractionation scheme were feasible. The in-house developed applicator was suitable for individual positioning at submillimeter accuracy of anesthetized mice during irradiation, altogether performed in less than 10 min. All mice tolerated the treatment well. Measured dose values perfectly matched the nominal values from treatment planning. Cellular response was restricted to the target volume.

Conclusion

Clinical LINAC-based irradiations of mice offer the potential to treat orthotopic tumors conformably. Especially with respect to lateral penumbra, dedicated small animal irradiation systems exceed the clinical LINAC solution.

Zusammenfassung

Hintergrund und Zielsetzung

Kleintierbestrahlungsanlagen wurden entwickelt um präklinische Studien in der Tumortherapie unter möglichst klinischen Bedingungen durchzuführen. Da an den meisten Instituten nur klinische LINACs zur Verfügung stehen, werden Standardprotokolle zur Kleintierbestrahlung benötigt, die konventionelle Systeme nutzen. In dieser Studie wird ein solches Protokoll für tumorkonforme Hirnbestrahlung von Mäusen definiert.

Materialien und Methoden

CT- und MRT-Bilder wurden aufgenommen, um Zielvolumen und Risikostrukturen festzulegen. Drei 6‑MV-Photonenfelder wurden auf eine Gesamtdosis von 10 × 1,8 Gy optimiert. Die Lage der Maus innerhalb eines selbstentwickelten Applikators wurde anhand eines Patientenpositionierungssystems vor jeder Bestrahlung verifiziert. Strahlungseffekte wurden dosimetrisch mittels Ionisationskammern und Filmen als auch biologisch auf zellulärer Ebene überprüft.

Ergebnisse

Das definierte Bestrahlungsprotokoll und das applizierte Fraktionierungsschema konnten erfolgreich angewendet werden. Mit Hilfe des eigens entwickelten Applikators wurde eine individuelle und millimetergenaue Positionierung der narkotisierten Mäuse für die Bestrahlung erreicht. Positionierung und Bestrahlung dauerten weniger als 10 min und wurden von allen Mäusen toleriert. Die berechneten Werte aus dem Planungssystem stimmten mit den gemessenen Dosiswerten überein und zeigten auf das Zielvolumen begrenzte zelluläre Effekte.

Schlussfolgerung

Mittels klinischer LINACs können orthotopische Tumore von Mäusen konform bestrahlt werden. Im Hinblick auf die laterale Penumbra sind jedoch Kleintierbestrahlungsanlagen überlegen.

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Acknowledgements

The presented work was performed in partial fulfillment of the requirements for obtaining the degree Dr. rer. biol. hum. at the Friedrich-Alexander-Universität (JH, JW).

Funding

The presented work was funded in parts by the German Research Council (DFG) (KFO 214/2 (JW), BU 2878/2-1 (AH, RB)), the European Commission (DoReMi, European Atomic Energy Community’s Seventh Framework Programme (FP7/2007–2011) under Grant Agreement No. 249689) (BF, USG), the German Federal Ministry of Education and Research (BMBF; GREWIS, 02NUK017G), and the Bavarian Equal Opportunities Sponsorship—Förderung von Frauen in Forschung und Lehre (FFL)—Promoting Equal Opportunities for Women in Research and Teaching (AD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstraße 27, 91054, Erlangen, Germany

    J. Hartmann, J. Wölfelschneider, A. Derer, R. Fietkau, U. S. Gaipl, C. Bert & B. Frey

  2. Institute of Neuropathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    C. Stache, R. Buslei & A. Hölsken

  3. Institute of Radiology, Preclinical Imaging Platform Erlangen (PIPE), Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    M. Schwarz & T. Bäuerle

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  1. J. Hartmann
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  2. J. Wölfelschneider
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  3. C. Stache
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  4. R. Buslei
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  5. A. Derer
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  6. M. Schwarz
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  7. T. Bäuerle
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  8. R. Fietkau
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  9. U. S. Gaipl
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  10. C. Bert
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  11. A. Hölsken
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  12. B. Frey
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Corresponding author

Correspondence to C. Bert.

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Conflict of interest

J. Hartmann, J. Wölfelschneider, C. Stache, R. Buslei, A. Derer, M. Schwarz, T. Bäuerle, R. Fietkau, U.S. Gaipl, C. Bert, A. Hölske, and B. Frey declare that they have no competing interests.

Ethical standards

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

J. Hartmann and J. Wölfelschneider contributed equally to this work. A. Hölsken and B. Frey contributed equally as senior authors.

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Hartmann, J., Wölfelschneider, J., Stache, C. et al. Novel technique for high-precision stereotactic irradiation of mouse brains. Strahlenther Onkol 192, 806–814 (2016). https://doi.org/10.1007/s00066-016-1014-8

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  • DOI: https://doi.org/10.1007/s00066-016-1014-8

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