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Journal ArticleDOI

Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100 Gy/s

TL;DR: This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate.
About: This article is published in Radiotherapy and Oncology.The article was published on 2017-05-22. It has received 363 citations till now.
Citations
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Journal ArticleDOI
TL;DR: The results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLash-RT in human patients.
Abstract: Purpose: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Experimental Design: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. Results: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. Conclusions: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients. See related commentary by Harrington, p. 3

403 citations


Cites background or methods or result from "Irradiation in a flash: Unique spar..."

  • ...Using CD34 as a surrogate marker of the epidermal stem cells (23), our results suggest that FLASH-irradiated skin area retain the expression of CD34 supporting the idea that FLASH-RT has minimal impact on stem cell consistently with what was already reported for neural (2) and intestinal stem cells (7)....

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  • ...Interestingly, the group of B. Loo at Stanford University (Palo Alto, CA) recently published a procedure on how to modify a clinical linac into an irradiator capable of delivering FLASH-RT, with dose rates exceeding 200 Gy/second (6) and produced preliminary data showing gut protection in mice (7)....

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  • ...In vivo dosimetry was performed withfilm (Gafchromic EBT3) and alaninepellets (2, 3) positioned on the skin surface in the center of the beams....

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  • ...With the objective of fostering innovation in radiotherapy, we have been the first to propose a completely novel modality of irradiation, named FLASH radiotherapy (FLASH-RT), that markedly increases the differential effect between tumors and normal tissues and is able to destroy tumors, while better protecting normal tissues and preventing side effects in experimental models (1, 2)....

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  • ...This enhanced tolerance of normal tissues appears at irradiation dose rates above 30–40 Gy/second, whereas on all the tumor models tested so far, FLASH-RT has been shown to be as effective for tumor control as Conv-RT (Montay-Gruel and Vozenin, in preparation; ref....

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Journal ArticleDOI
TL;DR: This first FLash-RT treatment was feasible and safe with a favorable outcome both on normal skin and the tumor, and prompt to further clinical evaluation of FLASH-RT.

340 citations

Journal ArticleDOI
TL;DR: The current knowledge about the FLASH effect is summarized and a synthesis of the observations that have been reported on various experimental animal models, various organs, and by various groups across 40 years of research are provided.

285 citations

Journal ArticleDOI
TL;DR: The tissue response to FLASH radiotherapy is examined, the evidence supporting hypotheses surrounding the biological basis of the FLASH effect is critically evaluated, and the potential for FLash radiotherapy to be translated into clinical contexts is considered.
Abstract: 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.

279 citations


Cites background or methods or result from "Irradiation in a flash: Unique spar..."

  • ...Whole brain irradiation of mice (14) Novel object recognition test >1...

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  • ...using a wide range of dose rates has helped to elucidate the extent to which dose rate modulates the FLASH effect (14)....

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  • ...The FLASH effect has been predominantly observed following FLASH-RT using dedicated electron linear accelerators as the source of radiation (10, 14, 15, 18, 37)....

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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)....

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  • ...Furthermore, there was no statistical difference in novel object recognition between mice irradiated at dose rates exceeding 100 Gy/s and non-irradiated mice (14)....

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Journal ArticleDOI
TL;DR: The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.
Abstract: Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy⋅s−1). Compared with conventional dose-rate (CONV; 0.07–0.1 Gy⋅s−1) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory. Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.

277 citations

References
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Journal ArticleDOI
TL;DR: The neurobiology and methodological modifications of the test commonly used in behavioral pharmacology are reviewed to review the novel object recognition paradigms in animals, as a valuable measure of cognition.
Abstract: Animal models of memory have been considered as the subject of many scientific publications at least since the beginning of the twentieth century. In humans, memory is often accessed through spoken or written language, while in animals, cognitive functions must be accessed through different kind of behaviors in many specific, experimental models of memory and learning. Among them, the novel object recognition test can be evaluated by the differences in the exploration time of novel and familiar objects. Its application is not limited to a field of research and enables that various issues can be studied, such as the memory and learning, the preference for novelty, the influence of different brain regions in the process of recognition, and even the study of different drugs and their effects. This paper describes the novel object recognition paradigms in animals, as a valuable measure of cognition. The purpose of this work was to review the neurobiology and methodological modifications of the test commonly used in behavioral pharmacology.

1,635 citations


"Irradiation in a flash: Unique spar..." refers methods in this paper

  • ...Dose rate effect on neuroprotection was evaluated by ‘‘Novel Object Recognition test” [18], performed on the mice two months post-irradiation, as described by Acharya et al....

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  • ...These cognitive impairments can be evaluated using the ‘‘Novel Object Recognition test” [18] on WBI murine models [19]....

