Ultra-High-Dose-Rate FLASH Irradiation Limits Reactive Gliosis in the Brain

Montay‐Gruel, Pierre; Markarian, Mineh; Allen, Barrett D.; Baddour, Jabra D.; Giedzinski, Erich; Jorge, Patrik Gonçalves; Petit, Benoît; Bailat, Claude; Vozenin, Marie‐Catherine; Limoli, Charles L.; Acharya, Munjal M.

doi:10.1667/rade-20-00067.1

Cited by 55 publications

(38 citation statements)

References 46 publications

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“… 1 The exact mechanism and the triggers behind the FLASH effect are not yet fully understood and different explanations are proposed (see, e.g., refs. 2 , 3 , 4 , 5 , 6 , 7 , 8 ). Nevertheless, the advantage of the FLASH effect was already seen on multiple animal models, where healthy tissue was shown to be better protected in FLASH conditions than in conventional conditions.…”

Section: Introductionmentioning

confidence: 99%

Implementation and validation of a beam‐current transformer on a medical pulsed electron beam LINAC for FLASH‐RT beam monitoring

Oesterle

Jorge

Grilj

et al. 2021

J Applied Clin Med Phys

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To implement and validate a beam current transformer as a passive monitoring device on a pulsed electron beam medical linear accelerator (LINAC) for ultra-high dose rate (UHDR) irradiations in the operational range of at least 3 Gy to improve dosimetric procedures currently in use for FLASH radiotherapy (FLASH-RT) studies. Methods: Two beam current transformers (BCTs) were placed at the exit of a medical LINAC capable of UHDR irradiations. The BCTs were validated as monitoring devices by verifying beam parameters consistency between nominal values and measured values, determining the relationship between the charge measured and the absorbed dose, and checking the short-and long-term stability of the charge-absorbed dose ratio. Results:The beam parameters measured by the BCTs coincide with the nominal values. The charge-dose relationship was found to be linear and independent of pulse width and frequency. Short-and long-term stabilities were measured to be within acceptable limits. Conclusions: The BCTs were implemented and validated on a pulsed electron beam medical LINAC, thus improving current dosimetric procedures and allowing for a more complete analysis of beam characteristics. BCTs were shown to be a valid method for beam monitoring for UHDR (and therefore FLASH) experiments.

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Section: Introductionmentioning

confidence: 99%

Implementation and validation of a beam‐current transformer on a medical pulsed electron beam LINAC for FLASH‐RT beam monitoring

Oesterle

Jorge

Grilj

et al. 2021

J Applied Clin Med Phys

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“…This absence of cognitive dysfunction was associated with reduced neuro-inflammation and preservation of the neuronal structure in the hippocampus of FLASH irradiated mice. Also, the brains of FLASH-RT animals had lower levels of activated glial cells, with lower expression of the pro-inflammatory receptor TLR-4 suggesting a reduced inflammatory response compared to conventional dose rates 29 . Similar results were reported after the delivery of a single dose of 30 Gy with an instantaneous dose rate of 8.75 x 10 5 Gy/s (mean dose rate of 200-300 Gy/s) 30 .…”

Section: -Brainmentioning

confidence: 97%

“…Compared to the same dose delivered at CONV dose rate, FLASH-RT reportedly spared mouse lung 3,25 , small intestine 42 and pig skin 39 from radio-induced fibrosis. A dramatic reduction of acute and late inflammation was observed in mouse lung 3,25 and in adult and juvenile mouse brain, with reduction of gliosis associated with preservation of memory skills [16][17][18]29,30 .…”

