{"corpus_id":157057630,"paper_sha":"ea79764a99e0450867031c8dada3cd6d4c2752ba","doi":"10.1073/pnas.1901777116","arxiv_id":null,"pmid":31097580,"pmcid":"PMC6561167","mag_id":2946753897,"dblp_id":null,"acl_id":null,"title":"Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species","year":2019,"publication_date":"2019-05-16","venue":"Proceedings of the National Academy of Sciences of the United States of America","journal":{"name":"Proceedings of the National Academy of Sciences","pages":"10943 - 10951","volume":"116"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, N.I.H., Extramural","Research Support, U.S. Gov't, Non-P.H.S."],"s2_fields_of_study":["Medicine","Environmental Science"],"reference_count":59,"citation_count":458,"influential_citation_count":25,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Brain","mj":false,"qs":[{"q":"pathology","mj":false,"ui":"Q000473"},{"q":"radiation effects","mj":false,"ui":"Q000528"}],"ui":"D001921"},{"d":"Cognitive Dysfunction","mj":true,"qs":[{"q":"etiology","mj":false,"ui":"Q000209"},{"q":"prevention & control","mj":false,"ui":"Q000517"}],"ui":"D060825"},{"d":"Female","mj":false,"ui":"D005260"},{"d":"Inflammation","mj":false,"ui":"D007249"},{"d":"Mice","mj":false,"ui":"D051379"},{"d":"Mice, Inbred C57BL","mj":false,"ui":"D008810"},{"d":"Neuroprotection","mj":false,"qs":[{"q":"radiation effects","mj":true,"ui":"Q000528"}],"ui":"D000066829"},{"d":"Radiation Dosage","mj":true,"ui":"D011829"},{"d":"Radiotherapy","mj":false,"qs":[{"q":"adverse effects","mj":false,"ui":"Q000009"},{"q":"methods","mj":true,"ui":"Q000379"}],"ui":"D011878"},{"d":"Reactive Oxygen Species","mj":false,"qs":[{"q":"analysis","mj":false,"ui":"Q000032"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D017382"}],"chemicals":[{"n":"Reactive Oxygen Species","ui":"D017382","reg":"0"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://www.pnas.org/content/pnas/116/22/10943.full.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/0ac53d4d4431ef348adeeaa9a0426d09300a5f0c","s2_open_access_license":null,"s2_open_access_status":"BRONZE","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Significance Ultra-high dose-rate (≥100 Gy⋅s−1) irradiation, termed FLASH radiotherapy, affords some remarkable (if not unexpected) normal tissue sparing in the irradiated brain when compared with conventional dose rates (0.07–0.1 Gy⋅s−1) used in clinical practice. Radiation-induced neurocognitive deficits, persistent neuroinflammation, and the structural degradation of mature neurons, typical of conventional dose-rate exposures, were resolved significantly in a preclinical mouse model exposed to FLASH radiotherapy. These benefits persisted over a 6-mon postirradiation interval and were caused, in part, by a mechanism involving reduced reactive oxygen species. Since normal tissue injury during and following radiotherapy dictates the maximum tolerated dose, the capability to ameliorate these adverse side effects holds significant promise for improving therapeutic outcome for cancer survivors worldwide. 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.","claims":[{"public_id":"cl_8a80c8011858fd8acddf3e0595c78224","status":"active","text":"FLASH radiotherapy preserved neuronal morphology and dendritic spine density in the irradiated brain.","confidence":0.95,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_8a80c8011858fd8acddf3e0595c78224"},{"public_id":"cl_f85c3cbade7ebe77ef7ab0e1a6caabff","status":"active","text":"FLASH radiotherapy prevented learning and memory deficits in mice compared with conventional dose-rate irradiation.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous 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