The sparing effect of FLASH-RT on synaptic plasticity is maintained in mice with standard fractionation

Limoli, Charles L.; Kramár, Enikö A.; Almeida, Aymeric; Petit, Benoît; Grilj, Veljko; Baulch, Janet E.; Ballesteros-Zebadúa, Paola; Loo, Billy W.; Wood, Marcelo A.; Vozenin, Marie‐Catherine

doi:10.1016/j.radonc.2023.109767

Cited by 8 publications

(12 citation statements)

References 22 publications

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“…To investigate the potential for FLASH to modulate early toxicities in the brain, we employed one of our most reliable late markers of the FLASH effect, namely LTP. When assessed at late times (> one month) CONV irradiated cohorts exhibit significant and persistent reductions in slope of the fEPSP, effects not evident after FLASH (8–10). While this finding was replicated after a single dose of 10 Gy at five months post-irradiation, no such change was found at two weeks post-irradiation.…”

Section: Discussionmentioning

confidence: 95%

“…The prolonged sparing of learning and memory deficits after FLASH suggests a preservation of synaptic elements involved in neurotransmission. In three recent studies, hypofractionated dosing regimens (2×10 Gy, 3×10 Gy) and standard of care fractionation (10×3 Gy) was shown to preserve LTP in FLASH cohorts when assessed months after irradiation, as opposed to the significant inhibition of LTP in the CONV cohorts (8–10). Therefore, we sought to test both the irradiated cohorts institutes in the same way to identify if LTP was adversely impacted by CONV at this single dose of 10 Gy and whether FLASH could spare this detrimental effect.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of whole-brain FLASH in mice have demonstrated sparing of long-term cognitive function evaluated with a multitude of neurobehavioral assessments, as opposed to the significant impairments found routinely in animals exposed to CONV (3)(4)(5)(6)(7)(8)(9). Behavioral outcomes correspond to similar sparing effects observed on electrophysiological assessments of long-term potentiation (LTP), protection of the cerebral vasculature and neuronal morphology along with reductions in neuroinflammation (5,6,(8)(9)(10).…”

Section: Introductionmentioning

confidence: 87%

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A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints

Drayson,

Melemenidis,

Katila

et al. 2024

Preprint

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Purpose: Ultra-high dose-rate radiotherapy (FLASH) has been shown to mitigate normal tissue toxicities associated with conventional dose rate radiotherapy (CONV) without compromising tumor killing in preclinical models. A prominent challenge in preclinical radiation research, including FLASH, is validating both the physical dosimetry and the biological effects across multiple institutions. Methods: We previously demonstrated dosimetric reproducibility of two different electron FLASH devices at separate institutions using standardized phantoms and dosimeters. In this study, we compared the outcome of FLASH and CONV 10 Gy whole brain irradiation on female adult mice at both institutions to evaluate the reproducibility and temporal evolution of multiple endpoints. Results: FLASH sparing of behavioral performance on novel object recognition (4 months post-irradiation) and electrophysiologic long-term potentiation (LTP, 5-months post-irradiation) was reproduced between institutions. Interestingly, differences between FLASH and CONV on the endpoints of hippocampal neurogenesis (Sox2, doublecortin), neuroinflammation (microglial activation), and electrophysiology (LTP) at late times were not observed at early times. Conclusions: In summary, we demonstrated reproducible FLASH sparing effects between two beams and two institutions with validated dosimetry. FLASH sparing effects on the endpoints evaluated manifested at late but not early time points.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

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A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints

Drayson,

Melemenidis,

Katila

et al. 2024

Preprint

Self Cite

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“…In future studies, it would be interesting also to explore the effects of fractionation and dose rate in relation to dose-response and cognitive side effects. Others have demonstrated that sparing effects on long-term potentiation is achieved by fractionation of FLASH-RT in doses of 3 Gy x 10, as compared to CONV-RT at the same dosage ( 26 ). We would like to explore cognitive and dermal side effects, comparing FLASH-RT and CONV-RT, but in order to get a better statistical power in long-term survivors, an irradiation dose resulting in an even higher degree of survival would be needed.…”

Section: Discussionmentioning

confidence: 99%

Comparable survival in rats with intracranial glioblastoma irradiated with single-fraction conventional radiotherapy or FLASH radiotherapy

Liljedahl,

Konradsson,

Linderfalk

et al. 2024

Front. Oncol.

