{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:03:47Z","timestamp":1792004627909,"version":"4.4.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,1,14]],"date-time":"2024-01-14T00:00:00Z","timestamp":1705190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Stophersenkanker.nu foundation"},{"name":"Foundation Vrienden UMC Utrecht"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Radiological progression may originate from progressive disease (PD) or pseudoprogression\/treatment-associated changes. We assessed radiological progression in O6-methylguanine-DNA methyltransferase (MGMT) promoter-methylated glioblastoma treated with standard-of-care chemoradiotherapy with or without the integrin inhibitor cilengitide according to the modified response assessment in neuro-oncology (RANO) criteria of 2017.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with \u2265\u20053 follow-up MRIs were included. Preliminary PD was defined as a \u2265\u200525% increase of the sum of products of perpendicular diameters (SPD) of a new or increasing lesion compared to baseline. PD required a second \u226525% increase of the SPD. Treatment-associated changes require stable or regressing disease after preliminary PD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of the 424 evaluable patients, 221 patients (52%) were randomized into the cilengitide and 203 patients (48%) into the control arm. After chemoradiation with or without cilengitide, preliminary PD occurred in 274 patients (65%) during available follow-up, and 88 of these patients (32%) had treatment-associated changes, whereas 67 patients (25%) had PD. The remaining 119 patients (43%) had no further follow-up after preliminary PD. Treatment-associated changes were more common in the cilengitide arm than in the standard-of-care arm (24% vs. 17%; relative risk, 1.3; 95% CI, 1.004\u20131.795; P\u2005=\u2005.047). Treatment-associated changes occurred mainly during the first 6 months after RT (54% after 3 months vs. 13% after 6 months).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>With the modified RANO criteria, the rate of treatment-associated changes was low compared to previous studies in MGMT promoter-methylated glioblastoma. This rate was higher after cilengitide compared to standard-of-care treatment. Confirmatory scans, as recommended in the modified RANO criteria, were not always available reflecting current clinical practice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noad247","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T16:36:05Z","timestamp":1704904565000},"page":"902-910","source":"Crossref","is-referenced-by-count":15,"title":["Treatment-associated imaging changes in newly diagnosed\n                    <i>MGMT<\/i>\n                    promoter-methylated glioblastoma undergoing chemoradiation with or without cilengitide"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9160-4058","authenticated-orcid":false,"given":"Christina Maria","family":"Flies","sequence":"first","affiliation":[{"name":"Department of Neurology & Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht , Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Medicine (INM-3, INM-4), Research Center Juelich , Juelich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-046X","authenticated-orcid":false,"given":"Philipp","family":"Lohmann","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Medicine (INM-3, INM-4), Research Center Juelich , Juelich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin Alida","family":"van Garderen","sequence":"additional","affiliation":[{"name":"Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Centre Rotterdam , Rotterdam , The Netherlands"},{"name":"Brain Tumour Centre, Erasmus MC Cancer Centre , Rotterdam , The Netherlands"},{"name":"Medical Delta , Delft , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5563-2871","authenticated-orcid":false,"given":"Marion","family":"Smits","sequence":"additional","affiliation":[{"name":"Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Centre Rotterdam , Rotterdam , The Netherlands"},{"name":"Brain Tumour Centre, Erasmus MC Cancer Centre , Rotterdam , The Netherlands"},{"name":"Medical Delta , Delft , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg-Christian","family":"Tonn","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Hospital Munich LMU , Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1748-174X","authenticated-orcid":false,"given":"Michael","family":"Weller","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich , Zurich , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2485-1796","authenticated-orcid":false,"given":"Norbert","family":"Galldiks","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Medicine (INM-3, INM-4), Research Center Juelich , Juelich , Germany"},{"name":"Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne , Cologne , Germany"},{"name":"Center for Integrated Oncology (CIO), Universities of Aachen, Bonn, Cologne, and Duesseldorf , Cologne , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0857-081X","authenticated-orcid":false,"given":"Tom Jan","family":"Snijders","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht , Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,14]]},"reference":[{"issue":"6","key":"2024050310211564000_CIT0001","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization classification of tumors of the central nervous system: a summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"issue":"Suppl 5","key":"2024050310211564000_CIT0002","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/noz150","article-title":"CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012","volume":"21","author":"Ostrom","year":"2019","journal-title":"Neuro Oncol"},{"issue":"10","key":"2024050310211564000_CIT0003","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":"10","key":"2024050310211564000_CIT0004","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1056\/NEJMoa043331","article-title":"MGMT gene silencing and benefit from temozolomide in glioblastoma","volume":"352","author":"Hegi","year":"2005","journal-title":"N Engl J Med."