Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation

Simmons, Danielle A.; Lartey, Frederick M.; Schüler, Emil; Rafat, Marjan; King, Gregory J.; Kim, Anna; Ko, Ryan B.; Semaan, Sarah; Gonzalez, Selena; Jenkins, Melissa J.; Pradhan, Pooja; Shih, Zion; Wang, Jinghui; Eyben, Rie von; Graves, Edward E.; Maxim, Peter G.; Longo, Frank M.; Loo, Billy W.

doi:10.1016/j.radonc.2019.06.006

Cited by 173 publications

(165 citation statements)

References 22 publications

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“…In addition to thoracic irradiation, it has been shown in several studies that whole brain irradiation using FLASH-RT confers neuroprotection compared to CONV-RT (13,14,24,25). In one such study, mice were exposed to varying dose rates, ranging from 0.1 Gy/s to 10 Gy delivered in a single 1.8 µs pulse; at all dose rates mice were exposed to 10 Gy in a single fraction (14).…”

Section: Flash-rt Limits Normal Tissue Toxicitymentioning

confidence: 99%

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

et al. 2020

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Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating a better tumor response. Initial pre-clinical studies have shown that irradiation at dose rates far exceeding those currently used in clinical contexts reduce radiation-induced toxicities whilst maintaining an equivalent tumor response. This is known as the FLASH effect. To date, a single patient has been subjected to FLASH radiotherapy for the treatment of subcutaneous T-cell lymphoma resulting in complete response and minimal toxicities. The mechanism responsible for reduced tissue toxicity following FLASH radiotherapy is yet to be elucidated, but the most prominent hypothesis so far proposed is that acute oxygen depletion occurs within the irradiated tissue. This review examines the tissue response to FLASH radiotherapy, critically evaluates the evidence supporting hypotheses surrounding the biological basis of the FLASH effect, and considers the potential for FLASH radiotherapy to be translated into clinical contexts.

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Section: Flash-rt Limits Normal Tissue Toxicitymentioning

confidence: 99%

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

et al. 2020

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“…11,12 It has also been suggested that the long-term neurocognitive benefits of FLASH radiotherapy might be driven by reduced reactive oxygen species (ROS) 14 and less hippocampal dendritic spine loss and neuroinflammation. 15 To date, FLASH irradiation has been realized using x rays generated in a synchrotron facility, 4 electrons generated by linear accelerators, [1][2][3]16,17 and protons using isochronous cyclotrons. [18][19][20] A summary of recent implementation of FLASH irradiation is provided in Table I.…”

Section: Introductionmentioning

confidence: 99%

Feasibility of proton FLASH irradiation using a synchrocyclotron for preclinical studies

et al. 2020

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It has been recently shown that radiotherapy at ultrahigh dose rates (>40 Gy/s, FLASH) has a potential advantage in sparing healthy organs compared to that at conventional dose rates. The purpose of this work is to show the feasibility of proton FLASH irradiation using a gantry-mounted synchrocyclotron as a first step toward implementing an experimental setup for preclinical studies. Methods: A clinical Mevion HYPERSCAN â synchrocyclotron was modified to deliver ultrahigh dose rates. Pulse widths of protons with 230 MeV energy were manipulated from 1 to 20 ls to deliver in conventional and ultrahigh dose rate. A boron carbide absorber was placed in the beam for range modulation. A Faraday cup was used to determine the number of protons per pulse at various dose rates. Dose rate was determined by the dose measured with a plane-parallel ionization chamber with respect to the actual delivery time. The integral depth dose (IDD) was measured with a Bragg ionization chamber. Monte Carlo simulation was performed in TOPAS as the secondary check for the measurements. Results: Maximum protons charge per pulse, measured with the Faraday cup, was 54.6 pC at 20 ls pulse width. The measured IDD agreed well with the Monte Carlo simulation. The average dose rate measured using the ionization chamber showed 101 Gy/s at the entrance and 216 Gy/s at the Bragg peak with a full width at half maximum field size of 1.2 cm. Conclusions: It is feasible to deliver protons at 100 and 200 Gy/s average dose rate at the plateau and the Bragg peak, respectively, in a small~1 cm 2 field using a gantry-mounted synchrocyclotron.

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“…The phenomenon of the increased therapeutic index of FLASH compared to conventional dose rate irradiation, or the “FLASH effect,” has now been reported in multiple preclinical models. Normal tissue sparing by FLASH of multiple organ systems including lung, brain, intestinal tract, and skin has been demonstrated in multiple mouse strains and even additional species (cat and mini‐pig), while demonstrating an equivalent (and in some cases superior) tumoricidal effect relative to conventional dose‐rate delivery in multiple in vivo tumor models . Given the nascent state of the field, a large portion of experimental observations to date remain preliminary and unpublished, and many questions remain unanswered particularly with respect to mechanism.…”

Section: For the Proposition: Peter G Maxim Phdmentioning

confidence: 99%

“…Given the nascent state of the field, a large portion of experimental observations to date remain preliminary and unpublished, and many questions remain unanswered particularly with respect to mechanism. While there are data suggesting a fundamental physical‐chemical effect, that is, radiochemical depletion of oxygen at FLASH dose rates, modulation of inflammatory cytokines, for example, TGF‐β and others, differential immunologic responses between tumor and normal tissues have also been observed. It remains to be determined if these are downstream effects rather than independent mechanisms.…”

Section: For the Proposition: Peter G Maxim Phdmentioning

confidence: 99%