Section: -Pathways To Radiation-induced Senescence and Fibrosismentioning

confidence: 99%

Radiobiology of the FLASH effect

et al. 2021

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Radiation exposures at ultra-high dose rates (UHDR) at several orders of magnitude greater than in current clinical radiotherapy have been shown to manifest differential radiobiological responses compared to conventional dose rates (CONV). This has led to studies investigating the application of UHDR for therapeutic advantage (FLASH-RT) which have gained significant interest since the initial discovery in 2014 that demonstrated reduced lung toxicity with equivalent levels of tumour control compared with conventional dose-rate radiotherapy. Many subsequent studies have demonstrated the potential protective role of FLASH-RT in normal tissues, yet the underlying molecular and cellular mechanisms of the FLASH effect remain to be fully elucidated. Here, we summarise the current evidence of the FLASH effect and review FLASH-RT studies performed in preclinical models of normal tissue response. To critically examine the underlying biological mechanisms of responses to UHDR radiation exposures, we evaluate in vitro studies performed with normal and tumour cells. Differential responses to UHDR vs CONV irradiation recurrently involve reduced inflammatory processes and differential expression of pro-and anti-inflammatory genes. In addition, frequently reduced levels of DNA damage or misrepair products are seen after UHDR irradiation. So far, it is not clear what signal elicits these differential responses, but there are indications for involvement of reactive species. Different susceptibility to FLASH effects observed between normal and tumour cells may result from altered metabolic and detoxification pathways and/or repair pathways used by tumour cells. We summarize the current theories that may explain the FLASH effect and highlight This article is protected by copyright. All rights reserved.3 important research questions which are key to a better mechanistic understanding and, thus, the future implementation of FLASH-RT in the clinic. -INTRODUCTIONRadiation therapy (RT) remains a critical part of clinical cancer care prescribed to > 50% of patients in high-income countries and contributes to more than 30% of all long-term cancer survivors 1,2 . Technological advances in imaging and RT delivery techniques have resulted in major improvements in patient survival through improved precision and ability to conform dose to the tumour targets whilst minimising dose to surrounding organs at risk (OARs). In addition to improvements in technical radiotherapy, major research efforts have been made to exploit the unique radiobiological responses that occur at ultra-high dose rates (UHDR). In comparison to conventional clinical dose rates (CONV) in the region of 0.01-0.40 Gy/s, UHDR radiotherapy was originally established using microsecond pulses of 5 MeV electrons with intra-pulse dose rate in the range 10 6 -10 7 Gy/s, time-averaged dose rate > 40 Gy/s and

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“…Attenuation of microglia activation in the hippocampus was detected in adult and juvenile mice following FLASH-RT [12,13,31,32]. At 10 weeks post-irradiation, the number of activated CD68 þ microglia was significantly increased in CONV-irradiated mice versus the control group, whereas FLASH using electrons showed comparable cell counts of CD68 þ microglia compared with the controls [32].…”

Section: Neuroinflammationmentioning

confidence: 95%

Can Rational Combination of Ultra-high Dose Rate FLASH Radiotherapy with Immunotherapy Provide a Novel Approach to Cancer Treatment?

et al. 2021

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FLASH radiotherapy (FLASH-RT) delivers radiation treatment at an ultra-high dose rate that is several orders of magnitude higher than current clinical practice. In multiple preclinical studies, FLASH-RT has shown consistent normal tissue sparing effects while preserving equivalent antitumour activity in comparison with conventional dose rate radiation treatment. This is known as the 'FLASH effect'. Given the recent research interest in combining hypofractionated radiotherapy with immunotherapy to try to improve clinical outcomes, there is an intriguing clinical question as to whether FLASH irradiation may be a rational partner to combine with immune modulating drugs? To better predict the synergistic effect of both modalities, here we review the biological mechanisms of how FLASH differentially impacts the immune landscape, including circulating immune cells, tumour microenvironment and the inflammatory response. In order to make recommendations for future research, we summarise all published studies that investigated the immune modulatory effects of FLASH-RT and further explore the scientific reasons for combining FLASH with immunotherapy for potential clinical applications.

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Ultra-High-Dose-Rate FLASH Irradiation Limits Reactive Gliosis in the Brain

Abstract: BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access titles in the biological, ecological, and environmental sciences published by nonprofit societies, associations, museums, institutions, and presses.

Cited by 55 publications

References 46 publications

Implementation and validation of a beam‐current transformer on a medical pulsed electron beam LINAC for FLASH‐RT beam monitoring

Implementation and validation of a beam‐current transformer on a medical pulsed electron beam LINAC for FLASH‐RT beam monitoring

Radiobiology of the FLASH effect

Can Rational Combination of Ultra-high Dose Rate FLASH Radiotherapy with Immunotherapy Provide a Novel Approach to Cancer Treatment?

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