},{"issue":"10","key":"2024050310211564000_CIT0005","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/S1470-2045(14)70379-1","article-title":"Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial","volume":"15","author":"Stupp","year":"2014","journal-title":"Lancet Oncol."},{"issue":"12","key":"2024050310211564000_CIT0006","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1177\/1947601912450586","article-title":"Cilengitide: a prototypic integrin inhibitor for the treatment of glioblastoma and other malignancies","volume":"2","author":"Reardon","year":"2011","journal-title":"Genes Cancer"},{"issue":"5","key":"2024050310211564000_CIT0007","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S1470-2045(08)70125-6","article-title":"Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas","volume":"9","author":"Brandsma","year":"2008","journal-title":"Lancet Oncol."},{"issue":"5","key":"2024050310211564000_CIT0008","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1093\/neuonc\/nos307","article-title":"Differentiating tumor recurrence from treatment necrosis: a review of neuro-oncologic imaging strategies","volume":"15","author":"Verma","year":"2013","journal-title":"Neuro Oncol"},{"issue":"3","key":"2024050310211564000_CIT0009","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s11060-017-2375-2","article-title":"Pseudoprogression, radionecrosis, inflammation or true tumor progression? Challenges associated with glioblastoma response assessment in an evolving therapeutic landscape","volume":"134","author":"Ellingson","year":"2017","journal-title":"J Neurooncol."},{"issue":"7","key":"2024050310211564000_CIT0010","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.2217\/fon.13.271","article-title":"Postradiation imaging changes in the CNS: how can we differentiate between treatment effect and disease progression","volume":"10","author":"Walker","year":"2014","journal-title":"Future Oncol."},{"issue":"9","key":"2024050310211564000_CIT0011","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1093\/neuonc\/noz048","article-title":"Treatment-induced brain tissue necrosis: a clinical challenge in neuro-oncology","volume":"21","author":"Winter","year":"2019","journal-title":"Neuro Oncol"},{"issue":"10","key":"2024050310211564000_CIT0012","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1093\/neuonc\/now091","article-title":"Evaluation of pseudoprogression rates and tumor progression patterns in a phase III trial of bevacizumab plus radiotherapy\/temozolomide for newly diagnosed glioblastoma","volume":"18","author":"Wick","year":"2016","journal-title":"Neuro Oncol"},{"issue":"11","key":"2024050310211564000_CIT0013","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":"2","key":"2024050310211564000_CIT0014","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s13311-016-0507-6","article-title":"Modified criteria for radiographic response assessment in glioblastoma clinical trials","volume":"14","author":"Ellingson","year":"2017","journal-title":"Neurotherapeutics"},{"issue":"13","key":"2024050310211564000_CIT0015","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1200\/JCO.2007.14.8163","article-title":"MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients","volume":"26","author":"Brandes","year":"2008","journal-title":"J Clin Oncol."},{"key":"2024050310211564000_CIT0016","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.clineuro.2016.10.004","article-title":"IDH mutation and MGMT promoter methylation are associated with the pseudoprogression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adjuvant temozolomide-based chemoradiotherapy","volume":"151","author":"Li","year":"2016","journal-title":"Clin Neurol Neurosurg."},{"issue":"1","key":"2024050310211564000_CIT0017","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s10147-014-0690-6","article-title":"Hypofractionated chemoradiotherapy with temozolomide as a treatment option for glioblastoma patients with poor prognostic features","volume":"20","author":"Lim","year":"2015","journal-title":"Int J Clin Oncol."},{"issue":"12","key":"2024050310211564000_CIT0018","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1002\/cam4.1242","article-title":"Pseudoprogression as an adverse event of glioblastoma therapy","volume":"6","author":"Balana","year":"2017","journal-title":"Cancer Med"},{"issue":"1","key":"2024050310211564000_CIT0019","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s11060-015-1774-5","article-title":"Characterization of pseudoprogression in patients with glioblastoma: is histology the gold standard","volume":"123","author":"Melguizo-Gavilanes","year":"2015","journal-title":"J Neurooncol."},{"issue":"10","key":"2024050310211564000_CIT0020","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1111\/ene.12192","article-title":"Defining pseudoprogression in glioblastoma multiforme","volume":"20","author":"Van Mieghem","year":"2013","journal-title":"Eur J Neurol."},{"issue":"4","key":"2024050310211564000_CIT0021","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1177\/0284185112474916","article-title":"Pseudoprogression in patients with glioblastoma: added value of arterial spin labeling to dynamic susceptibility contrast perfusion MR imaging","volume":"54","author":"Choi","year":"2013","journal-title":"Acta Radiol."