{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T17:11:16Z","timestamp":1784740276996,"version":"3.55.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Bevacizumab (BEV) plus temozolomide (TMZ) is increasingly used for glioblastoma, yet the immunosuppression-related adverse event spectrum and safety signals of this combination\u2014including potential interaction effects and time-to-onset patterns\u2014have not been comprehensively characterized in real-world pharmacovigilance data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A retrospective analysis was conducted using FAERS and CVARD; a multi-algorithm framework (Omega shrinkage model, PRR, and ROR) was applied for signal detection, and interaction analyses were conducted to explore potential drug\u2013drug interaction signals (more-than-additive reporting disproportionality patterns) in spontaneous reporting data; the Weibull model was used to evaluate time-dependent onset-hazard patterns based on TTO, and multivariate logistic regression was performed to identify factors associated with IRAE reporting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 1,076 reports in the BEV\u202f+\u202fTMZ combination therapy group, 2,633 reports in the BEV monotherapy group, and 3,156 reports in the TMZ monotherapy group were included. The combination regimen exhibited a unique IRAEs profile, showing strong reporting disproportionality signals for rare but serious immunosuppressive and opportunistic infection events, including hemophagocytic lymphohistiocytosis (HLH;\n                      <jats:italic>\u03a9<\/jats:italic>\n                      =\u202f0.648), strongyloidiasis (\n                      <jats:italic>\u03a9<\/jats:italic>\n                      =\u202f0.744), Epstein\u2013Barr virus infection (\n                      <jats:italic>\u03a9<\/jats:italic>\n                      =\u202f0.580), and cytomegalovirus pneumonitis (\n                      <jats:italic>\u03a9<\/jats:italic>\n                      =\u202f0.943). Drug interaction analysis suggested potential interaction signals between BEV and TMZ in spontaneous reporting data, with markedly elevated PRR\/interaction ORs for hematological (e.g., pancytopenia) and non-hematological toxicities (e.g., enteritis), exceeding the additive effect expected from the two monotherapies in spontaneous reporting data. Temporal dynamic analysis indicated that combination therapy altered the time-to-onset pattern for some events; for instance, the median time to onset for lymphocytopenia shifted from 34\u202fdays (BEV monotherapy) to 23\u202fdays, and the onset-hazard pattern shifted from an increasing type to a decreasing type. Multivariable logistic regression adjusting for sex, age group, body-weight group, and reporter type showed higher odds of IRAE reporting for BEV monotherapy versus TMZ monotherapy (OR\u202f=\u202f3.6037, 95% CI: 1.0378\u201312.652,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.05), while the overall IRAE reporting odds for BEV\u202f+\u202fTMZ were not significantly different from TMZ (OR\u202f=\u202f2.9677, 95% CI: 0.5018\u201315.2056,\n                      <jats:italic>p<\/jats:italic>\n                      =\u202f0.1988) or BEV (OR\u202f=\u202f0.8235, 95% CI: 0.1454\u20134.6642,\n                      <jats:italic>p<\/jats:italic>\n                      =\u202f0.8263).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>BEV\u202f+\u202fTMZ combination therapy shows disproportionality signals for severe immunosuppression and opportunistic infections. These signal patterns, including time-to-onset distributions, may help prioritize clinical vigilance and hypothesis generation, but do not estimate incidence or establish causality and require prospective confirmation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1773599","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T05:35:14Z","timestamp":1773207314000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A multi-database pharmacovigilance study reveals distinctive immunosuppressive and opportunistic infection disproportionality signals with bevacizumab and temozolomide combination therapy in glioblastoma"],"prefix":"10.3389","volume":"13","author":[{"given":"Yong","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, The Second People\u2019s Hospital of Guiyang (Jinyang Hospital), The Affiliated Jinyang Hospital of Guizhou Medical University","place":["Guiyang, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Second People\u2019s Hospital of Guiyang (Jinyang Hospital), The Affiliated Jinyang Hospital of Guizhou Medical University","place":["Guiyang, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaya","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Affiliated Hospital of Guizhou Medical University","place":["Guiyang, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1186\/s12885-023-10829-y","article-title":"Phase I\/II study testing the combination of AGuIX nanoparticles with radiochemotherapy and concomitant temozolomide in 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