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Journal ArticleDOI
TL;DR: This protocol represents a major simplification compared to the AAPM's TG-21 protocol in the sense that large tables of stopping-power ratios and mass-energy absorption coefficients are not needed and the user does not need to calculate any theoretical dosimetry factors.
Abstract: A protocol is prescribed for clinical reference dosimetry of external beam radiation therapy using photon beams with nominal energies between 60Co and 50 MV and electron beams with nominal energies between 4 and 50 MeV. The protocol was written by Task Group 51 (TG-51) of the Radiation Therapy Committee of the American Association of Physicists in Medicine (AAPM) and has been formally approved by the AAPM for clinical use. The protocol uses ion chambers with absorbed-dose-to-water calibration factors, N(60Co)D,w which are traceable to national primary standards, and the equation D(Q)w = MkQN(60Co)D,w where Q is the beam quality of the clinical beam, D(Q)w is the absorbed dose to water at the point of measurement of the ion chamber placed under reference conditions, M is the fully corrected ion chamber reading, and kQ is the quality conversion factor which converts the calibration factor for a 60Co beam to that for a beam of quality Q. Values of kQ are presented as a function of Q for many ion chambers. The value of M is given by M = PionP(TP)PelecPpolMraw, where Mraw is the raw, uncorrected ion chamber reading and Pion corrects for ion recombination, P(TP) for temperature and pressure variations, Pelec for inaccuracy of the electrometer if calibrated separately, and Ppol for chamber polarity effects. Beam quality, Q, is specified (i) for photon beams, by %dd(10)x, the photon component of the percentage depth dose at 10 cm depth for a field size of 10x10 cm2 on the surface of a phantom at an SSD of 100 cm and (ii) for electron beams, by R50, the depth at which the absorbed-dose falls to 50% of the maximum dose in a beam with field size > or =10x10 cm2 on the surface of the phantom (> or =20x20 cm2 for R50>8.5 cm) at an SSD of 100 cm. R50 is determined directly from the measured value of I50, the depth at which the ionization falls to 50% of its maximum value. All clinical reference dosimetry is performed in a water phantom. The reference depth for calibration purposes is 10 cm for photon beams and 0.6R50-0.1 cm for electron beams. For photon beams clinical reference dosimetry is performed in either an SSD or SAD setup with a 10x10 cm2 field size defined on the phantom surface for an SSD setup or at the depth of the detector for an SAD setup. For electron beams clinical reference dosimetry is performed with a field size of > or =10x10 cm2 (> or =20x20 cm2 for R50>8.5 cm) at an SSD between 90 and 110 cm. This protocol represents a major simplification compared to the AAPM's TG-21 protocol in the sense that large tables of stopping-power ratios and mass-energy absorption coefficients are not needed and the user does not need to calculate any theoretical dosimetry factors. Worksheets for various situations are presented along with a list of equipment required.

1,469 citations

Journal ArticleDOI
TL;DR: The multiple possible activation states microglia can be polarized to are examined and particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.
Abstract: The concept of multiple macrophage activation states is not new. However, extending this idea to resident tissue macrophages, like microglia, has gained increased interest in recent years. Unfortunately, the research on peripheral macrophage polarization does not necessarily translate accurately to their central nervous system (CNS) counterparts. Even though pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states, the specific functions of these states is still an area of intense debate. This review examines the multiple possible activation states microglia can be polarized to. This is followed by a detailed description of microglial polarization and the functional relevance of this process in both acute and chronic CNS disease models described in the literature. Particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.

1,257 citations


"Irradiation in a flash: Unique spar..." refers background in this paper

  • ...Both neuroinflammation [27] and synaptic changes [28] are known to interfere with cognitive functions after WBI and could be differentially induced after Flash WBI....

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Journal ArticleDOI
TL;DR: The results suggest that FLASH radiation may be a viable option for treating lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.
Abstract: In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤500 ms) of radiation delivered at ultrahigh dose rate (≥40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc + orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-b (transforming growth factor–b) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administrationofsystemicTNF-a(tumornecrosisfactor–a)beforeirradiation.Incontrast,FLASHwasasefficientasCONVinthe repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.

696 citations


"Irradiation in a flash: Unique spar..." refers background or result in this paper

  • ...Our previous results show that Flash-RT demonstrates an antitumor effect similar to conventional radiotherapy [1] in various tumor types, including glioblastoma (preliminary in vitro and in vivo data)....

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  • ...When compared to radiotherapy delivered at conventional dose rates (1–4 Gy/min), this so called ‘‘Flash” radiotherapy (>40 Gy/s; Flash-RT) was shown to enhance the differential effect between normal tissue and tumor in lung models [1,2] and consequently allowed for dose escalation....

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Journal ArticleDOI
TL;DR: Evidence is provided that irradiation of young animals induces a long-term impairment of dentate subgranular zone neurogenesis that is associated with hippocampal-dependent memory deficits.

668 citations


"Irradiation in a flash: Unique spar..." refers background in this paper

  • ...Cognitive impairments are the most described functional defects observed in mice and humans following WBI [4,16]....

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