{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:30:16Z","timestamp":1787009416837,"version":"build-2736575974"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T00:00:00Z","timestamp":1713830400000},"content-version":"vor","delay-in-days":113,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003156","name":"Musella Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003156","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["P30CA042014"],"award-info":[{"award-number":["P30CA042014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-\u03baB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3\u2005+\u20053 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The MTD of minocycline was 150\u00a0mg twice per day (N\u2005=\u200520); 1 patient (5%) experienced CTCAE grade 3\u2005+\u2005nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-\u03baB activation, were correlated with the microglia marker IBA-1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Minocycline at 150\u00a0mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-\u03baB activation correlates with microglia levels in high-grade glioma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/noajnl\/vdae063","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T11:31:34Z","timestamp":1713871894000},"source":"Crossref","is-referenced-by-count":4,"title":["D-TERMINED, a phase 1 trial in newly diagnosed high-grade glioma with temozolomide, radiation, and minocycline followed by adjuvant minocycline\/temozolomide"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8016-3738","authenticated-orcid":false,"given":"William B","family":"McKean","sequence":"first","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Division of Medical Oncology, University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingye","family":"Yang","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Department of Neurosurgery, University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Boucher","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Division of Medical Oncology, University of Utah School of Medicine , Salt Lake City, Utah , USA"},{"name":"Department of Epidemiology, University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis C","family":"Shrieve","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Department of Radiation Oncology, University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5933-211X","authenticated-orcid":false,"given":"Gita","family":"Suneja","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Department of Radiation Oncology, University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Salzman","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Department of Radiology, University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy","family":"Jensen","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Department of Neurosurgery, University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4027-7317","authenticated-orcid":false,"given":"Howard","family":"Colman","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Department of Neurosurgery, University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8541-2287","authenticated-orcid":false,"given":"Adam L","family":"Cohen","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah , Salt Lake City, Utah , USA"},{"name":"Division of Medical Oncology, University of Utah School of Medicine , Salt Lake City, Utah , USA"},{"name":"Division of Oncology, Inova Schar Cancer Institute , Fairfax, Virginia , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"issue":"10","key":"2024052417465386900_CIT0001","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N Engl J Med."},{"issue":"6","key":"2024052417465386900_CIT0002","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S1470-2045(21)00090-5","article-title":"Adjuvant and concurrent temozolomide for 1p\/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study","volume":"22","author":"van den Bent","year":"2021","journal-title":"Lancet Oncol."},{"issue":"23","key":"2024052417465386900_CIT0003","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1001\/jama.2017.18718","article-title":"Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial","volume":"318","author":"Stupp","year":"2017","journal-title":"JAMA."},{"issue":"3","key":"2024052417465386900_CIT0004","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ccr.2006.02.019","article-title":"Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis","volume":"9","author":"Phillips","year":"2006","journal-title":"Cancer Cell"},{"issue":"1","key":"2024052417465386900_CIT0005","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1","volume":"17","author":"Verhaak","year":"2010","journal-title":"Cancer Cell"},{"issue":"6190","key":"2024052417465386900_CIT0006","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1126\/science.1254257","article-title":"Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma","volume":"344","author":"Patel","year":"2014","journal-title":"Science."},{"issue":"1","key":"2024052417465386900_CIT0007","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/neuonc\/nop007","article-title":"A multigene predictor of outcome in glioblastoma","volume":"12","author":"Colman","year":"2010","journal-title":"Neuro Oncol"},{"issue":"3","key":"2024052417465386900_CIT0008","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ccr.2013.08.001","article-title":"Mesenchymal differentiation mediated by NF-\u03baB promotes radiation resistance in glioblastoma","volume":"24","author":"Bhat","year":"2013","journal-title":"Cancer Cell"},{"issue":"4","key":"2024052417465386900_CIT0009","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1093\/brain\/awz044","article-title":"The landscape of the mesenchymal signature in brain tumours","volume":"142","author":"Behnan","year":"2019","journal-title":"Brain."},{"issue":"9","key":"2024052417465386900_CIT0010","doi-asserted-by":"crossref","first-page":"3326","DOI":"10.1158\/1078-0432.CCR-04-1765","article-title":"YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma","volume":"11","author":"Pelloski","year":"2005","journal-title":"Clin Cancer Res."