},{"issue":"7","key":"2024050310211564000_CIT0022","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1200\/JCO.1990.8.7.1277","article-title":"Response criteria for phase II studies of supratentorial malignant glioma","volume":"8","author":"Macdonald","year":"1990","journal-title":"J Clin Oncol."},{"issue":"10","key":"2024050310211564000_CIT0023","doi-asserted-by":"crossref","first-page":"753","DOI":"10.2174\/187152010794728639","article-title":"The first anti-angiogenic small molecule drug candidate design, synthesis and clinical evaluation","volume":"10","author":"Mas-Moruno","year":"2010","journal-title":"Anticancer Agents Med Chem."},{"issue":"8","key":"2024050310211564000_CIT0024","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1634\/theoncologist.2009-0317","article-title":"Bevacizumab","volume":"15","author":"Kazazi-Hyseni","year":"2010","journal-title":"Oncologist"},{"issue":"4","key":"2024050310211564000_CIT0025","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.jocn.2012.09.011","article-title":"Cerebral radiation necrosis: a review of the pathobiology, diagnosis and management considerations","volume":"20","author":"Rahmathulla","year":"2013","journal-title":"J Clin Neurosci."},{"issue":"4","key":"2024050310211564000_CIT0026","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s00795-015-0123-2","article-title":"Delayed brain radiation necrosis: pathological review and new molecular targets for treatment","volume":"48","author":"Furuse","year":"2015","journal-title":"Med Mol Morphol."},{"issue":"2","key":"2024050310211564000_CIT0027","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1586\/ecp.11.1","article-title":"Corticosteroids in brain cancer patients: benefits and pitfalls","volume":"4","author":"Dietrich","year":"2011","journal-title":"Expert Rev Clin Pharmacol"},{"issue":"1","key":"2024050310211564000_CIT0028","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ccr.2006.11.021","article-title":"AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients","volume":"11","author":"Batchelor","year":"2007","journal-title":"Cancer Cell"},{"issue":"6","key":"2024050310211564000_CIT0029","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1097\/WCO.0b013e328332363e","article-title":"Pseudoprogression and pseudoresponse in the treatment of gliomas","volume":"22","author":"Brandsma","year":"2009","journal-title":"Curr Opin Neurol."},{"issue":"3","key":"2024050310211564000_CIT0030","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1093\/neuonc\/nov180","article-title":"Current status and future directions of anti-angiogenic therapy for gliomas","volume":"18","author":"Wick","year":"2016","journal-title":"Neuro Oncol"},{"issue":"7","key":"2024050310211564000_CIT0031","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1038\/s41390-020-01177-9","article-title":"The role of integrins in inflammation and angiogenesis","volume":"89","author":"Mezu-Ndubuisi","year":"2021","journal-title":"Pediatr Res."},{"issue":"4","key":"2024050310211564000_CIT0032","first-page":"851","article-title":"A mechanism for modulation of cellular responses to VEGF: activation of the integrins","volume":"6","author":"Byzova","year":"2000","journal-title":"Mol Cell."},{"issue":"2","key":"2024050310211564000_CIT0033","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s10456-009-9141-9","article-title":"Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis","volume":"12","author":"Somanath","year":"2009","journal-title":"Angiogenesis"},{"issue":"4","key":"2024050310211564000_CIT0034","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nm.1941","article-title":"Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors","volume":"15","author":"Reynolds","year":"2009","journal-title":"Nat Med."},{"issue":"Pt 17","key":"2024050310211564000_CIT0035","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1242\/jcs.00673","article-title":"Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the alpha 5 beta 1 integrin","volume":"116","author":"Orecchia","year":"2003","journal-title":"J Cell Sci."},{"issue":"12","key":"2024050310211564000_CIT0036","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.3390\/ijms17122037","article-title":"Integrins in the spotlight of cancer","volume":"17","author":"Bianconi","year":"2016","journal-title":"Int J Mol Sci ."},{"issue":"33","key":"2024050310211564000_CIT0037","doi-asserted-by":"crossref","first-page":"5187","DOI":"10.1200\/JCO.23.01059","article-title":"RANO 2.0: update to the response assessment in neuro-oncology criteria for high- and low-grade gliomas in adults","volume":"41","author":"Wen","year":"2023","journal-title":"J Clin Oncol."}],"container-title":["Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/advance-article-pdf\/doi\/10.1093\/neuonc\/noad247\/56534224\/noad247.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/26\/5\/902\/57393329\/noad247.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/26\/5\/902\/57393329\/noad247.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T06:21:49Z","timestamp":1714717309000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article\/26\/5\/902\/7534314"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,14]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,1,14]]},"published-print":{"date-parts":[[2024,5,3]]}},"URL":"https:\/\/doi.org\/10.1093\/neuonc\/noad247","relation":{},"ISSN":["1522-8517","1523-5866"],"issn-type":[{"value":"1522-8517","type":"print"},{"value":"1523-5866","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,5,1]]},"published":{"date-parts":[[2024,1,14]]}}}