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The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4\/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4\/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS.<\/jats:p>","DOI":"10.3390\/ijms241814219","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T05:59:06Z","timestamp":1695016746000},"page":"14219","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Presence of Activated (Phosphorylated) STAT3 in Radiation Necrosis Following Stereotactic Radiosurgery for Brain Metastases"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5830-8321","authenticated-orcid":false,"given":"Paola Anna","family":"Jablonska","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nuria","family":"Gal\u00e1n","sequence":"additional","affiliation":[{"name":"IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Barranco","sequence":"additional","affiliation":[{"name":"IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Leon","sequence":"additional","affiliation":[{"name":"IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain"},{"name":"Department of Pathological Anatomy, Clinica Universidad de Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ram\u00f3n","family":"Robledano","sequence":"additional","affiliation":[{"name":"Department of Pathological Anatomy, Clinica Universidad de Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Ignacio","family":"Echeveste","sequence":"additional","affiliation":[{"name":"Department of Pathological Anatomy, Clinica Universidad de Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4074-4242","authenticated-orcid":false,"given":"Alfonso","family":"Calvo","sequence":"additional","affiliation":[{"name":"IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain"},{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, ISCIII, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-2363","authenticated-orcid":false,"given":"Javier","family":"Aristu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Proton Therapy Unit, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3729-9195","authenticated-orcid":false,"given":"Diego","family":"Serrano","sequence":"additional","affiliation":[{"name":"IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain"},{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, ISCIII, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nec.2010.08.007","article-title":"Epidemiology of Metastatic Brain Tumors","volume":"22","author":"Fox","year":"2011","journal-title":"Neurosurg. 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