},{"key":"2024052417465386900_CIT0011","doi-asserted-by":"crossref","first-page":"964898","DOI":"10.3389\/fimmu.2022.964898","article-title":"Tumor-associated microglia and macrophages in glioblastoma: from basic insights to therapeutic opportunities","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol."},{"issue":"7","key":"2024052417465386900_CIT0012","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1002\/glia.22510","article-title":"Molecular definition of the pro-tumorigenic phenotype of glioma-activated microglia","volume":"61","author":"Ellert-Miklaszewska","year":"2013","journal-title":"Glia."},{"key":"2024052417465386900_CIT0013","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1476-4598-12-86","article-title":"The complexity of NF-\u03baB signaling in inflammation and cancer","volume":"12","author":"Hoesel","year":"2013","journal-title":"Mol Cancer."},{"issue":"2","key":"2024052417465386900_CIT0014","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1002\/ana.10614","article-title":"Minocycline and doxycycline are not beneficial in a model of Huntington\u2019s disease","volume":"54","author":"Smith","year":"2003","journal-title":"Ann Neurol."},{"issue":"4","key":"2024052417465386900_CIT0015","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.bbi.2011.01.015","article-title":"Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression","volume":"25","author":"Markovic","year":"2011","journal-title":"Brain Behav Immun."},{"issue":"2","key":"2024052417465386900_CIT0016","doi-asserted-by":"crossref","first-page":"166","DOI":"10.4161\/auto.7.2.14043","article-title":"Minocycline inhibits the growth of glioma by inducing autophagy","volume":"7","author":"Liu","year":"2011","journal-title":"Autophagy"},{"issue":"4","key":"2024052417465386900_CIT0017","doi-asserted-by":"crossref","first-page":"635","DOI":"10.3171\/jns.1995.82.4.0635","article-title":"The role of minocycline in the treatment of intracranial 9L glioma","volume":"82","author":"Weingart","year":"1995","journal-title":"J Neurosurg."},{"issue":"3","key":"2024052417465386900_CIT0018","doi-asserted-by":"crossref","first-page":"662","DOI":"10.3171\/2013.11.JNS13556","article-title":"Local delivery of angiogenesis-inhibitor minocycline combined with radiotherapy and oral temozolomide chemotherapy in 9L glioma","volume":"120","author":"Bow","year":"2014","journal-title":"J Neurosurg."},{"issue":"3","key":"2024052417465386900_CIT0019","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s11060-020-03551-3","article-title":"Repeat radiation with bevacizumab and minocycline in bevacizumab-refractory high grade gliomas: a prospective phase 1 trial","volume":"148","author":"Cohen","year":"2020","journal-title":"J Neurooncol."},{"issue":"34","key":"2024052417465386900_CIT0020","doi-asserted-by":"crossref","first-page":"5743","DOI":"10.1200\/JCO.2009.23.0805","article-title":"Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network","volume":"27","author":"Weller","year":"2009","journal-title":"J Clin Oncol."},{"issue":"11","key":"2024052417465386900_CIT0021","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1200\/JCO.2009.26.3541","article-title":"Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group","volume":"28","author":"Wen","year":"2010","journal-title":"J Clin Oncol."},{"issue":"1","key":"2024052417465386900_CIT0022","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s11060-006-9135-z","article-title":"Validation of the M.D. Anderson symptom inventory brain tumor module (MDASI-BT)","volume":"80","author":"Armstrong","year":"2006","journal-title":"J Neurooncol."},{"issue":"1","key":"2024052417465386900_CIT0023","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1038\/s41467-023-37361-8","article-title":"Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma","volume":"14","author":"Chen","year":"2023","journal-title":"Nat Commun."},{"issue":"12","key":"2024052417465386900_CIT0024","doi-asserted-by":"crossref","first-page":"e1900312","DOI":"10.1002\/adbi.201900312","article-title":"Extracellular vesicles induce mesenchymal transition and therapeutic resistance in glioblastomas through NF-\u03baB\/STAT3 signaling","volume":"4","author":"Schweiger","year":"2020","journal-title":"Adv Biosyst."},{"issue":"1","key":"2024052417465386900_CIT0025","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/s41420-023-01492-0","article-title":"MiR-146a-5p deficiency in extracellular vesicles of glioma-associated macrophages promotes epithelial-mesenchymal transition through the NF-\u03baB signaling pathway","volume":"9","author":"Xu","year":"2023","journal-title":"Cell Death Discov"},{"issue":"3","key":"2024052417465386900_CIT0026","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/his.12252","article-title":"Subtyping of gliomas of various WHO grades by the application of immunohistochemistry","volume":"64","author":"Popova","year":"2014","journal-title":"Histopathology."},{"issue":"15","key":"2024052417465386900_CIT0027","doi-asserted-by":"crossref","first-page":"e103790","DOI":"10.15252\/embj.2019103790","article-title":"Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment","volume":"39","author":"Dumas","year":"2020","journal-title":"EMBO J."}],"container-title":["Neuro-Oncology Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/noa\/advance-article-pdf\/doi\/10.1093\/noajnl\/vdae063\/57310676\/vdae063.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/noa\/article-pdf\/6\/1\/vdae063\/57887014\/vdae063.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/noa\/article-pdf\/6\/1\/vdae063\/57887014\/vdae063.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T13:56:19Z","timestamp":1716558979000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/noa\/article\/doi\/10.1093\/noajnl\/vdae063\/7656765"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,1]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1,1]]}},"URL":"https:\/\/doi.org\/10.1093\/noajnl\/vdae063","relation":{},"ISSN":["2632-2498"],"issn-type":[{"value":"2632-2498","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,1,1]]},"published":{"date-parts":[[2024,1,1]]},"article-number":"vdae063"}}