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BackgroundRadiotherapy increases survival in patients with glioblastoma. However, the prescribed dose is limited by unwanted side effects on normal tissue. Previous experimental studies have shown that FLASH radiotherapy (FLASH-RT) can reduce these side effects. Still, it is important to establish an equal anti-tumor efficacy comparing FLASH-RT to conventional radiotherapy (CONV-RT).MethodsFully immunocompetent Fischer 344 rats with the GFP-positive NS1 intracranial glioblastoma model were irradiated with CONV-RT or FLASH-RT in one fraction of 20 Gy, 25 Gy or 30 Gy. Animals were monitored for survival and acute dermal side effects. The brains were harvested upon euthanasia and tumors were examined post mortem.ResultsSurvival was significantly increased in animals irradiated with CONV-RT and FLASH-RT at 20 Gy and 25 Gy compared to control animals. The longest survival was reached in animals irradiated with FLASH-RT and CONV-RT at 25 Gy. Irradiation at 30 Gy did not lead to increased survival, despite smaller tumors. Tumor size correlated inversely with irradiation dose, both in animals treated with CONV-RT and FLASH-RT. Acute dermal side effects were mild, but only a small proportion of the animals were alive for evaluation of those side effects.ConclusionThe dose response was similar for CONV-RT and FLASH-RT in the present model. Tumor size upon the time of euthanasia correlated inversely with the irradiation dose.

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“…The recent study of Limoli et al., focused on C57BL/6J female mice subjected to 30 Gy in 10 fractions, a standard-of-care fractionation regimen employed for treating multiple brain metastases ( 30 ).The aim of achieving effective intracranial control and cognitive preservation is essential in medical practice due to the potential neurological effects of whole-brain radiotherapy (WBRT) and the relatively lower intracranial control rate of stereotactic body radiation therapy (SBRT). Limoli et al.…”

Section: In Vivo Studies On the Electron Flash-rtmentioning

confidence: 99%

Electron FLASH radiotherapy in vivo studies. A systematic review

Giannini,

Gadducci,

Fuentes

et al. 2024

Front. Oncol.

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FLASH-radiotherapy delivers a radiation beam a thousand times faster compared to conventional radiotherapy, reducing radiation damage in healthy tissues with an equivalent tumor response. Although not completely understood, this radiobiological phenomenon has been proved in several animal models with a spectrum of all kinds of particles currently used in contemporary radiotherapy, especially electrons. However, all the research teams have performed FLASH preclinical studies using industrial linear accelerator or LINAC commonly employed in conventional radiotherapy and modified for the delivery of ultra-high-dose-rate (UHDRs). Unfortunately, the delivering and measuring of UHDR beams have been proved not to be completely reliable with such devices. Concerns arise regarding the accuracy of beam monitoring and dosimetry systems. Additionally, this LINAC totally lacks an integrated and dedicated Treatment Planning System (TPS) able to evaluate the internal dose distribution in the case of in vivo experiments. Finally, these devices cannot modify dose-time parameters of the beam relevant to the flash effect, such as average dose rate; dose per pulse; and instantaneous dose rate. This aspect also precludes the exploration of the quantitative relationship with biological phenomena. The dependence on these parameters need to be further investigated. A promising advancement is represented by a new generation of electron LINAC that has successfully overcome some of these technological challenges. In this review, we aim to provide a comprehensive summary of the existing literature on in vivo experiments using electron FLASH radiotherapy and explore the promising clinical perspectives associated with this technology.

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The sparing effect of FLASH-RT on synaptic plasticity is maintained in mice with standard fractionation

Cited by 8 publications

References 22 publications

A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints

A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints

Comparable survival in rats with intracranial glioblastoma irradiated with single-fraction conventional radiotherapy or FLASH radiotherapy

Electron FLASH radiotherapy in vivo studies. A systematic review

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